Mucosal Plasma Cell Activation and Proximity to Nerve Fibres Are Associated with Glycocalyx Reduction in Diarrhoea-Predominant Irritable Bowel Syndrome: Jejunal Barrier Alterations Underlying Clinical Manifestations

Intestinal barrier dysfunction; Intestinal glycocalyx; Mucosal nerve fibresDisfunción de la barrera intestinal; Glicocálix intestinal; Fibras nerviosas de la mucosaDisfunció de la barrera intestinal; Glicocàlix intestinal; Fibres nervioses de la mucosaIrritable bowel syndrome (IBS) is a disorder of brain-gut interaction characterised by abdominal pain and changes in bowel habits. In the diarrhoea subtype (IBS-D), altered epithelial barrier and mucosal immune activation are associated with clinical manifestations. We aimed to further evaluate plasma cells and epithelial integrity to gain understanding of IBS-D pathophysiology. One mucosal jejunal biopsy and one stool sample were obtained from healthy controls and IBS-D patients. Gastrointestinal symptoms, stress, and depression scores were recorded. In the jejunal mucosa, RNAseq and gene set enrichment analyses were performed. A morphometric analysis by electron microscopy quantified plasma cell activation and proximity to enteric nerves and glycocalyx thickness. Immunoglobulins concentration was assessed in the stool. IBS-D patients showed differential expression of humoral pathways compared to controls. Activation and proximity of plasma cells to nerves and IgG concentration were also higher in IBS-D. Glycocalyx thickness was lower in IBS-D compared to controls, and this reduction correlated with plasma cell activation, proximity to nerves, and clinical symptoms. These results support humoral activity and loss of epithelial integrity as important contributors to gut dysfunction and clinical manifestations in IBS-D. Additional studies are needed to identify the triggers of these alterations to better define IBS-D pathophysiology.This study was funded in part by Fondo Europeo de Desarrollo Regional (FEDER), Fondo de Investigación Sanitaria and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Subdirección General de Investigación Sanitaria, Ministerio de Economía y Competitividad: CP18/00116 (C.M.), PI19/01643 (B.L.); PI17/01443 (D.G.); PI15/00301 (C.A.-C.), PI17/0190 (J.S.), PI19/01643 & CPII16/00031, (M.V.); CIBEREHD CB06/04/0021 (F.A., C.A.-C., J.S., M.V.); Ministerio de Educación, Dirección General de Investigación: SAF 2016-76648-R (F.A.); Agència de Gestió d’Ajuts Universitaris i de Recerca, de la Generalitat de Catalunya: 2014 SGR 1285 (F.A.); Vall d’Hebron Institut de Recerca, Programa de becas predoctorales Amics de Vall d’Hebron: PRED-VHIR-2016-34 (C.P.-C.), PRED-VHIR-2014-018 (M.F.), the Swedish Research Council dnr 2019-00653 (J.-P.G.M.), and the European Union’s Horizon research and innovation programme 2020, grant no. 848228 (E.E., A.R.-U., B.L., C.A.-C., J.S.)

Desarrollo de competencias profesionales a través de prácticas en empresa en la universidad politécnica de Cartagena (UPCT)

[SPA] El equipo docente de la Universidad Politécnica de Cartagena “Docencia Orientada a la Profesión” ha desarrollado un documento para servir de referencia en las prácticas en empresa de los títulos de la UPCT, prácticas que desde el RD 1791/2011 son curriculares y corresponden a créditos obligatorios u optativos y que requieren la elaboración de un proyecto formativo. El documento se ocupa de la definición y evaluación de competencias.[ENG] The teamwork “Docencia Orientada a la Profesión” of the Universidad Politécnica de Cartagena has developed a document aimed to be used as a reference in the internships of the UPCT degrees. Since the Royal Decree RD 1791/2011 was approved, internships are considered as curricular and correspond to compulsory or optional credits. Furthermore, the RD establishes that internships require the development of an educational project. The mentioned document deals with the definition and assessment of skills

Docencia orientada a la profesión: análisis de los informes de empleabilidad de la Universidad Politécnica de Cartagena (UPCT)

[SPA] Este trabajo recoge el análisis de los informes de empleabilidad de egresados de la Universidad Politécnica de Cartagena durante el periodo 2010 a 2012. Los egresados consultados se han dividido por grupos, que van desde los recién titulados hasta los que finalizaron 5 años atrás. El análisis se centra en las diez competencias transversales más demandadas por el mercado laboral. De los resultados obtenidos se ha evidenciado que cada competencia está asociada a un nivel de responsabilidad y cualificación diferente dentro de una empresa y estos niveles van cambiando con el tiempo, por lo que no todas las competencias son igualmente necesarias en cada uno de los niveles de la vida profesional. Igualmente se hace patente la necesidad de un acercamiento posterior del egresado a la universidad, en forma de másteres, doctorados o cursos de especialización, para actualizar conocimientos y adquirir competencias acorde a los requerimientos cambiantes de su profesión.[ENG] This work presents an employability analysis of the graduates from the Universidad Politécnica de Cartagena, during the period 2010-2012. Graduates have been divided into groups, ranging from recent graduates to those having graduated years ago. The analysis focuses on the ten most transferable skills demanded by the market. From the results, it has been shown that each skill is associated with a level of responsibility different in each company, and these levels change over time, so not all skills are equally necessary in each of the levels professional life. Furthermore, it becomes necessary an approach over the years of the graduate to the university. This approach in terms of a master, PhD or specialization courses to update skills and to acquire knowledge according to the changing requirements of their profession

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

The maternal genetic make-up of the Iberian Peninsula between the Neolithic and the Early Bronze Age

Abstract Agriculture first reached the Iberian Peninsula around 5700 BCE. However, little is known about the genetic structure and changes of prehistoric populations in different geographic areas of Iberia. In our study, we focus on the maternal genetic makeup of the Neolithic (~ 5500–3000 BCE), Chalcolithic (~ 3000–2200 BCE) and Early Bronze Age (~ 2200–1500 BCE). We report ancient mitochondrial DNA results of 213 individuals (151 HVS-I sequences) from the northeast, central, southeast and southwest regions and thus on the largest archaeogenetic dataset from the Peninsula to date. Similar to other parts of Europe, we observe a discontinuity between hunter-gatherers and the first farmers of the Neolithic. During the subsequent periods, we detect regional continuity of Early Neolithic lineages across Iberia, however the genetic contribution of hunter-gatherers is generally higher than in other parts of Europe and varies regionally. In contrast to ancient DNA findings from Central Europe, we do not observe a major turnover in the mtDNA record of the Iberian Late Chalcolithic and Early Bronze Age, suggesting that the population history of the Iberian Peninsula is distinct in character

Correction to: Comparative effectiveness and safety of non-vitamin K antagonists for atrial fibrillation in clinical practice: GLORIA-AF Registry

International audienceIn this article, the name of the GLORIA-AF investigator Anastasios Kollias was given incorrectly as Athanasios Kollias in the Acknowledgements. The original article has been corrected

Patterns of oral anticoagulant use and outcomes in Asian patients with atrial fibrillation: a post-hoc analysis from the GLORIA-AF Registry

Background: Previous studies suggested potential ethnic differences in the management and outcomes of atrial fibrillation (AF). We aim to analyse oral anticoagulant (OAC) prescription, discontinuation, and risk of adverse outcomes in Asian patients with AF, using data from a global prospective cohort study. Methods: From the GLORIA-AF Registry Phase II-III (November 2011-December 2014 for Phase II, and January 2014-December 2016 for Phase III), we analysed patients according to their self-reported ethnicity (Asian vs. non-Asian), as well as according to Asian subgroups (Chinese, Japanese, Korean and other Asian). Logistic regression was used to analyse OAC prescription, while the risk of OAC discontinuation and adverse outcomes were analysed through Cox-regression model. Our primary outcome was the composite of all-cause death and major adverse cardiovascular events (MACE). The original studies were registered with ClinicalTrials.gov, NCT01468701, NCT01671007, and NCT01937377. Findings: 34,421 patients were included (70.0 ± 10.5 years, 45.1% females, 6900 (20.0%) Asian: 3829 (55.5%) Chinese, 814 (11.8%) Japanese, 1964 (28.5%) Korean and 293 (4.2%) other Asian). Most of the Asian patients were recruited in Asia (n = 6701, 97.1%), while non-Asian patients were mainly recruited in Europe (n = 15,449, 56.1%) and North America (n = 8378, 30.4%). Compared to non-Asian individuals, prescription of OAC and non-vitamin K antagonist oral anticoagulant (NOAC) was lower in Asian patients (Odds Ratio [OR] and 95% Confidence Intervals (CI): 0.23 [0.22-0.25] and 0.66 [0.61-0.71], respectively), but higher in the Japanese subgroup. Asian ethnicity was also associated with higher risk of OAC discontinuation (Hazard Ratio [HR] and [95% CI]: 1.79 [1.67-1.92]), and lower risk of the primary composite outcome (HR [95% CI]: 0.86 [0.76-0.96]). Among the exploratory secondary outcomes, Asian ethnicity was associated with higher risks of thromboembolism and intracranial haemorrhage, and lower risk of major bleeding. Interpretation: Our results showed that Asian patients with AF showed suboptimal thromboembolic risk management and a specific risk profile of adverse outcomes; these differences may also reflect differences in country-specific factors. Ensuring integrated and appropriate treatment of these patients is crucial to improve their prognosis. Funding: The GLORIA-AF Registry was funded by Boehringer Ingelheim GmbH

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

BackgroundWe previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in similar to 80% of cases.MethodsWe report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.ResultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P=1.1x10(-4)) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70[95%CI 1.3-8.2], P=2.1x10(-4)). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR=19.65[95%CI 2.1-2635.4], P=3.4x10(-3)), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR=4.40[9%CI 2.3-8.4], P=7.7x10(-8)). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P=1.68x10(-5)).ConclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old