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La vigilancia epistemológica en la investigación formaliza el análisis crítico reflexivo de las relaciones teóricas, metodológicas, ontológicas que garantiza la práctica coherente de la significación del objeto y contexto social de estudio. El presente artículo es de naturaleza documental, el cual tiene como propósito develar la trascendencia de la vigilancia epistemológica en la investigación de las ciencias sociales en las escuelas de posgrado. Para ello, se realizó la sistematización y análisis de fuentes documentales referenciales, bajo una perspectiva teórica que proporcione un acercamiento a la realidad de las escuelas de posgrado, haciendo uso de la reflexividad que confiere la línea de pensamiento paradigmático del investigador y los hechos sociales que se suscitan para ser investigados. Por tanto, la perspectiva teórica y metodológica asumida en la investigación responde a la significación epistemológica que le consagra el investigador al objeto de estudio construido, proporcionando un sentido explicativo y resolutivo a los problemas planteados, siendo las escuelas de posgrado escenarios académicos donde se desarrollan investigaciones con fines de difusión y divulgación del conocimiento, que da cuenta de la calidad de sus resultados y la contribución a la comunidad científica, convirtiéndolas en el principal medio de contribución a las demandas y necesidades sociales.

En los últimos años se han generado en diversos escenarios científicos y académicos disputas frente a la posibilidad o alternativa de realizar investigación en Ciencias Sociales a través de la modalidad multimétodo. Por tal razón, el presente artículo tiene como finalidad analizar las posturas de diversos autores en torno a la modalidad del multimétodo como integración metodológica en la investigación. La revisión documental procura brindar algunas luces en cuanto al esclarecimiento de su significancia, implicancia, conveniencia en la práctica investigativa, cuyo análisis de contenido permite un acercamiento al tema. Además, precisa las estrategias de integración metodológica propuesto por Morgan (1997), y Bericat (1998). Se concluye que la implementación de la modalidad multimétodo debe corresponder de manera armónica a la situación en estudio y, por ende, la articulación coherente en el marco metodológico a través de que aporta cada enfoque.

The Nancy team is supported by the RHU Fight-HF, a public grant overseen by the French National Research Agency (ANR) as part of the second 'Investissements d'Avenir' programme (reference: ANR-15-RHUS-0004), by the French PIA project 'Lorraine Université d'Excellence' (reference: ANR-15-IDEX-04-LUE), the ANR FOCUS-MR (reference: ANR-15-CE14-0032-01), ERA-CVD EXPERT (reference: ANR-16-ECVD-0002-02), the Contrat de Plan Etat Lorraine IT2MP, and FEDER Lorraine. Aims: In ambulatory patients with chronic heart failure (HF), congestion and decongestion assessment may be challenging. The aim of this study is to assess the value of lung ultrasound (LUS) in outpatients with HF in characterizing decompensation and recompensation, and in outcomes prediction. Methods and results: Heart failure outpatients attended to establish HF decompensation were included. LUS was blindly performed at baseline (LUS1) and at clinical recompensation (LUS2). B-lines were counted in eight scanned areas. Diagnosis of no HF decompensation vs. right-sided, left-sided, or global HF decompensation, and patients' management were performed by physicians blinded to LUS1. Outcome was the composite of all-cause death or HF-related hospitalization. Two hundred and thirty-three suspicions of HF decompensation were included in 187 patients (71.4 ± 11.3 years, 66.8% men). Mean B-line (LUS1) was 17.6 ± 11.2 vs. 3.7 ± 4.5 for episodes with and without HF decompensation, respectively (P < 0.001). Global HF decompensation showed the highest number of B-lines (20.6 ± 11), followed by left-sided (19.7 ± 11.6) and right-sided (13.5 ± 9.8). B-lines declined to 6.9 ± 6.7 (LUS2) (P < 0.001 vs. LUS1) after treatment, within a mean time of 24.2 ± 23.7 days [median 13.5 days (interquartile range 6-40)]. B-lines were significantly associated with the composite endpoint at 30 days (hazard ratio [HR] 1.04 [95% confidence interval 1.01-1.07], P = 0.02), but not at 60 (P = 0.22) or 180 days (P = 0.54). In multivariable analysis, B-line number remained as an independent predictor of the composite endpoint at 30 days, [HR 1.04 (1.01-1.07), P = 0.014], with a 4% increase risk per B-line added. B-lines correlated significantly with CA125 (R = 0.30, P = 0.001). Conclusions: Lung ultrasound supports the diagnostic work-up of congestion and decongestion in chronic HF outpatients and identifies patients at high risk of short-term events.

Resumen Introduccion y objetivos La utilidad de la ecografia pulmonar (EP) en la insuficiencia cardiaca (IC) aguda esta bien definida, pero no asi en la IC cronica. Este estudio investigo el valor pronostico de la EP en pacientes estables con IC cronica. Metodos Se incluyo a pacientes ambulatorios consecutivos con visita programada en una unidad de IC. La EP se realizo in situ, con los datos clinicos enmascarados, y evaluo 8 areas toracicas. La suma de lineas B en todas las areas pulmonares y los cuartiles de dicha adicion se utilizaron para los analisis de regresion lineal y de Cox. Los objetivos principales fueron el compuesto de muerte por cualquier causa u hospitalizacion por IC y mortalidad por cualquier causa. Resultados Se incluyo a 577 individuos (edad, 69 ± 12 anos; el 72% varones). La media de lineas B fue de 5 ± 6. Durante un seguimiento de 31 ± 7 meses, en 157 pacientes se produjo el resultado compuesto y 111 fallecieron. Tener ≥ 8 lineas B (Q4) doblo el riesgo de padecer el evento compuesto (p Conclusiones La EP identifico a pacientes con IC cronica estable y alto riesgo de muerte u hospitalizacion por IC.

Summary Background & aims Nutritional status is an important prognostic factor in patients with heart failure (HF). In a pilot study we previously observed that the Mini Nutritional Assessment Short Form tool (MNA-SF) was the best approach for the screening of nutritional status in HF outpatients over other screening tools. The current study aimed to determine whether the MNA-SF has prognostic value in outpatients with HF and whether the impact of malnutrition differs depending on left ventricular ejection fraction (LVEF). Methods Prospective study performed in outpatients attending a HF clinic at a university hospital. All subjects completed the MNA-SF at study entry. The primary endpoint was all-cause mortality. Secondary end-points were the number of recurrent HF-related hospitalizations and the composite end-point of all-cause death or HF-related hospitalizations. Patients with malnutrition and at risk of malnutrition were merged and considered as having abnormal nutritional status for statistical analysis. Results From October 2016 to November 2017, 555 patients were included (age 69 ± 11.5 years, 71% male, LVEF 44.6 ± 13.2). Abnormal nutritional status was identified in 103 (18.6%) subjects. HF patients with preserved LVEF had a higher proportion of abnormal nutritional status (23%) than patients with HF and mid-range LVEF (HFmrEF) (16.4%) or those with HF with reduced LVEF (HFrEF) (15.9%.). During a mean follow-up of 23.8 ± 6.6 months, 99 patients died (17.8%), 74 were hospitalized due to HF (13.3%) and the composite end-point was observed in 181 (32.6%). In the univariate analysis, abnormal nutritional status was significantly associated with all-cause mortality (p = 0.02) and the composite end-point (p = 0.02) in the total cohort. However, in the multivariate analysis including age, sex, NYHA functional class, BMI, ischemic aetiology, diabetes, hypertension and HF duration, abnormal nutritional status remained significantly associated with all-cause mortality (HR 3.32 [95%CI 1.47–7.52], p = 0.004), and the composite end-point (HR 2.53 [95%CI 1.30–4.94], p = 0.006) only in HFmrEF patients. Patients with abnormal nutritional status suffered double the crude number of recurrent HF-related hospitalizations (16.4 vs. 8.4 per 100 patients-years, p Conclusions The implementation of MNA-SF as a routine screening tool allowed the detection of abnormal nutritional status in almost one out of five ambulatory HF patients. Nutritional status assessed by the MNA-SF was an independent predictor of all-cause death and the composite end-point of all-cause death or HF-related hospitalization in outpatients with HFmrEF. Furthermore, abnormal nutritional status was significantly related to recurrent hospitalizations across the HF spectrum.

Cuadernos de Debate 16 Los impactos generados en el mundo por la pandemia, producto de la COVID-19, hacen que se est�� en permanente b��squeda de informaci��n actualizada y especializada, que pueda compartirse y debatirse entre los integrantes del Sistema Nacional de Ciencia, Tecnolog��a e Innovaci��n. Uno de los actores de ese sistema es la Universidad, espacio donde se genera conocimiento por excelencia y donde se ubican investigaciones importantes que han servido de base para la construcci��n de las sociedades a lo largo de los a��os. Ahora bien, en un sistema social como el venezolano, donde se transita hacia la transformaci��n y decolonizaci��n del conocimiento y las formas como se ha producido el mismo, es clave conocer alternativas educativas que no solo presentan procesos de ense��anza aprendizaje colaborativos sino que insisten en nuevas formas de comprender los temas vitales para la vida como es la alimentaci��n, a trav��s de la ense��anza de la agroecolog��a como propuesta alternativa a las formas tradicionales de producci��n agroindustrial. De esta forma es de vital importancia conocer sobre esas alternativas que se constituyen, como lo indica en su introducci��n el Dr. Chac��n, en un modelo de producci��n alternativo, que se coloca de frente al impuesto por las empresas oligop��licas trasnacionales, gracias al esfuerzo desde el ��mbito universitario. Continuamos debatiendo para construir, resistir, transformar y vivir.

Cuadernos de Debate 16 Los impactos generados en el mundo por la pandemia, producto de la COVID-19, hacen que se esté en permanente búsqueda de información actualizada y especializada, que pueda compartirse y debatirse entre los integrantes del Sistema Nacional de Ciencia, Tecnología e Innovación. Uno de los actores de ese sistema es la Universidad, espacio donde se genera conocimiento por excelencia y donde se ubican investigaciones importantes que han servido de base para la construcción de las sociedades a lo largo de los años. Ahora bien, en un sistema social como el venezolano, donde se transita hacia la transformación y decolonización del conocimiento y las formas como se ha producido el mismo, es clave conocer alternativas educativas que no solo presentan procesos de enseñanza aprendizaje colaborativos sino que insisten en nuevas formas de comprender los temas vitales para la vida como es la alimentación, a través de la enseñanza de la agroecología como propuesta alternativa a las formas tradicionales de producción agroindustrial.De esta forma es de vital importancia conocer sobre esas alternativas que se constituyen, como lo indica en su introducción el Dr. Chacón, en un modelo de producción alternativo, que se coloca de frente al impuesto por las empresas oligopólicas trasnacionales, gracias al esfuerzo desde el ámbito universitario. Continuamos debatiendo para construir, resistir, transformar y vivir.

Most cancers are characterized by the somatic acquisition of genomic rearrangements during tumour evolution that eventually drive the oncogenesis. Here, using multiplatform sequencing technologies, we identify and characterize a remarkable mutational mechanism in human hepatocellular carcinoma caused by Hepatitis B virus, by which DNA molecules from the virus are inserted into the tumour genome causing dramatic changes in its configuration, including non-homologous chromosomal fusions, dicentric chromosomes and megabase-size telomeric deletions. This aberrant mutational mechanism, present in at least 8% of all HCC tumours, can provide the driver rearrangements that a cancer clone requires to survive and grow, including loss of relevant tumour suppressor genes. Most of these events are clonal and occur early during liver cancer evolution. Real-time timing estimation reveals some HBV-mediated rearrangements occur as early as two decades before cancer diagnosis. Overall, these data underscore the importance of characterising liver cancer genomes for patterns of HBV integration., Hepatitis B virus (HBV) infection and DNA integration is a frequent cause of hepatocellular carcinoma (HCC), but the consequences of this process are not fully understood. Here the authors use whole-genome and long-read sequencing data from HCC patient samples to study the timing and alterations induced by HBV insertions.

Background Real-life clinical practice has confirmed the value of pulmonary artery (PA) pressure-guided therapy in patients with heart failure (HF) and history of repeated HF hospitalizations (HFH), to greater extent to that reported in the pivotal clinical trial CHAMPION-HF. The value of hemodynamic monitoring in a population of patients with HF and elevated natriuretic peptides, but without recent HFH, is unknown. Objective To assess N-terminal-pro-brain natriuretic peptide (NTproBNP) dynamics before and 6 months after PA pressure sensor implantation. Methods Ten patients managed in a multidisciplinary HF clinic implanted with the CardioMEMS PA pressure sensor were consecutively included from June 2019 to July 2020. Mean age was 63.1±23.5 years, 30% were women, 40% had HF with reduced EF (EF Results Mean daily pressure transmission rate was 92.4±5.1%. During the six-month study period 90% of patients had a change in medication related to PA pressure, with an average of 0.21 [0.17–0.66] changes per patient per month. Mean PA pressure at baseline was 28.5±9.5 mmHg, and decreased by 5.5 mmHg at 6 months (p=0.01) (Figure 1). NTproBNP was also significantly lower six months post CardioMEMS implantation; decreasing from 1696 pg/ml [976–2930] at baseline to 1046 pg/ml [616–2076] after six months (p=0.04) (Figure 2). There was a weak correlation between the change in NTproBNP and the change in mean PA pressure (R2=0.22, p=0.17). Conclusions NTproBNP values were significantly lower 6-months following implantation of a PA pressure sensor to guide HF management. Mean PA pressures were also significantly reduced. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Hospital Universitari Germans Trias i Pujol Figure 1. Change in mean PA pressure over time.Figure 2. Change in NTproBNP after PAP monitoring.

Background Heart failure (HF) is the final stage of many cardiac disorders. Mortality in heart HF remains challenging despite improvement in outcomes proved in clinical trials in HF with reduced ejection fraction and it can be influenced by the aetiology of HF. Purpose To assess differences in long-term mortality (up to 18 years) in a real-life cohort of HF outpatients according to the aetiology of HF. Methods Consecutive patients with HF admitted at the HF Clinic from August 2001 to September 2019 were included. Follow-up was closed at 30.9.2020. HF aetiology was divided into ischemic heart disease (IHD), dilated cardiomyopathy (CM) –including non-compaction CM–, hypertensive CM, alcohol-derived CM, drug-derived CM, valvular disease, hypertrophic CM and others. For the present analysis, this latter group was excluded due to the big heterogeneity and limited number of patients in each subtype of aetiology. All-cause death and cardiovascular death were the primary end-points. Fine & Gray method for competing risk was used for cardiovascular mortality analysis. Results Out of 2387 patients included (age 66.5±12.5 years, 71.3% men, LVEF 35.4%±14.2, mainly in NYHA class II [65.5%] and III [26.5%]), 1317 deaths were recorded (731 from cardiovascular cause) during a maximum follow-up of 18 years (median 4.1 years [IQR 2–7.8] for the total cohort, 5.3 years [IQR 2.6–9.7] for survivors). Figure 1 shows Cox regression multivariable analysis for all-cause death and cardiovascular mortality. Considering IHD aetiology as reference, only dilated CM showed significantly lower risk of all-cause death, and only drug-induced CM showed higher risk of all-cause death. However, when cardiovascular mortality was considered almost all aetiologies showed significant lower risk of cardiovascular death than IHD. Figure 2 shows adjusted survival curves (A) and adjusted incidence curves of cardiovascular death (B) based on HF aetiology. Conclusions After adjusting for multiple prognostic factors among the studied HF aetiologies, dilated CM and drug-related CM showed the lowest and the highest risk of all-cause death, respectively. Patients with IHD showed the highest adjusted risk of cardiovascular death. Funding Acknowledgement Type of funding sources: None.

Background Limited data are available on the very long-term trajectory of glomerular filtration rate (GFR) in patients with chronic heart failure (HF). Purpose To assess the GFR dynamics estimated by CKD-EPI in a real-life cohort of HF patients over a 14-year follow-up. Methods In a prospective observational registry of real-life HF outpatients, estimated GFR (eGFR) was calculated by CKD-EPI at baseline and on a structured schedule every 3 months up to 14 years. We included in the analysis only eGFR values that were assessed at scheduled visits, discarding urgent renal function assessments. Loess (locally weighted error sum of squares) curves were plotted for the whole cohort and subgroups according to vital status up to 14 years of follow-up. Loess curves are useful to observe a trend or relationship on nonlinear data observed over time. Results 2423 patients were consecutively included from August 2001 to December 2018. Mean age was 67.0±12.7 years, 28,8% were women and 71.1% had HF with reduced ejection fraction (EF Significant changes occurred along the whole trajectory. An initial decline in eGFR was observed during the first three years of follow-up. Subsequently, there was an upward trend during the following five years and after that period a progressive decline was seen until the end of follow-up (Figure 1). In the sub-group of patients who died during follow-up the eGFR slope showed a persistent decline over time of ∼1ml/min/1.73m2 per year. On the contrary, patients who survived to follow-up maintained a stable eGFR (Figure 2). Conclusions The eGFR long-term trajectory in patients with chronic HF showed a snaky pattern with an early decrease, mid-term improvement and late progressive decline. Patients who died during follow-up presented a progressive decline from the beginning. Funding Acknowledgement Type of funding sources: None. Figure 1. Long-term evolution of eGFRFigure 2. eGFR evolution according to vital status

The phosphatidylinositol-3-kinase (PI3K)/AKT pathway is a major regulator of metabolism, migration, survival, proliferation, and antiviral immunity. Both an overactivation and an inhibition of the PI3K/AKT pathway are related to different pathologies. Activation of this signaling pathway is tightly controlled through a multistep process and its deregulation can be associated with aberrant post-translational modifications including SUMOylation. Here, we review the complex modulation of the PI3K/AKT pathway by SUMOylation and we discuss its putative involvement in human disease.

Altres ajuts: acords transformatius de la UAB Aims: Several heart failure (HF) web-based risk scores are currently used in clinical practice. Currently, we lack head-to-head comparison of the accuracy of risk scores. This study aimed to assess correlation and mortality prediction performance of Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC-HF) risk score, which includes clinical variables + medications; Seattle Heart Failure Model (SHFM), which includes clinical variables + treatments + analytes; PARADIGM Risk of Events and Death in the Contemporary Treatment of Heart Failure (PREDICT-HF) and Barcelona Bio-Heart Failure (BCN-Bio-HF) risk calculator, which also include biomarkers, like N-terminal pro B-type natriuretic peptide (NT-proBNP). Methods and results: A total of 1166 consecutive patients with HF from different aetiologies that had NT-proBNP measurement at first visit were included. Discrimination for all-cause mortality was compared by Harrell's C-statistic from 1 to 5 years, when possible. Calibration was assessed by calibration plots and Hosmer-Lemeshow test and global performance by Nagelkerke's R. Correlation between scores was assessed by Spearman rank test. Correlation between the scores was relatively poor (rho value from 0.66 to 0.79). Discrimination analyses showed better results for 1-year mortality than for longer follow-up (SHFM 0.817, MAGGIC-HF 0.801, PREDICT-HF 0.799, BCN-Bio-HF 0.830). MAGGIC-HF showed the best calibration, BCN-Bio-HF overestimated risk while SHFM and PREDICT-HF underestimated it. BCN-Bio-HF provided the best discrimination and overall performance at every time-point. Conclusions: None of the contemporary risk scores examined showed a clear superiority over the rest. BCN-Bio-HF calculator provided the best discrimination and overall performance with overestimation of risk. MAGGIC-HF showed the best calibration, and SHFM and PREDICT-HF tended to underestimate risk. Regular updating and recalibration of online web calculators seems necessary to improve their accuracy as HF management evolves at unprecedented pace.

Most cancers are characterized by the somatic acquisition of genomic rearrangements during tumour evolution that eventually drive the oncogenesis. There are different mutational mechanisms causing structural variation, some of which are specific to particular cancer types. Here, using multiplatform sequencing technologies, we identify and characterize a remarkable mutational mechanism in human hepatocellular carcinoma caused by Hepatitis B virus, by which DNA molecules from the virus are inserted into the tumour genome causing dramatic changes in its configuration, including non-homologous chromosomal fusions and megabase-size telomeric deletions. This aberrant mutational process, present in at least 8% of all HCC tumours, is active early during liver cancer evolution and can provide the driver rearrangements that a cancer clone requires to survive and grow.

Class I PI3K are heterodimers composed of a p85 regulatory subunit and a p110 catalytic subunit involved in multiple cellular functions. Recently, the catalytic subunit p110β has emerged as a class I PI3K isoform playing a major role in tumorigenesis. Understanding its regulation is crucial for the control of the PI3K pathway in p110β-driven cancers. Here we sought to evaluate the putative regulation of p110β by SUMO. Our data show that p110β can be modified by SUMO1 and SUMO2 in vitro, in transfected cells and under completely endogenous conditions, supporting the physiological relevance of p110β SUMOylation. We identify lysine residue 952, located at the activation loop of p110β, as essential for SUMOylation. SUMOylation of p110β stabilizes the protein increasing its activation of AKT which promotes cell growth and oncogenic transformation. Finally, we show that the regulatory subunit p85β counteracts the conjugation of SUMO to p110β. In summary, our data reveal that SUMO is a novel p110β interacting partner with a positive effect on the activation of the PI3K pathway., Funding at the laboratory of CR is provided by Ministry of Science, Innovation and Universities and FEDER (BFU-2017–88,880-P) and Xunta de Galicia (ED431G 2019/02). SV and RS are predoctoral fellows funded by Xunta de Galicia-Consellería de Cultura, Educación y Ordenación Universitaria (ED481A-2018/110 and ED481A-2020/160, respectively)

Ebola virus (EBOV) VP24 protein is a nucleocapsid-associated protein that inhibits interferon (IFN) gene expression and counteracts the IFN-mediated antiviral response, preventing nuclear import of signal transducer and activator of transcription 1 (STAT1). Proteomic studies to identify additional EBOV VP24 partners have pointed to the nuclear membrane component emerin as a potential element of the VP24 cellular interactome. Here, we have further studied this interaction and its impact on cell biology. We demonstrate that VP24 interacts with emerin but also with other components of the inner nuclear membrane, such as lamin A/C and lamin B. We also show that VP24 diminishes the interaction between emerin and lamin A/C and compromises the integrity of the nuclear membrane. This disruption is associated with nuclear morphological abnormalities, activation of a DNA damage response, the phosphorylation of extracellular signal-regulated kinase (ERK), and the induction of interferon-stimulated gene 15 (ISG15). Interestingly, expression of VP24 also promoted the cytoplasmic translocation and downmodulation of barrier-to-autointegration factor (BAF), a common interactor of lamin A/C and emerin, leading to repression of the BAF-regulated CSF1 gene. Importantly, we found that EBOV infection results in the activation of pathways associated with nuclear envelope damage, consistent with our observations in cells expressing VP24. In summary, here we demonstrate that VP24 acts at the nuclear membrane, causing morphological and functional changes in cells that recapitulate several of the hallmarks of laminopathy diseases. IMPORTANCE The Ebola virus (EBOV) VP24 protein is a nucleocapsid-associated protein with multiple functions. Proteomic studies have identified the cellular nuclear membrane component emerin as a potential VP24 interactor. Here, we demonstrate that VP24 not only interacts with emerin but also with lamin A/C and lamin B, prompting nuclear membrane disruption. This disruption is associated with nuclear morphological abnormalities, activation of a DNA damage response, the phosphorylation of extracellular signal-regulated kinase (ERK), and the induction of interferon-stimulated gene 15 (ISG15). Interestingly, VP24 also promotes the cytoplasmic translocation and downmodulation of barrier-to-autointegration factor (BAF), leading to repression of the BAF-regulated CSF1 gene. Finally, we show that EBOV infection also results in the activation of pathways associated with nuclear envelope damage, consistent with our observations in cells expressing VP24. These results reveal novel activities of EBOV VP24 protein, resulting in a cell phenotype similar to that of most laminopathies, with potential impact on EBOV replication.

Background Three heart failure (HF) web-based risk scores are currently used in clinical practice. Two only include clinical variables; one adds biomarkers, known to refine pathophysiological pathways in HF and to improve mortality prediction. Objective To assess inter-score agreement and to compare mortality prediction discrimination between MAGGIC-HF risk score, Seattle HF Model (SHFM) and Barcelona Bio-HF Risk Calculator (BCN Bio-HF), which includes both clinical and biomarker variables (NTproBNP). Methods Out of 1745 consecutive patients with HF from different etiologies admitted at our Unit from May 2006 to November 2018, 1689 with NTproBNP measurement at first visit were included. Absolute and consistency intraclass correlation coefficient (ICC) at individual level among the three risk estimation tools was assessed. Bland Altman graphics were used to illustrate the differences between scores across the broad spectrum of mortality risk. Discrimination of the three prediction tools was compared by AUC of the ROC curves for 1-, 3- and 5-year all-cause mortality. Patients used previously to derivate the BCN Bio-HF were excluded. Results Patients age 66.3±13.3 years, 70.4% men, LVEF 36.4%±14.4, ischemic etiology 43.7%. Absolute ICC was poor for the three tools (from 0.18 [–0.006 to 0.35] to 0.53 [0.42 to 0.62], while consistency ICC was slightly better (from 0.28 [0.24 to 0.33] to 0.57 [0.53 to 0.60], being highest the ICC of MAGGIC-HF and BCN Bio-HF. Correlation was better among scores in low-mortality risk profile patients but clinical scores tended to infraestimate the risk in comparison with the BCN Bio-HF in high-risk patients (Figure). Discrimination was numerically better with the BCN Bio-HF at every time risk (Table), significantly better when compared with SHFM. Conclusions In comparison with other clinical scores, the BCN Bio-HF calculator predicted better higher mortality risk. Correlation was globally poor for the three tools at individual level, although improved in the low risk patients. Discrimination tended to be numerically better with the BCN Bio-HF calculator, reaching statistical significance when compared with the SHFM. Bland Altman agreement among tools Funding Acknowledgement Type of funding source: None

Background Heart Failure (HF) is the first cause of hospitalizations in people older than 65 years. Often patients suffer recurrent hospital admissions. Objective To assess recurrent HF-related hospitalizations during very long-term follow-up in a cohort of HF outpatients managed in an ambulatory structured HF Unit. Methods End of follow-up was 31.8.2019 (at least 1-year follow-up for alive patients, up to 18 years). Heart failure hospitalizations were defined as unplanned hospitalizations of at least 24 hours due to worsening heart failure and were identified from clinic records, hospital wards, or electronic Catalan history record. Death was recorded from the same sources and Spanish Health System and Spanish Death Registry. Lost information during follow-up was adequately censored (1 patient for survival status and 37 for HF-related hospitalizations). Results A total of 2355 patients were included. Follow-up span a total of 12,472 patients-years. 1682 HF-related hospitalizations were recorded in 725 patients (13.5 per 100 patients-years). Number of admissions ranged from 0 in 1630 patients to 22 in 1 patient (patients with hospitalizations, median 2 [Q1-Q3, 1–3]; 118 patients had 4 or more hospitalizations). HF hospitalization density incidence was higher during the 10 first years in patients with HF hospitalizations in the precedent year before HF Clinic baseline visit (table). By contrast, if only patients who died during follow-up were considered (N=1299), hospitalization trends significantly increased in their last period of life: 11.7%, 8.9%, 13.6%, 20.8% and 44.9% from the first to the last period (quintile) of their trajectory, respectively. Conclusions HF hospitalizations occur during the whole HF trajectory, with an increasing trend at the end of the every patient trajectory. Funding Acknowledgement Type of funding source: None

SUMO is a ubiquitin-like protein that covalently binds to lysine residues of target proteins and regulates many biological processes such as protein subcellular localization or stability, transcription, DNA repair, innate immunity, or antiviral defense. SUMO has a critical role in the signaling pathway governing type I interferon (IFN) production, and among the SUMOylation substrates are many IFN-induced proteins. The overall effect of IFN is increasing global SUMOylation, pointing to SUMO as part of the antiviral stress response. Viral agents have developed different mechanisms to counteract the antiviral activities exerted by SUMO, and some viruses have evolved to exploit the host SUMOylation machinery to modify their own proteins. The exploitation of SUMO has been mainly linked to nuclear replicating viruses due to the predominant nuclear localization of SUMO proteins and enzymes involved in SUMOylation. However, SUMOylation of numerous viral proteins encoded by RNA viruses replicating at the cytoplasm has been lately described. Whether nuclear localization of these viral proteins is required for their SUMOylation is unclear. Here, we summarize the studies on exploitation of SUMOylation by cytoplasmic RNA viruses and discuss about the requirement for nuclear localization of their proteins.

The role of lung ultrasound (LUS) in acute heart failure (HF) has been widely studied, but little is known about its usefulness in chronic HF. This study assessed the prognostic value of LUS in a cohort of chronic HF stable ambulatory patients.We included consecutive outpatients who attended a scheduled follow-up visit in a HF clinic. LUS was performed in situ. The operators were blinded to clinical data and examined 8 thoracic areas. The sum of B-lines across all lung zones and the quartiles of this addition were used for the analyses. Linear regression and Cox regression analyses were performed. The main clinical outcomes were a composite of all-cause death or hospitalization for HF and mortality from any cause.A total of 577 individuals were included (72% men; 69± 12 years). The mean number of B-lines was 5±6. During a mean follow-up of 31±7 months, 157 patients experienced the main clinical outcome and 111 died. Having ≥ 8 B-lines (Q4) doubled the risk of experiencing the composite primary event (P.001) and increased the risk of death from any cause by 2.6-fold (P.001). On multivariate analysis, the total sum of B-lines remained independent predictive factor of the composite endpoint (HR, 1.04; 95%CI, 1.02-1.06; P=.002) and of all-cause death (HR, 1.04; 95%CI, 1.02-1.07; P=.001), independently of whether or not N-terminal pro-B-type natriuretic peptide (NT-proBNP) was included in the model (P=.01 and P=.008, respectively), with a 3% to 4% increased risk for each 1-line addition.LUS identified patients with stable chronic HF at high risk of death or HF hospitalization.

The zebrafish, Danio rerio, has become recognized as a valuable model for infectious diseases. Here we evaluated the susceptibility of zebrafish to be infected with the mammalian vesicular stomatitis virus (VSV). Both zebrafish cells and embryos were highly susceptible to VSV infection. Mortalities exceeded 80% in infected embryos and were preceded by the invasion of the central nervous system by VSV. Live imaging of the infection with GFP-VSV as well as virus titration from infected fish confirmed the viral replication. Immunohistochemical analysis of embryonic fish provided evidence of viral antigens as well as of the apoptosis marker caspase-3 in the brain, eye, liver, pronephros, and skeletal muscle. So far, this is the first report describing the susceptibility of zebrafish to the mammalian virus VSV.

Some viruses take advantage of conjugation of ubiquitin or ubiquitin-like proteins to enhance their own replication. One example is Ebola virus, which has evolved strategies to utilize these modification pathways to regulate the viral proteins VP40 and VP35 and to counteract the host defenses. Here, we show a novel mechanism by which Ebola virus exploits the ubiquitin and SUMO pathways. Our data reveal that minor matrix protein VP24 of Ebola virus is a bona fide SUMO target. Analysis of a SUMOylation-defective VP24 mutant revealed a reduced ability to block the type I interferon (IFN) pathway and to inhibit IFN-mediated STAT1 nuclear translocation, exhibiting a weaker interaction with karyopherin 5 and significantly diminished stability. Using glutathione S-transferase (GST) pulldown assay, we found that VP24 also interacts with SUMO in a noncovalent manner through a SIM domain. Mutation of the SIM domain in VP24 resulted in a complete inability of the protein to downmodulate the IFN pathway and in the monoubiquitination of the protein. We identified SUMO deubiquitinating enzyme ubiquitin-specific-processing protease 7 (USP7) as an interactor and a negative modulator of VP24 ubiquitination. Finally, we show that mutation of one ubiquitination site in VP24 potentiates the IFN modulatory activity of the viral protein and its ability to block IFN-mediated STAT1 nuclear translocation, pointing to the ubiquitination of VP24 as a negative modulator of the VP24 activity. Altogether, these results indicate that SUMO interacts with VP24 and promotes its USP7-mediated deubiquitination, playing a key role in the interference with the innate immune response mediated by the viral protein.IMPORTANCE The Ebola virus VP24 protein plays a critical role in escape of the virus from the host innate immune response. Therefore, deciphering the molecular mechanisms modulating VP24 activity may be useful to identify potential targets amenable to therapeutics. Here, we identify the cellular proteins USP7, SUMO, and ubiquitin as novel interactors and regulators of VP24. These interactions may represent novel potential targets to design new antivirals with the ability to modulate Ebola virus replication., Funding at the laboratory of C.R. is provided by Ministry of Science, Innovation and Universities and FEDER (BFU-2017-88880-P). C.R. also acknowledges grants GRC GI-2119 (Xunta de Galicia) and SAF2017-90900-REDT (UBIRed Program). S.V. is a predoctoral fellow funded by Xunta de Galicia. M.B.-M. is a postdoctoral fellow funded by Xunta de Galicia (Consellería de Cultura, Educación e Ordenación Universitaria). A.E.M. is the recipient of a fellowship of the Spanish FPI program. This work was partially funded by the German Center for Infection Research (DZIF TTU 01.702_00 to C.M.-F.). R.B. and J.D.S. acknowledge grants BFU2017-84653-P (MINECO/FEDER, EU), SEV-2016-0644 (Severo Ochoa Excellence Program), 765445-EU (UbiCODE Program), and SAF2017- 90900-REDT (UBIRed Program). C.S.M. acknowledges grant BFU2016-74868-P.

Background Nutritional status is an important prognostic factor in patients with heart failure (HF) beyond body mass index, although its prognostic value in patients with mid-range left ventricular ejection fraction (HFmrEF) is not completely elucidated. In a pilot study we observed that the Mini Nutritional Assessment Short Form (MNA-SF) was the best approach for the screening of nutritional status in HF outpatients over others screening tools. Purpose To assess the prognostic role of malnutrition or risk of malnutrition in HFmrEF outpatients after the implementation of the MNA-SF screening tool in a routine way in a multidisciplinary HF. Methods The MNA-SF screening tool was administered during the global nurse evaluation of patients. The scoring ranges from 0 to 14, being 0 to7 as malnutrition status, 8 to 11 as at risk of malnutrition and 12 to 14 as normal nutritional status. For the present study those patients with malnutrition and at risk of malnutrition were merged and considered abnormal nutritional status. All-cause death was the primary end-point. Univariate and multivariate (backward conditional stepwise) Cox regression analyses were performed. Results Since October 2016 to November 2017, 153 HFmrEF patients were studied (mean age 68.8±11.7 years, 72.5% men, body mass index 28.4±4.4, LVEF 44% ± 3, NYHA class I 5.9%, II 86.3%, and III 7.8%). According to the MNA-SF 25 patients were (16.3%) fulfilled criteria of malnutrition (4) or where at risk of malnutrition (21). During a mean follow-up of 17.4±6.1 months, 23 patients died (15%). In the univariate analysis, nutritional abnormal status was significantly associated with all-cause death (HR 2.93 [1.23–7], p=0.02). In the multivariate analysis which included age, sex, NYHA functional class, body mass index, ischemic aetiology of HF and years of duration of HF, abnormal nutritional status remained significantly associated with all-cause mortality (HR 3.64 [1.39–9.54], p=0.009), together with NYHA functional class (HR 7.93 [2.69–23.4], p Conclusions Nutritional status assessed with the screening MNA-SF was an independent predictor of all-cause death in ambulatory patients with HFmrEF – beyond BMI – together with NYHA functional class and HF duration.

Background Obesity is identified as an independent risk factor for developing congestive heart failure (HF). Paradoxically it has been reported that obesity is associated with improved survival in different cohorts of HF patients. Nevertheless, the presence of obesity paradox in HF with mid-range ejection fraction (HFmrEF) is not completely elucidated. Objective To analyse the relationship between body mass index (BMI) and mortality in a HFmrEF ambulatory cohort of different aetiologies followed in a HF unit, with especial focus on the role of obesity in prognosis. Methods Baseline BMI was analysed as continuous variable and categorized in 4 groups based on 2009 WHO classification: low weight (BMI Results Three-hundred thirty patients were included in the study (age 65.9±13.2 years, 68% men). The main aetiology was ischemic heart disease (52%, followed by dilated cardiomyopathy (11%) and hypertensive cardiomyopathy (11%). The majority of patients were in NYHA class II (65%) and III (26%). Mean ejection fraction was 43.2% ± 2.7. During a mean follow-up of 5.3±4.6 years 142 patients (42%) died. BMI showed a protective effect on survival in Cox regression analysis (HR 0.96 [95% CI 0.92–0.99], p=0.01). When categorized groups of BMI were analysed, obese patients showed a trend towards lower mortality than normal weight patients (reference): adjusted HR 0.65 [95% CI 0.40–1.03], p=0.07. Survival curves adjusted by age, sex and NYHA functional class according to BMI category are depicted in the figure. As a significant interaction (p=0.02) was found between BMI and ischemic aetiology of HF, separate analyses were performed for BMI categories for ischemic and non-ischemic patients, with remarkably different results: ischemic aetiology: HR 0.97 [95% CI 0.52–1.79], p=0.91; non-ischemic aetiology HR 0.28 [95% CI 0.13–0.64], p=0.003. Conclusions A greater BMI was associated with lower mortality rates in patients with HFmrEF during a mean follow-up of five years. Obesity showed a protective effect in HFmrEF patients, which remarkable in patients from non-ischemic aetiology and was absent in patients from ischemic aetiology.

Background The role of lung ultrasound (LUS) in diagnosis and response to diuretic treatment of patients with acute HF has been widely studied, but less is known about its value in chronic HF. Purpose To assess the prognostic value of LUS in a cohort of chronic HF stable ambulatory patients and to explore the relationship of LUS findings with clinical data, such as NYHA functional class, left ventricular ejection fraction (LVEF) and NTproBNP. Methods Consecutive stable ambulatory patients who attended a scheduled follow-up visit in a HF clinic were included. LUS were performed with a pocket device and examined 4 chest areas per side (two anterior and two lateral). Scans were analysed offline by two investigators blinded to clinical data, who evaluated the number of B-lines of each area. The addition number of B-lines of each area and the quartiles of such addition were used for the analyses. The primary outcome end-point was the composite of all-cause death or hospitalization due to HF at one year. Linear regression and Cox regression analyses were performed. Results Five-hundred seventy-seven patients were included between July 2016 and July 2017 (age 69±12 years, 72% men). The main HF aetiology was ischemic heart disease (43%) followed by dilated cardiomyopathy (20%). Median HF duration was 79 months (Q1-Q3 38–144). Mean LVEF was 45%±13 (mean LVEF when admitted at the Unit 34%±13). Most patients were in NYHA functional class II (70%), 13% were in class I and 17% in class III. Median NTproBNP was 722 ng/L (Q1-Q3 262–1760). Mean number of B-lines was 5±6 (Q1, 0; Q2, 1–3; Q3, 4–7; Q4, ≥8). The number of B-lines was associated with age (beta-coefficient 0.11, p Conclusion In outpatients with stable chronic HF, the number of B-lines detected in LUS was associated with age, NYHA functional class and NTproBNP. Patients having ≥8 B-lines had a significant double risk of HF related hospitalization or all-cause death at one year. However, when strongly powerful prognostic variables such as NYHA class and NTproBNP were included in the model LUS did not retain an independent prognostic role.

The ribosomal protein L11 (RPL11) integrates different types of stress into a p53-mediated response. Here, we analyzed the impact of the ubiquitin-like protein SUMO on the RPL11-mouse double-minute 2 homolog-p53 signaling. We show that small ubiquitin-related modifier (SUMO)1 and SUMO2 covalently modify RPL11. We find that SUMO negatively modulates the conjugation of the ubiquitin-like protein neural precursor cell-expressed developmentally downregulated 8 (NEDD8) to RPL11 and promotes the translocation of the RP outside of the nucleoli. Moreover, the SUMO-conjugating enzyme, Ubc9, is required for RPL11-mediated activation of p53. SUMOylation of RPL11 is triggered by ribosomal stress, as well as by alternate reading frame protein upregulation. Collectively, our data identify SUMO protein conjugation to RPL11 as a new regulator of the p53-mediated cellular response to different types of stress and reveal a previously unknown SUMO-NEDD8 interplay.-El Motiam, A, Vidal, S., de la Cruz-Herrera, C. F., Da Silva-Álvarez, S., Baz-Martínez, M., Seoane, R., Vidal, A., Rodríguez, M. S., Xirodimas, D. P., Carvalho, A. S., Beck, H. C., Matthiesen, R., Collado, M., Rivas, C. Interplay between SUMOylation and NEDDylation regulates RPL11 localization and function.

Objective: To assess the effects of comorbidities, fragility, and quality of life (QOL) on long-term prognosis in ambulatory patients with heart failure (HF) with midrange left ventricular ejection fraction (HFmrEF), an unexplored area. Patients and Methods: Consecutive patients prospectively evaluated at an HF clinic between August 1, 2001, and December 31, 2015, were retrospectively analyzed on the basis of left ventricular ejection fraction category. We compared patients with HFmrEF (n=185) to those with reduced (HFrEF; n=1058) and preserved (HFpEF; n=162) ejection fraction. Fragility was defined as 1 or more abnormal evaluations on 4 standardized geriatric scales (Barthel Index, Older Americans Resources and Services scale, Pfeiffer Test, and abbreviated-Geriatric Depression Scale). The QOL was assessed with the Minnesota Living with Heart Failure Questionnaire. A comorbidity score (0-7) was constructed. All-cause death, HF-related hospitalization, and the composite end point of both were assessed. Results: Comorbidities and QOL scores were similar in HFmrEF (2.41±1.5 and 30.1±18.3, respectively) and HFrEF (2.30±1.4 and 30.8±18.5, respectively) and were higher in HFpEF (3.02±1.5, P