Clinical and genetic characterization of 145 spanish patients diagnosed with PTEN hamartoma tumor syndrome

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 20-01-2020Esta tesis tiene embargado el acceso al texto completo hasta el 20-07-2021The PTEN hamartoma tumor syndrome (PHTS) is a rare disease characterized by a large phenotypic variability of benign lesions together with a high predisposition to develop several cancer types (breast, thyroid, endometrial, renal, colorectal and melanoma). This hereditary syndrome is associated to germline mutations in the PTEN gene, although a considerable proportion of patients are not explained by this gene. Altogether, this results in the lack of awareness on the PHTS, underdiagnosis and poor management of these patients. The first general objective is to characterize the disease in Spanish patients, both at a genetic level and at a clinical level, together with the comparison of our results with that obtained in other studied populations and the evaluation of the usefulness of the diagnostic criteria. The second objective is to look for other genetic factors that can be involved in the phenotype of the PHTS patients who do not harbor PTEN mutations. To accomplish these objectives, we have gathered a series of 145 Spanish patients diagnosed with PHTS with their respective clinical information and biological samples. The use of a specific checklist allowed us to review the clinical features of interest, and the use of conventional genetic techniques (Sanger, MLPA, aCGH), together with high-throughput procedures (NGS and WES) enabled the molecular characterization, focusing not only in PTEN but also searching for other genes. Moreover, the functional studies gave insights into the implications in pathogenicity of different variants of unknown significance in PTEN. The results of this work were used to state several recommendations for the diagnosis: the application of the most useful clinical features to drive genetic testing and the performance of this through multigene panels to detect other possibly altered genes that might confer additional clinical risks. Regarding the follow-up, it is relevant to do obesity check-ups and to anticipate the cancer screenings. Moreover, several findings of this study set the basis for future research. Overall, this work contributes to accelerate and improve the diagnosis and patient care of the PHTS patients.El síndrome de PTEN-tumores hamartomatosos (PHTS) es una enfermedad rara que se caracteriza por una gran variabilidad fenotípica que incluye lesiones benignas, pero también una alta predisposición a desarrollar varios tipos de cáncer (cáncer de mama, tiroides, endometrio, renal, colorrectal y melanoma). Este síndrome hereditario se asocia a mutaciones germinales en el gen PTEN, aunque una proporción considerable de pacientes no pueden explicarse por este gen. Todo ello resulta en el desconocimiento de esta enfermedad, la falta de diagnóstico y el mal manejo de estos pacientes. Los objetivos generales de este proyecto son, en primer lugar, caracterizar la enfermedad en pacientes españoles, tanto a nivel genético como clínico, comparar nuestros hallazgos con los obtenido en otras poblaciones y evaluar la utilidad de los criterios diagnóstico; y en segundo lugar, la búsqueda de otros factores que puedan estar implicados en el fenotipo PHTS de los pacientes que no portan mutaciones en PTEN. Para llevar a cabo estos objetivos, hemos reunido una serie de 145 pacientes españoles diagnosticados con PHTS, con su respectiva información clínica y muestras biológicas. El uso de un cuestionario específico nos permitió revisar las manifestaciones clínicas de interés, y el empleo de técnicas genéticas convencionales (Sanger, MLPA, aCGH), junto con técnicas de mayor rendimiento (NGS y WES) ha permitido la caracterización molecular, centrada no sólo en PTEN sino también en la búsqueda de otros genes. Además, los estudios funcionales han arrojado luz acerca de las implicaciones deletéreas de diferentes variantes de significado incierto en PTEN. Los resultados de este trabajo se han empleado para proponer varias recomendaciones para el diagnóstico: el empleo de las manifestaciones clínicas más útiles para derivar al paciente para estudio genético, y realizar este mediante paneles de genes que permitan detectar otros posibles genes alterados que confieran riesgos clínicos añadidos. De cara al seguimiento de los pacientes, es relevante el control del peso y anticipar las revisiones para la detección precoz de cáncer. Por otra parte, varios hallazgos de nuestro trabajo sientan las bases para continuar investigando en esta enfermedad. En resumen, este trabajo contribuye a acelerar y mejorar el diagnóstico y la atención de los pacientes con PHTS.This doctoral thesis has been elaborated in the Familial Cancer Clinical Unit at the Spanish National Cancer Research Centre (CNIO) in Madrid under the supervision of Dr. Miguel Urioste Azcorra. The following grants and fellowships supported this work: - Fondo de Investigaciones Sanitarias (FIS) project PI14/00459, funded by the Spanish Ministerio de Economía y Competitividad (MINECO) and the Fondo Europeo de Desarrollo Regional (FEDER). - Short contract funded by donation through Federación Española de Enfermedades Raras (FEDER). - Severo Ochoa Excellence Programme PhD fellowship (BES-2015-071383) 2015-2019, funded by MINECO and the European Social Fund (ESF)

Optimization and cooperation with logistics applications

Operations Research (OR) is a discipline in which advanced analytical methods are developed and used to solve problems and aid in decision-making. There are a wide variety of fields where OR can be applied, one of which is logistics. Optimizing and scheduling a certain network is a fundamental task, accomplished by proposing models and solving algorithms for each particular situation. Logistic problems are also often treated by the practitioners of OR from a cooperative standpoint, which can be approached through game theory. This thesis addresses several OR and game theoretical problems that have applications in the logistics domain. The performance of the proposed methodologies is analyzed and illustrated with real data applications

Pediatric Providers\u27 Perceptions of their Role in Early Detection of Postpartum Depression

The birth of a child is usually a happy occasion in a woman\u27s life. It is also often a time of overwhelming anxiety, stress and hormonal changes. Postpartum depression (PPD) could occur during the first year of childbirth in approximately 10-20% of mothers (Waldrop, Ledford, Perry, & Beeber, 2017). PPD is the most common maternal health problem within the first year after childbirth (the American College of Obstetricians and Gynecologists, 2018). Recognition of mothers who are at risk for PPD allows health professionals to initiate care that can prevent further problems for the mother, infant, and the rest of their family. Screening, assessing, and treating maternal mental health problems should be a main concern in pediatric care, since maternal depression has major effects on children. There is overwhelming evidence of the long-term impact maternal PPD has on infant well-being throughout various research articles. Although there is evidence of the impact PPD has on the mother-infant dyad, there continues to be a lack of implementation within the pediatric care areas, and the lack of national guidelines and policies. Pediatric providers play a significant role in the prevention of negative outcomes for the infant and the maternal-infant dyad (Kurtz, Levine, & Safyer, 2018). Pediatric providers are in a perfect position to support healthy positive outcomes for maternal/infant health. Eleven providers who see infants within their first year of life from five different organizations were interviewed. the participants were interviewed regarding their perceptions of their role in early detection of PPD. Using a descriptive, qualitative methodology, the data from the interviews were analyzed. the data from the interviews were coded into 7 codes, and consisting of thirteen sub-codes. the codes that emerged consisted of a wide range of perceptions from healthcare providers who see infants and their mothers during the first year of life. Data from the interviews demonstrated how providers perceive their role as a critical aspect of early detection. Participants unanimously stated the importance of their role in early detection. Although participants were in accordance with the importance of their role in early detection, many issues and concerns did develop from the interviews. These issues ranged from inconsistencies regarding the lack of resources available to offer mothers, lack of collaboration, lack of screening protocols, and the lack of education the providers felt they received. Findings from this study offer much insight into the perceptions providers that see infants within their first year of life have regarding their role in early detection of PPD. in conclusion, this study demonstrates the need to increase awareness, and ensure that proper national guidelines are implemented among healthcare providers, policy makers, and organizations to secure a proper and efficient protocol to ensure the practice of screening all mothers. in addition, the results from this study have major implications in public policy, nursing practice, education, and further research

Polígono industrial A Tomada

Traballo fin de mestrado (UDC.ETSA). Arquitectura. Curso 2021/202

Interacción en el equipo de salud para una asistencia segura y fiable

[Resumen] El equipo de salud es un grupo multidisciplinar formado por distintos profesionales que tienen como objetivo principal conseguir promover una asistencia sanitaria con las máximas garantías de seguridad y fiabilidad. En los últimos años la preocupación por la seguridad de la atención ha aumentado ya que los problemas que se vienen observando dependen en gran medida de la colaboración interdisciplinaria y de la comunicación entre los miembros del equipo. Objetivos: Explorar la percepción de los profesionales de salud sobre la importancia de las relaciones interpersonales para garantizar una atención segura y fiable, indagar acerca de esa importancia en los componentes del equipo, identificar la magnitud de la comunicación como proceso ineludible en la relaciones, detectar la percepción sobre la enfermería como vehículo fundamental en ellas, y descubrir propuestas de mejora. Metodología: En este estudio se seguirá un diseño observacional, descriptivo y transversal, con recogida de datos mediante un cuestionario ad hoc cumplimentado de forma anónima y voluntaria y que cuenta con un documento informativo sobre lo que se pretende hacer con el mismo, que va dirigido principalmente, a los que decidan participar en la investigación.[Abstract] A health team is a multidisciplinary group formed by different professionals whose principal objective is to promote health assistance with high guaranties about safety and reliability. In the last years, the worry for the safety of the attention has increased since the problems that they have been observing depend on the collaboration and communication team between the members of the equipment. Objectives: To explore health professional perception on the interpersonal relationship of the importance to guarantee a sure, trustworthy attention; to investigate about that importance into health team; to identify magnitude communication as unavoidable process in relationships; to detect the perception on nursing as essential vehicle in them and to discover improvement offers. Methodology: In this investigation we will use an observational, descriptive and transversal design, picking up information by ad hoc questionnaire completed in an anonymous and voluntary form and giving an informative documentary about the pretension of the study.Traballo fin de grao (UDC.FEP). Enfermarí

Dispersion of carbon nanotubes in vinyl ester polymer composites

This work focused on a parametric study of dispersions of different types of carbon nanotubes in a polymer resin. Single-walled (SWNTs), double-walled (DWNTs), multi-walled (MWNTs) and XD-grade carbon nanotubes (XD-CNTs) were dispersed in vinyl ester (VE) using an ultra-sonic probe at a fixed frequency. The power, amplitude, and mixing time parameters of sonication were correlated to the electrical and mechanical properties of the composite materials in order to optimize dispersion. The quality of dispersion was quantified by Raman spectroscopy and verified through optical and scanning electron microscopy. By Raman, the CNT distribution, unroping, and damage was monitored and correlated with the composite properties for dispersion optimization. Increasing the ultrasonication energy was found to improve the distribution of all CNT materials and to decrease the size of nanotube ropes, enhancing the electrical conductivity and storage modulus. However, excessive amounts of energy were found to damage CNTs, which negatively affected the properties of the composite. Based on these results the optimum dispersion energy inputs were determined for the different composite materials. The electrical resistivity was lowered by as much as 14, 13, 13, and 11 orders of magnitude for SWNT/VE, DWNT/VE, MWNT/VE, and XD-CNT/VE respectively, compared to the neat resin. The storage modulus was also increased compared to the neat resin by 77%, 82%, 45%, 40% and 85% in SWNT, SAP-f-SWNT, DWNT, MWNT and XD-CNT/VE composites, respectively. This study provides a detailed understanding of how the properties of, nanocomposites are determined by the composite mixing parameters and the distribution, concentration, shape and size of the CNTs. Importantly, it indicates the importance of the need for dispersion metrics to correlate and understand these properties

Assessment of the influence of features on a classification problem: an application to COVID-19 patients

This paper deals with an important subject in classification problems addressed by machine learning techniques: the evaluation of the influence of each of the features on the classification of individuals. Specifically, a measure of that influence is introduced using the Shapley value of cooperative games. In addition, an axiomatic characterisation of the proposed measure is provided based on properties of efficiency and balanced contributions. Furthermore, some experiments have been designed in order to validate the appropriate performance of such measure. Finally, the methodology introduced is applied to a sample of COVID-19 patients to study the influence of certain demographic or risk factors on various events of interest related to the evolution of the diseaseThe authors are grateful to Ricardo Cao Abad and to the Dirección Xeral de Saúde Pública of the Xunta de Galicia in Spain. This work has been supported by the ERDF, the Government of Spain/AEI [grants MTM2017-87197-C3-1-P and MTM2017-87197-C3-3-P]; the Xunta de Galicia [Grupos de Referencia Competitiva ED431C2016-015, ED431C2017/38, and ED431C 2021/24, and Centro Singular de Investigación de Galicia ED431G/01]; and by the collaborative research project of the IMAT “Mathematical, statistical and dynamic study of the epidemic COVID-19”, subsidized by the Vice-Rector’s Office for Research and Innovation at the University of Santiago de Compostela, Spain. The research of Laura Davila-Pena has been funded by the Government of Spain [grant FPU17/02126]. We would also like to thank the three anonymous referees and the editor for their constructive comments and suggestions, which helped us to improve the final version of this paperS

Assessment of the Influence of Features on a Classification Problem: An Application to COVID-19 Patients

Financiado para publicación en acceso aberto: Universidade da Coruña/CISUG[Abstract] This paper deals with an important subject in classification problems addressed by machine learning techniques: the evaluation of the influence of each of the features on the classification of individuals. Specifically, a measure of that influence is introduced using the Shapley value of cooperative games. In addition, an axiomatic characterisation of the proposed measure is provided based on properties of efficiency and balanced contributions. Furthermore, some experiments have been designed in order to validate the appropriate performance of such measure. Finally, the methodology introduced is applied to a sample of COVID-19 patients to study the influence of certain demographic or risk factors on various events of interest related to the evolution of the disease.The authors are grateful to Ricardo Cao Abad and to the Dirección Xeral de Saúde Pública of the Xunta de Galicia in Spain. This work has been supported by the ERDF, the Government of Spain/AEI [grants MTM2017-87197-C3-1-P and MTM2017-87197-C3-3-P]; the Xunta de Galicia [Grupos de Referencia Competitiva ED431C2016-015, ED431C2017/38, and ED431C 2021/24, and Centro Singular de Investigación de Galicia ED431G/01]; and by the collaborative research project of the IMAT “Mathematical, statistical and dynamic study of the epidemic COVID-19”, subsidized by the Vice-Rector’s Office for Research and Innovation at the University of Santiago de Compostela, Spain. The research of Laura Davila-Pena has been funded by the Government of Spain [grant FPU17/02126]Xunta de Galicia; ED431C2016-015Xunta de Galicia; ED431C2017/38Xunta de Galicia; ED431C 2021/24Xunta de Galicia; ED431G/0

Exposición crónica a hongos productores de aflatoxinas relacionada a daños hepáticos en chinchillas (chinchilla lanigera) destinadas a la producción de piel

Chinchilla pelt is a rare and expensive fur. Therefore, breeding these animals is a profitable activity. Confirmed acute cases of aflatoxin intoxication have been reported in Argentinean farms. The aims of this study were i) to evaluate mycobiota and AFB1 -producing species in chinchilla feeds ii) to investigate their natural AFB1 contamination and iii) to analyze histopathological lesions in chinchilla livers. Feed samples (A: fur chinchillas, B: mother chinchillas, C: lucerne cubes) were collected from a factory and a farm. Livers of sacrificed chinchilla from the farm were macroscopically and microscopically examined. Total fungal counts of feed C exceeded 1x104 CFU g-1. Aspergillus, Fusarium and Penicillium were the prevalent genera, while A. flavus, A. fumigatus, F. verticillioides and F. proliferatum were the prevalent species. 50 % of A. flavus strains from factory samples and 69.7 % from farm samples produced 2.78 to 8. 64 µg g-1 and 0.66 to 58.8 µg g-1 AFB1 , respectively. Aflatoxin B1 was detected only in feeds from the farm, finding the highest incidence in feed C. Toxin levels varied between 1.90 and 97.34 µg kg-1 AFB1 . Mean levels in feed A and C exceeded 20 µg kg-1. Macroscopic examination of livers revealed normal appearance, size and color. However, histopathological examination indicated 63.3 % showed slight to moderate lipid degeneration with diffuse cytoplasm vacuolation, 9 % intense lipid cytoplasm vacuolation and 27.3 % hydropic degeneration and nuclear vacuolation in hepatocytes. A periodic monitoring of aflatoxins in feeds and their ingredients can prevent acute outbreaks and economic losses caused by chronic exposure.La piel de chinchilla es una de las más exóticas y apreciadas en el mercado internacional. La cría de estos animales es una actividad muy rentable. En Argentina, se han detectado casos de aflatoxicosis aguda en criaderos. Los objetivos de este trabajo fueron: i) estudiar la micobiota y los hongos productores de aflatoxina B1 (AFB1 ) presentes en alimento para chinchillas. ii) analizar la contaminación natural con AFB1 de estos alimentos iii) buscar lesiones histopatológicas en hígados de chinchillas de los criaderos. Se recolectaron muestras de diferentes alimentos (A: chinchilla piel, B: chinchilla madre, C: cubos de alfalfa) en una fábrica y un criadero localizados en la ciudad de Rio Cuarto, en la región central de Argentina. Los hígados de las chinchillas sacrificadas en el criadero fueron analizados macroscópica y microscópicamente. Los recuentos fúngicos totales fueron mayores a 1x104 UFC g-1. Aspergillus, Fusarium y Penicillium fueron los géneros prevalentes, mientras que A. flavus, A. fumigatus, F. verticillioides y F. proliferatum fueron las especies aisladas con mayor frecuencia. 50 % de las cepas de A. flavus aisladas de la fábrica y 69.7 % de las aisladas del criadero produjeron 2.78 a 8.64 µg g-1 y 0.66 a 58.8 µg g-1 de AFB1 , respectivamente. Se detectó AFB1 sólo en las muestras del criadero, con mayor incidencia en el alimento C. Los niveles de toxina variaron entre 1.90 y 97.34 µg kg-1. Los niveles promedios en A y C fueron superiores a 20 µg kg-1. El análisis macroscópico de los hígados reveló apariencia, tamaño y color normal. El análisis microscópico indicó que 63.3 % de los hígados presentaron degeneración lipídica leve a moderada con vacuolización difusa del citoplasma, 9 % presentaron vacuolización lipídica intensa y 27.3 % degeneración hidrópica y vacuolización nuclear en los hepatocitos. El monitoreo periódico de La calidad de los alimentos e ingredientes usados en la alimentación de chinchillas puede evitar intoxicaciones agudas y pérdidas económicas causadas por la exposición crónica a aflatoxinas.Fil: Landa, Maria Florencia. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas, Fisicoquímicas y Naturales. Departamento de Microbiología e Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gonzalez Pereyra, Maria Laura. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas, Fisicoquímicas y Naturales. Departamento de Microbiología e Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Pena, Gabriela Alejandra. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas, Fisicoquímicas y Naturales. Departamento de Microbiología e Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bagnis, Guillermo. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas, Fisicoquímicas y Naturales. Departamento de Microbiología e Inmunología; ArgentinaFil: Cavaglieri, Lilia Reneé. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas, Fisicoquímicas y Naturales. Departamento de Microbiología e Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Rosa, Carlos Alberto da Rocha. Conselho Nacional de Pesquisas Científicas; BrasilFil: Dalcero, Ana Maria. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas, Fisicoquímicas y Naturales. Departamento de Microbiología e Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Extrinsic allergic alveolitis. Case report

La alveolitis alérgica extrínseca engloba un conjunto de entidades mediadas inmunológicamente, causadas por la inhalación repetida de antígenos. Su incidencia a nivel mundial oscila entre 0,3 y 0,9 casos por cada 100 000 habitantes. Se presenta el caso de un paciente de 18 años, ayudante de carpintería, que comienza con falta de aire, tos y fiebre después de cortar madera. Ante dicha sintomatología y el hallazgo de crepitantes en la base del hemitórax izquierdo se maneja como una neumonía adquirida en la comunidad. Los exámenes complementarios mostraron aumento de la inmunoglobulina G, eosinofilia y un patrón restrictivo en la espirometría. Se diagnosticó una alveolitis alérgica extrínseca y se indicó tratamiento con esteroides por vía oral, con evolución satisfactoria. La alveolitis alérgica extrínseca ocupacional es una patología de difícil diagnóstico por su escasa frecuencia y similitud con otras enfermedades pulmonares intersticiales, pero una vez diagnosticada evoluciona favorablemente con el uso de esteroides.  Extrinsic allergic alveolitis encompasses a set of immunologically mediated entities, caused by repeated inhalation of antigens. Its worldwide incidence ranges between 0,3 and 0,9 cases per 100 000 inhabitants. The case of an 18-year-old patient, a carpenter's assistant, is presented, who begins with shortness of breath, cough and fever after cutting wood. Given this symptomatology and the finding of crackles at the base of the left hemithorax, it is managed as community-acquired pneumonia. The complementary tests showed an increase in IgG, eosinophilia and a restrictive pattern in spirometry. An extrinsic allergic alveolitis was diagnosed and treatment with oral steroids was indicated, showing satisfactory evolution. Occupational extrinsic allergic alveolitis is a pathology that is difficult to diagnose due to its low frequency and similarity to other interstitial lung diseases, but once diagnosed it evolves favorably with the use of steroids.