Tiempo de estancia hospitalaria en pacientes ingresados por insuficiencia cardiaca aguda. Factores asociados

La presente tesis doctoral persigue los siguientes objetivos: 1. Estudiar los factores asociados con una estancia prolongada de los pacientes ingresados por insuficiencia cardiaca aguda en las unidades de corta estancia españolas; 2. Identificar los factores asociados al tiempo de estancia hospitalaria prolongada en los pacientes ingresados por insuficiencia cardiaca aguda; 3. Identificar factores asociados a un tiempo de estancia hospitalaria corto en pacientes ingresados por insuficiencia cardiaca aguda en hospitales con unidad de corta estancia; 4. Determinar si la presencia de una unidad de corta estancia en un hospital influye en el porcentaje de ingresos, en el tiempo de estancia hospitalaria y en los resultados de los pacientes atendidos con insuficiencia cardiaca aguda en un servicio de urgencias hospitalario.Departamento de Medicina, Dermatología y ToxicologíaDoctorado en Investigación en Ciencias de la Salu

AKT inhibition impairs PCNA ubiquitylation and triggers synthetic lethality in homologous recombination-deficient cells submitted to replication stress

Translesion DNA synthesis (TLS) and homologous recombination (HR) cooperate during S-phase to safeguard replication forks integrity. Thus, the inhibition of TLS becomes a promising point of therapeutic intervention in HR-deficient cancers, where TLS impairment might trigger synthetic lethality (SL). The main limitation to test this hypothesis is the current lack of selective pharmacological inhibitors of TLS. Herein, we developed a miniaturized screening assay to identify inhibitors of PCNA ubiquitylation, a key post-translational modification required for efficient TLS activation. After screening a library of 627 kinase inhibitors, we found that targeting the pro-survival kinase AKT leads to strong impairment of PCNA ubiquitylation. Mechanistically, we found that AKT-mediated modulation of Proliferating Cell Nuclear Antigen (PCNA) ubiquitylation after UV requires the upstream activity of DNA PKcs, without affecting PCNA ubiquitylation levels in unperturbed cells. Moreover, we confirmed that persistent AKT inhibition blocks the recruitment of TLS polymerases to sites of DNA damage and impairs DNA replication forks processivity after UV irradiation, leading to increased DNA replication stress and cell death. Remarkably, when we compared the differential survival of HR-proficient vs HR-deficient cells, we found that the combination of UV irradiation and AKT inhibition leads to robust SL induction in HR-deficient cells. We link this phenotype to AKT ability to inhibit PCNA ubiquitylation, since the targeted knockdown of PCNA E3-ligase (RAD18) and a non-ubiquitylable (PCNA K164R) knock-in model recapitulate the observed SL induction. Collectively, this work identifies AKT as a novel regulator of PCNA ubiquitylation and provides the proof-of-concept of inhibiting TLS as a therapeutic approach to selectively kill HR-deficient cells submitted to replication stress.Fil: Villafañez, Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: García, Iris Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Carbajosa González, Sofía. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Pansa, Maria Florencia. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Departamento de Biología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Mansilla, Sabrina Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Llorens de Los Ríos, María Candelaria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Angiolini, Virginia Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones y Transferencia de Villa María. Universidad Nacional de Villa María. Centro de Investigaciones y Transferencia de Villa María; ArgentinaFil: Guantay, Maria Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Jacobs, Heinz. Tumor Biology And Immunology-netherlands Cancer Institu; Países BajosFil: Madauss, Kevin P.. Glaxosmithkline; Reino UnidoFil: Gloger, Israel. Glaxosmithkline; Reino UnidoFil: Gottifredi, Vanesa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Bocco, Jose Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Soria, Ramiro Gaston. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentin

Length of stay in patients admitted for acute heart failure

Objective: To identify the factors associated with prolonged length of hospital stay in patients admitted for acute heart failure. Methods: Multipurpose observational cohort study including patients from the EAHFE registry admitted for acute heart failure in 25 Spanish hospitals. Data were collected on demographic and clinical variables and on the day and place of admission. The primary outcome was length of hospital stay longer than the median. Results: We included 2,400 patients with a mean age of 79.5 (9.9) years; of these, 1,334 (55.6%) were women. Five hundred and ninety (24.6%) were admitted to the short stay unit (SSU), 606 (25.2%) to cardiology, and 1,204 (50.2%) to internal medicine or gerontology. The mean length of hospital stay was 7.0 (RIC 4-11) days. Fifty-eight (2.4%) patients died and 562 (23.9%) were readmitted within 30 days after discharge. The factors associated with prolonged length of hospital stay were chronic pulmonary disease; being a device carrier; having an unknown or uncommon triggering factor; the presence of renal insufficiency, hyponatremia and anaemia in the emergency department; not being admitted to an SSU or the lack of this facility in the hospital; and being admitted on Monday, Tuesday or Wednesday. The factors associated with length of hospital stay <= 7days were hypertension, having a hypertensive episode, or a lack of treatment adherence. The area under the curve of the mixed model adjusted to the center was 0.78 (95% CI: 0.76-0.80; p < 0.001). Conclusions: A series of factors is associated with prolonged length of hospital stay and should be taken into account in the management of acute heart failure

Polo-like kinase 1 inhibition as a therapeutic approach to selectively target BRCA1-deficient cancer cells by synthetic lethality induction

Purpose: BRCA1 and BRCA2 deficiencies are widespread drivers of human cancers that await the development of targeted therapies. We aimed to identify novel synthetic lethal relationships with therapeutic potential using BRCA-deficient isogenic backgrounds. Experimental Design: We developed a phenotypic screening technology to simultaneously search for synthetic lethal (SL) interactions in BRCA1- and BRCA2-deficient contexts. For validation, we developed chimeric spheroids and a dualtumor xenograft model that allowed the confirmation of SL induction with the concomitant evaluation of undesired cytotoxicity on BRCA-proficient cells. To extend our results using clinical data, we performed retrospective analysis on The Cancer Genome Atlas (TCGA) breast cancer database. Results: The screening of a kinase inhibitors library revealed that Polo-like kinase 1 (PLK1) inhibition triggers strong SL induction in BRCA1-deficient cells. Mechanistically, we found no connection between the SL induced by PLK1 inhibition and PARP inhibitors. Instead, we uncovered that BRCA1 downregulation and PLK1 inhibition lead to aberrant mitotic phenotypes with altered centrosomal duplication and cytokinesis, which severely reduced the clonogenic potential of these cells. The penetrance of PLK1/BRCA1 SL interaction was validated using several isogenic and nonisogenic cellular models, chimeric spheroids, and mice xenografts. Moreover, bioinformatic analysis revealed high-PLK1 expression in BRCA1-deficient tumors, a phenotype that was consistently recapitulated by inducing BRCA1 deficiency in multiple cell lines as well as in BRCA1-mutant cells. Conclusions: We uncovered an unforeseen addiction of BRCA1-deficient cancer cells to PLK1 expression, which provides a new means to exploit the therapeutic potential of PLK1 inhibitors in clinical trials, by generating stratification schemes that consider this molecular trait in patient cohorts.Fil: Carbajosa González, Sofía. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Pansa, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Paviolo, Natalia Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Fundación Instituto Leloir; ArgentinaFil: Castellaro, Andrés Marcos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Andino, Diego Leonardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigación y Desarrollo en Inmunología y Enfermedades Infecciosas. Universidad Católica de Córdoba. Centro de Investigación y Desarrollo en Inmunología y Enfermedades Infecciosas; ArgentinaFil: Nigra, Ayelén Denise. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: García, Iris Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Racca, Ana Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Rodriguez, María Celeste. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Angiolini, Virginia Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Guantay, Maria Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Villafañez, Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Federico, Maria Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Rodríguez, Lucía. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Caputto, Beatriz Leonor. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Drewes, Gerard. Cellzome AG; AlemaniaFil: Madauss, Kevin P.. Global Observatory on Health Research and Development; Estados UnidosFil: Gloger, Israel. Global Observatory on Health Research and Development; Estados UnidosFil: Fernandez, Elmer Andres. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigación y Desarrollo en Inmunología y Enfermedades Infecciosas. Universidad Católica de Córdoba. Centro de Investigación y Desarrollo en Inmunología y Enfermedades Infecciosas; ArgentinaFil: Gil, German Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Bocco, Jose Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Gottifredi, Vanesa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Soria, Ramiro Gaston. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentin

Length of stay in patients admitted for acute heart failure

Objective: To identify the factors associated with prolonged length of hospital stay in patients admitted for acute heart failure. Methods: Multipurpose observational cohort study including patients from the EAHFE registry admitted for acute heart failure in 25 Spanish hospitals. Data were collected on demographic and clinical variables and on the day and place of admission. The primary outcome was length of hospital stay longer than the median. Results: We included 2,400 patients with a mean age of 79.5 (9.9) years; of these, 1,334 (55.6\%) were women. Five hundred and ninety (24.6\%) were admitted to the short stay unit (SSU), 606 (25.2\%) to cardiology, and 1,204 (50.2\%) to internal medicine or gerontology. The mean length of hospital stay was 7.0 (RIC 4-11) days. Fifty-eight (2.4\%) patients died and 562 (23.9\%) were readmitted within 30 days after discharge. The factors associated with prolonged length of hospital stay were chronic pulmonary disease; being a device carrier; having an unknown or uncommon triggering factor; the presence of renal insufficiency, hyponatremia and anaemia in the emergency department; not being admitted to an SSU or the lack of this facility in the hospital; and being admitted on Monday, Tuesday or Wednesday. The factors associated with length of hospital stay <= 7days were hypertension, having a hypertensive episode, or a lack of treatment adherence. The area under the curve of the mixed model adjusted to the center was 0.78 (95\% CI: 0.76-0.80; p < 0.001). Conclusions: A series of factors is associated with prolonged length of hospital stay and should be taken into account in the management of acute heart failure. (C) 2016 SESPAS. Published by Elsevier Espana, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).S

Length of stay in patients admitted for acute heart failure

Objective: To identify the factors associated with prolonged length of hospital stay in patients admitted for acute heart failure. Methods: Multipurpose observational cohort study including patients from the EAHFE registry admitted for acute heart failure in 25 Spanish hospitals. Data were collected on demographic and clinical variables and on the day and place of admission. The primary outcome was length of hospital stay longer than the median. Results: We included 2,400 patients with a mean age of 79.5 (9.9) years; of these, 1,334 (55.6%) were women. Five hundred and ninety (24.6%) were admitted to the short stay unit (SSU), 606 (25.2%) to cardiology, and 1,204 (50.2%) to internal medicine or gerontology. The mean length of hospital stay was 7.0 (RIC 4-11) days. Fifty-eight (2.4%) patients died and 562 (23.9%) were readmitted within 30 days after discharge. The factors associated with prolonged length of hospital stay were chronic pulmonary disease; being a device carrier; having an unknown or uncommon triggering factor; the presence of renal insufficiency, hyponatremia and anaemia in the emergency department; not being admitted to an SSU or the lack of this facility in the hospital; and being admitted on Monday, Tuesday or Wednesday. The factors associated with length of hospital stay <= 7days were hypertension, having a hypertensive episode, or a lack of treatment adherence. The area under the curve of the mixed model adjusted to the center was 0.78 (95% CI: 0.76-0.80; p < 0.001). Conclusions: A series of factors is associated with prolonged length of hospital stay and should be taken into account in the management of acute heart failure

Accuracy of prehospital point-of-care lactate in early in-hospital mortality

Background: Emergency medical services (EMS) routinely face complex scenarios where decisions should be taken with limited clinical information. The development of fast, reliable and easy to perform warning biomarkers could help in such decision-making processes. The present study aims at characterizing the validity of point-of-care lactate (pLA) during prehospital tasks for predicting in-hospital mortality within two days after the EMS assistance. Materials and methods: Prospective, multicentric, ambulance-based and controlled observational study without intervention, including six advanced life support and five hospitals. The pLA levels were recorded during EMS assistance of adult patients. The validity of pLA to determine the in-hospital mortality was assessed by the area under the curve (AUC) of the receiver operating curve (ROC). Results: A total of 2997 patients were considered in the study, with a median of 69 years (IQR 54-81) and 41.4% of women. The median pLA value was 2.7 mmol/L (1.9-3.8) in survivors and 5.7 mmol/L (4.4-7.6) in nonsurvivors. The global discrimination level of pLA reached an AUC of 0.867, being 1.9 mmol/L and 4 mmol/L the cut-off point for low and high mortality. The discrimination value of pLA was not affected by sex, age or pathology. Conclusions: Our results highlight the clinical importance of prehospital pLA to determine the in-hospital risk of mortality. The incorporation of pLA into the EMS protocols could improve the early identification of risky patients, leading to a better care of such patients.Fil: Martín Rodríguez, Francisco. Universidad de Valladolid; España. Paseo Hospital Militar; EspañaFil: López Izquierdo, Raúl. Universidad de Valladolid; España. Hospital Universitario Rio Hortega; EspañaFil: Medina Lozano, Elena. Universidad de Valladolid; EspañaFil: Ortega, Guillermo José. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Autonoma de Madrid. Hospital Universitario de la Princesa; EspañaFil: del Pozo Vegas, Carlos. Hospital Clínico Universitario; EspañaFil: Carbajosa Rodríguez, Virginia. Hospital Universitario Rio Hortega; EspañaFil: Castro Villamor, Miguel Ángel. Universidad de Valladolid; EspañaFil: Sánchez Soberon, Irene. Paseo Hospital Militar; EspañaFil: Sanz García, Ancor. Universidad Autonoma de Madrid. Hospital Universitario de la Princesa; Españ

Blood Biomarkers for Assessing Headaches in Healthcare Workers after Wearing Biological Personal Protective Equipment in a COVID-19 Field Hospital

The coronavirus disease 2019 (COVID-19) has led to a pandemic, which among other things, has highlighted biosafety as a key cornerstone in the management of disease transmission. The aim of this work was to analyze the role played by different blood biomarkers in predicting the appearance of headaches in healthcare workers wearing personal protective equipment (PPE) in a COVID-19 treatment unit. A prospective cohort study of 38 healthcare workers was performed during April 2020. Blood analysis, performed just before the start of a 4 hour shift, was carried out on all volunteers equipped with PPE. At the end of their shifts and after decontamination, they were asked if they had suffered from headache in order to obtain a binary outcome. The baseline creatinine value reflected a specific odds ratio of 241.36 (95% CI: 2.50&ndash;23,295.43; p = 0.019) and an area under the curve (AUC) value of 0.737 (95%CI: 0.57&ndash;0.90; p &lt; 0.01). Blood creatinine is a good candidate for predicting the appearance of a de novo headache in healthcare workers after wearing PPE for four hours in a COVID-19 unit