Computational tools for splicing defect prediction in breast/ovarian cancer genes: how efficient are they at predicting RNA alterations?

In silico tools for splicing defect prediction have a key role to assess the impact of variants of uncertain significance. Our aim was to evaluate the performance of a set of commonly used splicing in silico tools comparing the predictions against RNA in vitro results. This was done for natural splice sites of clinically relevant genes in hereditary breast/ovarian cancer (HBOC) and Lynch syndrome. A study divided into two stages was used to evaluate SSF-like, MaxEntScan, NNSplice, HSF, SPANR, and dbscSNV tools. A discovery dataset of 99 variants with unequivocal results of RNA in vitro studies, located in the 10 exonic and 20 intronic nucleotides adjacent to exon-intron boundaries of BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS2, ATM, BRIP1, CDH1, PALB2, PTEN, RAD51D, STK11, and TP53, was collected from four Spanish cancer genetic laboratories. The best stand-alone predictors or combinations were validated with a set of 346 variants in the same genes with clear splicing outcomes reported in the literature. Sensitivity, specificity, accuracy, negative predictive value (NPV) and Mathews Coefficient Correlation (MCC) scores were used to measure the performance. The discovery stage showed that HSF and SSF-like were the most accurate for variants at the donor and acceptor region, respectively. The further combination analysis revealed that HSF, HSF+SSF-like or HSF+SSF-like+MES achieved a high performance for predicting the disruption of donor sites, and SSF-like or a sequential combination of MES and SSF-like for predicting disruption of acceptor sites. The performance confirmation of these last results with the validation dataset, indicated that the highest sensitivity, accuracy, and NPV (99.44%, 99.44%, and 96.88, respectively) were attained with HSF+SSF-like or HSF+SSF-like+MES for donor sites and SSF-like (92.63%, 92.65%, and 84.44, respectively) for acceptor sites. We provide recommendations for combining algorithms to conduct in silico splicing analysis that achieved a high performance. The high NPV obtained allows to select the variants in which the study by in vitro RNA analysis is mandatory against those with a negligible probability of being spliceogenic. Our study also shows that the performance of each specific predictor varies depending on whether the natural splicing sites are donors or acceptors

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Vaccine hesitancy among paediatric nurses: Prevalence and associated factors.

ObjectiveThis study describes the prevalence of vaccine hesitancy associated with the Catalan systematic childhood vaccination calendar and some related psychosocial determinants among paediatric primary care nurses in Barcelona (Spain).MethodsCross-sectional descriptive study. In 2017 we invited the paediatric nurses (N = 165) working in Barcelona public primary health centres with paediatric departments (N = 41) to participate. They answered a questionnaire with sociodemographic and behavioural variables: severity and perceived probability of contracting the diseases of the vaccines in the vaccination schedule; safety and protection offered by each vaccine; and beliefs, social norms, and knowledge about vaccines. Outcome variable was vaccine hesitancy, dichotomized into not hesitant (nurses who would vaccinate their own offspring), and hesitant (including those who would not vaccinate them, those who had doubts and those who would delay the administration of one or more vaccines). We performed bivariate analysis and adjusted logistic regression models.Results83% of paediatric nurses (N = 137) agreed to participate. 67.9% had the intention to vaccinate their children of all the vaccines in the systematic schedule. 32.1% of nurses experienced vaccine hesitancy, especially about the HPV (21.9%) and varicella (17.5%) vaccines. The multivariate analysis suggests associations between hesitancy and low perception of the severity of whooping cough (aOR: 3.88; 95%CI:1.32-11.4), low perception of safety of the HPV vaccine (aOR:8.5;95%CI:1.24-57.8), the belief that vaccines are administered too early (aOR:6.09;95%CI:1.98-18.8), and not having children (aOR:4.05;95%CI:1.22-13.3).ConclusionsAlthough most paediatric nurses had the intention to vaccinate their own children, almost one-third reported some kind of vaccine hesitancy, mainly related to doubts about HPV and varicella vaccines, as well as some misconceptions. These factors should be addressed to enhance nurses' fundamental role in promoting vaccination to families

Efectos de una intervención de consejo anticonceptivo en adolescentes de barrios desfavorecidos con alta proporción de inmigrantes

Objetivo: Evaluar la efectividad de una intervención de consejo contraceptivo en adolescentes según sexo y origen. Métodos: Diseño pre-post con entrevista a los 3 meses. Participaron adolescentes de tres barrios desfavorecidos de Barcelona que recibieron una intervención de consejo contraceptivo. Se compararon el uso de contracepción en la última relación sexual, y diversos conocimientos, creencias y autoeficacias, estratificando por sexo y origen (autóctono o inmigrante), con pruebas de McNemar y χ2. Resultados: 138 adolescentes completaron el seguimiento (76%). El 55% eran chicas, el 85% tenían 16-19 años y el 71% eran inmigrantes. Tras la intervención mejoraron los conocimientos y diversas autoeficacias. El uso de contracepción efectiva aumentó en todos los grupos. En la muestra total, el uso de preservativo aumentó un 5,4% y la ausencia de método se redujo un 7,7%. Conclusiones: Tras la intervención mejoró el uso de contracepción y sus determinantes en los adolescentes, particularmente en los inmigrantes

Characteristics and contents of the Master's programs in public health in Spain

Objetivo: Comparar las principales características académicas y los contenidos de los distintos programas de máster en salud pública ofertados actualmente en España. Método: Se realizó una búsqueda sistemática en el Registro de Universidades, Centros y Títulos del Ministerio de Educación, Cultura y Deporte. Se analizaron las principales características académicas y los contenidos (obligatorios y optativos) de los programas de 11 másteres oficiales con la acreditación renovada en 2018 de acuerdo con los datos publicados en las páginas web de las universidades. Resultados: La mayoría de los programas son de 60 ECTS (European Credit Transfer and Accumulation System), presenciales, se imparten en español e incluyen en su plan de estudios la realización de un trabajo de fin de máster, pero no las prácticas profesionales. Los contenidos relacionados con estadística y epidemiología básica, y la actividad formativa del trabajo de fin de máster, son las únicas materias en las que coinciden todos los programas. Conclusiones: La mayoría de los programas de máster en salud pública muestran una cierta homogeneidad respecto a sus características académicas, pero una gran heterogeneidad en relación con sus contenidos. También existe mucha variabilidad en los créditos que se otorgan a las diferentes asignaturas, sobre todo a las optativas. Sería recomendable definir un core común, especialmente en los contenidos obligatorios.Objective: To compare the main academic characteristics and contents of the different master's programs in public health currently offered in Spain. Method: A systematic search has been carried out in the Register of Universities, Centers and Degrees of the Ministry of Education, Culture and Sports. The main academic characteristics and the contents (mandatory and optional) of the programs of 11 official master's degrees with the renewed accreditation in 2018 were analyzed based on the data published on the universities’ web pages. Results: Most programs are 60 ECTS (European Credit Transfer and Accumulation System), face-to-face, taught in Spanish, include in their curriculum the completion of a master's thesis but not professional practices. Only contents related to statistics and basic epidemiology, and the training activity of master's thesis, are offers by all programs. Conclusions: The majority of public health master's programs in Spain shows a certain homogeneity regarding their academic characteristics, but a great heterogeneity in relation to their contents. There is also a great heterogeneity in the credits granted to the different subjects, especially optional subjects. It would be advisable to standardize a common core, especially in the mandatory contents

Sistema de aprendizaje personalizado en asignaturas básicas y fundamentales de ingeniería y arquitectura

En el ámbito de la arquitectura y la ingeniería, las materias básicas aplicadas u obligatorias de primeros cursos como las matemáticas, la física o la introducción a la ingeniería química son consideradas de especial relevancia y fundamentales en el proceso de aprendizaje como base para poder afrontar el resto de las asignaturas. Prueba de ello, es patente la presencia de asignaturas correspondientes a dichas materias en todas las titulaciones de grado de las ingenierías o arquitecturas, especialmente en el primer curso. Debido su importancia, se hace necesario proponer metodologías y herramientas que permitan una docencia de calidad, permitiendo al estudiante alcanzar las competencias y objetivos de aprendizaje establecidos. En este proyecto se propone un sistema de aprendizaje basado en tecnologías de la información, que permitirá una docencia flexible, pudiendo ser adaptado a diferentes asignaturas fundamentales impartidas en el área de la ingeniería y la arquitectura, y pudiendo ser aplicado de forma personalizada a cada estudiante en función de su nivel y progreso