Physical activity trajectories, mortality, hospitalization, and disability in the Toledo Study of Healthy Aging

Background: Physical activity (PA) is a recognized contributor to healthy aging. However, the majority of studies exploring its associations with adverse outcomes in cohorts of older adults use single-time PA estimates, which do not consider its dynamic nature. The aim of the present study is to explore the presence of different PA trajectories in the Toledo Study of Healthy Aging and their association with adverse outcomes. Our hypothesis is that prospectively maintaining or increasing PA is associated with a reduced risk of adverse outcomes. Methods: We used data from 1679 participants enrolled in the Toledo Study of Healthy Aging. Trajectories based on the Physical Activity Scale for the Elderly were identified using group-based trajectory modelling. Cox and logistic regression were used to investigate associations between PA trajectories and mortality and hospitalization, and incident and worsening disability, respectively. Mortality was ascertained by linkage to the Spanish National Death Index; disability was evaluated through the Katz Index; and hospitalization was defined as the first admission to Toledo Hospital. Models were adjusted by age, sex, smoking, Charlson Index, education, cognitive impairment, polypharmacy, and Katz Index at Wave 2. Results: We found four PA-decreasing and one PA-increasing trajectories: high PA-consistent (n = 566), moderate PA-mildly decreasing (n = 392), low PA-increasing (n = 237), moderate PA-consistent (n = 191), and low PA-decreasing (n = 293). Belonging to the high PA-consistent trajectory group was associated with reduced risks of mortality as compared with the low PA-decreasing group [hazard ratio (HR) 1.68; 95% confidence interval (CI) = 1.21–2.31] and hospitalization compared with the low PA-increasing and low PA-decreasing trajectory groups (HR 1.24; 95% CI = 1.004–1.54 and HR 1.25; 95% CI = 1.01–1.55, respectively) and with lower rates of incident [odds ratio (OR) 3.14; 95% CI = 1.59–6.19] and worsening disability (OR 2.16; 95% CI = 1.35–3.45) in relation to the low PA-decreasing trajectory group and at follow-up. Increasing PA during late life (low PA-increasing group) was associated with lower incident disability rates (OR 0.38; 95% CI = 0.19–0.82) compared with decreasing PA (low PA-decreasing group), despite similar baseline PA. Conclusions: Our results suggest that sustaining higher PA levels during aging might lead to healthy aging, characterized by a reduction in adverse outcomes. Our study supports the need for enhancing PA participation among older populations, with the goal of reducing personal and economic burden in a worldwide aging population.The present work was funded by grants from the Spanish Ministry of Economy, Industry and Competitiveness, cofinanced by the European Regional Development Funds (RD120001/0043) and the Centro de Investigación Biomédica en Red en Fragilidad y Envejecimiento Saludable (CB16/10/00464)

Impact of a TAK-1 inhibitor as a single or as an add-on therapy to riociguat on the metabolic reprograming and pulmonary hypertension in the SUGEN5416/hypoxia rat model.

Background: Despite increasing evidence suggesting that pulmonary arterial hypertension (PAH) is a complex disease involving vasoconstriction, thrombosis, inflammation, metabolic dysregulation and vascular proliferation, all the drugs approved for PAH mainly act as vasodilating agents. Since excessive TGF-β signaling is believed to be a critical factor in pulmonary vascular remodeling, we hypothesized that blocking TGFβ-activated kinase 1 (TAK-1), alone or in combination with a vasodilator therapy (i.e., riociguat) could achieve a greater therapeutic benefit. Methods: PAH was induced in male Wistar rats by a single injection of the VEGF receptor antagonist SU5416 (20 mg/kg) followed by exposure to hypoxia (10%O2) for 21 days. Two weeks after SU5416 administration, vehicle, riociguat (3 mg/kg/day), the TAK-1 inhibitor 5Z-7-oxozeaenol (OXO, 3 mg/kg/day), or both drugs combined were administered for 7 days. Metabolic profiling of right ventricle (RV), lung tissues and PA smooth muscle cells (PASMCs) extracts were performed by magnetic resonance spectroscopy, and the differences between groups analyzed by multivariate statistical methods. Results: In vitro, riociguat induced potent vasodilator effects in isolated pulmonary arteries (PA) with negligible antiproliferative effects and metabolic changes in PASMCs. In contrast, 5Z-7-oxozeaenol effectively inhibited the proliferation of PASMCs characterized by a broad metabolic reprogramming but had no acute vasodilator effects. In vivo, treatment with riociguat partially reduced the increase in pulmonary arterial pressure (PAP), RV hypertrophy (RVH), and pulmonary vascular remodeling, attenuated the dysregulation of inosine, glucose, creatine and phosphocholine (PC) in RV and fully abolished the increase in lung IL-1β expression. By contrast, 5Z-7-oxozeaenol significantly reduced pulmonary vascular remodeling and attenuated the metabolic shifts of glucose and PC in RV but had no effects on PAP or RVH. Importantly, combined therapy had an additive effect on pulmonary vascular remodeling and induced a significant metabolic effect over taurine, amino acids, glycolysis, and TCA cycle metabolism via glycine-serine-threonine metabolism. However, it did not improve the effects induced by riociguat alone on pulmonary pressure or RV remodeling. None of the treatments attenuated pulmonary endothelial dysfunction and hyperresponsiveness to serotonin in isolated PA. Conclusion: Our results suggest that inhibition of TAK-1 induces antiproliferative effects and its addition to short-term vasodilator therapy enhances the beneficial effects on pulmonary vascular remodeling and RV metabolic reprogramming in experimental PAH.This work was supported by the Instituto de Salud Carlos III-ISCIII (Grant numbers: PI15/01100 and PI19/01616 to LM), the Spanish Ministry of Science and Innovation MCIN (Grant numbers: PID 2019-107363RB-I00 to FP-V, PID 2020-117939RBI00 to AC and PID 2021-123238OB-I00, PDC 2021-121696-I00 to JRC and PID2019-106564RJ-I00 to JI-G), the Comunidad de Madrid-CAM (CM S2017/BMD-3727 to AC and LM and B2017/ BMD3875 to JI-G) and, as appropriate, by “ERDF A way of making Europe”, co-funded by the “European Union”. FP-V received funding from Fundación Contra la Hipertensión Pulmonar (Empathy grant) and JR-C from La Caixa Foundation (Health Research Call 2020: HR20-00075). This work was performed under the Maria de Maeztu Units of Excellence Programme–Grant MDM-2017-0720 funded by MCIN/AEI/10.13039/501100011033.S

Urine NMR-based TB metabolic fingerprinting for the diagnosis of TB in children

Tuberculosis (TB) is a major cause of morbidity and mortality in children, and early diagnosis and treatment are crucial to reduce long-term morbidity and mortality. In this study, we explore whether urine nuclear magnetic resonance (NMR)-based metabolomics could be used to identify differences in the metabolic response of children with different diagnostic certainty of TB. We included 62 children with signs and symptoms of TB and 55 apparently healthy children. Six of the children with presumptive TB had bacteriologically confirmed TB, 52 children with unconfirmed TB, and 4 children with unlikely TB. Urine metabolic fingerprints were identified using high- and low-field proton NMR platforms and assessed with pattern recognition techniques such as principal components analysis and partial least squares discriminant analysis. We observed differences in the metabolic fingerprint of children with bacteriologically confirmed and unconfirmed TB compared to children with unlikely TB (p = 0.041 and p = 0.013, respectively). Moreover, children with unconfirmed TB with X-rays compatible with TB showed differences in the metabolic fingerprint compared to children with non-pathological X-rays (p = 0.009). Differences in the metabolic fingerprint in children with different diagnostic certainty of TB could contribute to a more accurate characterisation of TB in the paediatric population. The use of metabolomics could be useful to improve the prediction of TB progression and diagnosis in children

Impact of a TAK-1 inhibitor as a single or as an add-on therapy to riociguat on the metabolic reprograming and pulmonary hypertension in the SUGEN5416/hypoxia rat model

Background: Despite increasing evidence suggesting that pulmonary arterial hypertension (PAH) is a complex disease involving vasoconstriction, thrombosis, inflammation, metabolic dysregulation and vascular proliferation, all the drugs approved for PAH mainly act as vasodilating agents. Since excessive TGF-β signaling is believed to be a critical factor in pulmonary vascular remodeling, we hypothesized that blocking TGFβ-activated kinase 1 (TAK-1), alone or in combination with a vasodilator therapy (i.e., riociguat) could achieve a greater therapeutic benefit.Methods: PAH was induced in male Wistar rats by a single injection of the VEGF receptor antagonist SU5416 (20 mg/kg) followed by exposure to hypoxia (10%O2) for 21 days. Two weeks after SU5416 administration, vehicle, riociguat (3 mg/kg/day), the TAK-1 inhibitor 5Z-7-oxozeaenol (OXO, 3 mg/kg/day), or both drugs combined were administered for 7 days. Metabolic profiling of right ventricle (RV), lung tissues and PA smooth muscle cells (PASMCs) extracts were performed by magnetic resonance spectroscopy, and the differences between groups analyzed by multivariate statistical methods.Results:In vitro, riociguat induced potent vasodilator effects in isolated pulmonary arteries (PA) with negligible antiproliferative effects and metabolic changes in PASMCs. In contrast, 5Z-7-oxozeaenol effectively inhibited the proliferation of PASMCs characterized by a broad metabolic reprogramming but had no acute vasodilator effects. In vivo, treatment with riociguat partially reduced the increase in pulmonary arterial pressure (PAP), RV hypertrophy (RVH), and pulmonary vascular remodeling, attenuated the dysregulation of inosine, glucose, creatine and phosphocholine (PC) in RV and fully abolished the increase in lung IL-1β expression. By contrast, 5Z-7-oxozeaenol significantly reduced pulmonary vascular remodeling and attenuated the metabolic shifts of glucose and PC in RV but had no effects on PAP or RVH. Importantly, combined therapy had an additive effect on pulmonary vascular remodeling and induced a significant metabolic effect over taurine, amino acids, glycolysis, and TCA cycle metabolism via glycine-serine-threonine metabolism. However, it did not improve the effects induced by riociguat alone on pulmonary pressure or RV remodeling. None of the treatments attenuated pulmonary endothelial dysfunction and hyperresponsiveness to serotonin in isolated PA.Conclusion: Our results suggest that inhibition of TAK-1 induces antiproliferative effects and its addition to short-term vasodilator therapy enhances the beneficial effects on pulmonary vascular remodeling and RV metabolic reprogramming in experimental PAH

Indicaciones y contraindicaciones del trasplante y retrasplante hepático

Este documento nació por la inciativa conjunta de la Organización Nacional de Trasplantes (ONT) y la Agencia de Evaluación de Tecnologías Sanitarias (AETS), ante la necesidad compartida por los diferentes equipos de trasplante hepático de disponer de un documento marco que exprese la realidad actual del trasplante y retrasplante hepático en España, y que recoja las indicaciones y contraindicaciones comúnmente aceptadas de estas técnicas, y los criterios de prioridad para el acceso a esta terapéutica.Abreviaturas, Metodología, Introducción, Aspectos generales de las indicaciones, contraindicaciones y factores de riesgo para el trasplante hepático, Trasplante en enfermedades colestásicas Indicaciones y contraindicaciones de crónica parenquimaosa, Trasplantes en hepatitis virales, Fallo hepático fulminante, Tumores, Trasplante hepático pediátrico, Retrasplante, Criterios de prioridad para trasplante y retrasplante hepático, Resumen y conclusiones, Bibliografía, Summary and conclusions, Abstract

How does neighbourhood socio-economic status affect the interrelationships between functioning dimensions in first episode of psychosis? A network analysis approach

The links between psychosis and socio-economic disadvantage have been widely studied. No previous study has analysed the interrelationships and mutual influences between functioning dimensions in first episode of psychosis (FEP) according to their neighbourhood household income, using a multidimensional and transdiagnostic perspective. 170 patients and 129 controls, participants in an observational study (AGES-CM), comprised the study sample. The WHO Disability Assessment Schedule (WHODAS 2.0) was used to assess functioning, whereas participants' postcodes were used to obtain the average household income for each neighbourhood, collected by the Spanish National Statistics Institute (INE). Network analyses were conducted with the aim of defining the interrelationships between the different dimensions of functioning according to the neighbourhood household income. Our results show that lower neighbourhood socioeconomic level is associated with lower functioning in patients with FEP. Moreover, our findings suggest that “household responsibilities” plays a central role in the disability of patients who live in low-income neighbourhoods, whereas “dealing with strangers” is the most important node in the network of patients who live in high-income neighbourhoods. These results could help to personalize treatments, by allowing the identification of potential functioning areas to be prioritized in the treatment of FEP according to the patient's neighbourhood characteristic

The interplay between functioning problems and symptoms in first episode of psychosis: an approach from network analysis

The relationship between psychotic symptoms and global measures of functioning has been widely studied. No previous study has assessed so far the interplay between specific clinical symptoms and particular areas of functioning in first-episode psychosis (FEP) using network analysis methods. A total of 191 patients with FEP (age 24.45 ± 6.28 years, 64.9% male) participating in an observational and longitudinal study (AGES-CM) comprised the study sample. Functioning problems were assessed with the WHO Disability Assessment Schedule (WHODAS), whereas the Positive and Negative Syndrome Scale (PANSS) was used to assess symptom severity. Network analysis were conducted with the aim of analysing the patterns of relationships between the different dimensions of functioning and PANSS symptoms and factors at baseline. According to our results, the most important nodes were “conceptual disorganization”, “emotional withdrawal”, “lack of spontaneity and flow of conversation”, “delusions”, “unusual thought content”, “dealing with strangers” and “poor rapport”. Our findings suggest that these symptoms and functioning dimensions should be prioritized in the clinical assessment and management of patients with FEP. These areas may also become targets of future early intervention strategies, so as to improve quality of life in this populationThis work was supported by the Madrid Regional Government (R&D activities in Biomedicine (grant number S2017/BMD-3740 - AGES-CM 2-CM)) and Structural Funds of the European Union. Ana Izquierdo’s work is supported by the PFIS predoctoral program (FI17/00138) from the Instituto de Salud Carlos III (Spain) and co-funded by the European Union (ERDF/ESF, "A way to make Europe”/ “Investing in your future”) and The Biomedical Research Foundation of La Princesa University Hospital. Angela Ib´a˜nez thanks the support of CIBERSAM and of the Spanish Ministry of Science, Innovation and Universities. Instituto de Salud Carlos III (PI16/00834 and PI19/01295) co-financed by ERDF Funds from the European Commission. Covadonga M. Díaz-Caneja holds a Juan Rod´es Grant from Instituto de Salud Carlos III (JR19/00024). Celso Arango was supported by the Spanish Ministry of Science and Innovation. Instituto de Salud Carlos III (SAM16PE07CP1, PI16/02012, PI19/ 024), co-financed by ERDF Funds from the European Commission, “A way of making Europe”, CIBERSAM. Madrid Regional Government (B2017/BMD-3740 AGES-CM-2), European Union Structural Funds. European Union Seventh Framework Program under grant agreements FP7-4-HEALTH-2009-2.2.1-2-241909 (Project EU-GEI), FP7- HEALTH- 2013-2.2.1-2-603196 (Project PSYSCAN) and FP7- HEALTH-2013- 2.2.1-2-602478 (Project METSY); and European Union H2020 Program under the Innovative Medicines Initiative 2 Joint Undertaking (grant agreement No 115916, Project PRISM, and grant agreement No 777394, Project AIMS-2-TRIALS), Fundaci´on Familia Alonso, Fundaci´on Alicia Koplowitz and Fundaci´on Mutua Madrile˜n

Actualización e internacionalización del catálogo "OSCAR" de experiencias de Física General

En convocatorias anteriores de la convocatorias de Proyectos de Innovación Docente de l UCM, la última de ellas correspondiente a 2014, desarrollamos un Catálogo de experiencias de cátedra para la docencia de Física General, OSCAR. En esta edición los hemos ampliado con nuevas experiencias. Asimismo se ha desarrollado un programa de visitas de colegios a la Facultad de Ciencias Físicas de la UCM

Estado del arte del proyecto

Desde diversos ámbitos es reconocido que la formación de alto nivel es fundamental para el desarrollo científico y tecnológico de las naciones. Consciente de este hecho desde la universidad de la Costa se vienen impulsando la creación de programas doctorales desde hace varios años en el seno de varios Departamentos. En línea con el propósito institucional se elabora el presente proyecto que busca crear el Programa de Doctorado en Innovación y Competitividad. La creación de dicho programa doctoral, es un proyecto conjunto entre dos Departamentos de la universidad de la Costa que son referentes por su alta calidad y su desarrollo científico-tecnológico en el país a saber: el Departamento de gestión industrial, agroindustrial y operaciones; y el Departamento de Ciencias Económicas. La trayectoria de los grupos de investigación de los Departamentos involucrados, avalan el programa de doctorado propuesto. Asimismo, el programa cuenta con un cuerpo docente de calidad, lo cual se ve reflejado por una sostenida actividad en investigación, la cual cuenta con redes académicas tanto a nivel nacional como internaciona