Proposal, evaluation and application of two new methodologies for genetic profiling in association studies

L'objectiu de l'epidemiologia genètica és comprendre els efectes dels gens i els factors ambientals en la salut humana. Un aspecte important és l’estudi del paper de la variabilitat genètica en el risc de malalties comunes com la diabetis, malalties cardiovasculars, càncer, Alzheimer, etc. Aquesta tesi es centra en la identificació de múltiples variants genètiques per predir el risc a la malaltia i presenta dues aproximacions metodològiques per a la identificació de perfils genètics en presència d'epistasi. Un efecte epistàtic o una interacció genètica apareix quan l'efecte conjunt de diversos marcadors genètics sobre el fenotip observat no queda explicat pels seus efectes marginals. La principal dificultat en l'estudi de les interaccions genètiques és que generalment s'analitzen centenars o milers de marcadors genètics, i això fa inviable l'anàlisi de totes les possibles interaccions, des del punt de vista computacional. Les metodologies presentades permeten explorar interaccions d'ordre alt amb un cost computacional raonable. També s’aborda la simulació de dades amb propietats similars a les d’estudis d’associació genètica.The aim of genetic epidemiology is to understand the effects of genes and environmental factors on human health. An important issue is the role of the genetic variability in the risk for common diseases such as diabetes, cardiovascular disease, cancer, Alzheimer's, etc. This thesis is focused on the identification of genetic variants at multiple loci for prediction of disease risk and presents two new methodological approaches to address genomic profiling in presence of epistasis. An epistatic effect or a genetic interaction is present when the combined effect of several genetic markers on the observed phenotype is not explained by their marginal effects. The main difficulty in the study of genetic interactions is that usually hundreds or thousands of genetic markers are analysed, which makes the analysis of all possible interactions unfeasible, from a computational point of view. The proposed methodologies allow higher order interactions to be explored with a reasonable computational cost. Another prominent issue addressed in this thesis is the simulation of data with similar properties to real genetic association studies

Detección de interacciones genéticas asociadas a enfermedades complejas. Aplicación al cáncer de vejiga

El proyecto en el que he participado se engloba dentro del Estudio Español de Cáncer de Vejiga/EPICURO, que comenzó en 1997 con el propósito de avanzar en el conocimiento de este cáncer respecto a las causas genéticas y ambientales, prevención, prognosis y tratamiento, y que aglutina esfuerzos de distintos grupos de nvestigación. El proyecto está coordinado por Núria Malats, jefa del Grupo de Epidemiología Genética y Molecular del CNIO (Centro Nacional de Investigaciones Oncológicas) y es uno de los mayores estudios sobre cáncer de vejiga que se han realizado. Sus objetivos principales son: (a) analizar el riesgo al cáncer de vejiga en relación a factores de susceptibilidad genética, tabaco, ocupación, exposiciones ambientales, dieta, drogas e historial médico; y (b) identi car marcadores moleculares que permitan pronosticar el cáncer de vejiga

MB-MDR: Model-Based Multifactor Dimensionality Reduction for detecting interactions in high-dimensional genomic data

L’anàlisi de l’efecte dels gens i els factors ambientals en el desenvolupament de malalties complexes és un gran repte estadístic i computacional. Entre les diverses metodologies de mineria de dades que s’han proposat per a l’anàlisi d’interaccions una de les més populars és el mètode Multifactor Dimensionality Reduction, MDR, (Ritchie i al. 2001). L’estratègia d’aquest mètode és reduir la dimensió multifactorial a u mitjançant l’agrupació dels diferents genotips en dos grups de risc: alt i baix. Tot i la seva utilitat demostrada, el mètode MDR té alguns inconvenients entre els quals l’agrupació excessiva de genotips pot fer que algunes interaccions importants no siguin detectades i que no permet ajustar per efectes principals ni per variables confusores. En aquest article il•lustrem les limitacions de l’estratègia MDR i d’altres aproximacions no paramètriques i demostrem la conveniència d’utilitzar metodologies parametriques per analitzar interaccions en estudis cas-control on es requereix l’ajust per variables confusores i per efectes principals. Proposem una nova metodologia, una versió paramètrica del mètode MDR, que anomenem Model-Based Multifactor Dimensionality Reduction (MB-MDR). La metodologia proposada té com a objectiu la identificació de genotips específics que estiguin associats a la malaltia i permet ajustar per efectes marginals i variables confusores. La nova metodologia s’il•lustra amb dades de l’Estudi Espanyol de Cancer de Bufeta

Modelo gerencial en dirección de proyectos (PMBOK®) para la electrificadora de santander

Anexos formatos.El presente documento, propone un modelo en gerencia de proyectos basado en las buenas prácticas a implementar para centrales hidroeléctricas de generación de energía de la Electrificadora de Santander, las cuales se contemplan a partir de la descripción del problema y como caso de estudio genera el siguiente interrogante: ¿Cuál es el modelo gerencial a implementar en la Electrificadora de Santander para la dirección de proyectos en el área de generación de energía? Para dar respuesta a lo anterior, se realizará una revisión conceptual de lo visto en la Maestría De Gerencia De Proyectos (MGP), ofertada por la UNAD y factores externos como: revistas indexadas, normatividad legal vigente aplicables en este tipo de proyectos; mediante el análisis documental no aplicado, basado en las buenas prácticas a implementar del “Project Management Institute” la guía PMBOK® sexta edición y la extensión para la construcción PMI cuarta edición, en relación con lo anterior y como resultado de este trabajo se presenta el modelo a adoptar por la Electrificadora de Santander, al momento de surgir un proyecto en el área de generación de energía para sus centrales hidroeléctricas. Palabras Clave: Dirección de Proyectos, Metodología, Procesos, Gestión, Generación de Energía y Modelo Gerencial.This document proposes a project management model based on the best practices to be implemented for hydroelectric power generation plants of Electrificadora de Santander, which are contemplated from the description of the problem and as a case study generates the following question: What is the management model to be implemented in Electrificadora de Santander for project management in the area of power generation? To respond to the above, a conceptual review of what was seen in the master's degree in project management, offered by the UNAD and external factors such as: indexed journals, current legal regulations applicable in this type of projects; through the non-applied documentary analysis, based on the good practices to be implemented by the Project Management Institute the PMBOK® guide sixth edition and the extension for construction PMI fourth edition, in relation to the above and as a result of this work the model to be adopted by the Electrificadora de Santander is presented, when a project arises in the area of power generation for its hydroelectric power plants. Keywords: Project Management, Methodology, Processes, Management, Power Generation and Management Model

Noticias falsas y creencias infundadas en la era de la posverdad

The dissemination of fake news embodies a pressing problem for democracy that is exacerbated by theubiquity of information available on the Internet and by the exploitation of those who, appealing to theemotionality of audiences, have capitalized on the injection of falsehoods into the social fabric. In thisstudy, through a cross-sectional, correlational and non-experimental design, the relationship betweencredibility in the face of fake news and some types of dysfunctional thoughts was explored in a sampleof Chilean university students. The results reveal that greater credibility in fake news is associated withhigher scores of magical, esoteric and naively optimistic thinking, beliefs that would be the meetingpoint for a series of cognitive biases that operate in the processing of information. The highest correlationis found with the paranormal beliefs facet and, particularly, with ideas about the laws of mentalattraction, telepathy and clairvoyance. Significant differences were also found in credibility in fake newsas a function of the gender of the participants, with the female gender scoring higher on average thanthe male gender. These findings highlight the need to promote critical thinking, skepticism and scientificattitude in all segments of society.La difusión de noticias falsas encarna un apremiante problema para la democracia que se ve agudizadopor la ubicuidad de la información disponible en el internet y por el aprovechamiento de quienes, apelandoa la emocionalidad de las audiencias, han capitalizado a su favor la inyección de falsedades en elentramado social. En este estudio a través de un diseño transversal, correlacional y no experimental seexploró la relación entre credibilidad frente a las noticias falsas y algunos tipos de pensamientos disfuncionales en una muestra de estudiantes universitarios chilenos. Los resultados develan que una mayorcredibilidad en noticias falsas va aparejada con mayores puntajes de pensamiento mágico, esotérico eingenuamente optimista, creencias que serían el punto de encuentro para una serie de sesgos cognitivosque operan en el procesamiento de la información. La correlación más alta se encuentra con la faceta decreencias paranormales y, particularmente, con las ideas acerca de las leyes de atracción mental, la telepatíay la clarividencia. También se hallaron diferencias significativas en la credibilidad en noticias falsasen función del género de los participantes, encontrando que el género femenino puntúa una media másalta que el género masculino. Estos hallazgos ponen en relieve la necesidad de promover el pensamientocrítico, el escepticismo y la actitud científica en todos los segmentos de la sociedad

Aprendizaje por retos en el ámbito de las elaboraciones de productos alimentarios

Esta propuesta de intervención trata de implantar una metodología basada en retos en la que los alumnos realizarán una elaboración de un alimento, para ello, tendrán que tener en cuenta todas las actividades que se deben realizar, incluyendo procesos de elaboración, análisis de materia prima, producto intermedio y final, así como controles de calidad a aplicar. El alumno/a, con la tutorización de los docentes será, el responsable de buscar toda la información y el conocimiento necesario para poder realizar todas las actividades. Se busca una mayor motivación, autonomía, trabajo en equipo así como una mejor comprensión de los distintos procesos de la industria alimentaria por parte del alumnado. A demás, se ha realizado una reflexión sobre mi actividad docente, así como un análisis de mejora sobre la misma y sobre la intervención antes citada.<br /

Analgesic effect and side effects of celecoxib and meloxicam in canine hip osteoarthritis

Objective. To evaluate the pharmacological, clinical and toxicological effects of celecoxib and meloxicam for analgesia for 30 days in dogs with hip osteoarthritis. Materials and methods. Twenty-four patients were evaluated, 75% were females with an average age of 7.16 ± 2.06 years and twenty five percent were males with an average age of 7.83 ± 2.22 years. All patients had hip osteoarthritis and they were randomized into two groups; one group received oral celecoxib 5 mg/kg every 12 hours during one month and the second group received oral meloxicam 0.2 mg/kg every 24 hours during 1 month. The patients were evaluated for analgesia, and hematological, renal, liver, and coagulation tests on days 0, 10th and 30th after treatment initiation, and a gastric endoscopy on day 30. Statistical analysis was performed using a HSD Tukey test and c2 with a 5% level of statistical significance. Results. Both drugs reduced articular pain according to the Melbourne scale during the 30 days of treatment (p≤0.05). Hematological, renal, hepatic and coagulation tests were normal in both treatment groups. All patients presented chronic gastritis on endoscopy on day 30th. Conclusions. Both drugs decreased pain at day 30th without causing alterations in hematological, renal, hepatic or coagulation tests after 30 days of treatment. However, both drugs induced chronic gastritis

Clinical course impacts early kinetics,magnitude, and amplitude of SARS-CoV-2 neutralizing antibodies beyond 1 year after infection

To understand the determinants of long-term immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the concurrent impact of vaccination and emerging variants, we follow a prospective cohort of 332 patients with coronavirus disease 2019 (COVID-19) over more than a year after symptom onset. We evaluate plasma-neutralizing activity using HIV-based pseudoviruses expressing the spike of different SARS-CoV-2 variants and analyze them longitudinally using mixed-effects models. Long-term neutralizing activity is stable beyond 1 year after infection in mild/asymptomatic and hospitalized participants. However, longitudinal models suggest that hospitalized individuals generate both short- and long-lived memory B cells, while the responses of non-hospitalized individuals are dominated by long-lived B cells. In both groups, vaccination boosts responses to natural infection. Long-term (>300 days from infection) responses in unvaccinated participants show a reduced efficacy against beta, but not alpha nor delta, variants. Multivariate analysis identifies the severity of primary infection as an independent determinant of higher magnitude and lower relative cross-neutralization activity of long-term neutralizing responses.This work was partially funded by Grifols, the Departament de Salut of the Generalitat de Catalunya (grants SLD016 to J.B. and SLD015 to J.C.), the Spanish Health Institute Carlos III and the European Regional Development Fund (grant PI17/01518 and PI20/00093 to J.B. and PI18/01332 to J.C.), CERCA Programme/Generalitat de Catalunya 2017 SGR 252, and the crowdfunding initiatives #joemcorono, BonPreu/Esclat, and Correos. The funders had no role in study design, data collection and analysis, the decision to publish, or the preparation of the manuscript. E.P. was supported by a doctoral grant from the National Agency for Research and Development of Chile (ANID) (72180406). We are grateful to all participants and the technical staff of IrsiCaixa for sample processing. Francesc López-Seguí provided medical writing support during the preparation of the manuscript.Peer Reviewed"Article signat per 22 autors/es: Edwards Pradenas, Benjamin Trinité, Víctor Urrea, Silvia Marfil, Ferran Tarrés-Freixas, Raquel Ortiz, Carla Rovirosa, Jordi Rodon, Júlia Vergara-Alert, Joaquim Segalés, Victor Guallar, Alfonso Valencia, Nuria Izquierdo-Useros, Marc Noguera-Julian, Jorge Carrillo, Roger Paredes, Lourdes Mateu, Anna Chamorro, Ruth Toledo, Marta Massanella, Bonaventura Clotet, Julià Blanco"Postprint (published version

Remodeling the bladder tumor immune microenvironment by mycobacterial species with changes in their cell envelope composition

Intravesical BCG instillation after bladder tumor resection is the standard treatment for non-muscle invasive bladder cancer; however, it is not always effective and frequently has undesirable side effects. Therefore, new strategies that improve the clinical management of patients are urgently needed. This study aimed to comprehensively evaluate the bladder tumor immune microenvironment profile after intravesical treatment with a panel of mycobacteria with variation in their cell envelope composition and its impact on survival using an orthotopic murine model to identify more effective and safer therapeutic strategies. tumor-bearing mice were intravesically treated with a panel of BCG and M. brumae cultured under different conditions. Untreated tumor-bearing mice and healthy mice were also included as controls. After mycobacterial treatments, the infiltrating immune cell populations in the bladder were analysed by flow cytometry. We provide evidence that mycobacterial treatment triggered a strong immune infiltration into the bladder, with BCG inducing higher global absolute infiltration than M. brumae. The induced global immune microenvironment was strikingly different between the two mycobacterial species, affecting both innate and adaptive immunity. Compared with M. brumae, BCG treated mice exhibited a more robust infiltration of CD4 + and CD8 + T-cells skewed toward an effector memory phenotype, with higher frequencies of NKT cells, neutrophils/gMDSCs and monocytes, especially the inflammatory subset, and higher CD4 + T/CD4 + T and CD8 + T/CD4 + T ratios. Conversely, M. brumae treatment triggered higher proportions of total activated immune cells and activated CD4 + and CD8 + T cells and lower ratios of CD4 + T cells/CD4 + T, CD8 + T cells/CD4 + T and inflammatory/reparative monocytes. Notably, the mycobacterial cell envelope composition in M. brumae had a strong impact on the immune microenvironment, shaping the B and myeloid cell compartment and T-cell maturation profile and thus improving survival. Overall, we demonstrate that the bladder immune microenvironment induced by mycobacterial treatment is species specific and shaped by mycobacterial cell envelope composition. Therefore, the global bladder immune microenvironment can be remodelled, improving the quality of infiltrating immune cells, the balance between inflammatory and regulatory/suppressive responses and increasing survival

Impact of Long-Term Cryopreservation on Blood Immune Cell Markers in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome : Implications for Biomarker Discovery

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex neuroimmune disorder characterized by numerous symptoms of unknown etiology. The ME/CFS immune markers reported so far have failed to generate a clinical consensus, perhaps partly due to the limitations of biospecimen biobanking. To address this issue, we performed a comparative analysis of the impact of long-term biobanking on previously identified immune markers and also explored additional potential immune markers linked to infection in ME/CFS. A correlation analysis of marker cryostability across immune cell subsets based on flow cytometry immunophenotyping of fresh blood and frozen PBMC samples collected from individuals with ME/CFS (n = 18) and matched healthy controls (n = 18) was performed. The functionality of biobanked samples was assessed on the basis of cytokine production assay after stimulation of frozen PBMCs. T cell markers defining Treg subsets and the expression of surface glycoprotein CD56 in T cells and the frequency of the effector CD8 T cells, together with CD57 expression in NK cells, appeared unaltered by biobanking. By contrast, NK cell markers CD25 and CD69 were notably increased, and NKp46 expression markedly reduced, by long-term cryopreservation and thawing. Further exploration of Treg and NK cell subsets failed to identify significant differences between ME/CFS patients and healthy controls in terms of biobanked PBMCs. Our findings show that some of the previously identified immune markers in T and NK cell subsets become unstable after cell biobanking, thus limiting their use in further immunophenotyping studies for ME/CFS. These data are potentially relevant for future multisite intervention studies and cooperative projects for biomarker discovery using ME/CFS biobanked samples. Further studies are needed to develop novel tools for the assessment of biomarker stability in cryopreserved immune cells from people with ME/CFS