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European CF Society Neonatal Screening Working Group (ECFS NSWG): Sabine Renner , Max Zeyda , Elke de Wachter , Luc Regal , Felix Votava, Andrea Holubova, Marianne Skov , Tessa Morgan, Paul Bregeaut , Loretta O'Grady, Ines Bucci , Stefano Pantano , Simonetta Simonetti, Domenica De Venuto, Donatello Salvatore, Nicola Perrotti, Mimma Caloiero, Giuseppe Castaldo, Antonella Tosco, Francesca Righetti, Giovanna Pisi, Fiorella Battistini, Antonio Angeloni, Giuseppe Cimino, Giovanni Fiocchi, Antonella Angiolillo, Michela Cassanello, Luisella Alberti, Laura E Claut, Raffaele Badolato, Enza Pavanello, Benedetta Fabrizzi, Elisabetta Bignamini, Anna Cardillo, Mariangela Lombardo, Letizia Cocciadiferro, Lisa Termini, Daniela Dolce, Vito Terlizzi, Anna Tamanini, Francesca Pauro, Giancarlo la Marca, Elina Aleksejeva, Dita Gaidule-Logina, Stoika Fustik, Violeta Anastasovska, Marelle Bouva, Alastair Reid, Jennifer Cundick, Emma Lundman, Egil Bakkeheim, Katarzyna Zybert, Mariusz Oltarzewski, Laura Vilarinho, Victoria Sherman, Elena Kondratyeva, Sarah Smith, Gordana Vilotijevic Dautovic, Maria Knapkova, Zuzana Mydlova, Rosa Mª López, Valle Velasco, Felicitas Díaz Flores, Cristóbal Colón Mejeras, Eva Sl Pedersen, Ugur Ozcelik, Bulent Karadag, Halyna Makukh, Moat Stuart. European CF Society Neonatal Screening Working Group (ECFS NSWG): INSA - Laura Vilarinho Background: The aim of this study was to record the current status of newborn bloodspot screening (NBS) for CF across Europe and assess performance. Methods: Survey of representatives of NBS for CF programmes across Europe. Performance was assessed through a framework developed in a previous exercise. Results: In 2022, we identified 22 national and 34 regional programmes in Europe. Barriers to establishing NBS included cost and political inertia. Performance was assessed from 2019 data reported by 21 national and 21 regional programmes. All programmes employed different protocols, with IRT-DNA the most common strategy. Six national and 11 regional programmes did not use DNA analysis. Conclusions: Integrating DNA analysis into the NBS protocol improves PPV, but at the expense of increased carrier and CFSPID recognition. Some programmes employ strategies to mitigate these outcomes. Programmes should constantly strive to improve performance but large datasets are needed to assess outcomes reliably. Highlights: In 2022, newborn bloodspot screening (NBS) for CF is undertaken in 30 European countries, 26 of them are national programmes; Some programmes are still not achieving ECFS standards. Compared to 2014, there is an improvement in sensitivity but a deterioration in achieving a sufficient PPV; There continues to be a wide variety of approaches, but the majority of national programmes are now using DNA analysis as a 2nd tier; This survey demonstrates areas of good practice, but there is considerable scope for improvement in the quality of NBS for CF across Europe; The framework of the 20 parameters to calculate the 8 key outcomes should be part of any annual report of a CF NBS programme, and thus improve future surveys. The survey was funded by the European CF Society info:eu-repo/semantics/publishedVersion

Introduction Viral infections are associated with pulmonary exacerbations in children with Cystic Fibrosis (cwCF), but after 3 years of SARS-CoV-2 pandemic, whether cwCF are at higher risk of developing COVID-19 or its adverse consequences remains controversial. Methods We conducted an observational, multicenter, cross-sectional study of cwCF infected by SARS-CoV-2 between March 2020 and June 2022, (1 to 6 COVID-19 pandemic waves) in Spain. The study aimed to describe patients’ basal characteristics, SARS-CoV-2 clinical manifestations and outcomes, and whether there were differences across the pandemic waves. Results During study time, 351 SARS-CoV2 infections were reported among 341 cwCF. Median age was 8.5 years (range 0-17) and 51% were female. Cases were unevenly distributed across the pandemic, with most cases (82%) clustered between November 2021 and June 2022 (6 wave, also known as Omicron Wave due to the higher prevalence of this strain in that period in Spain). Most cwCF were asymptomatic (24.8%) or presented with mild Covid-19 symptoms (72.9%). Among symptomatic, most prevalent symptoms were fever (62%) and increased cough (53%). No multisystem inflammatory syndrome (MIS-C), persisting symptoms, long-term sequelae or deaths were reported. Conclusions Spanish current data indicate that cwCF do not experience higher risks of SARS-CoV-2 infection nor worse health outcomes or sequelae. Changes in patients’ basal characteristics, clinical courses and outcomes were detected across waves. While the pandemic continues, and new SARS-CoV-2 variants are being identified, a worldwide monitoring of COVID-19 in pediatric CF patients is needed.

[Background] Children's diffuse lung disease, also known as children's Interstitial Lung Diseases (chILD), are a heterogeneous group of rare diseases with relevant morbidity and mortality, which diagnosis and classification are very complex. Epidemiological data are scarce. The aim of this study was to analyse incidence and prevalence of chILD in Spain., [Methods] Multicentre observational prospective study in patients from 0 to 18 years of age with chILD to analyse its incidence and prevalence in Spain, based on data reported in 2018 and 2019., [Results] A total of 381 cases with chILD were notified from 51 paediatric pulmonology units all over Spain, covering the 91.7% of the paediatric population. The average incidence of chILD was 8.18 (CI 95% 6.28–10.48) new cases/million of children per year. The average prevalence of chILD was 46.53 (CI 95% 41.81–51.62) cases/million of children. The age group with the highest prevalence were children under 1 year of age. Different types of disorders were seen in children 2–18 years of age compared with children 0–2 years of age. Most frequent cases were: primary pulmonary interstitial glycogenosis in neonates (17/65), neuroendocrine cell hyperplasia of infancy in infants from 1 to 12 months (44/144), idiopathic pulmonary haemosiderosis in children from 1 to 5 years old (13/74), hypersensitivity pneumonitis in children from 5 to 10 years old (9/51), and scleroderma in older than 10 years old (8/47)., [Conclusions] We found a higher incidence and prevalence of chILD than previously described probably due to greater understanding and increased clinician awareness of these rare diseases., [Antecedentes] Las neumopatías intersticiales pediátricas, también conocidas con el acrónimo chILD (del inglés children's Interstitial Lung Diseases), es un grupo heterogéneo de enfermedades raras con morbimortalidad relevante, cuyo diagnóstico y clasificación son complejos. Los estudios epidemiológicos son escasos. El objetivo de este trabajo fue analizar la incidencia y la prevalencia de chILD en España., [Métodos] Estudio prospectivo observacional multicéntrico en pacientes de 0 a 18 años afectos de chILD para analizar la incidencia y la prevalencia en España, a partir de datos recogidos en 2018 y 2019., [Resultados] Se recogieron 381 casos de chILD entre 51 unidades de neumología pediátrica de toda España, que cubrían el 91,7% de la población pediátrica. La incidencia promedio fue 8,18 (IC 95%: 6,28-10,48) casos nuevos/millón de niños por año. La prevalencia promedio fue de 46,53 (IC 95%: 41,81-51,62) casos/millón de niños. El grupo de edad con mayor prevalencia fue el de niños menores de un año. Se observaron diferentes entidades en niños de 2 a 18 años en comparación con niños de 0 a 2 años. Los diagnósticos más frecuentes fueron: glucogenosis intersticial pulmonar primaria en neonatos (17/65), hiperplasia de células neuroendocrinas en lactantes de uno a 12 meses (44/144), hemosiderosis pulmonar idiopática en niños de uno a 5 años (13/74), neumonía por hipersensibilidad en niños de 5 a 10 años (9/51) y esclerodermia en mayores de 10 años (8/47)., [Conclusiones] Encontramos una mayor incidencia y prevalencia de chILD que las descritas previamente, probablemente debido a un mayor conocimiento y detección de estas enfermedades raras., ATV was supported by a grant from the Spanish Society of Paediatric Pulmonology and a Short Term Scientific Mission of the Cost CA 16125 ENTeR-chILD. This work was supported by a grant from the Spanish Society of Pneumology and Thoracic Surgery (SEPAR 2017/492). AMG was supported by a grant from the project HCQ4Surfdefect, in E-Rare-3, the ERA-Net for Research on Rare Diseases (Acciones complementarias en Salud, Instituto Carlos III, Madrid, Spain, AC16/00027) and Cost CA 16125 ENTeR-chILD.

[ES] Este trabajo es un proyecto de investigación de naturaleza intermedia en torno a la apreciación de movimiento gestual como experiencia plástica, tomando como referencia los experimentos lingüísticos de la poesía fonética y la escritura asemántica, y combinando sus modos de operación con las herramientas del arte de acción, hacia un nuevo tratamiento creativo con la acción gestual y su lenguaje., [EN] This work is a research project of an intermediate nature around the appreciation of gestural movement as a plastic experience, taking as reference the linguistic experiments of phonetic poetry, and asemic writing, and combining their modes of operation with the Performance Art ones, towards a new creative treatment with gestural action and its language.

Volcanic eruptions emit gases and particulate matter into the atmosphere which, if inhaled, can have an impact on health. The eruption of the volcano situated in the Cumbre Vieja Nature Reserve (La Palma, Canary Islands, Spain) affords a unique opportunity to study the effect of such a phenomenon on health. The aim of the proposed study is to assess the short-, medium- and long-term respiratory health effects of exposure to volcanic emissions from the eruption in three different population groups.We propose to undertake a multidesign study: an ambispective cohort study to analyze the effect of the eruption on the general population, the highly exposed population, and the childhood population; and a pre-post quasi-experimental study on subjects with previously diagnosed respiratory diseases. The information will be collected using a personal interview, biologic specimens, air pollution data, data from medical records, respiratory tests and imaging tests. The study has an envisaged follow-up of five years, to run from the date of initial recruitment, with annual data-collection. This study has been approved by the Santa Cruz de Tenerife Provincial Research Ethics Committee (Canary Island Health Service) on March 10, 2022.This study will make it possible to advance our knowledge of the effect a volcano eruption has on population health, both short- and long-term, and to assess the potential respiratory injury attributable to volcanic eruptions. It may serve as a model for future studies of new volcanic eruptions in the coming years.

Introduction: There are limited studies describing the evolution of lung function and its relationship with phenotypes in young individuals aged between 16 and 26 years. Objective: To evaluate the prevalence of spirometric dysfunction in medical students at the enrollment visit of the study. Methods: Incoming medical students at 4 universities (3 in Spain, one in Mexico) underwent anthropometric measurements, a spirometry and a structured questionnaire which assessed exposure history, symptoms, family and personal history. Following standard guidelines, the spirometric dysfunction was classified as normal, obstructed or restricted pattern. Results: The 95 men (32%) and 199 women (68%), had a mean age of 19 ± 2 years. The BMI (Kg/m2) distribution was: 7% low weight ( 30). The current smokers were 8% (60% women, 40% men) while 2% were current users of e-cigarette but 24% had tried them. The mean FVC for men was 95% ± 16 and for women 95% ± 13 (p=0.074). Mean FEV1: men 97% ± 14, women100% ± 58 (p=0.575). Mean FEV1/FVC: men 88% ± 9, women 90% ± 7 (p=0.042). The spirometric values were normal in 91% (268/294), had an obstructive pattern in 1.7% (5/294) and consistent with restriction in 7.4% (22/294). Conclusions: These preliminary findings indicate that a substantial proportion of otherwise “normal” individuals manifest abnormal lung development at early adulthood. The natural course of lung function in this cohort is the objective of the LEVANTE study. Project supported by SEPAR (Sociedad Espanola Neumologia y Cirugia Toracica)

CF-COVID19-Spain Registry Group., [Background] Given the high incidence of confirmed infection by SARS-CoV-2 and mortality by COVID-19 in the Spanish population, its impact was analysed among persons with Cystic Fibrosis (CF) as a group at risk of a worse evolution. The possible causes of the incidence observed in them are explained and how CF Units have faced this health challenge is detailed., [Methods] Retrospective descriptive observational study, for which a Spanish CF Patients with Confirmed COVID-19 Registry is created, requesting information on number of people affected between 8 March–16 May 2020 and their clinical-demographic characteristics from the CF Units participating in the European Cystic Fibrosis Society Patient Registry (ECFSPR). The accumulated incidence is calculated, compared with that of the general population. Additionally, a survey (CF-COVID19-Spain) is carried out on prevention of SARS-CoV-2 infection, workings of CF Units and possible reasons for the incidence observed., [Results] COVID-19 was diagnosed in eight CF patients, one of whom had received a lung transplant. The accumulated incidence was 32/10000 in CF patients and 49/10000 in the general population. General death rate was 5.85/10000 while no CF patients included in the ECFSPR died. The characteristics of those affected and the results of the survey are described., [Conclusions] Despite being considered a disease at high risk of severe COVID-19, the low incidence and mortality in CF patients in Spain contrasts with the figures for the general population. The possible factors that would explain such findings are discussed, with the help of the results of the CF-COVID19-Spain survey.

Background Data addressing short- and long-term respiratory morbidity in moderate-late preterm infants are limited. We aim to determine the incidence of recurrent wheezing and associated risk and protective factors in these infants during the first 3 years of life. Methods Prospective, multicenter birth cohort study of infants born at 32+0 to 35+0 weeks' gestation and followed for 3 years to assess the incidence of physician-diagnosed recurrent wheezing. Allergen sensitization and pulmonary function were also studied. We used multivariate mixed-effects models to identify risk factors associated with recurrent wheezing. Results A total of 977 preterm infants were enrolled. Rates of recurrent wheezing during year (Y)1 and Y2 were similar (19%) but decreased to 13.3% in Y3. Related hospitalizations significantly declined from 6.3% in Y1 to 0.75% in Y3. Independent risk factors for recurrent wheezing during Y2 and Y3 included the following: day care attendance, acetaminophen use during pregnancy, and need for mechanical ventilation. Atopic dermatitis on Y2 and male sex on Y3 were also independently associated with recurrent wheezing. Palivizumab prophylaxis for RSV during the first year of life decreased the risk or recurrent wheezing on Y3. While there were no differences in rates of allergen sensitization, pulmonary function tests (FEV0.5 ) were significantly lower in children who developed recurrent wheezing. Conclusions In moderate-to-late premature infants, respiratory symptoms were associated with lung morbidity persisted during the first 3 years of life and were associated with abnormal pulmonary function tests. Only anti-RSV prophylaxis exerted a protective effect in the development of recurrent wheezing.

Notwithstanding guidelines, indications for mechanical thrombectomy (MT) in acute ischemic stroke are multifactorial and can be complex. Our aim was to exploratively evaluate decision-making on the advisability of performing MT in cases presented as an interview-administered questionnaire. Fifty international raters assessed 12 cases and decided to recommend or exclude MT. Each case contained a brief summary of clinical information and eight representative images of the initial multimodal CT. The demographic characteristics and stroke protocols were recorded for raters. For each case, the reasons for excluding MT were recorded. Uni- and multivariate logistic regression analysis were performed for the different demographic and case characteristics to identify factors that might influence decision-making. All raters performed MT (median MTs/hospital/year [IQR], 100 [50–141]) with a median of 7 years of experience as first operator (IQR, 4–12). Per case, diversity in decision-making ranged between 1 (case 6, 100% yes MT) and 0.50 (case 12, 54.2% yes MT and 45.8% no MT). The most common reasons for excluding MT were small CBV/CBF mismatch (17%, 102/600), size of infarct core on the CBV map (15.2%, 91/600), and low NIHSS score (National Institute of Health Stroke Scale, 8.3%, 50/600). All clinical and radiological characteristics significantly affected the decision regarding MT, but the general characteristics of the raters were not a factor. Clinical and imaging characteristics influenced the decision regarding MT in stroke. Nevertheless, a consensus was reached in only a minority of cases, revealing the current divergence of opinion regarding therapeutic decisions in difficult cases. • This is the first study to explore differences in decision-making in respect of mechanical thrombectomy in ischemic stroke with complex clinical and radiological constellations. • Fifty experienced international neurointerventionalists answered this interview-administered stroke questionnaire and made decisions as to whether to recommend or disadvise thrombectomy in 12 selected cases. • Diversity in decision-making for thrombectomy ranged from 1 (100% of raters offered the same answer) to 0.5 (50% indicated mechanical thrombectomy). There was a consensus in only a minority of cases, revealing the current disparity of opinion regarding therapeutic decisions in difficult cases.

Introduction: Survival in Cystic Fibrosis (CF) is permanently increasing due to several factors, in particular the CF early diagnosis by implementation of the Newborn Screening Program (NBSP). In Spain, the NBSP was launched in 1999 in Catalonia, Castilla-Leon and Balearic Islands and in 2015 has been expanded to all communities. Objective: to describe the data of the NBSP of the different autonomous communities (ACs) in Spain. Method: Retrospective data from the NBSP through a survey sent to the 12 ACs that screening was already available in the year 2014. Resultados: in Spain the NBSP has been applied globally to nearly 3,000,000 newborns detecting 460 cases with CF. Examples of incidence are: Catalonia 1 / 6631; Castilla y Leon 1/5007, Balearic Islands 1/5853, Madrid 1 / 6160, Basque Country 1 / 7,700. Three different strategies for NBSP have been implemented: 1) TIR TIR + sweat test in three ACs ; 2) TIR TIR + genetic test + sweat test: in five; 3) TIR + genetic test in seven. The three most frequent identified mutations were: F508del, G542X and N1303K. The average age of diagnosis was within 50 days of life except in a community that one diagnosis was made after 2 months. The presence of pancreatic insufficiency ranged from 40% to 80%; Pseudomonas aeruginosa chronic infection from 0 to 20% and Staphylococcus aureus from 0 to 40%. Conclusion: this is the first global data of NBSP for CF in Spain. Results from the different programs provide an opportunity to compare all current strategies and results.

Background Airway diseases are highly prevalent in infants and cause significant morbidity. We aimed to determine the incidence and risk factors for respiratory morbidity in a Spanish cohort of moderate-to-late preterm (MLP) infants prospectively followed during their first year of life. Methods SAREPREM is a multicenter, prospective, longitudinal study. Preterm infants born at 32–35 weeks of gestation with no comorbidities were enrolled within 2 weeks of life and followed at 2–4 weeks, 6, and 12 months of age. Multivariate mixed-models were performed to identify independent risk factors associated with (i) development of bronchiolitis, (ii) recurrent wheezing, or (iii) related hospital admissions. Results Overall, 977 preterm infants were included, and 766 (78.4%) completed follow-up. Of those, 365 (47.7%) developed bronchiolitis during the first year, 144 (18.8%) recurrent wheezing, and 48 (6.3%) were hospitalized. While low birthweight, day care attendance (DCA) and school-age siblings were significantly and independently associated with both the development of bronchiolitis and recurrent wheezing, lower maternal age increased the risk for bronchiolitis and respiratory-related hospitalizations. Lastly, mechanical ventilation was associated with a higher risk of bronchiolitis and history of asthma in any parent increased the likelihood of developing recurrent wheezing. Conclusions In this study, several non-modifiable parameters (family history of asthma, low birthweight, need for mechanical ventilation) and modifiable parameters (young maternal age, DCA, or exposure to school-age siblings) were identified as significant risk factors for the development of bronchiolitis and recurrent wheezing during the first year of life in MLP infants.

The prevalence and clinical consequences of gastro-oesophageal reflux disease (GERD) in chronic obstructive pulmonary disease (COPD) are not well characterised. The present study prospectively studied 42 males with COPD (forced expiratory volume in one second % predicted: 35%, range 20-49) and 16 healthy volunteers of similar age without respiratory or gastro-oesophageal symptoms. The diagnosis of GERD was confirmed using oesophageal 24 h pH monitoring. In the current study group, reflux symptoms were measured using the Vigneri score, cough and dyspnoea with the modified Medical Research Council questionnaire, and pulmonary function with bronchodilator response and health status using St George's Respiratory Questionnaire. Pathological reflux was documented in 26 out of 42 patients (62%) and in three volunteers (19%). In patients with GERD, 15 patients (58%) did not report any reflux symptoms. There were no differences in symptoms, health status, bronchodilator treatment and pulmonary function test between patients with and without GERD. Oxygen desaturation coincided with episodes of increased oesophageal acidity in 40% of patients with GERD. Patients with severe chronic obstructive pulmonary disease have a high prevalence of asymptomatic gastro-oesophageal reflux. The association between this reflux and oxygen desaturation deserves further attention.

La presente investigación sobre la aplicación de un modelo informático empleadas en la en el aprendizaje de resolución de ecuaciones diferenciales en el cuarto semestre de la Facultad de ingenia civil y mecánica periodo septiembre 2010, febrero 2011 este presente tesis es un instrumento que ayuda a fortalecer la enseñanza de ecuaciones diferenciales y fortalezca el aprendizaje en los distintos procedimientos puesto que este tipo de aplicación es importante porque desarrolla criterios de resolución y comparación en los resultados . Basado en el desarrollo del programa visual Basic 6.0 se genera ventanas de trabajo de fácil utilización que reduce el tiempo de resolución. Los software matemáticos son aplicaciones que resuelven ecuaciones diferenciales de segundo orden de acuerdo al modelo presentado. La Operacionalización de variables han permitido precisarlas y proyectar las preguntas de la encuesta para los estudiantes así como las encuestas a los docentes en estas encuestas se podido dilucidar los resultados gracias al aporte de 91 estudiantes encuestados y 2 docentes encargados de la asignatura de ecuaciones deferenciales, encontrando una visión completa del proceso de aprendizajes de esta cátedra, en la utilización y manipulación de las aplicaciones anteriormente mencionadas se establece que muy poco son utilizadas estas, y entonces se aplico un curso básico de inducción al personal docente y estudiantes lo cual genere el mejor aprendizaje en la resolución de ecuaciones diferenciales con esta herramienta para el docente y los estudiantes a la par de su enseñanza aprendizaje. En cuanto a la parte administrativa se cuanta con la colaboración del Sr. Decano Ing. Francisco Pazmiño.

Study objectives: To determine the 1-year efficacy of noninvasive positive pressure ventilation (NPPV) added to long-term oxygen therapy (LTOT) in patients with stable severe COPD. Patient selection and methods: We prospectively randomized 52 patients with severe COPD (FEV1 < 45%) to either NPPV plus “standard care” (96% patients with LTOT) or to standard care alone (93% patients with LTOT). The outcomes measured included the following: rate of acute COPD exacerbations; hospital admissions; intubations; and mortality at 3 months, 6 months, and 12 months. The patients were also evaluated at 3 months and 6 months for dyspnea using the Medical Research Council and Borg scales, gas exchange, hematocrit, pulmonary function, cardiac function with echocardiogram, and neuropsychological performance. Results: One-year survival was similar in both groups (78%). The number of acute exacerbations was similar at all time points in patients receiving NPPV, compared with control subjects. The number of hospital admissions was decreased at 3 months in the NPPV group (5% vs 15% of patients, p < 0.05), but this difference was not seen at 6 months (18% vs 19%, respectively). The only beneficial differences were observed in the Borg dyspnea rating, which dropped from 6 to 5( p< 0.039), and in one of the neuropsychological tests (psychomotor coordination) for the NPPV group at 6 months. Conclusions: Our study indicates that over 1 year, NPPV does not affect the natural course of the disease and is of marginal benefit in outpatients with severe COPD who are in stable condition. (CHEST 2000; 118:1582‐1590)

Desde el mes de Octubre de 1981 se inicio en la Refinería La Pampilla la aplicación de un plan de ahorro y Conservación de Energía con objetivos definidos de reducción de su consumo en el corto y mediano plazo, estimándose esta reducción en el orden del 10% hasta 1986. Este objetivo de reducción considera la implementación de un Programa de Ahorro de Energía con dos etapas consecutivas y no excluyentes. La primera etapa agrupa a todas aquellas actividades que requieren de una inversión mínima o nula, como son la optimización de procedimientos, el mantenimiento preventivo y proyectos menores. Esta etapa se inicio en Octubre de 1981 y se considera de plazo ilimitado. La segunda etapa abarca aquellas actividades que requieren estudios e inversiones mayores y que involucran nuevos equipos o modificación de procesos. Esta etapa empezará en 1984, y continuará paralela a la primera. El presente estudio es una evaluación de los resultados logrados en el primer año de aplicación de este plan (1982) incidiendo de manera específica en el comportamiento de las principales variables del proceso de repercusión en el consumo de enrgía. Trabajo de suficiencia profesional

La presente tesis doctoral consta de 4 proyectos independientes centrados en el estudio de las causas genéticas del cáncer colorrectal (CCR) hereditario: A) Estudio de una variante común (rs2075786) en el gen de la telomerasa como modificador de riesgo de cáncer en síndrome de Lynch: Identificamos un incremento de riesgo de desarrollar un cáncer asociado al síndrome de Lynch (SL) en los pacientes jóvenes (, The herein thesis “Caracterización molecular y búsqueda de causas genéticas del cáncer colorrectal hereditario no polipósico” (in English, “Molecular characterization and search for genetic causes in the hereditary non-polyposis colorectal cancer”) comprises four different studies: A) Genetic variant rs2075786 in the telomerase gene modifies cancer risk in Lynch syndrome: We found an association between the rs2075786 A allele, specially in homozygosity, with increased cancer risk of developing cancer in Lynch syndrome (LS) carriers under the age of 45. Besides, cancer-affected LS patients with the AA genotype have shorter telomeres than those with GG. In silico studies predicted that the SNP causes the disruption of a transcription binding site for a retinoid receptor, probably provoking early telomerase activation. B) Comprehensive molecular characterisation of hereditary non-polyposis colorectal tumours with mismatch repair proficiency. Hereditary non-polyposis colorectal tumours showed presence of high chromosomal instability and a higher frequency of chromosome 2p and 2q gains and of 10 q loss, when comparing to sporadic colorectal tumors with mismatch repair proficiency. No statistically significant differences between these two groups were found in the frequency of BRAF, KRAS, PIK3CA and TP53 mutations. Besides, hereditary non-polyposis colorectal tumours showed a low degree of CpG islands methylation. C) Study of the impact of POLE and POLD1 mutations in the familial colorectal cancer and/or polyposis. The exonuclease domains of POLE and POLD1 were studied 441 kindreds with familial non-polyposis colorectal cancer (CRC) and 88 with polyposis. Six novel or rare POLD1 variants, four of them with strong evidence for pathogenicity, were identified in non-polyposis CRC families. We also suggested some recommendations for POLE and POLD1 mutation screening and to define the clinical management of mutation carriers D) Search for the genetic cause of the colorectal cancer type X by whole-exome sequencing. In order to find the genetic cause of the familial colorectal cancer type-X, we sequenced the whole exome of three CRC affected relatives from the same type-X family. After several steps of mutations filtering and extensive experimental and in silico studies, we proposed a poly-genic model to explain the CRC aggregation within the family, in which mutations in BRF1, BARD1 and CLCA1 would be contributing to the familiar CRC predisposition.

[spa] Aunque se estima la proporción de casos de cáncer colorrectal (CCR) atribuibles a factores genéticos entre el 20 y 35%, gran parte de la herencia genética al CCR queda por descubrir. Dentro de ese conglomerado de casos de CCR con agregación familiar sin una causa subyacente clara, se encuentra el CCR familiar tipo X (CCRf-X). Estas familias cumplen los criterios clínicos más estrictos para el CCR hereditario no polipósico (criterios de Ámsterdam) pero no presentan defectos en el sistema de reparación de bases desapareadas, rasgo definitorio de los pacientes con SL. El estudio de dos de estas familias mediante secuenciación de exomas nos ha permitido identificar el gen causal de la predisposición. La primera familia ha resultado ser un caso de CCR asociado a MUTYH enmascarado bajo unas características fenotípicas y moleculares atípicas. Estas son: Herencia aparentemente dominante debido al riesgo que aportan las variantes monoalélicas en MUTYH, ausencia de pólipos y presencia de tumores con inestabilidad de microsatélites. En la segunda familia hemos identificado un nuevo gen de predisposición al CCR que podría explicar aproximadamente un 3% de las familias CCRf-X. La haploinsuficiencia de este gen podría causar una reparación defectuosa del ADN con la consiguiente acumulación de un tipo específico de errores. Se ha sugerido que mutaciones en el gen que codifica la glicosilasa GALNT12 confieren un riesgo incrementado a padecer CCR. Hemos estudiado el gen en 103 familias CCRf-X pero no se han identificado cambios relevantes que afecten la actividad enzimática, desestimando a GALNT12 como un gen de alta penetrancia para CCR. Por otro lado, hemos evaluado el papel de la longitud telomérica como modulador del riesgo a desarrollar cáncer en las formas de CCR hereditario no polipósico. Hemos observado que muestran un patrón distinto en función del estado de la maquinaria de reparación de bases desapareadas: Acortamiento para pacientes con SL y elongamiento para el CCRf-X. Además, descartamos el acortamiento de los telómeros como mecanismo molecular que explique el fenómeno de la anticipación genética observada en el SL., [eng] Family history is thought to involve approximately 20% of all colorectal cancers (CRC). However, only a minority are explained by germline genetic mutations in well-known high penetrance genes. To identify novel hereditary CRC genes, we studied by exome sequencing two familial CRC of type X (fCRC-X) families. That is, Amsterdam-positive families with mismatch repair proficient tumors, and which genetic etiology is unknown. The first family examined resulted to be a case of MUTYH-associated CRC with an atypical phenotype. The analysis of the second family prompted us to the identification of a new CRC susceptibility gene that could explain ~3% of fCRC-X. Moreover, we have studied the gene GALNT12, suggested as a candidate gene that might cause a fraction of the unexplained familial CRC cases. Our results rule out GALNT12 as a major high penetrance gene for CRC. On the other hand, we have evaluated the role of blood telomere length in the risk of hereditary non-polyposis CRC. We have identified different patterns of telomere length according to the status of the MMR system: shortening for Lynch syndrome patients and elongation for fCRC-X. Additionally, we discard telomere length attrition as the common cause of genetic anticipation in Lynch syndrome.

En este trabajo de tesis se emplean el método de elementos finitos y la técnica de la fotoelasticidad para el análisis de esfuerzos que se producen sobre ciertos modelos a los cuales se les aplican diferentes tipos de carga, como por ejemplo tensión, compresión y flexión. Para poder realizar los ensayos de estas probetas primero se diseñó y construyó un polariscopio de transmisión, con el cual se obtuvieron los resultados del análisis fotoelástico. Debido a que la confiabilidad de la técnica de la fotoelasticidad depende de la calibración del material que se esté usando, es decir de la constante fotoelástica, el análisis estadístico se enfocó a esta variable. Luego en base a la constante fotoelástica se determinaron los esfuerzos en un modelo, los cuales fueron comparados con los resultados del análisis por elementos finitos, determinándose el error entre los dos valores y demostrándose de esta manera la hipótesis. Finalmente se analizó un caso práctico utilizando los dos métodos.

El presente trabajo muestra la investigación realizada en juntas de Acero AISI 1018 soldadas con electrodo AWS E-7018, las que fueron sometidas a tratamiento térmico de recocido, con la finalidad de comparar las propiedades mecánicas de una junta sin tratamiento térmico posterior a la soldadura y las analizadas a tres temperaturas diferentes 600ºC, 780ºC, 870ºC, y a dos tiempos distintos una y tres horas. Se realizaron ensayos de tracción, dureza, impacto y análisis metalográfico en los laboratorios de la Facultad de Ingeniería Civil y Mecánica de la Universidad Técnica de Ambato para determinar la variación de las propiedades mecánicas con las seis condiciones de recocido, posteriormente los registros fueron tabulados y analizados. Se obtuvo conclusiones y recomendaciones en función de los resultados obtenidos, que contribuyen a generar procesos de recocido posterior a la soldadura que pueden ser aplicados en el campo industrial. Finalmente se determinó el proceso que mejor combinación de propiedades mecánicas produjo, y se desarrollaron los procedimientos respectivos.