Análisis comparativo entre el ajuste por regresión lineal múltiple y Propensity Score ordinal basado en ponderación media Marginal por estratificación (MMWS) en el control de la confusión en estudios observacionales

Resumen Introducción: Desde la perspectiva epidemiológica, existen dos metodologías que permiten determinar la asociación entre variables o factores biológicos: estudios experimentales o no experimentales (1). Se tiene a los estudios epidemiológicos experimentales y específicamente al ensayo clínico como "la herramienta más definitiva para la evaluación de la aplicabilidad de la investigación clínica” (2). Cuando no es factible desarrollar un ensayo clínico aleatorizado, es menester tener en cuenta el fenómeno de la confusión; no ajustar el efecto de un determinado tratamiento configura un sesgo en el análisis que puede invalidar los resultados encontrados (2). Entre los métodos de ajuste más comunes está el modelo de regresión convencional (3,4) y el uso del Propensity score (4,5). En este estudio se busca determinar bajo distintos escenarios de tamaño de muestra, número de variables predictoras y razón expuesto - no expuesto, cual metodología produce los mejores resultados en términos de precisión del estimador del efecto de una exposición o intervención establecida, usando un estimador propuesto para tratamientos ordinales conocido como MMWS y una alternativa de este basado en estimadores doblemente robustos (DR-MMWS). Métodos: Simulación de Monte Carlo se usa para comparar el estimador MMWS con el ajuste de regresión convencional. Se plantearon diversos escenarios en cuanto al de tamaño de muestra, número de variables predictoras y razón expuesto - no expuesto para evaluar el rendimiento de estos modelos. Resultados: Los estimadores basados en Propensity Score ordinal basado en ponderación media marginal por estratificación (MMWS), son ligeramente inferiores a la regresión lineal múltiple en la estimación insesgada del efecto en una intervención o exposición de tipo ordinal. El estimador DR-MMWS equipara a los estimadores de una regresión por mínimos cuadrados ordinarios para tamaños de muestra superiores a 500 sujetos. Aumentar el número de no expuestos por expuestos, aumenta la precisión de los estimadores independiente de la metodología de ajuste. Conclusiones: Debe considerarse el uso de estimadores DR-MMWS en estudios observacionales, ya que, en comparación con los estimadores dados por una regresión lineal múltiple, este estimador presenta iguales indicadores de desempeño y las estimaciones dadas por esta metodología son consistentes y presentan una reducción del sesgo importante.Abstract: Introduction: From the epidemiological perspective, there are two methodologies that allow to determine the association between variables or biological factors: experimental or nonexperimental studies (1). We have experimental epidemiological studies and specifically the clinical trial as "the most definitive tool for the evaluation of the applicability of clinical research" (2). Where it is not feasible to develop a randomized clinical trial, it is necessary to take into account the phenomenon of the confusion, not adjusting the effect of a given treatment creates a bias in the analysis that can invalidate the results found. The most common adjustment methods are the conventional regression model (3,4) and the use of the Propensity score (4,5). This study seeks to determine under different scenarios of sample size, number of predictor variables and exposed ratio - not exposed, which methodology produces the best results in terms of the estimator's precision of the effect of an exposure or intervention established, using additionally a proposed estimator for ordinal treatments known as MMWS. Methods: Monte Carlo simulation is used to compare the MMWS estimator with the conventional regression adjustment. Several scenarios were raised regarding the sample size, the number of prediction variables and the reason why it is exposed, not exposed to evaluate the performance of these models. Results: The estimators based on ordinal Propensity Score based on marginal average weighting by stratification (MMWS), are slightly lower than the multiple linear regression in the unbiased estimate of the effect in an intervention or ordinal exposure. The DR-MMWS estimator equates the estimators of an ordinary least squares regression for sample sizes greater than 500 subjects. Increasing the number of unexposed by exposed, increases the accuracy of the estimators independent of the adjustment methodology. Conclusions: The use of DR-MMWS estimators in observational studies should be considered, since, in comparison with the estimators given by a multiple linear regression, this estimator presents the same performance indicators and the estimations given by this methodology are consistent and show a reduction of the bias important.Maestrí

Fire in confined spaces: reality and numerical simulations

Fire and smoke in enclosed spaces behave differently from those in open ones. Depending on scenario dimensions, fuel and ventilation, the fire passes through different stages after ignition. Together with the performance of real experiments, the use of Computational Fluid Dynamic models can be very useful to understand fire propagation behavior. In this work, we compare numerical results with real observations and measurements. The “Fire Dynamics Simulator” (FDS), based on Large Eddy Simulation techniques, is used to reproduce some real scenarios under the same fuel and ventilation conditions. Dynamical evolution of several magnitudes such as temperature, pressure, oxygen concentration and combustion products is evaluated and discussed.Peer ReviewedPostprint (author's final draft

Patrimonio natural y cultural de Tepotzotlán

324 páginas. Especialización en Diseño, Planificación y Conservación de Paisajes y Jardines.El presente documento muestra el trabajo realizado para la intervención paisajística en pueblo de Tepotzotlán. Al ser catalogado en el programa de pueblos mágicos dada su riqueza tangible e intangible; resulta relevante su estudio a fin de rescatar y/o enaltecer algunas de las virtudes que lo resguardan. La zona de intervención se enfocó esencialmente en el polígono patrimonial del centro histórico, los caminos constituidos a lo largo de Rio Chiquito y calles aledañas que conectan los tesoros patrimoniales de la zona. Dicho estudio fue abordado principalmente por grupos de trabajo interdisciplinario, conformados por alumnos de la especialidad en Paisajes y Jardines Históricos de la UAM Azcapotzalco. Se cotejaron 5 proyectos detonadores: Centro Histórico/Atrio de los Olivos, Par vial, Rio Chiquito, Camino Real de Lluvias y Acequia Real. Durante la primera etapa, se establecieron las limitaciones y potencialidades del sitio. Se recopiló información cualitativa y cuantitativa para la formulación y ejecución de un plan maestro que regirían los parámetros y objetivos en cada proyecto. El desarrollo conceptual y anteproyecto para cada zona de intervención, se reflejó en la segunda etapa de este proceso. Paralelamente, la elaboración de la propuesta de vegetación, las fichas de cada especie vegetal y la preparación de catálogos de paisaje, complementan el carácter de este trabajo. El proyecto realizado en Tepotzotlán: “Patrimonio Natural y Cultural De Tepotzotlán”, emerge, como el título del trabajo indica: desde la visión del rescate patrimonial, constituido por elementos materiales y naturales relevantes para la población local y todos sus visitantes. La última etapa comprende la puesta en marcha del proyecto ejecutivo, donde se plasmaron los detalles que dan cuerpo a cada elemento de las propuestas de diseño, la información necesaria para su construcción y la síntesis de toda la documentación consultada y elaborada, como sostén de diseño. En las siguientes páginas y capítulos, se explicará de manera extensa y particular: la metodología planteada y utilizada en el abordaje de cada proyecto. En general, se podrá observar la construcción de un trabajo paisajístico integral, llevado a cabo a lo largo de un año de esfuerzo y dedicación, vertidos en la presente tesis.Consejo Nacional de Ciencia y Tecnología (México)

Teachers’ Perception on the Inclusion of Students with Disabilities in the Regular Education Classroom in Ecuador

Nowadays, contradictory viewpoints are showed when defining disability. On the one hand, there are theoretical frameworks focused on the personal limitations, while, on the other hand, each time it is more extended those ones which highlight the restrictions on the social fabric. It becomes essential to integrate both frameworks considering disability as a social phenomenon besides the collective responsibility that demands further action by society as a whole.Currently, Ecuador is suffering an economic recession due to the drop in the price of oil and the appreciation of the dollar, together with the catastrophic effects of the earthquake recorded in 2016. Before 2014, Ecuador was experiencing economic growth resulting in major investment in social areas such as education, thus promoting educational and labour market inclusion of people with disabilities.This study shows the perspective of teachers in Ecuador towards students with disabilities before the development of a program of postgraduate studies for specializing them to cater for the special educational needs. Moreover, the aim is to assess abilities and barriers that teachers have to face up with regard to inclusion of disability in the regular classroom. The majority of teachers in Ecuador are unanimous in stating that academic career training on the issue of education inclusion and accessibility will entail a maximum support carrying out their teaching assignments as well as materials adapted to suit the students’ needs. Furthermore, a wide range of teachers were aware of the case of students with disabilities in the classroom. Besides, among the main problems, architectural barriers and the lack of inclusion were the most important for the participants.Taking all of this into consideration, it is perceived that teachers from Ecuador are not fully prepared for having students with disabilities. That is why a deeper training in special educational needs should be necessary

Proteomic characterization of human coronary thrombus in patients with ST-segment elevation acute myocardial infarction

Acute myocardial infarction with ST-segment elevation (STEMI) initiates with intraluminal thrombosis and results in total occlusion of the coronary artery. To date, characterization of the coronary thrombus proteome in STEMI patients has not been yet accomplished. Therefore, we aimed to perform an in-depth proteomic characterization of the human coronary thrombus by means of three different approaches: 2-DE followed by mass spectrometry (MALDI MS/MS), 1-DE combined either with liquid chromatography coupled to mass spectrometry in a MALDI TOF/TOF (LC-MALDI-MS/MS), or in a LTQ-Orbitrap (LC-ESI-MS/MS). This approach allowed us to identify a total of 708 proteins in the thrombus. Expression in coronary thrombi (n=20) of 14 proteins was verified, and the expression of fibrin and 6 cell markers (platelets, monocytes, neutrophils, eosinophils, T-cells and B-cells) quantified by selected reaction monitoring (SRM). A positive correlation of 5 proteins (fermitin homolog 3, thrombospondin-1, myosin-9, beta parvin and ras-related protein Rap-1b) with CD41 was found, pointing out the potential activation of a focal adhesion pathway within thrombus platelets. DIDO1 protein was found to correlate negatively with thrombus fibrin, and was found up-regulated in the plasma of these STEMI patients, which may constitute a starting point for further analyses in the search for biomarkers of thrombosis. BIOLOGICAL SIGNIFICANCE: The proteomic characterization of the human coronary thrombus may contribute to a better understanding of the mechanisms involved in acute coronary syndrome, and thus pave the road for the identification of new therapeutic targets that may help addressing this and other thrombotic diseases. A novel methodology to characterize thrombus composition and expression of a sub-group of proteins is hereby described, which allowed linking protein expression with cellular and ECM matrix composition of the thrombus. Five proteins (fermitin homolog 3, thrombospondin-1, myosin-9, beta parvin and ras-related protein Rap-1b) co-express within the human coronary thrombus with CD41, pointing out the potential activation of a focal adhesion pathway within thrombus platelets during thrombus formation. Besides, the protein death-inducer obliterator 1, found to be expressed within the human coronary thrombus, has been proved to increase in the plasma of STEMI patients, which constitutes an important starting point for further analyses in the search for biomarkers of thrombosis.This work was supported by grants from the Instituto de Salud Carlos III (FIS PI070537, PI11/02239), Fondos Feder, Redes temáticas de Investigación Cooperativa en Salud (RD12/0042/ 0071, RD06/0014/1015), and Fundación para la Investigación Sanitaria de Castilla-La Mancha (FISCAM PI2008-08, PI2008-28, PI2008-52). These results are lined up with the Spanish initiative on the Human Proteome Project (SpHPP). The CNIC is supported by the Spanish Ministerio de Economia y Competitividad and the Fundacion Pro-CNIC. We would like to thank Dr. Gloria Alvarez-Llamas for her kind suggestions for the manuscript; Gemma Barroso from Proteomic Unit, Hospital Nacional de Paraplejicos, for her help and dedication to this work, as well as Veronica Moral and Ana Gallardo from the same Unit, and TamaraSastre andCarmenBermudez for their technical support.S

Longitudinal analysis of blood DNA methylation identifies mechanisms of response to tumor necrosis factor inhibitor therapy in rheumatoid arthritis

Epigenetics; Rheumatoid arthritis; Treatment responseEpigenètica; Artritis reumatoide; Resposta al tractamentEpigenética; Artritis reumatoide; Respuesta al tratamientoBackground Rheumatoid arthritis (RA) is a chronic, immune-mediated inflammatory disease of the joints that has been associated with variation in the peripheral blood methylome. In this study, we aim to identify epigenetic variation that is associated with the response to tumor necrosis factor inhibitor (TNFi) therapy. Methods Peripheral blood genome-wide DNA methylation profiles were analyzed in a discovery cohort of 62 RA patients at baseline and at week 12 of TNFi therapy. DNA methylation of individual CpG sites and enrichment of biological pathways were evaluated for their association with drug response. Using a novel cell deconvolution approach, altered DNA methylation associated with TNFi response was also tested in the six main immune cell types in blood. Validation of the results was performed in an independent longitudinal cohort of 60 RA patients. Findings Treatment with TNFi was associated with significant longitudinal peripheral blood methylation changes in biological pathways related to RA (FDR<0.05). 139 biological functions were modified by therapy, with methylation levels changing systematically towards a signature similar to that of healthy controls. Differences in the methylation profile of T cell activation and differentiation, GTPase-mediated signaling, and actin filament organization pathways were associated with the clinical response to therapy. Cell type deconvolution analysis identified CpG sites in CD4+T, NK, neutrophils and monocytes that were significantly associated with the response to TNFi. Interpretation Our results show that treatment with TNFi restores homeostatic blood methylation in RA. The clinical response to TNFi is associated to methylation variation in specific biological pathways, and it involves cells from both the innate and adaptive immune systems.This study was funded by the Instituto de Salud Carlos III

Long-Term Changes of Inflammatory Biomarkers in Individuals on Suppressive Three-Drug or Two-Drug Antiretroviral Regimens

Background: Because inflammation is associated with mortality and has been linked to HIV transcription in lymphoid tissues during ART, it is necessary to address the long-term effects of switching 3-drug (3DR) to 2-drug regimens (2DR) on inflammation. Methods: Nested study in the Spanish AIDS Research Network. We selected PWH ART-naive initiating 3DR who achieved viral suppression in the first 48 weeks and either remained on 3DR or switched to 2DR (3TC+bPI; 3TC+DTG; DTG+RPV). We assessed the trajectories on inflammatory markers during ART using multivariate piecewise mixed models. Results: We analyzed 619 plasma samples from 148 patients (3DR, N=90; 2DR, N=58), the median follow-up was 4.6 (IQR 3.2-6.2) years. There were no significant differences in baseline characteristics between groups. After adjusting for potential confounders, patients with 3DR experienced a slow decline of IL6, hs-CRP, sCD14, sCD163, and D-dimer over time. In contrast, compared to 3DR, switching to 2DR was associated with increases in IL-6 (p=0.001), hs-CRP (p=0.003), and D-dimer (p=0.001) after year 3 from virologic suppression. 2DR was associated with a higher risk of hs-CRP quartile increase (aOR 3.3, 95%CI 1.1-10) and D-dimer quartile increase (aOR 3.7, 95%CI 1.1-13). The adjusted biomarker trajectories did not reveal a distinct pattern according to the type of 2DR used (bPI vs DTG). Conclusions: In this study in virally suppressed individuals, maintaining 3DR was associated with a more favorable long-term inflammatory profile than switching to 2DR. The potential clinical implications of these findings on the development of non-AIDS events deserve further investigation.The HIV BioBank, integrated in the Spanish AIDS Research Network, is supported by Instituto de Salud Carlos III, Spanish Health Ministry (Grant n° proyectos RD06/0006/0035, RD12/0017/0037 and RD16/0025/0019) as part of the Plan Nacional R + D + I and co-financed by the European Development Regional Fund ‘‘A way to achieve Europe’’ (ERDF). The RIS Cohort (CoRIS) is funded by the Instituto de Salud Carlos III through the Red Temática de Investigación Cooperativa en SIDA (RIS C03/173, RD12/0017/0018 and RD16/0002/0006) as part of the Plan Nacional R+D+I and cofinanced by ISCIII-Subdirección General de Evaluacion and Fondo Europeo de Desarrollo Regional (FEDER)”. This work was supported by the Instituto de Salud Carlos III projects AC17/00019, PI18/00154, ICI20/00058, CIBER de Enfermedades Infecciosas, and Gilead Sciences (Investigator Sponsored Research ISR-17-10192). The funders had no role in the study design, data analysis, or in the interpretation of the results.S

Role of ACE2 genetic polymorphisms in susceptibility to SARS-CoV-2 among highly exposed but non infected healthcare workers

We aim to evaluate the role of single-nucleotide polymorphisms of the angiotensin-converting enzyme 2 in susceptibility to SARS-CoV-2 infection. We included 28 uninfected but highly exposed healthcare workers and 39 hospitalized patients with COVID-19. Thirty-five SNPs were rationally selected. Two variants were associated with increased risk of being susceptible to SARS-CoV-2: the minor A allele in the rs2106806 variant (OR 3.75 [95% CI 1.23-11.43]) and the minor T allele in the rs6629110 variant (OR 3.39 [95% CI 1.09-10.56]). Evaluating the role of genetic variants in susceptibility to SARS-CoV-2 infection could help identify more vulnerable individuals and suggest potential drug targets for COVID-19 patients.This work was supported by Instituto de Salud Carlos III: [grant number AC17/00019,COV20/00349,PI18/00154,PT17/0019]; Merck, Sharp & Dohme: [Ref IISP 59181].S