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ObjectivesThe Inside CKD programme implemented a microsimulation modelling approach to project the clinical and economic burden of chronic kidney disease (CKD) between 2024 and 2027 in Hungary.MethodsUsing the peer-reviewed Inside CKD microsimulation, a virtual Hungarian population was generated that was derived from national records, local demographic data and published epidemiological data. These inputs defined the likelihood of a change in health state for each individual as they progressed through the model in annual increments. Individual CKD status, including disease progression, cardiorenal complications and associated costs, was tracked annually to generate the population-level projections of the clinical and economic burden of CKD.ResultsBy 2027, people with CKD were projected to constitute 13.3% of the Hungarian national population. The prevalence of heart failure, myocardial infarction and stroke in people with CKD were projected to remain consistently high, reaching 323 447, 69 188 and 120 118 by 2027, respectively. Kidney replacement therapy cases were predicted to remain high at 20 515 in 2024 and 22 325 in 2027, with associated costs increasing from 71.4 billion HUF in 2024 to 79.6 billion HUF in 2027. Total annual healthcare costs associated with treating CKD were projected to constitute 5.4% of the overall national healthcare budget in 2027.ConclusionsInside CKD demonstrates that the future burden of CKD in Hungary will be substantial unless current management strategies change. The high prevalence of undiagnosed CKD and associated cardiorenal complications highlight the urgent need for policy interventions focused on early diagnosis and timely intervention to mitigate the future burden of CKD.

Abstract Background Knowledge, attitudes, and practices related to oral health among parents play a crucial role in shaping oral hygiene and preventing early childhood caries. This study was intended to determine the effect of a neuroeducational strategy in improving knowledge, attitudes, and practices related to early childhood caries among mothers or caregivers of children. Methods A quasi-experimental study was conducted, implementing an educational strategy involving 33 mothers or female caregivers of children who met specific selection criteria. The strategy consisted of three key elements derived from neuroeducation: (1) experiment, (2) surprise and play, and (3) learn. Based on the participants’ attendance at the sessions, they were categorized into two groups: those who underwent in-person intervention (G1) and those who received a combined in-person and virtual intervention (G2). The impact of the strategy was evaluated by comparing the participants’ knowledge and attitudes, as well as their children’s plaque index, before and after the intervention (immediate and 6-month impact). Results The participants exhibited a favorable and statistically significant effect on the median number of correct answers related to knowledge (G1 immediate effect (IE): p = 0.03, 6-month effect (ME): p = 0.002; G2 IE p = 0.002, ME: p = 0.001), and in the children’s plaque index (G1 IE: p = 0.003, ME: p = 0.003; G2 IE: p = 0.033, ME: p = 0.003). Furthermore, there was an increase in the number of participants with a high level of knowledge (G1 IE: 41.5%; ME: 75%; G2 IE: 45.5%, ME: 42.9%), and of children with a good level of oral hygiene (G1 IE: 50%; ME: 73.0%; G2 IE: 27.3%, ME: 84.6%). Finally, qualitative interviews revealed a lasting clarity in concepts and sustained knowledge and attitudes at the six-month mark. However, a slightly diminished understanding of the relationship between bacteria, sugar, and caries was observed in G2 group, and some loss of association in the G1 group, at six months. Conclusion The implementation of this strategy resulted in significant and lasting impacts on knowledge, attitudes, and practices, especially in the G1 group. Nevertheless, there is a need for further reinforcement of the association between bacteria, sugar, and caries.

This article presents an investigation carried out within the Regional Observatory Project for Quality and Equity in Latin America (ORACLE), an Erasmus + initiative financed by the European Union (with more than 35 Latin American Universities involved), conducted in 2018 and 2019 in the Institute of of Education (IE) at Universidad ORT Uruguay. The objective was to identify vulnerable groups and to gather information about the visibility and impact of the developed policies on quality of inclusion in higher education, as well as gathering data about possible improvements in the management system to achieve equity. The methodology approach is mixed. In terms of the visibility of inclusive practices in the postgraduate degrees, all bodies identify a positive impact, especially due to the access to scholarships, the blended modality of the courses, the ease of access to bibliography and learning resources, and the personalized accompaniment of teachers during all stages of their educational process at the Institute of Education. Some guidelines for new strategies to ensure quality for equity have been presented to other universities involved in the project and are being taken as an example of good inclusion practices in the region and for the joint development of equity management tools.

Education on the selection of low-sugar ultra-processed foods (UPF) plays a crucial role in promoting good oral health. This study aimed to assess the impact of a virtual educational strategy, developed in the field of dentistry, on improve Knowledge, Attitudes, and Practices (KAPs) related to oral health and the appropriate selection of sweet-tasting UPF. A quasi-experimental study with a pre-test and post-test design was conducted, involving parents and caregivers of children and pre-adolescents. Thirteen virtual learning objects (VLO) were delivered via Facebook. To measure the impact of the strategy, a validated instrument was used before the intervention, immediately after, and again six months later to assess Knowledge, Attitudes, and Practices (KAPs) on the subject. The median scores before and after the intervention were compared using the Friedman test for related samples, followed by multiple comparisons with Dunn's test. Participants' KAP levels were analyzed using Pearson's Chi-square test and multiple comparisons of column proportions with Bonferroni correction. Finally, a satisfaction and applicability survey was conducted. A significant improvement (p < 0.01) was observed in the participants' median KAP scores both immediately after the intervention and six months later. A greater number of participants reached the highest level in knowledge (Before (B): 43.8%, Immediately After (IA): 86%, After six months (A6): 81.3%), attitudes (B: 34.2%, IA: 69.4%, A6: 65.2%), and practices (B: 22.5%, IA: 53.7%, A6: 47.3%). Most participants described the course as consistently dynamic, well-organized, and appropriate timing. They also expressed their intention to apply the knowledge in their daily lives. The implemented strategy improved participants' KAPs concerning oral health and the appropriate selection of sweet-tasting UPF. It also resulted in participants' children consuming fewer sweet bakery products, candies, and flavored milk. Additionally, more participants reported consistently reading food labels after the intervention, although this behavior was not adopted by the majority.

Artificial intelligence (AI) holds immense promise for accelerating and improving all aspects of drug discovery, not least target discovery and validation. By integrating a diverse range of biological data modalities, AI enables the accurate prediction of drug target properties, ultimately illuminating biological mechanisms of disease and guiding drug discovery strategies. Despite the indisputable potential of AI in drug target discovery, there are many challenges and obstacles yet to be overcome, including dealing with data biases, model interpretability and generalisability, and the validation of predicted drug targets, to name a few. By exploring recent advancements in AI, this review showcases current applications of AI for drug target discovery and offers perspectives on the future of AI for the discovery and validation of drug targets, paving the way for the generation of novel and safer pharmaceuticals.

This research addresses a network analysis in three teacher education centers for teachers and professors in Uruguay to determine the degree to which they function in professional communities according to four aspects: innovation initiatives, information exchange, digital inclusion, and collaboration in planning. The study is based on a previous categorization regarding the level of digital inclusion for deep learning on the basis of an online survey applied to 32 principals of public teacher education centers (high, medium, and low levels). One case was identified at each level, taking into account the geographic characteristics and the type of teacher education center. In each case, information-gathering techniques were applied: in-depth interviews, surveys for the network analysis, and focus groups. Results show that in all three cases, professional learning communities lite (as defined by Dufour & Reeves, 2016). In two of the centers, those with the higher rate of digital inclusion for learning, there is a diversity in the actors who form the ties that make up the networks. Last, the innovation network is the weakest in terms of the number and variety of the ties.

Imaging plays a fundamental role in the effective diagnosis, staging, management, and monitoring of various cardiac pathologies. Successful radiological analysis relies on accurate image segmentation, a technically arduous process, prone to human-error. To overcome the laborious and time-consuming nature of cardiac image analysis, deep learning approaches have been developed, enabling the accurate, time-efficient, and highly personalised diagnosis, staging and management of cardiac pathologies.Here, we present a review of over 60 papers, proposing deep learning models for cardiac image segmentation. We summarise the theoretical basis of Convolutional Neural Networks, Fully Convolutional Neural Networks, U-Net, V-Net, No-New-U-Net (nnU-Net), Transformer Networks, DeepLab, Generative Adversarial Networks, Auto Encoders and Recurrent Neural Networks. In addition, we identify pertinent performance-enhancing measures including adaptive convolutional kernels, atrous convolutions, attention gates, and deep supervision modules.Top-performing models in ventricular, myocardial, atrial and aortic segmentation are explored, highlighting U-Net and nnU-Net-based model architectures achieving state-of-the art segmentation accuracies. Additionally, key gaps in the current research and technology are identified, and areas of future research are suggested, aiming to guide the innovation and clinical adoption of automated cardiac segmentation methods.

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P

Introduction Flow diverters (FD) are stent‐type devices that enable the exclusion of intracranial aneurysms in clinical scenarios where coil‐type devices exhibit high failure rates. However, its effectiveness hasn't been examined in countries with low and middle incomes, like Mexico. Methods Longitudinal, retrospective study of the patients who received care at a tertiary center between November 2020 and April 2022. Adults older than 18 with non‐ruptured intracranial aneurysms were included. After treatment with FD, post‐procedure control angiograms were performed between three and six months later. The occlusion rate was evaluated using the O'Kelly‐Marotta scale. Results There were 23 patients —2 of whom had double aneurisms—, 20 women, with an average age of 51.4 years (±13.3). 19 saccular aneurysms, 4 fusiform aneurysms, and 2 dissecting aneurysms were treated. Neck measurements were in the range of 1.9 to 19 mm. Angioplasties were performed as part of the procedure on four patients, and successful liberation was achieved in all procedures. Between three and six months of follow up, total occlusion was observed in 14 aneurisms, and three had less than 5% residuals. Only three late procedural related complications were found. Conclusion The patients treated with FD at our reference center had complex aneurysms. Complete occlusion was achieved in 56% of the treated aneurysms during follow up. The use of the FD appears to be safe and to have a high level of effectiveness, similar to what has been described in international reports.

Resumen Este trabajo se basa en la concepción de modelización como estrategia didáctica que propicia hacer ciencia en el aula y desarrollar competencias científicas. Se propuso conocer qué competencias científicas se desarrollan cuando los estudiantes construyen modelos explicativos de procesos biológicos. La experiencia en estudio, a nivel terciario, se enmarca en un curso de biofísica, en formación docente de modalidad híbrida. Se valoró el desarrollo de competencias científicas en 81 estudiantes de profesorado de ciencias biológicas, mientras construían modelos explicativos de respuestas a estímulos, en situaciones biofísicas ficticias. Para identificar las competencias en desarrollo, se aplicó un repertorio de competencias científicas pretesteado y validado. Se aplicó la técnica de análisis de contenido con enfoque cualitativo. Los resultados permiten afirmar que la modelización constituye una instancia de aprendizaje rica en cuanto a las competencias científicas que habilita. Se sugirieron mejoras para aumentar la usabilidad del repertorio utilizado.

En esta oportunidad, la revista Cuadernos de Investigación Educativa presenta el monográfico: “Aportes de actualidad en investigación desde la perspectiva de la gestión”, en el que se ofrecen perspectivas relevantes de investigaciones de Uruguay, Chile, Brasil, Ecuador y Europa. El propósito principal de esta publicación es la difusión de procesos de investigación actualizados que hacen foco en la gestión educativa.

There are various neurological manifestations of coronavirus disease 2019 (COVID-19). Recent data suggest a connection between hemifacial paralysis, or Bell’s palsy, and COVID-19. Although the etiology of Bell’s palsy is unknown, the leading proposed etiology is viral in nature. Since the onset of the pandemic, numerous studies have investigated the relationship between Bell’s palsy, COVID-19 infection, and COVID-19 vaccination. The researchers studied the current literature on the topic of COVID-19 as it relates to Bell’s palsy.

Abstract Objectives Diet is one of the main factors influencing the diversity and interactions of the oral microbiota. The purpose of this study is to determine the impact of sugar intake on the microbial diversity and bacteria that predominate under these conditions. Material and Methods A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guide, using the PubMed, Scopus, and Science Direct databases and combinations of the words “microbiota,” “microbiology,” “bacteria,” “sugars,” “dysbiosis,” “caries,” “microbiome,” “oral microbial,” and “oral microbiota profile pattern.” The selection criteria included year, language, type of publication, comparison of microbiota during low and high sugar intake, and bacterial identification by molecular sequencing of the 16S subunit of ribosomal RNA. Results Out of a total of 374 papers that came up after the initial search, 8 met the criteria for this review. The papers included research on populations comprising children, young adults, and adults, with most of the studies reporting selection criteria for the participants and using validated instruments to determine sugar intake. Apart from one study, all others reported for high sugar intake conditions a significant decrease in microbial diversity of the oral microbiome and the predominance of several bacterial genera or species, including Streptococcus, Scardovia, Veillonella, Rothia, Actinomyces, and Lactobacillus. Conclusions Sugar‐rich diets have a significantly unfavorable effect on the diversity and balance of oral microbiota; however, further studies are required to determine the exact role of sugar in microbial interactions.

The psychometric properties of the scale of knowledge and pedagogical practice of teachers against inattention, hyperactivity and impulsivity behaviors in school contexts in Cúcuta, Norte de Santander are validated. It was carried out under a quantitative, non-experimental approach, of the exploratory, cross-sectional type, in terms of the population to be taken into account, they were the teachers assigned to the municipal education secretary, in relation to the sample, it was obtained by proportional fixing; the data will be processed in SPSS applying exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) based on reliability and reproducibility Cronbach's alpha, test-retest with Lin's intraclass correlation coefficient and the kappa index Cohen's. It is concluded that the test has the pertinent psychometric properties for use in Colombian school contexts.

This work proposes a study on two recurrent themes in the narrative of Juan Marsé (1933-2020): memory and cinematography in a specific story: “Historia de detectives”. The short stories and novels of the Catalan author are usually based on his own experiences during the post-war period, but also on what he saw, read, heard and imagined. For this reason, in addition to his wanderings through the streets of Barcelona, his work incorporates elements from books, comics and films that merge with his memories sifted through the years. In this article we will discuss the way in which certain discursive strategies typical of the seventh art, as well as some of its characters, become part of this tale.

Acute ischemic stroke is a leading cause of death and major disability worldwide. Approximately 50% of ischemic strokes are caused by atherothrombotic occlusion of the cerebral arteries, and antiplatelets are the mainstay of secondary stroke preventative treatment. Aspirin is beneficial if given early, and short‐term treatment using aspirin and clopidogrel is increasingly used for patients with intracranial atherosclerotic disease, minor stroke, and or transient ischemic attack. However, up to 50% of patients continue to have recurrent stroke and major vascular events, which may be partly attributable to resistance to aspirin and or clopidogrel. Although the precise mechanisms are unknown, clinical and genetic factors associated with bioavailability and binding to target receptors are implicated. This narrative review begins with the concept of aspirin and clopidogrel resistance in ischemic stroke and transient ischemic attack, potential mechanisms including genetic polymorphisms, and an overview of platelet function measures and limitations. We conclude by highlighting practical issues in the management of patients with aspirin andclopidogrel resistance including the emerging interest in ticagrelor, prasugrel, and cilostazol as well as directions for future trials in transient ischemic attack and acute ischemic stroke.

It has been proposed that oral commensal bacteria are potential reservoirs of a wide variety of antimicrobial resistance genes (ARGs) and could be the source of pathogenic bacteria; however, there is scarce information regarding this. In this study, three common streptococci of the mitis group (S. oralis, S. sanguinis, and S. gordonii) isolated from dental plaque (DP) were screened to identify if they were frequent reservoirs of specific ARGs (blaTEM, cfxA, tetM, tetW, tetQ, ermA, ermB, and ermC). DP samples were collected from 80 adults; one part of the sample was cultured, and from the other part DNA was obtained for first screening of the three streptococci species and the ARGs of interest. Selected samples were plated and colonies were selected for molecular identification. Thirty identified species were screened for the presence of the ARGs. From those selected, all of the S. sanguinis and S. oralis carried at least three, while only 30% of S. gordonii strains carried three or more. The most prevalent were tetM in 73%, and blaTEM and tetW both in 66.6%. On the other hand, ermA and cfxA were not present. Oral streptococci from the mitis group could be considered frequent reservoirs of specifically tetM, blaTEM, and tetW. In contrast, these three species appear not to be reservoirs of ermA and cfxA.

Abstract Colorectal cancer (CRC) is one of the most common and deadliest forms of cancer. Myeloid Cell Leukemia 1 (MCL1), a pro-survival member of the Bcl-2 protein family is associated with chemo-resistance in CRC. The ability of MCL1 to inhibit apoptosis by binding to the BH3 domains of pro-apoptotic Bcl-2 family members is a well-studied means by which this protein confers resistance to multiple anti-cancer therapies. We found that specific DNA damaging chemotherapies promote nuclear MCL1 translocation in CRC models. In p53null CRC, this process is associated with resistance to chemotherapeutic agents, the mechanism of which is distinct from the classical mitochondrial protection. We previously reported that MCL1 has a noncanonical chemoresistance capability, which requires a novel loop domain that is distinct from the BH3-binding domain associated with anti-apoptotic function. Herein we disclose that upon treatment with specific DNA-damaging chemotherapy, this loop domain binds directly to alpha-enolase which in turn binds to calmodulin; we further show these protein−protein interactions are critical in MCL1’s nuclear import and chemoresistance. We additionally observed that in chemotherapy-treated p53−/− CRC models, MCL1 nuclear translocation confers sensitivity to Bcl-xL inhibitors, which has significant translational relevance given the co-expression of these proteins in CRC patient samples. Together these findings indicate that chemotherapy-induced MCL1 translocation represents a novel resistance mechanism in CRC, while also exposing an inherent and targetable Bcl-xL co-dependency in these cancers. The combination of chemotherapy and Bcl-xL inhibitors may thus represent a rational means of treating p53−/− CRC via exploitation of this unique MCL1-based chemoresistance mechanism.

Como parte del espectro de la literatura no mimética, encontramos una diversidad de textos influidos por la presencia de la divinidad, las distintas tradiciones religiosas o los libros sagrados. Para distinguirlos de lo fantástico, se han empleado términos como lo milagroso y lo maravilloso cristiano; sin embargo, considero necesario precisar y extender esta terminología para que resulte funcional para todas las narraciones en las que interviene lo divino, partiendo del paradigma de realidad intratextual y sin importar el sistema de creencias en el que estén ancladas. Este trabajo propone una nomenclatura que distinga lo milagroso de lo maravilloso y lo fantástico cuando el hecho sobrenatural entraña la mediación de una divinidad o de un ser proveniente de alguna tradición religiosa: lo maravilloso divino y lo fantástico divino.

Abstract Developmental abnormalities of the gonadotropin-releasing hormone (GnRH) neuronal network result in a range of conditions from idiopathic hypogonadotropic hypogonadism to self-limited delayed puberty. We aimed to discover important underlying regulators of self-limited delayed puberty through interrogation of GnRH pathways. Whole exome sequencing (WES) data consisting of 193 individuals, from 100 families with self-limited delayed puberty, was analysed using a virtual panel of genes related to GnRH development and function (n = 12). Five rare predicted deleterious variants in Coiled-Coil Domain Containing 141 (CCDC141) were identified in 21 individuals from 6 families (6% of the tested cohort). Homology modeling predicted all five variants to be deleterious. CCDC141 mutant proteins showed atypical subcellular localization associated with abnormal distribution of acetylated tubulin, and expression of mutants resulted in a significantly delayed cell migration, demonstrated in transfected HEK293 cells. These data identify mutations in CCDC141 as a frequent finding in patients with self-limited delayed puberty. The mis-localization of acetylated tubulin and reduced cell migration seen with mutant CCDC141 suggests a role of the CCDC141-microtubule axis in GnRH neuronal migration, with heterozygous defects potentially impacting the timing of puberty.

Introducción: La estomatitis subprótesis es una de las alteraciones más frecuentes de la cavidad bucal, se relaciona con una corrección removible acrílica o metálica desajustada, asociada de forma general a una deficiente higiene bucal y hábitos personales, con el uso de las prótesis. Objetivos: Caracterizar la estomatitis subprótesis en pacientes que asisten a la Consulta de Estomatología en la Clínica de Santa Cruz del Norte. Métodos: Se realizó un estudio descriptivo transversal, en pacientes mayores de 15 años, portadores de prótesis removibles parciales y totales. El universo lo constituyeron 154 que asistieron a consulta, coincidió con la muestra de estudio. Se realizaron interrogatorios y exámenes bucales. Se recogieron los datos mediante un cuestionario, las preguntas respondieron a las variables estudiadas. Resultados: La estomatitis subprótesis predominó en los mayores de 60 años con un 34.42 %, el 40.91 % resultaron ser hombres; el 73.17 % presentó el grado I, el 54.88 % usaron prótesis por más de 10 años; el 46.34 % de forma continua, la prótesis desajustada se observó en un 86.59 % y el 40.91 % eran portadores de prótesis acrílicas. Conclusiones. La estomatitis subprótesis constituye una de las alteraciones más frecuente de la mucosa bucal, son los pacientes mayores de 60 años y del sexo masculino, los más afectados. Predomina el grado I de la enfermedad, la mayoría portan prótesis por más de 10 años y se encuentran desajustadas, la base acrílica constituye un factor de riesgo importante.

El presente artículo refiere al uso de la anécdota como instrumento metodológico en investigaciones socioeducativas de índole cualitativo. Específicamente se vincula la anécdota con la identificación de factores favorecedores de la afiliación educativa, en una investigación de maestría realizada en la Universidad ORT Uruguay durante 2019 y 2021. El abordaje metodológico corresponde a un estudio de caso en el que se aplica como técnica la entrevista en profundidad dirigida a estudiantes y a docentes de una escuela técnica de Uruguay. La estrategia de validación estuvo dada fundamentalmente por la triangulación de fuentes. Otra decisión relevante fue realizar el pretesteo de los guiones, sobre todo para adaptarlos a población de adolescentes. Los resultados evidencian la puesta en práctica del modelo de análisis interpretativo que se lleva a cabo a partir del uso de la anécdota. El foco en esta comunicación está puesto en mostrar la potencialidad de la anécdota para la recolección de datos y la capacidad de este recurso para develar lo que, a priori, está oculto. A partir del uso de anécdotas realizado, se lograron distinguir, categorizar y jerarquizar factores que facilitan la afiliación educativa de los estudiantes comprendidos en el estudio. Un aspecto a destacar de la discusión de los resultados refiere al análisis y reflexión sobre el rol del investigador para obtener profundidad y datos asertivos a partir de las anécdotas recabadas.

Este trabajo elabora una configuración de la autora implícita de Fondo de armario (2019), de Patricia Esteban Erlés (Zaragoza, 1972), con base en sus columnas. En una primera instancia, se presentan las similitudes entre estas, los microrrelatos y otros géneros literarios. Dado que muchas son autobiográficas, se infieren aspectos de la vida de la autora y sus intereses tamizados por la memoria y la escritura autobiográfica. Los textos de denuncia muestran sus principales inquietudes y su empatía hacia los desprotegidos, entre ellos las mujeres, a quienes se dedica un buen número de artículos, por lo que se abordará la perspectiva feminista de los textos. Finalmente, la tendencia de la autora a destacar los aspectos crudos y gráficos de ciertos episodios remiten a su afición por los detalles macabros de las historias, los cuales, fuera del mundo ficcional, resultan más aterradores y cobran una nueva dimensión.

The Food and Drug Administration currently approves the combination of hypomethylating agents (HMA), azacytidine or decitabine with venetoclax (VEN) for acute myeloid leukemia (AML) patients aged more than 75 years and for patients unsuitable for intensive chemotherapy. The risk of fungal infection in the early phase of treatment is not negligible; therefore, posaconazole (PCZ) is commonly administered as primary prophylaxis. A drug–drug interaction between VEN and PCZ is well known, but the trend of serum levels of venetoclax when both drugs are overlapped is not clear. In total, 165 plasma samples from 11 elderly AML patients receiving combined treatment with HMA, VEN and PCZ were analyzed by a validated analytical method (high-pressure liquid chromatography–tandem mass spectrometry). Venetoclax trough plasma concentrations were detected during the 3 days of ramp-up as well as on day 7 and day 12 of treatment when the exposure as the area under the plasma concentration–time curve and the accumulation ratio were also calculated. The results were compared with the expected data for 400 mg/dose VEN administered alone—the confirmed high inter-individual variability in pharmacokinetics suggests the need for therapeutic drug monitoring.

ObjectiveThis study examined patient-, care team- and clinic-level factors associated with human papillomavirus (HPV) vaccine initiation and completion.MethodsHPV vaccine initiation and completion rates among adolescents aged 9-18years were assessed using administrative data (n=38,277) from a large federally qualified health center serving predominantly Latino patients. Four clinics with particularly high and low adolescent HPV vaccine uptake were selected for in-depth case study analyses. Semi-structured interviews with clinic leaders, providers, and support staff in these clinics (n=36) examined multilevel factors perceived as affecting vaccine initiation and completion.ResultsOn average, less than half (45%) of patients had initiated the HPV vaccine; of these, 52% of patients completed all recommended doses. Vaccine uptake varied significantly across clinics but was higher among patients seen by providers specializing in pediatrics. Qualitative findings confirmed the importance of provider communication strategies but indicated that other health care team structures and processes also play an important role in vaccine uptake. Care team members in higher performing clinics were more likely to describe vaccination as a team effort rather than solely the provider's responsibility. Support staff in higher performing clinics also spent more time reviewing patient preventive care needs and preparing patients for the provider encounter. Clinic-level factors such as performance management systems and the use of immunization champions were described as important for developing an organizational climate supportive of vaccination. Tracking and reminder systems were described as important but insufficient for ensuring vaccine uptake in the absence of other supports.ConclusionsEfforts to improve HPV initiation and completion could benefit from additional attention to factors at the health care team and clinic levels. Interventions that target factors at multiple levels of influence are most likely to achieve higher vaccination rates. Quality monitoring programs may influence clinic investment in improving vaccination rates.

Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. Genome-wide association study analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9% of the variation. This study aims to discover new genetic loci associated with heart rate from Exome Chip meta-analyses.Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104 452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134 251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods.We discovered five novel heart rate loci, and one new independent low-frequency non-synonymous variant in an established heart rate locus (KIAA1755). Lead variants in four of the novel loci are non-synonymous variants in the genes C10orf71, DALDR3, TESK2 and SEC31B. The variant at SEC31B is significantly associated with SEC31B expression in heart and tibial nerve tissue. Further candidate genes were detected from long-range regulatory chromatin interactions in heart tissue (SCD, SLF2 and MAPK8). We observed significant enrichment in DNase I hypersensitive sites in fetal heart and lung. Moreover, enrichment was seen for the first time in human neuronal progenitor cells (derived from embryonic stem cells) and fetal muscle samples by including our novel variants.Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies.

Esta comunicación da cuenta de las interacciones y de los procesos vinculados a la Investigación Formativa (IF) que surgen a la interna de una Comunidad Profesional de Aprendizaje (CPA), conformada por docentes y estudiantes de profesorado de un Centro Regional de Profesores. Se encuentra enmarcada en un proyecto de investigación donde se planteó el objetivo de desarrollar Estrategias Investigativas (EI) y evaluar su grado de desarrollo en estudiantes de formación docente en el marco del Aprendizaje Ubicuo (AU). Se buscó que los estudiantes desarrollaran competencias investigativas (CI) a través de la construcción de experiencias de investigación que articularan pedagogías, tecnologías y estrategias culturalmente relevantes y coherentes con su formación profesional. Se enmarcó en la investigación-acción con enfoque mixto. Los datos analizados en esta comunicación surgen de la aplicación de instrumentos tales como observaciones de los espacios de encuentro sincrónicos y documentos, así como focus group de docentes y de estudiantes. El análisis fue eminentemente cualitativo. Algunos hallazgos dan cuenta de la interacción genuina que se dio a la interna de la comunidad. En lo que refiere al trabajo en la CPA conformada, el “profesionalismo dialógico” jugó un rol protagónico. Asimismo, se identificó que la reflexión actuó como eje vertebrador de los acuerdos y decisiones. En cuanto a las tensiones, la flexibilidad fue la piedra angular para la búsqueda de soluciones. En relación con los procesos, se constató que la conformación de CPA y el trabajo en IF supone afrontar múltiples dificultades, pero como contrapartida se destaca el despliegue de diferentes estrategias. En este contexto, caracterizado por la ubicuidad, la inclusión de tecnologías digitales fue clave. A modo de conclusión, es posible afirmar que el trabajo en IF llevado adelante por la comunidad conformada en esta investigación logró potenciar procesos de reflexión que favorecieron el desarrollo profesional de sus integrantes.

Mitochondria are implicated in the pathogenesis of cardiovascular diseases (CVDs) but the reasons for this are not well understood. Maternally-inherited population variants of mitochondrial DNA (mtDNA) which affect all mtDNA molecules (homoplasmic) are associated with cardiometabolic traits and the risk of developing cardiovascular disease. However, it is not known whether mtDNA mutations only affecting a proportion of mtDNA molecules (heteroplasmic) also play a role. To address this question, we performed a high-depth (~1000-fold) mtDNA sequencing of blood DNA in 1,399 individuals with hypertension (HTN), 1,946 with ischemic heart disease (IHD), 2,146 with ischemic stroke (IS), and 723 healthy controls. We show that the per individual burden of heteroplasmic single nucleotide variants (mtSNVs) increases with age. The age-effect was stronger for low-level heteroplasmies (heteroplasmic fraction, HF, 5-10%), likely reflecting acquired somatic events based on trinucleotide mutational signatures. After correcting for age and other confounders, intermediate heteroplasmies (HF 10-95%) were more common in hypertension, particularly involving non-synonymous variants altering the amino acid sequence of essential respiratory chain proteins. These findings raise the possibility that heteroplasmic mtSNVs play a role in the pathophysiology of hypertension.

To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure-related pathways and highlight tissues beyond the classical renal system in blood pressure regulation.

Abstract Introduction Maintenance treatment strategies in COPD recommend inhaled corticosteroid (ICS) + long-acting muscarinic antagonist (LAMA) + long-acting β2-agonist (LABA) triple therapy after initial dual therapy. Little is known about how treatment pathways to triple therapy vary across countries in clinical practice. Methods This multi-country, retrospective cohort study (conducted 1 January 2005–1 May 2016) included patients with a COPD diagnosis, and (UK only) evidence of smoking history, or (France, Italy, Germany, and Australia) an indicator confirming COPD diagnosis, a first instance of triple therapy recorded during the study period and ≥ 12 months of data prior to this date. Treatment pathways to triple therapy were analyzed in patients whose first instance of triple therapy was on or after the initial COPD diagnosis. The proportion of patients who initiated triple therapy prior to initial COPD diagnosis was also estimated. Meta-analyses of the main results were performed. Results In 130,729 patients across all countries, mean age (standard deviation) ranged from 63.4 (10.4) years (Germany) to 69.8 (9.9) years (Italy), and median time (interquartile range) from initial COPD diagnosis to first prescription of triple therapy ranged from 16.9 (5.7–36.2) months (Australia) to 42.5 (13.9–87.4) months (UK). ICS + LABA was the most common treatment pathway prior to triple therapy in the UK, Germany, and Italy (27.3%–31.6%); no previous maintenance therapy prior to triple therapy was the most common pathway in France and Australia (32.5% and 37.9%, respectively). Meta-analyses provided a pooled estimate of 20.4% (95% confidence interval: 13.8%–29.1%) for the proportion of patients initiating triple therapy at or before initial COPD diagnosis. Conclusions In this retrospective cohort study, treatment pathways to triple therapy were diverse within and between countries. The differing impact of treatments may affect quality of life and disease control in patients with COPD. Further analyses should investigate factors influencing pathways to triple therapy.

Introduction: It remains unclear whether an increased progression rate of chronic kidney disease (CKD) adds predictive information regarding cardiovascular disease (CVD) risk. The aim of this study was to evaluate the association between CKD progression, based on estimated glomerular filtration rate (eGFR) slope estimates and the risk for CVD. Methods: We compared the updated eGFR slope calculated over multiple overlapping 2-year periods and the updated mean eGFR. Incident CKD subjects were selected from a prevalent population with diabetes (T2DM). Subjects from the UK Clinical Practice Research Data Link GOLD (CPRD) were followed from CKD diagnosis (n = 30,222) until heart failure (HF), myocardial infarction (MI), ischemic stroke (IS), or a composite end point including all 3 event types (MACE plus), mortality, database dropout, or end of study follow-up. Results: Both the updated eGFR slope and updated mean eGFR were associated with MACE plus and HF. Updated eGFR slope decline of > –3 ml/min/1.73 m2 increased the risk for MACE plus (adjusted hazard ratio [HR] = 1.45; 95% confidence interval [CI], 1.26–1.67), HF (HR = 1.50; 95% CI, 1.27–1.76), and MI (HR = 1.39; 95% CI, 1.01–1.91). Conclusions: This study strongly supports current evidence that CKD is an independent risk factor for CVD. From a clinical perspective, both rate of progression and cumulative status of CKD describe distinct aspects of the cardiorenal risk among persons with diabetes. This evidence is essential to enable more timely and improved use of treatments in this population.

La obra de la escritora mexicana Amparo Dávila (1928) ha sido leída y estudiada de manera intermitente durante los últimos sesenta años. Gracias a la edición del Fondo de Cultura Económica de sus Cuentos reunidos, de 2009, la autora zacatecana ha obtenido nuevos lectores. Asimismo, durante la última década la crítica nacional e internacional se ha interesado nuevamente por su narrativa. No obstante, poco se ha explorado el vínculo entre sus relatos y la filosofía. Este trabajo propone establecer un diálogo entre “Fragmento de un diario”, uno de los cuentos que conforman Tiempo destrozado (1959), y la filosofía de Immanuel Kant, Longino y Eugenio Trías en torno a lo bello, lo sublime y lo siniestro, considerando también las aportaciones de Sigmund Freud acerca de lo ominoso. The work of Mexican writer Amparo Dávila (b. 1928) has been read and studied intermittently over the past sixty years. Thanks to the publication of her Cuentos reunidos (2009) by Fondo de Cultura Econó-mica, the author from the State of Zacatecas, has obtained new readers, as national and international critics have once again taken an interest in her narrative. However, little has been done to explore the link between her stories and philosophy. This work proposes to establish a dialogue between “Fragment of a Diary”, one of the tales included in Tiempo des-trozado (1959), and the philosophy of Plato, Longino, Immanuel Kant and Eugenio Trías about the beautiful, the sublime, and the sinister, also considering Sigmund Freud’s contributions about the uncanny.