Role of age and comorbidities in mortality of patients with infective endocarditis

[Purpose]: The aim of this study was to analyse the characteristics of patients with IE in three groups of age and to assess the ability of age and the Charlson Comorbidity Index (CCI) to predict mortality. [Methods]: Prospective cohort study of all patients with IE included in the GAMES Spanish database between 2008 and 2015.Patients were stratified into three age groups:<65 years,65 to 80 years,and ≥ 80 years.The area under the receiver-operating characteristic (AUROC) curve was calculated to quantify the diagnostic accuracy of the CCI to predict mortality risk. [Results]: A total of 3120 patients with IE (1327 < 65 years;1291 65-80 years;502 ≥ 80 years) were enrolled.Fever and heart failure were the most common presentations of IE, with no differences among age groups.Patients ≥80 years who underwent surgery were significantly lower compared with other age groups (14.3%,65 years; 20.5%,65-79 years; 31.3%,≥80 years). In-hospital mortality was lower in the <65-year group (20.3%,<65 years;30.1%,65-79 years;34.7%,≥80 years;p < 0.001) as well as 1-year mortality (3.2%, <65 years; 5.5%, 65-80 years;7.6%,≥80 years; p = 0.003).Independent predictors of mortality were age ≥ 80 years (hazard ratio [HR]:2.78;95% confidence interval [CI]:2.32–3.34), CCI ≥ 3 (HR:1.62; 95% CI:1.39–1.88),and non-performed surgery (HR:1.64;95% CI:11.16–1.58).When the three age groups were compared,the AUROC curve for CCI was significantly larger for patients aged <65 years(p < 0.001) for both in-hospital and 1-year mortality. [Conclusion]: There were no differences in the clinical presentation of IE between the groups. Age ≥ 80 years, high comorbidity (measured by CCI),and non-performance of surgery were independent predictors of mortality in patients with IE.CCI could help to identify those patients with IE and surgical indication who present a lower risk of in-hospital and 1-year mortality after surgery, especially in the <65-year group

Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

Background Genome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkinson's disease. Methods We did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation. Findings Between Oct 1, 2017, and Aug 9, 2018, we analysed 7·8 million single nucleotide polymorphisms in 37 688 cases, 18 618 UK Biobank proxy-cases (ie, individuals who do not have Parkinson's disease but have a first degree relative that does), and 1·4 million controls. We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16–36% of the heritable risk of Parkinson's disease depending on prevalence. Integrating methylation and expression data within a Mendelian randomisation framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested Parkinson's disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes (false discovery rate-adjusted p=0·0035 for intracranial volume, p=0·024 for putamen volume), smoking status (p=0·024), and educational attainment (p=0·038). Mendelian randomisation between cognitive performance and Parkinson's disease risk showed a robust association (p=8·00 × 10−7). Interpretation These data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified. These associations derived from European ancestry datasets will need to be followed-up with more diverse data. Funding The National Institute on Aging at the National Institutes of Health (USA), The Michael J Fox Foundation, and The Parkinson's Foundation (see appendix for full list of funding sources)

El reto de la inclusión de los Objetivos de Desarrollo Sostenible en la formación inicial de profesores de secundaria: creación del MOOC curso cero sobre educación y ODS, inclusión en asignaturas y en trabajos fin de máster

Memoria ID-041. Ayudas de la Universidad de Salamanca para la innovación docente, curso 2021-2022

Synthesis of 2'-O-Methyl/2'-O-MOE-L-Nucleoside Derivatives and Their Applications: Preparation of G-Quadruplexes, Their Characterization, and Stability Studies

Nucleosides and their analogues constitute an important family of molecules with potential antiviral and antiproliferative activity. The enantiomers of natural nucleosides, l-nucleoside derivatives, which have comparable biological activity but more favorable toxicological properties and greater metabolic stability than d-nucleosides, have emerged as a new class of therapeutic agents. Furthermore, l-nucleosides can be used as a building block to prepare l-oligonucleotides, which have identical physical properties in terms of solubility, hybridization kinetics, and duplex thermal stability as d-oligonucleotides but completely orthogonal in nature. Consequently, they are resistant to nuclease degradation, nontoxic, and immunologically passive, which are desirable properties for biomedical applications. Herein, we describe the synthesis of several 2'-O-methyl/2'-O-MOE-l-nucleoside pyrimidine derivatives and their incorporation into G-rich oligonucleotides. Finally, we evaluated the stability and resistance against nucleases of these new G-quadruplexes, demonstrating the potential of the l-nucleosides described in this work in providing enhanced nuclease resistance with a minimal impact in the nucleic acid structural properties.Financial support of this work by the Regional Government of Principado de Asturias (Project SV-PA-21-AYUD-2021-51542) and by the Spanish Ministerio de Ciencia e Innovación (MICINN) (project PID2020-118145RB-I00) are gratefully acknowledged. This research was also supported by CIBER─Consorcio Centro de Investigación Biomédica en Red (CB06/01/0019), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación and European Regional Development Fund (ERDF). Oligonucleotide synthesis was performed by the ICTS ‘‘NANBIOSIS” and specifically by the oligonucleotide synthesis platform (OSP) U29 at IQAC-CSIC (https://www.nanbiosis.es/portfolio/u29-oligonucleotide-synthesis-platform-osp/).Peer reviewe

The synthesis of solid supports carrying base labile linkers to generate 3'-phosphate oligonucleotides

Oligonucleotides carrying 3'-terminal phosphates and conjugates are important tools in molecular biology and diagnostic purposes. We described the preparation of solid supports carrying the base labile linker 4-((2-hydroxyethyl)sulfonyl)benzamide for the solid-phase synthesis of 3'-phosphorylated oligonucleotides. These supports are fully compatible with the phosphoramidite chemistry yielding the desired 3'-phosphate oligonucleotides in excellent yields. The use of mild deprotection conditions allows the generation of partially protected DNA fragments.This work was financially supported by the Spanish Ministerio de Ciencia e Innovación (MICINN) (Projects PID2020-118145RB-I00, CPP2021-008792 and PID2022-137893OB-I00), and NRF-South Africa. This research was also supported by CIBER - Consorcio Centro de Investigación Biomédica en Red (CB06/01/0019), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación and the European Regional Development Fund (ERDF). The oligonucleotide synthesis was performed by the ICTS ‘‘NANBIOSIS” and specifically by the oligonucleotide synthesis platform (OSP) U29 at IQAC-CSIC (https://www.nanbiosis.es/portfolio/u29-oligonucleotide-synthesis-platform-osp/). We thank Dr. Ramon Güimil-Garcia (BioNTech RNA Pharmaceuticals) for his encouragement and discussions.Peer reviewe

Live Imaging Reveals Cerebellar Neural Stem Cell Dynamics and the Role of VNUT in Lineage Progression

Little is known about the intrinsic specification of postnatal cerebellar neural stem cells (NSCs) and to what extent they depend on information from their local niche. Here, we have used an adapted cell preparation of isolated postnatal NSCs and live imaging to demonstrate that cerebellar progenitors maintain their neurogenic nature by displaying hallmarks of NSCs. Furthermore, by using this preparation, all the cell types produced postnatally in the cerebellum, in similar relative proportions to those observed in vivo, can be monitored. The fact that neurogenesis occurs in such organized manner in the absence of signals from the local environment, suggests that cerebellar lineage progression is to an important extent governed by cell-intrinsic or pre-programmed events. Finally, we took advantage of the absence of the niche to assay the influence of the vesicular nucleotide transporter inhibition, which dramatically reduced the number of NSCs in vitro by promoting their progression toward neurogenesis.Ministerio de Educación y Ciencia (BFU2015-70067REDC y BFU2014-53654-P)BRADE-CM (S2013/ICE-2958)UCMSantander (PR26/16-18B-3; PR75/18; PR65/19-22453)Fundación Ramón Areces (PR2018/16-02)7.765 JCR (2020) Q1, 5/29 Cell & Tissue Engineering3.207 SJR (2020) Q1, 23/438 BiochemistryNo data IDR 2020UE

El registro continuo de imagen revela la dinámica de las células madre neurales cerebelosas y el papel de VNUT en la progresión del linaje

Little is known about the intrinsic specification of postnatal cerebellar neural stem cells (NSCs) and to what extent they depend on information from their local niche. Here, we have used an adapted cell preparation of isolated postnatal NSCs and live imaging to demonstrate that cerebellar progenitors maintain their neurogenic nature by displaying hallmarks of NSCs. Furthermore, by using this preparation, all the cell types produced postnatally in the cerebellum, in similar relative proportions to those observed in vivo, can be monitored. The fact that neurogenesis occurs in such organized manner in the absence of signals from the local environment, suggests that cerebellar lineage progression is to an important extent governed by cell-intrinsic or pre-programmed events. Finally, we took advantage of the absence of the niche to assay the influence of the vesicular nucleotide transporter inhibition, which dramatically reduced the number of NSCs in vitro by promoting their progression toward neurogenesis.Comunidad de MadridUniversidad Complutense de MadridFundación Ramón ArecesMinisterio de Educación y Cultura (España)Spanish Ministerio de Ciencia, Innovacio´n y UniversidadesSección Deptal. de Farmacología y Toxicología (Veterinaria)Fac. de VeterinariaTRUEpu

Currículo Educación Secundaria Obligatoria y relaciones entre sus elementos

Se recoge el articulado del Decreto 43/2015, de 10 de junio, por el que se regula la ordenación y se establece el currículo de Educación Secundaria Obligatoria en el Principado de Asturias, publicado en el BOPA (Boletín Oficial del Principado de Asturias) el 30 de junio de 2015. La publicación incluye además la metodología didáctica, los contenidos, los criterios de valuación y estándares de aprendizaje evaluables de las distintas materias troncales, específicas y de aquéllas de libre configuración autonómica, y el total de sesiones lectivas de las distintas asignaturas de los ciclos educativos de la Educación Secundaria Obligatoria.ES

Currículo Bachillerato y relaciones entre sus elementos

Contiene el Decreto 42/2015, de 10 de junio, por el que se regula la ordenación y se establece el currículo del Bachillerato en el Principado de Asturias. Publicado en el BOPA (Boletín Oficial del Principado de Asturias) el 29 de junio de 2015. Incluye además, la metodología didáctica, los contenidos, los criterios de valuación y estándares de aprendizaje evaluables de las distintas materias troncales, específicas y de aquéllas de libre configuración autonómica, y el total de sesiones lectivas de las distintas asignaturas del Bachillerato.ES