Implementación de la metodología aprendizaje-servicio (ApS) como medio generador de conocimiento y reflexión en los estudiantes de los grados de Educación Infantil y Educación Primaria

Memoria ID2019/045. Ayudas de la Universidad de Salamanca para la innovación docente, curso 2019-2020

D-dimer levels and risk of recurrence following provoked venous thromboembolism: findings from the RIETE registry.

Patients with venous thromboembolism (VTE) secondary to transient risk factors may develop VTE recurrences after discontinuing anticoagulation. Identifying at-risk patients could help to guide the duration of therapy. We used the RIETE database to assess the prognostic value of d-dimer testing after discontinuing anticoagulation to identify patients at increased risk for recurrences. Transient risk factors were classified as major (postoperative) or minor (pregnancy, oestrogen use, immobilization or recent travel). In December 2018, 1655 VTE patients with transient risk factors (major 460, minor 1195) underwent d-dimer measurements after discontinuing anticoagulation. Amongst patients with major risk factors, the recurrence rate was 5.74 (95% CI: 3.19-9.57) events per 100 patient-years in those with raised d-dimer levels and 2.68 (95% CI: 1.45-4.56) in those with normal levels. Amongst patients with minor risk factors, the rates were 7.79 (95% CI: 5.71-10.4) and 3.34 (95% CI: 2.39-4.53), respectively. Patients with major risk factors and raised d-dimer levels (n = 171) had a nonsignificantly higher rate of recurrences (hazard ratio [HR]: 2.14; 95% CI: 0.96-4.79) than those with normal levels. Patients with minor risk factors and raised d-dimer levels (n = 382) had a higher rate of recurrences (HR: 2.34; 95% CI: 1.51-3.63) than those with normal levels. On multivariate analysis, raised d-dimers (HR: 1.74; 95% CI: 1.09-2.77) were associated with an increased risk for recurrences in patients with minor risk factors, not in those with major risk factors. Patients with raised d-dimer levels after discontinuing anticoagulant therapy for VTE provoked by a minor transient risk factor were at an increased risk for recurrences

EUROMAC: A European registry for patients with McArdle disease and other very rare muscle glycogenoses

EUROMAC is a European registry of McArdle Disease patients and other very rare muscle glycogenosis (glycogenosis types 0, IV, VII, IX, X, XIII; phosphoglycerate kinase 1 deficiency and muscle lactate dehydrogenase deficiency) presenting with exercise intolerance as the key symptom. EUROMAC aims to promote awareness and understanding of McArdle disease and related conditions to harmonize standards of diagnosis and care and to promote research. EUROMAC was created and developed by a network of 15 partners from 7 EU countries, Turkey and US. Initially funded by the European Commission's Directorate General for Health and Consumers, the registry is currently supported by a grant received from the Fondo de Investigaciones Sanitarias (PI116/01492). Following informed consent from the participant, data (demographics, main clinical symptoms, comorbidities, age at diagnosis and genetic diagnosis) were uploaded onto a safe, encrypted web-based registry (https://www.registryeuromac.eu/en/). In parallel, education, training and dissemination activities were performed. EUROMAC is the largest international registry for patients with McArdle disease. As of March 2018, 313 patients from 10 different countries were recruited. The first Polish patient diagnosed with McArdle disease followed a EUROMAC teaching course, held in Warsaw. The implementation of the EUROMAC project and the setting-up of an international registry have significantly contributed to the effective dissemination of rare muscle GSDs, raising the awareness of these conditions. Additionally, it provided a unique insight into the co-comorbidities affecting people with McArdle disease that should lead to strategies to reduce and manage them in the future.Sin financiación3.115 JCR (2019) Q3, 76/204 Clinical Neurology1.177 SJR (2019) Q1, 85/378 Neurology (clinical)No data IDR 2019UE

Analysis of the structural and metabolic consequences of McArdle disease using the murine model

McArdle disease is an autosomal recessive disorder caused by the absence of the muscle glycogen phosphorylase, which leads to impairment of glycogen breakdown. The McArdle mouse, a model heavily affected by glycogen accumulation and exercise intolerance, was used to characterize disease progression at three different ages. The molecular and histopathological consequences of the disease were analyzed in five different hind-limb muscles (soleus, extensor digitorum longus, tibialis anterior, gastrocnemius and quadriceps) of young (8-week-old), adult (35-week-old) and old (70-week-old) mice. We observed progressive muscle degeneration, fibrosis and inflammation process that was not associated with an increase in muscle glycogen content during aging. Additionally, this progressive degeneration varied among muscle and fiber types. The lack of glycogen content increase was associated with the inactivation of glycogen synthase and not with compensatory expression of the Pygl and/or Pygb genes in mature muscle. Furthermore, the molecular interconnection between skeletal muscle-liver and adipose tissue was assessed in these mice in order to determine whether there was an upregulation of the oxidative metabolism during disease progression as McArdle mice presented a clear reduction in abdominal fat and liver glycogen content. In this regard, mitochondrial content and activity were assessed in both oxidative and glycolytic muscles as oxidative fibers (specially IIa fibers) presented more structural damage caused by higher glycogen accumulation than glycolytic fibers (IIx and IIx/IIb fibers). Lower levels of mitochondrial content and activity were found in the skeletal muscle of McA mice with respect to their wild-type counterparts.Sin financiación3.115 JCR (2019) Q3, 76/204 Clinical Neurology1.177 SJR (2019) Q1, 85/378 Neurology (clinical)No data IDR 2019UE

MAPT H1 haplotype is associated with late-onset Alzheimer's disease risk in APOE epsilon 4 noncarriers: results from the dementia genetics Spanish consortium

The MAPT H1 haplotype has been linked to several disorders, but its relationship with Alzheimer's disease (AD) remains controversial. A rare variant in MAPT (p.A152T) has been linked with frontotemporal dementia (FTD) and AD. We genotyped H1/H2 and p.A152T MAPT in 11,572 subjects from Spain (4,327 AD, 563 FTD, 648 Parkinson's disease (PD), 84 progressive supranuclear palsy (PSP), and 5,950 healthy controls). Additionally, we included 101 individuals from 21 families with genetic FTD. MAPT p.A152T was borderline significantly associated with FTD [odds ratio (OR)=2.03; p=0.063], but not with AD. MAPT H1 haplotype was associated with AD risk (OR=1.12; p=0.0005). Stratification analysis showed that this association was mainly driven by APOE epsilon4 noncarriers (OR=1.14; p=0.0025). MAPT H1 was also associated with risk for PD (OR=1.30; p=0.0003) and PSP (OR=3.18; p=8.59 × 10-8) but not FTD. Our results suggest that the MAPT H1 haplotype increases the risk of PD, PSP, and non-APOE epsilon4 AD

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