Investigación de la distribución de los alelos HLA en poblaciones sanas y enfermas mediante la aplicación de nuevas metodologías de secuenciación

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Medicina, Departamento de Inmunología, Oftalmología y ORL, leída el 09/03/2021Increasing our knowledge of the HLA system, including both the complete sequence description and the assessment of its diversity at the worldwide human population-level, is of great importance for elucidating the molecular functional mechanisms of the immune system and its regulation in health and disease. Furthermore, assessment of HLA allelic and haplotypic diversity of each human population is essential in the clinical histocompatibility and transplantation setting as well as in the pharmacogenetics, immunotherapy and anthropology fields. Nevertheless, the inherent vast polymorphism and high complexity presented by the HLA system have been an important challenge for its unambiguous and in-depth (high-resolution) characterization by previously available legacy molecular HLA genotyping methods (e.g. SSP, SSO and even SBT). Recent application of novel next-generation sequencing (NGS) technology for high-resolution molecular HLA genotyping has enabled to obtain, at a high-throughput mode and larger scale, full-length and/or extended sequences and genotypes of all major HLA genes, thus overcoming most of these previous limitations. Objectives: I) Characterization of HLA allele and haplotype diversity of all major classical HLA genes (HLA-A, -B, -C, -DPA1, -DPB1, -DQA1, -DQB1, -DRB1 and -DRB3/4/5) by application of NGS of a first representative cohort of the Spanish population that could also serve as a healthy control reference group. Respective statistical analyses were performed for this immunogenetic population data. II) Characterization of HLA allele and haplotype diversity of all major classical HLA genes (HLA-A, -B, -C, -DPA1, -DPB1, -DQA1, -DQB1, -DRB1 and -DRB3/4/5) by application of NGS of a respective cohort of multiple sclerosis (MS) patients in the Spanish population (recruited at the Department of Neurology, Hospital Clínic, Barcelona, Catalonia, Spain). A first case-control study was carried out to examine HLA-disease associations with MS in these Spanish population cohorts as well as to attempt a fine-mapping of these allele and haplotype associations by full gene resolution level via NGS. In addition, a second analysis exercise (i.e. test case) of this case-control study was carried out using an alternative healthy control group dataset, exclusively from the Spanish northeastern region of Catalonia in this second case, to evaluate possible differences in the findings of HLA-disease association with MS due to plausible regional HLA genetic variation within mainland Spain (i.e. as a statistical way to try controlling for any possible existing population stratification)...El estudio del sistema HLA, incluyendo la descripción completa de su secuencia y de la diversidad de este complejo HLA a nivel poblacional, es de gran importancia de cara a poder entender los mecanismos moleculares y funciones del sistema inmune así como su regulación en individuos sanos y enfermos. Además, la caracterización exhaustiva de la diversidad de alelos y haplotipos HLA de cada población humana es esencial en el campo de la inmunología de trasplante e histocompatibilidad al igual que en las áreas de farmacogenética e inmunoterapia. El inmenso polimorfismo y gran complejidad que presenta el sistema HLA han sido hasta ahora importantes barreras de cara a poder caracterizarlo en gran detalle (por alta resolución) y sin ambigüedades mediante métodos de genotipaje HLA tradicionales disponibles (como son SSP, SSO o incluso SBT). La reciente aplicación de la novedosa tecnología de secuenciación masiva NGS para el genotipaje molecular HLA por alta resolución ha posibilitado obtener secuencias completas o mucho más extendidas para genotipos de los principales genes de HLA, superándose así estas previas limitaciones. Objetivos: I) Caracterización de la diversidad alélica y haplotípica de los principales genes HLA (HLA-A, -B, -C, -DPA1, -DPB1, -DQA1, -DQB1, -DRB1 y -DRB3/4/5) mediante la aplicación de NGS en una primera cohorte representativa de la población española que, igualmente, constituirá una población control de referencia para estudios de asociación de HLA y enfermedades. También, respectivos análisis estadísticos se realizaron para estos resultados de genotipaje HLA. II) Caracterización de la diversidad alélica y haplotípica de los principales genes HLA (HLA-A, -B, -C, -DPA1, -DPB1, -DQA1, -DQB1, -DRB1 y -DRB3/4/5) mediante la aplicación de NGS en una correspondiente cohorte de pacientes con esclerosis múltiple (EM) de la población española (reclutados y procedentes del Departamento de Neurología del Hospital Clínic (Barcelona, Cataluña)). Un primer estudio de asociación HLA tomando casos (pacientes EM) frente a controles sanos se llevó a cabo para examinar la asociación de genes HLA y la enfermedad de EM en estas cohortes de población española antes mencionadas. Así se buscaba realizar un mapeo fino de las respectivas asociaciones alélicas y haplotípicas de HLA mediante la gran resolución alélica proporcionada por esta metodología de secuenciación masiva. De modo adicional, y como un segundo ejercicio de análisis en este estudio de asociación HLA, se utilizó un grupo control sano alternativo al previo, que incluía individuos procedentes de la región de Cataluña (situada al noreste de España) exclusivamente en este caso, para evaluar así posibles diferencias dadas en la asociación de HLA con EM debido a la probable variación genética en HLA existente a nivel regional dentro del territorio de España...Fac. de MedicinaTRUEunpu

Assessment of airflow and oximetry signals to detect pediatric sleep apnea-hypopnea syndrome using AdaBoost

Producción CientíficaThe reference standard to diagnose pediatric Obstructive Sleep Apnea (OSA) syndrome is an overnight polysomnographic evaluation. When polysomnography is either unavailable or has limited availability, OSA screening may comprise the automatic analysis of a minimum number of signals. The primary objective of this study was to evaluate the complementarity of airflow (AF) and oximetry (SpO2) signals to automatically detect pediatric OSA. Additionally, a secondary goal was to assess the utility of a multiclass AdaBoost classifier to predict OSA severity in children. We extracted the same features from AF and SpO2 signals from 974 pediatric subjects. We also obtained the 3% Oxygen Desaturation Index (ODI) as a common clinically used variable. Then, feature selection was conducted using the Fast Correlation-Based Filter method and AdaBoost classifiers were evaluated. Models combining ODI 3% and AF features outperformed the diagnostic performance of each signal alone, reaching 0.39 Cohens’s kappa in the four-class classification task. OSA vs. No OSA accuracies reached 81.28%, 82.05% and 90.26% in the apnea–hypopnea index cutoffs 1, 5 and 10 events/h, respectively. The most relevant information from SpO2 was redundant with ODI 3%, and AF was complementary to them. Thus, the joint analysis of AF and SpO2 enhanced the diagnostic performance of each signal alone using AdaBoost, thereby enabling a potential screening alternative for OSA in children.Ministerio de Ciencia e Innovación - FEDER (DPI2017-84280-R y RTC-2017-6516-1)Comisión Europea - FEDER (Programa de Cooperación Interreg V-A España-Portugal POCTEP 2014–2020)Ministerio de Ciencia e Innovación - Ministerio de Universidades (PRE2018-085219)US National Institutes of Health (grants HL130984 and HL140548

Pediatric sleep apnea: Characterization of apneic events and sleep stages using heart rate variability

Producción CientíficaHeart rate variability (HRV) is modulated by sleep stages and apneic events. Previous studies in children compared classical HRV parameters during sleep stages between obstructive sleep apnea (OSA) and controls. However, HRV-based characterization incorporating both sleep stages and apneic events has not been conducted. Furthermore, recently proposed novel HRV OSA-specific parameters have not been evaluated. Therefore, the aim of this study was to characterize and compare classic and pediatric OSA-specific HRV parameters while including both sleep stages and apneic events. A total of 1610 electrocardiograms from the Childhood Adenotonsillectomy Trial (CHAT) database were split into 10-minute segments to extract HRV parameters. Segments were characterized and grouped by sleep stage (wake, W; non-rapid eye movement, NREMS; and REMS) and presence of apneic events (under 1 apneic event per segment, e/s; 1–5 e/s; 5–10 e/s; and over 10 e/s). NREMS showed significant changes in HRV parameters as apneic event frequency increased, which were less marked in REMS. In both NREMS and REMS, power in BW2, a pediatric OSA-specific frequency domain, allowed for the optimal differentiation among segments. Moreover, in the absence of apneic events, another defined band, BWRes, resulted in best differentiation between sleep stages. The clinical usefulness of segment-based HRV characterization was then confirmed by two ensemble-learning models aimed at estimating apnea-hypopnea index and classifying sleep stages, respectively. We surmise that basal sympathetic activity during REMS may mask apneic events-induced sympathetic excitation, thus highlighting the importance of incorporating sleep stages as well as apneic events when evaluating HRV in pediatric OSA.Ministerio de Ciencia, Innovación y Universidades y el Fondo Europeo de Desarrollo Regional (FEDER) under projects (PID2019-104881RB-I00), (PID2020-115468RB-I00), (PDC2021-120775-I00) and (PID2021-126734OB-C21)Sociedad Española de Sueño (SES) en el marco del proyecto “Beca de Investigación SES 2019”, by 'CIBER-Consorcio Centro de Investigación Biomédica en Red- (CB19/01/00012)' a través del 'Instituto de Salud Carlos III' co- financiado con fondos FEDER, así como bajo el proyecto SleepyHeart de la convocatoria de valorización 2020, y por el Gobierno de Aragón (Grupo de Referencia BSICoS T39-20R).The National Sleep Research Resource was supported by the National Heart, Lung, and Blood Institute (R24 HL114473, 75N92019R002).Ministerio de Ciencia, Innovación y Universidades, “Ayudas para contratos predoctorales para la Formación de Doctores” grant (PRE2018-085219) and “Ramón y Cajal” (MICIU/FSE) grant (RYC2019-028566-I)Institutos Nacionales de Salud-"Ensayo de adenoamigdalectomía infantil (CHAT)"- (HL083075, HL083129, UL1-RR-024134, UL1 RR024989) and (grant AG061824)

Analysis of the information about Doctoral Degrees presented in the Spanish universities websites.

Globalization has intensified competition, as evidenced by the growing number of international classification systems (rankings) and the attention paid to them. Doctoral education has an international character in itself. It should promote opportunities for graduate students lo participate in these international studies. The quality and competitiveness are two of the most important issues for universities. To promote the interest of graduates to continue their education after the graduate level, it would be necessary to improve the published information of ihe doctoral programs. It should increase the visibility and provide high-quality, easily accessible and comparable information which includes all the relevant aspects of these programs. The authors analysed the website contents of doctoral programs, it was observed a lack of quality of them and very poor information about the contents, so that it was decided that any of them could constitute a model for creating new websites. The recommendations on the format and contents in the web were made by a discussion group. They recommended an attractive design; a page with easy access to contents and easy to find on Ihe net and with the information in more than one language. It should include complete program and academic staff information. It should also be included the study's results which should be easily accessible and includes quantitative data, such as number of students who completed scholars, publications, research projects, average duration of the studies, etc. It will facilitate the choice of progra

Integrated water vapor obtained by satellite-borne instruments: evaluation with GPS measurements in the Iberian Peninsula

Ponencia presentada en: XVIII Congreso de la Asociación Española de Teledetección celebrado en Valladolid del 24 al 27 septiembre 2019.[ES]Este trabajo se centra en comparar los productos de vapor de agua integrado (IWV) de varios satélites respecto a un conjunto de datos en tierra obtenidos de GPS en nueve estaciones de la Península Ibérica. Los instrumentos satelitales son: Global Ozone Monitoring Instrument (GOME-2), Moderate-Resolution Imaging Spectroradiometer (MODIS), Ozone Monitoring Instrument (OMI), Spining Enhanced Visible and InfraRed Imager (SEVIRI), Atmospheric Infrared Sounder (AIRS), y Scanning Imaging Absorption Spectrometer for Atmospheric Chartography (SCIAMACHY). Los productos de estos satélites muestran una buena correlación con respecto al producto de GPS (R2 ~ 0.7). Todos los satélites muestran cierta tendencia a sobrestimar los valores bajos de vapor de agua y a subestimar los altos. Además, la precisión, medida mediante el rango intercuartílico (IQR) también disminuye rápidamente al aumentar el IWV. Por otro lado, otro factor importante es el ángulo solar zenital (SZA) que influye en el rendimiento de los instrumentos satelitales, especialmente aquellos que dependen de la radiación solar. Al aumentar el SZA acercándose a 90°, los instrumentos pierden rendimiento aumentando la sobrestimación y el IQR. Sin embargo, a valores de SZA mayores de 90° (esto es, la noche) los índices calculados no tienen grandes dependencias con el SZA.[EN]This work focuses in the comparison of several integrated water vapor (IWV) from several satellites with respect to a dataset from ground-based GPS IWV, in nine stations at the Iberian Peninsula. The satellite instruments are Global Ozone Monitoring Instrument (GOME-2), Moderate-Resolution Imaging Spectroradiometer (MODIS), Ozone Monitoring Instrument (OMI), Spinning Enhanced Visible and InfraRed Imager (SEVIRI), Atmospheric Infrared Sounder (AIRS), and Scanning Imaging Absorption Spectrometer for Atmospheric Chartography (SCIAMACHY). The products of this instruments show a fair correlation with respect to GPS product (R2 ~ 0.7). All satellites show a certain tendency to overestimation of low IWV values, while underestimating large IWV values. Moreover, the precision is studied using the inter-quartile range (IQR), which also decreases quickly when IWV increases. Another important factor is the solar zenith angle (SZA), which affects the performance of satellite instruments, especially those that are dependent on solar radiation. When SZA increases, going closer to 90°, the instruments had worse performance, increasing overestimation and IQR. Nevertheless, for SZA larger than 90° (that is to say, the night), the indexes do not show large dependencies on SZA

Una alabarda argárica en la motilla del Retamar (Argamasilla de Alba, Ciudad Real): contexto, datación, procedencia e interpretación.

En 2019 se recuperó en la motilla de El Retamar la única alabarda argárica de la Meseta; es el primer arma especializada en la Cultura de las Motillas. El hallazgo se produjo en un contexto no funerario -el Corte A-, asociado a recipientes cerámicos, un horno y semillas (trigo harinero y duro, cebada vestida, escanda melliza y lino. El arma, de 118 g y 15,7 cm, cuenta con dos remaches y es de hoja asimétrica. Puede clasificarse dentro del tipo San Antón (tipo 2 de Lull), con paralelos formales similares en la alabarda de la tumba 999 de El Argar o en otra de la colección Gómez-Moreno. La pieza no contiene estaño; es de cobre arsenicado (3,4% As), con porcentajes significativos de plomo y plata (2-3% Pb; 0,47% Ag). El análisis de sus isótopos de plomo revela la probable procedencia del área minera de Linares (Jaén). La datación de la madera del enmangue (Beta-591414, 3590±30, 2010-1895 cal BC) fecha la alabarda en el primer siglo del segundo milenio cal BC. Este hallazgo confirma que las poblaciones argáricas y del Bronce de La Mancha establecieron intensas redes de intercambio, por las que circularon objetos de alto valor social, como el marfil, la copa argárica de La Encantada o la alabarda de la motilla de El Retamar

Sports, morality and body. The voices of sportswomen under Franco's dictatorship

The aim of this research is to study sportswomen's perceptions and experiences of women's sport in Francoist Spain (1939-1975). The main objective is to analyse the social, moral and aesthetic elements that are present in the experience of these athletes. This study was carried out with an intentional sample of 24 women from Andalusia, Aragon, Asturias, Basque Country, Catalonia and Valencia. They were interviewed by a network of researchers from six universities. Outstanding results show the existence of social limitations to start sports practice (particularly in the post-war period); the importance of sport as a character-building aspect; sport's remarkable influence on their body self-concept; and the incidence on sports of the mainstream moral discourse, which created a female model that even affected sports clothing. The main conclusion is that sportswomen in that period were pioneers and had to fight against most of society in order to develop their facet as athletes, as they would not follow the established model

Detection of kinase domain mutations in BCR::ABL1 leukemia by ultra-deep sequencing of genomic DNA

The screening of the BCR::ABL1 kinase domain (KD) mutation has become a routine analysis in case of warning/failure for chronic myeloid leukemia (CML) and B-cell precursor acute lymphoblastic leukemia (ALL) Philadelphia (Ph)-positive patients. In this study, we present a novel DNA-based next-generation sequencing (NGS) methodology for KD ABL1 mutation detection and monitoring with a 1.0E-4 sensitivity. This approach was validated with a well-stablished RNA-based nested NGS method. The correlation of both techniques for the quantification of ABL1 mutations was high (Pearson r = 0.858, p < 0.001), offering DNA-DeepNGS a sensitivity of 92% and specificity of 82%. The clinical impact was studied in a cohort of 129 patients (n = 67 for CML and n = 62 for B-ALL patients). A total of 162 samples (n = 86 CML and n = 76 B-ALL) were studied. Of them, 27 out of 86 harbored mutations (6 in warning and 21 in failure) for CML, and 13 out of 76 (2 diagnostic and 11 relapse samples) did in B-ALL patients. In addition, in four cases were detected mutation despite BCR::ABL1 < 1%. In conclusion, we were able to detect KD ABL1 mutations with a 1.0E-4 sensitivity by NGS using DNA as starting material even in patients with low levels of disease