Transparent information and access to citizen participation on municipal websites

This study analyses the information and tools for citizen participation on the institutional websites of local bodies to improve participation in the management of local resources in a context following the introduction of Spain's Transparency Law. The method is based on applying 14 indicators to analyse the institutional websites of 605 municipalities that have over 10,000 residents, located in 9 autonomous communities of the Spanish state. The main results show how the institutional information offered on the websites of the councils analysed does not follow journalistic criteria in terms of accountability, meaning that citizens' decisions regarding their local governments cannot be based on precise, reliable information. In this regard, in this study we have confirmed that council websites publish very little information on the activity of the opposition or on the plenary sessions, debates and agreements, but do publish information on the activity of the government. Furthermore, they do not make use of web resources for citizen participation, which impedes the transparent, collaborative management of political processes between leaders and citizens. Nonetheless, the results show how political and technical managers are not averse to change if they have access to guidance and incentives to improve the management of information and participation on municipal websites

Functional Impact and Regulation of Alternative Splicing in Mouse Heart Development and Disease.

Alternative splicing (AS) plays a major role in the generation of transcript diversity. In the heart, roles have been described for some AS variants, but the global impact and regulation of AS patterns are poorly understood. Here, we studied the AS profiles in heart disease, their relationship with heart development, and the regulatory mechanisms controlling AS dynamics in the mouse heart. We found that AS profiles characterized the different groups and that AS and gene expression changes affected independent genes and biological functions. Moreover, AS changes, specifically in heart disease, were associated with potential protein-protein interaction changes. While developmental transitions were mainly driven by the upregulation of MBNL1, AS changes in disease were driven by a complex regulatory network, where PTBP1 played a central role. Indeed, PTBP1 over-expression was sufficient to induce cardiac hypertrophy and diastolic dysfunction, potentially by perturbing AS patterns.S

Efecto neuroprotector de IGF-II en situaciones de estrés neuronal inducido por corticosterona

Presentado en el 15º Congreso Nacional de la SENC 2013El daño por estrés en tejido neuronal mediado por la presencia de elevados niveles de corticosterona, se relaciona con la producción de alteraciones en funciones cognitivas. Así, el estrés agudo induce un aumento importante en los niveles plasmáticos de corticosterona que se asocia con alteraciones de plasticidad neuronal. Datos previos de nuestro grupo demuestran un efecto neuroprotector a dosis bajas del factor de crecimiento similar a insulina (IGF-II) en ratas de edad avanzada, donde el estrés de tipo oxidativo se encuentra involucrado en el propio proceso senil y en el desarrollo de diferentes enfermedades neurodegenerativas. Objetivos: En el presente trabajo se pretenden estudiar las propiedades antioxidantes de dosis bajas de IGF-II en cultivos primarios de corteza neuronal de ratas adultas, sometidos a elevadas concentraciones transitorias de corticosterona. Métodos: Los parámetros de estrés oxidativo se determinaron mediante citometria de flujo y espectrofotometría. Resultados: Las neuronas corticales incubadas con corticosterona mostraron un aumento de especies reactivas de oxígeno (ROS), del consumo de reserva antioxidante celular (etax), y de la peroxidación lipídica (LOOH) todo ello corno consecuencia de un desequilibrio entre factores pro-oxidantes (ej. daño mitocondrial, NOS) y factores antioxidantes (ej. GSH, SOD). La co-incubación de corticosterona y dosis bajas de IGF-II reequilibra estos factores. Este efecto neuroprotector podría estar mediado al menos en parte por la interacción de IGF-II con sus receptores específicos, ya que su bloqueo origina de nuevo un desequilibro entre los factores antioxidantes/pro-oxidantes. Conclusión: Las dosis bajas de IGF-II ejercen un efecto neuroprotector en situaciones de estrés oxidativo inducido por altos niveles de corticosterona.Laboratorios Lilly (Madrid) por cesion del IGF-II y Ayuda de la Universidad de Malaga. Campus de Excelencia Andalucia Tec

Health and economic impact of the correct diagnosis of transthyretin cardiac amyloidosis in Spain

Objective: to estimate the health and economic impact of the reduction in mortality and cardiovascular hospitalizations, associated with correct diagnosis of cardiac transthyretin amyloidosis (ATTR-CM), from the Spanish National Health System (NHS) perspective. Methods: a costs and effects analysis were performed (probabilistic Markov model) with time horizons between 1 and 15 years, comparing the correct diagnosis of ATTR-CM versus the non-diagnosis. Transition probabilities were obtained from the ATTR-ACT study (placebo arm) and from the literature. Costs and healthcare resources were obtained from Spanish sources ( 2019) and from a panel of Spanish clinical experts. Results: after 1, 5, 10 and 15 years, the diagnosis of ATTR-CM would generate a gain of 0.031 (95%CI 0.025; 0.038); 0.387 (95%CI 0.329; 0.435); 0.754 (95%CI 0.678; 0.781) and 0.944 (95%CI 0.905; 0.983) life years per patient, respectively, with savings of 212 (95%CI -632; 633), 2,289 (95%CI 2,250; 2,517), 2,859 (95%CI 2,584; 3,149) and 2,906 (95%CI 2,669; 3,450) per patient, respectively, versus the non-diagnosis. Conclusions: just by correctly diagnosing ATTR-CM, years of life would be gained, cardiovascular hospitalizations would be avoided, and savings would be generated for the NHS, compared to the non-diagnosis of the disease

Epileptogenic Zone Localization With 18FDG PET Using a New Dynamic Parametric Analysis

Introduction: [18F]fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) is part of the regular preoperative work-up in medically refractory epilepsy. As a complement to visual evaluation of PET, statistical parametric maps can help in the detection of the epileptogenic zone (EZ). However, software packages currently available are time-consuming and little intuitive for physicians. We develop a user-friendly software (referred as PET-analysis) for EZ localization in PET studies that allows dynamic real-time statistical parametric analysis. To evaluate its performance, the outcome of PET-analysis was compared with the results obtained by visual assessment and Statistical Parametric Mapping (SPM).Methods: Thirty patients with medically refractory epilepsy who underwent presurgical 18F-FDG PET with good post-operative outcomes were included. The 18F-FDG PET studies were evaluated by visual assessment, with SPM8 and PET-analysis. In SPM, parametric T-maps were thresholded at corrected p < 0.05 and cluster size k = 50 and at uncorrected p < 0.001 and k = 100 (the most used parameters in the literature). Since PET-analysis rapidly processes different threshold combinations, T-maps were thresholded with multiple p-value and different clusters sizes. The presurgical EZ identified by visual assessment, SPM and PET-analysis was compared to the confirmed EZ according to post-surgical follow-up.Results: PET-analysis obtained 66.7% (20/30) of correctly localizing studies, comparable to the 70.0% (21/30) achieved by visual assessment and significantly higher (p < 0.05) than that obtained with the SPM threshold p < 0.001/k = 100, of 36.7% (11/30). Only one study was positive, albeit non-localizing, with the SPM threshold corrected p < 0.05/k = 50. Concordance was substantial for PET-analysis (κ = 0.643) and visual interpretation (κ = 0.622), being fair for SPM (κ = 0.242).Conclusion: Compared to SPM with the fixed standard parameters, PET-analysis may be superior in EZ localization with its easy and rapid processing of different threshold combinations. The results of this initial proof-of-concept study validate the clinical use of PET-analysis as a robust objective complementary tool to visual assessment for EZ localization

Genetically Confirmed Familial Hypercholesterolemia in Patients With Acute Coronary Syndrome

BACKGROUND: Genetic screening programs in unselected individuals with increased levels of low-density lipoprotein cholesterol (LDL-C) have shown modest results in identifying individuals with familial hypercholesterolemia (FH). OBJECTIVES: This study assessed the prevalence of genetically confirmed FH in patients with acute coronary syndrome (ACS) and compared the diagnostic performance of FH clinical criteria versus FH genetic testing. METHODS: Genetic study of 7 genes (LDLR, APOB, PCSK9, APOE, STAP1, LDLRAP1, and LIPA) associated with FH and 12 common alleles associated with polygenic hypercholesterolemia was performed in 103 patients with ACS, age ≤65 years, and LDL-C levels ≥160 mg/dl. Dutch Lipid Clinic (DLC) and Simon Broome (SB) FH clinical criteria were also applied. RESULTS: The prevalence of genetically confirmed FH was 8.7% (95% confidence interval [CI]: 4.3% to 16.4%; n = 9); 29% (95% CI: 18.5% to 42.1%; n = 18) of patients without FH variants had a score highly suggestive of polygenic hypercholesterolemia. The prevalence of probable to definite FH according to DLC criteria was 27.2% (95% CI: 19.1% to 37.0%; n = 28), whereas SB criteria identified 27.2% of patients (95% CI: 19.1% to 37.0%; n = 28) with possible to definite FH. DLC and SB algorithms failed to diagnose 4 (44%) and 3 (33%) patients with genetically confirmed FH, respectively. Cascade genetic testing in first-degree relatives identified 6 additional individuals with FH. CONCLUSIONS: The prevalence of genetically confirmed FH in patients with ACS age ≤65 years and with LDL-C levels ≥160 mg/dl is high (approximately 9%). FH clinical algorithms do not accurately classify patients with FH. Genetic testing should be advocated in young patients with ACS and high LDL-C levels to allow prompt identification of patients with FH and relatives at risk.This research was supported in part by the Instituto de Salud Carlos III (grants RD012/0042/0066 and CB16/11/00432), Spanish Ministry of Economy and Competitiveness (grant SAF2015-71863-REDT), and Alexion through an Investigator Initiated Research Grant. Grants from the Instituto de Salud Carlos III and the Spanish Ministry of Economy and Competitiveness are supported by the Plan Estatal de I+D+I 2013-2016 European Regional Development Fund (FEDER), "A way of making Europe." The sponsors played no role in the design, collection, analysis, or interpretation of the data or in the decision to submit the manuscript for publication. Drs. Castillo, Lluis-Ganella, and Quintana are employees of Gendiag.exe/Ferrer inCode.S

Titin domains with reduced core hydrophobicity cause dilated cardiomyopathy.

The underlying genetic defect in most cases of dilated cardiomyopathy (DCM), a common inherited heart disease, remains unknown. Intriguingly, many patients carry single missense variants of uncertain pathogenicity targeting the giant protein titin, a fundamental sarcomere component. To explore the deleterious potential of these variants, we first solved the wild-type and mutant crystal structures of I21, the titin domain targeted by pathogenic variant p.C3575S. Although both structures are remarkably similar, the reduced hydrophobicity of deeply buried position 3575 strongly destabilizes the mutant domain, a scenario supported by molecular dynamics simulations and by biochemical assays that show no disulfide involving C3575. Prompted by these observations, we have found that thousands of similar hydrophobicity-reducing variants associate specifically with DCM. Hence, our results imply that titin domain destabilization causes DCM, a conceptual framework that not only informs pathogenicity assessment of gene variants but also points to therapeutic strategies counterbalancing protein destabilization.S

A spect scanner for rodent imaging based on small-area gamma cameras

We developed a cost-effective SPECT scanner prototype (rSPECT) for in vivo imaging of rodents based on small-area gamma cameras. Each detector consists of a position-sensitive photomultiplier tube (PS-PMT) coupled to a 30 30 NaI(Tl) scintillator array and electronics attached to the PS-PMT sockets for adapting the detector signals to an in-house developed data acquisition system. The detector components are enclosed in a leadshielded case with a receptacle to insert the collimators. System performance was assessed using for a high-resolution parallel- hole collimator, and for a 0.75-mm pinhole collimator with a 60 aperture angle and a 42-mm collimator length. The energy resolution is about 10.7% of the photopeak energy. The overall system sensitivity is about and planar spatial resolution ranges from 2.4 mm at 1 cm source-to-collimator distance to 4.1 mm at 4.5 cm with parallel-hole collimators. With pinhole collimators planar spatial resolution ranges from 1.2 mm at 1 cm source-to-collimator distance to 2.4 mm at 4.5 cm; sensitivity at these distances ranges from 2.8 to . Tomographic hot-rod phantom images are presented together with images of bone, myocardium and brain of living rodents to demonstrate the feasibility of preclinical small-animal studies with the rSPECT.This work was supported in part by the CD-TEAM project, CENIT program, Spanish Ministerio de Industria and with grants from the Ministerio de Educación y Ciencia, Projects TEC2007-64731/TCM, TEC2008-06715-C02-01, SAF2009-08076, program ARTEMIS S2009/DPI-1802, Comunidad de Madrid, and the RECAVA-RETIC NetworkPublicad

POT1 and Damage Response Malfunction Trigger Acquisition of Somatic Activating Mutations in the VEGF Pathway in Cardiac Angiosarcomas

Background: Mutations in the POT1 gene explain abnormally long telomeres and multiple tumors including cardiac angiosarcomas (CAS). However, the link between long telomeres and tumorigenesis is poorly understood. Methods and Results: Here, we have studied the somatic landscape of 3 different angiosarcoma patients with mutations in the POT1 gene to further investigate this tumorigenesis process. In addition, the genetic landscape of 7 CAS patients without mutations in the POT1 gene has been studied. Patients with CAS and nonfunctional POT1 did not repress ATR (ataxia telangiectasia RAD3-related)-dependent DNA damage signaling and showed a constitutive increase of cell cycle arrest and somatic activating mutations in the VEGF (vascular endothelial growth factor)/angiogenesis pathway (KDR gene). The same observation was made in POT1 mutation carriers with tumors different from CAS and also in CAS patients without mutations in the POT1 gene but with mutations in other genes involved in DNA damage signaling. Conclusions: Inhibition of POT1 function and damage-response malfunction activated DNA damage signaling and increased cell cycle arrest as well as interfered with apoptosis, which would permit acquisition of somatic mutations in the VEGF/angiogenesis pathway that drives tumor formation. Therapies based on the inhibition of damage signaling in asymptomatic carriers may diminish defects on cell cycle arrest and thus prevent the apoptosis deregulation that leads to the acquisition of driver mutations

Clinical characteristics of wild-type transthyretin cardiac amyloidosis: disproving myths.

Wild-type transthyretin amyloidosis (ATTRwt) is mostly considered a disease predominantly of elderly male, characterized by concentric LV hypertrophy, preserved LVEF, and low QRS voltages. We sought to describe the characteristics of a large cohort of ATTRwt patients to better define the disease. Clinical findings of consecutive ATTRwt patients diagnosed at 2 centres were reviewed. ATTRwt was diagnosed histologically or non-invasively (LV hypertrophy ≥12 mm, intense cardiac uptake at 99mTc-DPD scintigraphy and AL exclusion). Mutations in TTR were excluded in all cases. The study cohort comprised 108 patients (78.6 ± 8 years); 67 (62%) diagnosed invasively and 41 (38%) non-invasively. Twenty patients (19%) were females. An asymmetric hypertrophy pattern was observed in 25 (23%) patients. Mean LVEF was 52 ± 14%, with 39 patients (37%) showing a LVEF < 50%. Atrial fibrillation (56%) and a pseudo-infarct pattern (63%) were the commonest ECG findings. Only 22 patients fulfilled QRS low-voltage criteria while 10 showed LV hypertrophy on ECG. Although heart failure was the most frequent profile leading to diagnosis (68%), 7% of individuals presented with atrioventricular block and 11% were diagnosed incidentally. Almost one third (35; 32%) were previously misdiagnosed. The clinical spectrum of ATTRwt is heterogeneous and differs from the classic phenotype: women are affected in a significant proportion; asymmetric LV hypertrophy and impaired LVEF are not rare and only a minority have low QRS voltages. Clinicians should be aware of the broad clinical spectrum of ATTRwt to correctly identify an entity for which a number of disease-modifying treatments are under investigation.This work was supported in part by the Spanish Society of Cardiology [Grant 2016 to E.G-L.] and by the Instituto de Salud Carlos III (ISCIII) [grants RD012/0042/0066 and CB16/11/00432] and by the Spanish Ministry of Economy and Competitiveness [grant SAF2015-71863-REDT]. Grants are supported by the Plan Estatal de IþDþI 2013-2016–European Regional Development Fund (FEDER) “A way of making Europe”.S