Aprendizaje de las habilidades no técnicas en las nuevas generaciones de estudiantes de medicina: nueva estrategia docente en un escenario bélico real

Establecer una nueva estrategia docente en el aprendizaje de las habilidades no técnicas (conciencia situacional, tomar decisiones, comunicación, trabajo en equipo y liderazgo) del estudiante en un escenario real reforzaría sus habilidades técnicas

Innovación en la docencia del grado de medicina: Aerotransporte de pacientes con alto riesgo de contaminación por enfermedad infecciosa en un escenario real

Depto. de Farmacología y ToxicologíaFac. de MedicinaFALSEsubmitte

Aeroevacuación en un escenario real: nueva herramienta de aprendizaje en las futuras generaciones de estudiantes de Medicina

La aeroevacuación en un escenario real podría ser una nueva herramienta de aprendizaje en las futuras generaciones de estudiantes de sexto de medicina, no siendo tan eficaz en los estudiantes de cursos inferiores

Randomized-controlled trial of the DIALIVE liver dialysis device vs. standard of care in patients with acute-on-chronic liver failure

BACKGROUND AND AIMS: Acute on chronic liver failure (ACLF) is characterized by severe systemic inflammation, multi-organ failure and high mortality rates. Its treatment is an urgent unmet need. DIALIVE is a novel liver dialysis device that aims to exchange d ysfunctional albumin and remove damage- and pathogen-associated molecular patterns. This first-in-man randomized, controlled clinical trial was performed with the primary aim of assessing its safety in ACLF patients with secondary aims to evaluate its clinical effects, device performance and effect on pathophysiologically-relevant biomarkers. METHODS: 32 alcoholic cirrhosis patients with ACLF were included. Patients were treated with DIALIVE for up to 5-days and end points were assessed at Day-10. Safety was assessed in all patients (n=32). The secondary aims were assessed in a pre-specified subgroup that had at least 3-treatment sessions with DIALIVE (n=30). RESULTS: There were no significant differences in 28-day mortality or occurrence of serious adverse events between the groups. Significant reduction in the severity of endotoxemia and improvement in albumin function was observed in DIALIVE group, which translated into a significant reduction in the CLIF-C (Chronic Liver Failure consortium) organ failure (p=0.018) and CLIF-C ACLF scores (p=0.042) at Day-10. Time to resolution of ACLF was significantly faster in DIALIVE group (p=0.036). Biomarkers of systemic inflammation such as IL-8 (p=0.006), cell death [cytokeratin-18: M30 (p=0.005) and M65 (p=0.029)], endothelial function [asymmetric dimethylarginine (p=0.002)] and, ligands for toll-like receptor 4 (p=0.030) and inflammasome (p=0.002) improved significantly in DIALIVE group. CONCLUSIONS: These data indicate that DIALIVE appears to be safe and impacts positively on prognostic scores and pathophysiologically relevant biomarkers in patients with ACLF. Larger, adequately powered studies are warranted to further confirm its safety and efficacy. LAY SUMMARY: This is the first-in-man clinical trial which tested DIALIVE, a novel liver dialysis device for the treatment of liver cirrhosis and acute on chronic liver failure, a condition associated with severe inflammation, organ failures and a high risk of death. The study met the primary end point confirming DIALIVE system to be safe. Additionally, it reduced inflammation with improved clinical parameters. It did not, however, reduce mortality in this small study and requires further larger clinical trials to re-confirm its safety and evaluate efficacy. CLINICAL TRIAL NUMBER: NCT03065699

A Shortcut from Metabolic-Associated Fatty Liver Disease (MAFLD) to Hepatocellular Carcinoma (HCC): c-MYC a Promising Target for Preventative Strategies and Individualized Therapy

Background: Metabolic-associated fatty liver disease (MAFLD) has risen as one of the leading etiologies for hepatocellular carcinoma (HCC). Oncogenes have been suggested to be responsible for the high risk of MAFLD-related HCC. We analyzed the impact of the proto-oncogene c-MYC in the development of human and murine MAFLD and MAFLD-associated HCC. Methods: alb-myctg mice were studied at baseline conditions and after administration of Western diet (WD) in comparison to WT littermates. c-MYC expression was analyzed in biopsies of patients with MAFLD and MAFLD-associated HCC by immunohistochemistry. Results: Mild obesity, spontaneous hyperlipidaemia, glucose intolerance and insulin resistance were characteristic of 36-week-old alb-myctg mice. Middle-aged alb-myctg exhibited liver steatosis and increased triglyceride content. Liver injury and inflammation were associated with elevated ALT, an upregulation of ER-stress response and increased ROS production, collagen deposition and compensatory proliferation. At 52 weeks, 20% of transgenic mice developed HCC. WD feeding exacerbated metabolic abnormalities, steatohepatitis, fibrogenesis and tumor prevalence. Therapeutic use of metformin partly attenuated the spontaneous MAFLD phenotype of alb-myctg mice. Importantly, upregulation and nuclear localization of c-MYC were characteristic of patients with MAFLD and MAFLD-related HCC. Conclusions: A novel function of c-MYC in MAFLD progression was identified opening new avenues for preventative strategies

Rebleeding and mortality risk are increased by ACLF but reduced by pre-emptive TIPS

En este estudio, en el cual el solicitante es autor senior (último autor) se analizó, sobre la base de una gran cohorte internacional colaborativa, si los pacientes con enfermedad hepatica crónica agudizada (ACLF por su acrónimo inglés de Acute on Chronic liver failure) presentaban peor pronóstico de la hemorragia aguda por varices esofágicas y si era factible, en términos de seguridad y eficacia la realizacion de una derivacion portosistémica percutánea intrahepática (TIPS). En el estudio, se demuestra que el pronóstico de la hemorragia en estos pacientes es marcadamente peor que en los pacientes sin ACLF y que, a pesar de una mayor mortalidad que en los pacientes sin ACLF, la realización del TIPS mejora la supervivencia de la hemorragia aguda por varices en pacientes con ACLF. El estudio sustenta claramente la posibilidad y el beneficio terapéutico del TIPS en estos enfermos, respondiento a una pregunta de gran trascendencia en el tratamiento de estos complejos pacientes. Desde el punto de vista de las líneas de investigación del solicitante, el articulo supone una contribución más a esta tradicional línea, fundamental en su carrera investigadora.Background & aims: The relationship between acute-on-chronic liver failure (ACLF) and acute variceal bleeding (AVB) is poorly understood. Specifically, the prevalence and prognosis of ACLF in the context of AVB is unclear, while the role of transjugular intrahepatic portosystemic shunt (TIPS) in the management in patients with ACLF has not been described to date. Methods: A multicenter, international, observational study was conducted in 2,138 patients from 34 centers between 2011 and 2015. ACLF was defined and graded according to the EASL-CLIF consortium definition. Placement of pre-emptive TIPS (pTIPS) was based on individual center policy. Patients were followed-up for 1 year, until death or liver transplantation. Cox regression and competing risk models (Gray's test) were used to identify independent predictors of rebleeding or mortality. Results: At admission, 380/2,138 (17.8%) patients had ACLF according to EASL-CLIF criteria (grade 1: 38.7%; grade 2: 39.2%; grade 3: 22.1%). The 42-day rebleeding (19% vs. 10%; p <0.001) and mortality (47% vs. 10%; p <0.001) rates were higher in patients with ACLF and increased with ACLF grades. Of note, the presence of ACLF was independently associated with rebleeding and mortality. pTIPS placement improved survival in patients with ACLF at 42 days and 1 year. This effect was also observed in propensity score matching analysis of 66 patients with ACLF, of whom 44 received pTIPs and 22 did not. Conclusions: This large multicenter international real-life study identified ACLF at admission as an independent predictor of rebleeding and mortality in patients with AVB. Moreover, pTIPS was associated with improved survival in patients with ACLF and AVB. Lay summary: Acute variceal bleeding is a deadly complication of liver cirrhosis that results from severe portal hypertension. This study demonstrates that the presence of acute-on-chronic liver failure (ACLF) is the strongest predictor of mortality in patients with acute variceal bleeding. Importantly, patients with ACLF and acute variceal (re)bleeding benefit from pre-emptive (early) placement of a transjugular intrahepatic portosystemic shunt.Depto. de MedicinaFac. de MedicinaTRUEpu

Randomized, controlled clinical trial of the DIALIVE liver dialysis device versus standard of care in patients with acute-on-chronic liver failure

Se trata de un artículo que describe, por primera vez en humanos, la seguridad y el impacto fisiopatológico de un nuevo dispositivo de soporte hepático artificial, diseñado específicamente para antagonizar los mecanismos fisiopatológicos de la cirrosis descompensada. El estudio , financiado mediante un proyecto europeo, indica que el dispositivo es seguro, aplicable, tiene influencia en los numerosos aspectos mecanísticos explorados y, finalmente, apuntando a datos de posible eficacia clínica. Globalmente, se puede considerar que el estudio es una evidente prueba de concepto positiva. Desde el punto de vista de la trascendencia social y sanitaria, si los estudios en fase III determinan la eficacia sobre variables clínicas, representaría una herramienta de gran valor para el tratamiento de pacientes con cirrosis y con fracaso hepático agudo sobre crónico. La revista Journal of Hepatology está en el primer decil de la especialidad con un FI de XXX. El investigador solicitante del sexenio es primer firmante del artículo habiendo participado en el diseño y ejecución del proyecto así como en la elaboración de los resultados y del manuscrito en todas sus fases. Representa además la continuacion en una línea de investigación con numerosas publicaciones previas (Banares R et al. Hepatology 2013; Saliba F, Bañares R et al. Intensive Care Medicine 2022)Background & Aims: Acute-on-chronic liver failure (ACLF) is characterized by severe systemic inflammation, multi-organ failure and high mortality rates. Its treatment is an urgent unmet need. DIALIVE is a novel liver dialysis device that aims to exchange dysfunctional albumin and remove damage- and pathogen-associated molecular patterns. This first-in-man randomizedcontrolled trial was performed with the primary aim of assessing the safety of DIALIVE in patients with ACLF, with secondary aims of evaluating its clinical effects, device performance and effect on pathophysiologically relevant biomarkers. Methods: Thirty-two patients with alcohol-related ACLF were included. Patients were treated with DIALIVE for up to 5 days and end points were assessed at Day 10. Safety was assessed in all patients (n = 32). The secondary aims were assessed in a prespecified subgroup that had at least three treatment sessions with DIALIVE (n = 30). Results: There were no significant differences in 28-day mortality or occurrence of serious adverse events between the groups. Significant reduction in the severity of endotoxemia and improvement in albumin function was observed in the DIALIVE group, which translated into a significant reduction in the CLIF-C (Chronic Liver Failure consortium) organ failure (p = 0.018) and CLIF-C ACLF scores (p = 0.042) at Day 10. Time to resolution of ACLF was significantly faster in DIALIVE group (p = 0.036). Biomarkers of systemic inflammation such as IL-8 (p = 0.006), cell death [cytokeratin-18: M30 (p = 0.005) and M65 (p = 0.029)], endothelial function [asymmetric dimethylarginine (p = 0.002)] and, ligands for Toll-like receptor 4 (p = 0.030) and inflammasome (p = 0.002) improved significantly in the DIALIVE group. Conclusions: These data indicate that DIALIVE appears to be safe and impacts positively on prognostic scores and pathophysiologically relevant biomarkers in patients with ACLF. Larger, adequately powered studies are warranted to further confirm its safety and efficacy. Clinical trial number: NCT03065699.Unión EuropeaDepto. de MedicinaFac. de MedicinaTRUEpu

A Model Based on Noninvasive Markers Predicts Very Low Hepatocellular Carcinoma Risk After Viral Response in Hepatitis C Virus-Advanced Fibrosis

En este estudio se describe un modelo de predicción del riesgo de desarrollar hepatocarcinoma en pacientes con enfermedad hepática avanzada por virus C tras alcanzar la curación virológica. Se demuestra en el estudio que variables de fácil obtención (FIB-4, elastografía) que evalúan el grado de rigidez hepática y su dinámica influyen en el riesgo de desarrollar cáncer hepático. Se trata de un estudio multicéntrico coordinado desde el grupo del solicitante que pretende responder a una pregunta clave con claras connotaciones relacionadas con la práctica clínica. Además de su publicación en una revista de primer decil, este artículo ha supuesto el desarrollo de una colaboración multinacional que ha dado lugar a diversoss artículos posteriores.virus (HCV) and advanced fibrosis remain at risk of hepatocellular carcinoma (HCC) after sustained viral response (SVR) and need lifelong surveillance. Because HCC risk is not homogenous and may decrease with fibrosis regression, we aimed to identify patients with low HCC risk based on the prediction of noninvasive markers and its changes after SVR. APP ROA CH AND RESULT S: This is a multicenter cohort study, including patients with HCV and compensated advanced fibrosis that achieved SVR after direct antivirals. Clinical and transient elastography (TE) data were registered at baseline, 1 year, and 3 years after the end of treatment (EOT). All patients underwent liver ultrasound scan every 6 months. Patients with clinical evaluation 1 year after EOT were eligible. Univariate and multivariate Cox regression analysis were performed, and predictive models were constructed. HCC occurrence rates were evaluated by Kaplan-Meier. Nine hundred and ninety-three patients were eligible (56% male; 44% female; median age 62 years), 35 developed HCC (3.9%), and the median follow-up was 45 months (range 13-53). Baseline liver stiffness measurement (LSM) (HR 1.040; 95% CI 1.017-1.064), serum albumin (HR 0.400; 95% CI 0.174- 0.923), 1-year DeltaLSM (HR 0.993; 95% CI 0.987-0.998), and 1-year FIB-4 score (HR 1.095; 95% CI 1.046-1.146) were independent factors associated with HCC. The TE-based HCC risk model predicted 0% of HCC occurrence at 3 years in patients with score 0 (baseline LSM ≤ 17.3 kPa, albumin >4.2 g/dL, and 1-year DeltaLSM > 25.5%) versus 5.2% in patients with score 1-3 (Harrell’s C 0.779; log-rank 0.002). An alternative model with FIB-4 similarly predicted HCC risk. CONCLUSIONS: A combination of baseline and dynamic changes in noninvasive markers may help to identify patients with a very low risk of HCC development after SVR.Depto. de MedicinaFac. de MedicinaTRUEpu

Genetic susceptibility to the develpment of acute alcoholic hepatitis: role of genetic mutations in dehydrogenae alcohol, aldehyde dehydrogenase and cytochrome P450 2E1

Sin financiación0.273 JCR (2005) Q4, 93/105 Medicine, general & internalUE

Activation of the Unfolded Protein Response (UPR) Is Associated with Cholangiocellular Injury, Fibrosis and Carcinogenesis in an Experimental Model of Fibropolycystic Liver Disease

Fibropolycystic liver disease is characterized by hyperproliferation of the biliary epithelium and the formation of multiple dilated cysts, a process associated with unfolded protein response (UPR). In the present study, we aimed to understand the mechanisms of cyst formation and UPR activation in hepatocytic c-Jun N-terminal kinase 1/2 (Jnk1/2) knockout mice. Floxed JNK1/2 (Jnkf/f) and Jnk∆hepa animals were sacrificed at different time points during progression of liver disease. Histological examination of specimens evidenced the presence of collagen fiber deposition, increased α-smooth muscle actin (αSMA), infiltration of CD45, CD11b and F4/80 cells and proinflammatory cytokines (Tnf, Tgfβ1) and liver injury (e.g., ALT, apoptosis and Ki67-positive cells) in Jnk∆hepa compared with Jnkf/f livers from 32 weeks of age. This was associated with activation of effectors of the UPR, including BiP/GRP78, CHOP and spliced XBP1. Tunicamycin (TM) challenge strongly induced ER stress and fibrosis in Jnk∆hepa animals compared with Jnkf/f littermates. Finally, thioacetamide (TAA) administration to Jnk∆hepa mice induced UPR activation, peribiliary fibrosis, liver injury and markers of biliary proliferation and cholangiocarcinoma (CCA). Orthoallografts of DEN/CCl4-treated Jnk∆hepa liver tissue triggered malignant CCA. Altogether, these results suggest that activation of the UPR in conjunction with fibrogenesis might trigger hepatic cystogenesis and early stages of CCA.Ministerio de Economía, Comercio y EmpresaGerman Research FoundationDepto. de Inmunología, Oftalmología y ORLFac. de MedicinaTRUEpu