Effectiveness of training in expressing positive emotions, reacting to change and greeting peers after childhood traumatic brain injury: a single-case experimental study

Background: Social cognitive deficits are common after traumatic brain injury (TBI). The participant in this single-case experimental design (SCED) was 7 years old when he sustained a severe TBI. After 2 years in rehabilitation, he continues to show deficits in social cognition. Objective: To determine the effectiveness of three interventions, each aimed at improving a behavior altered by social cognition deficits. These behaviors were: (1) expression of positive emotions, (2) reacting to changes in plans, and (3) greeting classmates. Method: An A-B-A’ design was used for each behavior. In addition, each behavior was targeted with a rehabilitation program applied over 10 sessions. Results: For the first behavior, changes between phases B-A’ (NAP = 0.712) and A-A’ (NAP = 0.864) indicated improvements in the child’s ability to express positive emotions. In the second behavior, changes in the intensity of reactions between phases B and A’ (NAP = 0.815) and A vs. A’ (NAP = 0.834) indicated that the child adapted to changes in a plan and to unexpected situations in a more adaptive way. For the third behavior, changes in the number of greetings between phases A and B (NAP = 0.883) and A vs. A’ (NAP = 0.844) suggested that during the third phase of the study, the participant fully acquired the habit of greeting peers and increased his interactions with others. Conclusion: While the participant showed improvements in all three targeted behaviors, due to the complexity of the third behavior, it is recommended that in future research, the intervention targeting social interactions should be applied over a longer timeframe to ensure that improvements are more stable in the long term.FPU16/03165 grant from the Spanish Ministry of EducationUniversity of Cadiz, Spai

Effectiveness of training in expressing positive emotions, reacting to change and greeting peers after childhood traumatic brain injury: a single-case experimental study

Background: Social cognitive deficits are common after traumatic brain injury (TBI). The participant in this single-case experimental design (SCED) was 7 years old when he sustained a severe TBI. After 2 years in rehabilitation, he continues to show deficits in social cognition. Objective: To determine the effectiveness of three interventions, each aimed at improving a behavior altered by social cognition deficits. These behaviors were: (1) expression of positive emotions, (2) reacting to changes in plans, and (3) greeting classmates. Method: An A-B-A’ design was used for each behavior. In addition, each behavior was targeted with a rehabilitation program applied over 10 sessions. Results: For the first behavior, changes between phases B-A’ (NAP = 0.712) and A-A’ (NAP = 0.864) indicated improvements in the child’s ability to express positive emotions. In the second behavior, changes in the intensity of reactions between phases B and A’ (NAP = 0.815) and A vs. A’ (NAP = 0.834) indicated that the child adapted to changes in a plan and to unexpected situations in a more adaptive way. For the third behavior, changes in the number of greetings between phases A and B (NAP = 0.883) and A vs. A’ (NAP = 0.844) suggested that during the third phase of the study, the participant fully acquired the habit of greeting peers and increased his interactions with others. Conclusion: While the participant showed improvements in all three targeted behaviors, due to the complexity of the third behavior, it is recommended that in future research, the intervention targeting social interactions should be applied over a longer timeframe to ensure that improvements are more stable in the long term

Development of the Theory of Mind in children of Pre-elementary education

Recepción: 29 de julio de 2016 | Revisión: 6 de septiembre de 2016 | Aceptado: 19 septiembre de 2016Correspondencia: Natalia Hidalgo Ruzzante | Orcid ID: 0000-0002-9952-9478 | Email: [email protected]: Conceptos como empatía y Teoría de la Mente (ToM) han resurgido en educación gracias a la evidencia sobre su importancia en la vida de las personas. Objetivo: Estudiar la relación entre los diferentes componentes de la ToM y determinar la relación de variables sociodemográficas y educativas en el desarrollo de la ToM en alumnado de Educación Infantil. Método: 25 niños/as con edades comprendidas entre 5 y 6 años fueron evaluados. Se empleó una escala validada para evaluar ToM (EToM). Los ítems consisten en seis situaciones conflictivas como diversidad de creencias, deseos, emociones o conocimientos, presentados utilizando personajes y materiales lúdicos. Resultados: Los ítems de la escala, correspondientes a diferentes componentes de la ToM, están relacionados entre ellos con los adyacentes, no con los más distantes en el orden teórico establecido en la escala. No se han obtenido resultados significativos que indiquen la relación de edad, sexo, dificultades del lenguaje y tener hermanos/as con el desarrollo de la ToM. Conclusiones: EToM contiene ítems que pueden ser considerados indicadores del desarrollo evolutivo de la ToM en preescolares. Investigaciones con muestras más amplias podrán determinar la relación de la ToM con el sexo, la edad, el lenguaje y la convivencia con hermanos.Background: In recent years the concepts of empathy and Theory of Mind (ToM) have reemerged in the area of education, due to evidence of their value in people’s lives. Objective: To study what relation exists between the components of ToM, and determine the relationship of sociodemographic and educational variables in the development of ToM in children of Pre-elementary education. Method: 25 children between 5 and 6 years old were evaluated; a validated scale to assess ToM in children was used. The items consist of six conflict situations about differences in beliefs, desires and emotions among others, presented to the students using characters and play-based materials. Results: The items of the scale, corresponding to different components of ToM are related to each other but only with adjacent items, not with the more distant ones in the theoretical order established in the scale. No significant results were obtained indicating the relationship of between age, sex, language problems and having siblings in the development of ToM. Conclusion: The ToM Scale contains items that can be considered as indicators of an evolutionary development of ToM in children in pre-elementary Education. Studies with broader samples are needed to determine the relationship between ToM and sex, age, language and living with siblings.Universidad de Granada. Departamento de Psicología Social. Proyecto de Innovación Docente ReiDoCre

CRISPR-ERA for Switching Off (Onco) Genes

Genome-editing nucleases like the popular CRISPR/Cas9 enable the generation of knockout cell lines and null zygotes by inducing site-specific double-stranded breaks (DSBs) within a genome. In most cases, when a DNA template is not present, the DSB is repaired by nonhomologous end joining (NHEJ), resulting in small nucleotide insertions or deletions that can be used to construct knockout alleles. However, for several reasons, these mutations do not produce the desired null result in all cases, instead generating a similar protein with functional activity. This undesirable effect could limit the therapeutic efficiency of gene therapy strategies focused on abrogating oncogene expression by CRISPR/Cas9 and should be taken into account. This chapter reviews the irruption of CRISPR technology for gene silencing and its application in gene therapy

Prevalence of antinuclear antibodies in inflammatory bowel disease and seroconversion after biological therapy

Background: Estimates of detectable antinuclear antibodies (ANA) prevalence vary widely, from 6% in healthy populations to 50-80% in patients with autoimmune disease. However, there is a lack of evidence about the overall prevalence in inflammatory bowel disease (IBD) and ANA seroconversion after the beginning of biological therapy. Objectives: The aim of the study was to investigate the overall prevalence of ANA in IBD patients, their relationship with different treatments, clinical outcomes and the seroconversion rate of ANA in patients treated with biological therapy. Methods: Ambispective observational study including all consecutive IBD patients was carried out. Information about the presence of ANA, disease phenotype, duration, activity, complications, and past and current treatments were transversally collected. Retrospectively, in patients with detectable ANA, data regarding previous ANA detection and the diagnosis of lupus-like syndrome (LLS) was gathered. Results: A total of 879 IBD patients were included. We observed a detectable ANA prevalence of 13.6%. The presence of ANA was frequently associated with biological therapy (36/118) and decreased when immunomodulators were combined to this therapy (7/32). Of 78 patients with ANA prior to the beginning of biological therapy, a seroconversion rate of 28.8% was observed after a mean of 3.14 years. Only 1 patient suffered LLS. Conclusion: Our study showed a prevalence of detectable ANA higher than the expected in healthy population. The presence of ANA was lower when immunomodulator therapy is associated. The ANA seroconversion rate is relevant after the initiation of biological treatment nevertheless, the risk of LLS appeared to be marginal.Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The authors report funding support from the Spanish Instituto de Salud Carlos III Grant (FIS–PI18/01304) related to this article

Splice donor site sgRNAs enhance CRISPR/Cas9-mediated knockout efficiency

[EN]CRISPR/Cas9 allows the generation of knockout cell lines and null zygotes by inducing site-specific double-stranded breaks. In most cases the DSB is repaired by non-homologous end joining, resulting in small nucleotide insertions or deletions that can be used to construct knockout alleles. However, these mutations do not produce the desired null result in all cases, but instead generate a similar, functionally active protein. This effect could limit the therapeutic efficiency of gene therapy strategies based on abrogating oncogene expression, and therefore needs to be considered carefully. If there is an acceptable degree of efficiency of CRISPR/Cas9 delivery to cells, the key step for success lies in the effectiveness of a specific sgRNA at knocking out the oncogene, when only one sgRNA can be used. This study shows that the null effect could be increased with an sgRNA targeting the splice donor site (SDS) of the chosen exon. Following this strategy, the generation of null alleles would be facilitated in two independent ways: the probability of producing a frameshift mutation and the probability of interrupting the canonical mechanism of pre-mRNA splicing. In these contexts, we propose to improve the loss-of-function yield driving the CRISPR system at the SDS of critical exons

Dissecting the role of TP53 alterations in del(11q) chronic lymphocytic leukemia

[EN]Background Several genetic alterations have been identified as driver events in chronic lymphocytic leukemia (CLL) pathogenesis and oncogenic evolution. Concurrent driver alterations usually coexist within the same tumoral clone, but how the cooperation of multiple genomic abnormalities contributes to disease progression remains poorly understood. Specifically, the biological and clinical consequences of concurrent high-risk alterations such as del(11q)/ATM-mutations and del(17p)/TP53-mutations have not been established. Methods We integrated next-generation sequencing (NGS) and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 techniques to characterize the in vitro and in vivo effects of concurrent monoallelic or biallelic ATM and/or TP53 alterations in CLL prognosis, clonal evolution, and therapy response. Results Targeted sequencing analysis of the co-occurrence of high-risk alterations in 271 CLLs revealed that biallelic inactivation of both ATM and TP53 was mutually exclusive, whereas monoallelic del(11q) and TP53 alterations significantly co-occurred in a subset of CLL patients with a highly adverse clinical outcome. We determined the biological effects of combined del(11q), ATM and/or TP53 mutations in CRISPR/Cas9-edited CLL cell lines. Our results showed that the combination of monoallelic del(11q) and TP53 mutations in CLL cells led to a clonal advantage in vitro and in in vivo clonal competition experiments, whereas CLL cells harboring biallelic ATM and TP53 loss failed to compete in in vivo xenotransplants. Furthermore, we demonstrated that CLL cell lines harboring del(11q) and TP53 mutations show only partial responses to B cell receptor signaling inhibitors, but may potentially benefit from ATR inhibition. Conclusions Our work highlights that combined monoallelic del(11q) and TP53 alterations coordinately contribute to clonal advantage and shorter overall survival in CLL

UGR Empática: programa de intervención para el desarrollo de la empatía en el alumnado de Ciencias de la Salud y Ciencias de la Educación

La capacidad empática es fundamental para garantizar el éxito profesional en las carreras de Ciencias de la Educación y Ciencias de la Salud. En tanto que se trata de una capacidad que puede entrenarse, este proyecto pretende desarrollar la empatía en el estudiantado de estas ramas del conocimiento. Para ello se diseñó una acción de innovación docente consistente en una serie de materiales didácticos en formato multimedia en los que se abordan diferentes aspectos de la empatía y que han sido empleados por los docentes de diferentes materias durante sus clases. Los materiales se han agrupado en 8 sesiones, cada una de ellas conteniendo dos actividades breves. Las actividades han sido presentaciones en videos en torno a 5 minutos y casos prácticos de elaboración propia de los componentes del equipo del PID. En cada sesión se ha incluido un ejercicio de aprendizaje por autoevaluación. La duración ha sido de 8 semanas, a razón de una sesión compuesta por las 2 actividades cada semana. Para determinar la eficacia de la acción innovadora se ha evaluado la capacidad de empatía en el estudiantado antes de iniciar el proyecto y tras la finalización del mismo, a través del Índice de Reactividad Interpersonal (IRI), una escala que mide la empatía de forma multidimensional. El IRI ofrece una medida compuesta de la empatía, incluyendo su dimensión cognitiva y afectiva. La empatía cognitiva se mide mediante el grado en el que la persona comprende el punto de vista de otra persona. El IRI tiene 2 escalas para medir empatía cognitiva: a) la Escala de Toma de Perspectiva, que evalúa cómo la persona intenta adoptar las perspectivas de otras personas y ver las cosas desde su punto de vista; y b) la Escala de fantasía, que mide la tendencia a identificarse con los personajes de las películas, novelas, obras teatrales y otras situaciones ficticias. La de mayor interés para este proyecto es la primera. En cuanto a la empatía afectiva o emocional, el IRI intenta captar la respuesta emocional de la persona cuando observa el estado afectivo de otras personas, y lo hace con otras 2 escalas: c) Escala de Preocupación Empática consta de ítems sobre los sentimientos de simpatía, compasión y preocupación por los demás; y d) la Escala de Angustia Personal, que valora si la persona experimenta ansiedad y malestar cuando observa que otros están atravesando por experiencias negativas. En nuestro estudio, el interés estaba en que aumentase la puntuación en la escala de preocupación empática, pero no en la de angustia personal. Los objetivos específicos fueron la mejora en las dimensiones de la capacidad empática más relevantes, considerando que la toma de perspectiva y la preocupación empática son las más relacionadas con el desempeño profesional del estudiantado al que iba dirigido el proyecto. En general, los resultados indican que el conjunto del alumnado que ha participado en el PID ha mejorado su capacidad empática. Por tanto, podemos considerar que los materiales creados son válidos para tal fin y pueden ser de aplicación práctica a la docencia.Empathic skills are fundamental to ensure professional success in the fields of Education and Health Sciences. As it is an ability that can be trained, this project aims to develop empathy in students of these branches of knowledge. To this end, a teaching innovation action was designed consisting of a series of teaching materials in multimedia format in which different aspects of empathy are addressed and which have been used by teachers of different subjects during their classes. The materials have been grouped into 8 sessions, each containing two short activities. The activities consisted of 5-minute video presentations and case studies developed by the IDP team. Each session included a self-assessment learning exercise. The duration was 8 weeks, with one session consisting of the 2 activities each week. To determine the effectiveness of the innovative action, the students' capacity for empathy was assessed before the start of the project and after its completion, using the Interpersonal Reactivity Index (IRI), a scale that measures empathy in a multidimensional way. The IRI provides a composite measure of empathy, including both cognitive and affective dimensions. Cognitive empathy is measured by the degree to which a person understands another person's point of view. The IRI has 2 scales to measure cognitive empathy: a) the Perspective Taking Scale, which assesses how the person tries to adopt other people's perspectives and see things from their point of view; and b) the Fantasy Scale, which measures the tendency to identify with characters in films, novels, plays and other fictional situations. Of most interest for this project is the first one. As for affective or emotional empathy, the IRI attempts to capture the person's emotional response when observing the affective state of other people, and does so with 2 other scales: c) the Empathic Concern Scale consists of items on feelings of sympathy, compassion and concern for others; and d) the Personal Distress Scale, which assesses whether the person experiences anxiety and discomfort when observing that others are going through negative experiences. In our study, the focus was on increasing scores on the empathic concern scale, but not on the personal distress scale. The specific objectives were to improve the most relevant dimensions of empathic ability, considering that perspective-taking and empathic concern are the most related to the professional performance of the target students. In general, the results indicate that the students who participated in the IDP as a whole have improved their empathic ability. Therefore, we can consider that the materials created are valid for this purpose and can be of practical application in teaching

TRAF3 alterations are frequent in del-3′IGH chronic lymphocytic leukemia patients and define a specific subgroup with adverse clinical features

Interstitial 14q32 deletions involving IGH gene are infrequent events in chronic lymphocytic leukemia (CLL), affecting less than 5% of patients. To date, little is known about their clinical impact and molecular underpinnings, and its mutational landscape is currently unknown. In this work, a total of 871 CLLs were tested for the IGH break-apart probe, and 54 (6.2%) had a 300 kb deletion of 3′IGH (del-3′IGH CLLs), which contributed to a shorter time to first treatment (TFT). The mutational analysis by next-generation sequencing of 317 untreated CLLs (54 del-3′IGH and 263 as the control group) showed high mutational frequencies of NOTCH1 (30%), ATM (20%), genes involved in the RAS signaling pathway (BRAF, KRAS, NRAS, and MAP2K1) (15%), and TRAF3 (13%) within del-3′IGH CLLs. Notably, the incidence of TRAF3 mutations was significantly higher in del-3′IGH CLLs than in the control group (p < .001). Copy number analysis also revealed that TRAF3 loss was highly enriched in CLLs with 14q deletion (p < .001), indicating a complete biallelic inactivation of this gene through deletion and mutation. Interestingly, the presence of mutations in the aforementioned genes negatively refined the prognosis of del-3′IGH CLLs in terms of overall survival (NOTCH1, ATM, and RAS signaling pathway genes) and TFT (TRAF3). Furthermore, TRAF3 biallelic inactivation constituted an independent risk factor for TFT in the entire CLL cohort. Altogether, our work demonstrates the distinct genetic landscape of del-3′IGH CLL with multiple molecular pathways affected, characterized by a TRAF3 biallelic inactivation that contributes to a marked poor outcome in this subgroup of patients.Funding information: Universidad de Salamanca; Fundación Española de Hematología y Hemoterapia (FEHH); Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Grant/Award Number: CB16/12/00233; Red Temática de Investigación Cooperativa en Cáncer (RTICC); “Fundación Memoria Don Samuel Solórzano Barruso”: FS/33–2020, Grant/Award Number: RD12/0036/0069; “Gerencia Regional de Salud, SACYL”:, Grant/Award Numbers: GRS2385/A/21, GRS2140/A/20; Consejería de Educación, Junta de Castilla y León, Grant/Award Number: SA118P20; European Regional Development Fund and Instituto de Salud Carlos III, Grant/Award Numbers: CD19/00222, FI19/00191; Spanish Fondo de Investigaciones Sanitarias, Grant/Award Numbers: PI21/00983, PI18/0150

Dissecting the role of TP53 alterations in del(11q) chronic lymphocytic leukemia

© 2021 The Authors.[Background]: Several genetic alterations have been identified as driver events in chronic lymphocytic leukemia (CLL) pathogenesis and oncogenic evolution. Concurrent driver alterations usually coexist within the same tumoral clone, but how the cooperation of multiple genomic abnormalities contributes to disease progression remains poorly understood. Specifically, the biological and clinical consequences of concurrent high-risk alterations such as del(11q)/ATM-mutations and del(17p)/TP53-mutations have not been established.[Methods]: We integrated next-generation sequencing (NGS) and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 techniques to characterize the in vitro and in vivo effects of concurrent monoallelic or biallelic ATM and/or TP53 alterations in CLL prognosis, clonal evolution, and therapy response.[Results]: Targeted sequencing analysis of the co-occurrence of high-risk alterations in 271 CLLs revealed that biallelic inactivation of both ATM and TP53 was mutually exclusive, whereas monoallelic del(11q) and TP53 alterations significantly co-occurred in a subset of CLL patients with a highly adverse clinical outcome. We determined the biological effects of combined del(11q), ATM and/or TP53 mutations in CRISPR/Cas9-edited CLL cell lines. Our results showed that the combination of monoallelic del(11q) and TP53 mutations in CLL cells led to a clonal advantage in vitro and in in vivo clonal competition experiments, whereas CLL cells harboring biallelic ATM and TP53 loss failed to compete in in vivo xenotransplants. Furthermore, we demonstrated that CLL cell lines harboring del(11q) and TP53 mutations show only partial responses to B cell receptor signaling inhibitors, but may potentially benefit from ATR inhibition.[Conclusions]: Our work highlights that combined monoallelic del(11q) and TP53 alterations coordinately contribute to clonal advantage and shorter overall survival in CLL.Spanish Fondo de Investigaciones Sanitarias, Grant/Award Numbers: PI15/01471, PI18/01500); Fundación Memoria Don Samuel Solórzano Barruso, Grant/Award Number: RD12/0036/006