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Acyl-CoA synthetase 4 (ACSL4) is an isoenzyme of the fatty acid ligase-coenzyme-A family taking part in arachidonic acid metabolism and steroidogenesis. ACSL4 is involved in the development of tumor aggressiveness in breast and prostate tumors through the regulation of various signal transduction pathways. Here, a bioinformatics analysis shows that the ACSL4 gene expression and proteomic signatures obtained using a cell model was also observed in tumor samples from breast and cancer patients. A well-validated ACSL4 inhibitor, however, has not been reported hindering the full exploration of this promising target and its therapeutic application on cancer and steroidogenesis inhibition. In this study, ACSL4 inhibitor PRGL493 was identified using a homology model for ACSL4 and docking based virtual screening. PRGL493 was then chemically characterized through nuclear magnetic resonance and mass spectroscopy. The inhibitory activity was demonstrated through the inhibition of arachidonic acid transformation into arachidonoyl-CoA using the recombinant enzyme and cellular models. The compound blocked cell proliferation and tumor growth in both breast and prostate cellular and animal models and sensitized tumor cells to chemotherapeutic and hormonal treatment. Moreover, PGRL493 inhibited de novo steroid synthesis in testis and adrenal cells, in a mouse model and in prostate tumor cells. This work provides proof of concept for the potential application of PGRL493 in clinical practice. Also, these findings may prove key to therapies aiming at the control of tumor growth and drug resistance in tumors which express ACSL4 and depend on steroid synthesis. Fil: Castillo, Ana Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Orlando, Ulises Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Maloberti, Paula Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Prada, Jesica Giselle. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Dattilo, Melina Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Solano, Angela Rosario. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Bigi, Maria de Las Mercedes. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Ríos Medrano, Mayra Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina Fil: Torres, María T.. Universidad de Chile. Facultad de Medicina.; Chile Fil: Indo, Sebastián. Universidad de Chile. Facultad de Medicina.; Chile Fil: Caroca, Graciela. Universidad de Chile. Facultad de Medicina.; Chile Fil: Contreras, Hector R.. Universidad de Chile. Facultad de Medicina.; Chile Fil: Marelli, Belkis Ester. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Ciencias Veterinarias del Litoral. Universidad Nacional del Litoral. Facultad de Ciencias Veterinarias. Instituto de Ciencias Veterinarias del Litoral; Argentina Fil: Salinas, Facundo José. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Ciencias Veterinarias del Litoral. Universidad Nacional del Litoral. Facultad de Ciencias Veterinarias. Instituto de Ciencias Veterinarias del Litoral; Argentina Fil: Salvetti, Natalia Raquel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Ciencias Veterinarias del Litoral. Universidad Nacional del Litoral. Facultad de Ciencias Veterinarias. Instituto de Ciencias Veterinarias del Litoral; Argentina Fil: Ortega, Hugo Hector. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Ciencias Veterinarias del Litoral. Universidad Nacional del Litoral. Facultad de Ciencias Veterinarias. Instituto de Ciencias Veterinarias del Litoral; Argentina Fil: Lorenzano Menna, Pablo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Szajnman, Sergio Hernan. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina Fil: Gómez, Daniel Eduardo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina Fil: Rodriguez, Juan Bautista. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina Fil: Podesta, Ernesto Jorge. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina

Purpose We hypothesized that neurally adjusted ventilatory assist (NAVA) compared to conventional lung-protective mechanical ventilation (MV) decreases duration of MV and mortality in patients with acute respiratory failure (ARF). Methods We carried out a multicenter, randomized, controlled trial in patients with ARF from several etiologies. Intubated patients ventilated for ≤ 5 days expected to require MV for ≥ 72 h and able to breathe spontaneously were eligible for enrollment. Eligible patients were randomly assigned based on balanced treatment assignments with a computerized randomization allocation sequence to two ventilatory strategies: (1) lung-protective MV (control group), and (2) lung-protective MV with NAVA (NAVA group). Allocation concealment was maintained at all sites during the trial. Primary outcome was the number of ventilator-free days (VFDs) at 28 days. Secondary outcome was all-cause hospital mortality. All analyses were done according to the intention-to-treat principle. Results Between March 2014 and October 2019, we enrolled 306 patients and randomly assigned 153 patients to the NAVA group and 153 to the control group. Median VFDs were higher in the NAVA than in the control group (22 vs. 18 days; between-group difference 4 days; 95% confidence interval [CI] 0 to 8 days; p = 0.016). At hospital discharge, 39 (25.5%) patients in the NAVA group and 47 (30.7%) patients in the control group had died (between-group difference − 5.2%, 95% CI − 15.2 to 4.8, p = 0.31). Other clinical, physiological or safety outcomes did not differ significantly between the trial groups. Conclusion NAVA decreased duration of MV although it did not improve survival in ventilated patients with ARF. Electronic supplementary material The online version of this article (10.1007/s00134-020-06181-5) contains supplementary material, which is available to authorized users.

OBJECTIVES: To develop a scoring model for stratifying patients with acute respiratory distress syndrome into risk categories (Stratification for identification of Prognostic categories In the acute RESpiratory distress syndrome score) for early prediction of death in the ICU, independent of the underlying disease and cause of death. DESIGN: A development and validation study using clinical data from four prospective, multicenter, observational cohorts. SETTING: A network of multidisciplinary ICUs. PATIENTS: One-thousand three-hundred one patients with moderate-to-severe acute respiratory distress syndrome managed with lung-protective ventilation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The study followed Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis guidelines for prediction models. We performed logistic regression analysis, bootstrapping, and internal-external validation of prediction models with variables collected within 24 hours of acute respiratory distress syndrome diagnosis in 1,000 patients for model development. Primary outcome was ICU death. The Stratification for identification of Prognostic categories In the acute RESpiratory distress syndrome score was based on patient's age, number of extrapulmonary organ failures, values of end-inspiratory plateau pressure, and ratio of Pao2to Fio2assessed at 24 hours of acute respiratory distress syndrome diagnosis. The pooled area under the receiver operating characteristic curve across internal-external validations was 0.860 (95% CI, 0.831-0.890). External validation in a new cohort of 301 acute respiratory distress syndrome patients confirmed the accuracy and robustness of the scoring model (area under the receiver operating characteristic curve = 0.870; 95% CI, 0.829-0.911). The Stratification for identification of Prognostic categories In the acute RESpiratory distress syndrome score stratified patients in three distinct prognostic classes and achieved better prediction of ICU death than ratio of Pao2to Fio2at acute respiratory distress syndrome onset or at 24 hours, Acute Physiology and Chronic Health Evaluation II score, or Sequential Organ Failure Assessment scale. CONCLUSIONS: The Stratification for identification of Prognostic categories In the acute RESpiratory distress syndrome score represents a novel strategy for early stratification of acute respiratory distress syndrome patients into prognostic categories and for selecting patients for therapeutic trials.

Background There is no proven specific pharmacological treatment for patients with the acute respiratory distress syndrome (ARDS). The efficacy of corticosteroids in ARDS remains controversial. We aimed to assess the effects of dexamethasone in ARDS, which might change pulmonary and systemic inflammation and result in a decrease in duration of mechanical ventilation and mortality. Methods We did a multicentre, randomised controlled trial in a network of 17 intensive care units (ICUs) in teaching hospitals across Spain in patients with established moderate-to-severe ARDS (defined by a ratio of partial pressure of arterial oxygen to the fraction of inspired oxygen of 200 mm Hg or less assessed with a positive end-expiratory pressure of 10 cm H2O or more and FiO(2) of 0.5 or more at 24 h after ARDS onset). Patients with brain death, terminal-stage disease, or receiving corticosteroids or immunosuppressive drugs were excluded. Eligible patients were randomly assigned based on balanced treatment assignments with a computerised randomisation allocation sequence using blocks of 10 opaque, sealed envelopes to receive immediate treatment with dexamethasone or continued routine intensive care (control group). Patients in the dexamethasone group received an intravenous dose of 20 mg once daily from day 1 to day 5, which was reduced to 10 mg once daily from day 6 to day 10. Patients in both groups were ventilated with lung-protective mechanical ventilation. Allocation concealment was maintained at all sites during the trial. Primary outcome was the number of ventilator-free days at 28 days, defined as the number of days alive and free from mechanical ventilation from day of randomisation to day 28. Secondary outcome was all-cause mortality 60 days after randomisation. All analyses were done according to the intention-to-treat principle. This study is registered with ClinicalTrials.gov, NCT01731795. Findings Between March 28, 2013, and Dec 31, 2018, we enrolled 277 patients and randomly assigned 139 patients to the dexamethasone group and 138 to the control group. The trial was stopped by the data safety monitoring board due to low enrolment rate after enrolling more than 88% (277/314) of the planned sample size. The mean number of ventilator-free days was higher in the dexamethasone group than in the control group (between-group difference 4.8 days [95% CI 2.57 to 7.03]; p

Objectives:Although there is general agreement on the characteristic features of the acute respiratory distress syndrome, we lack a scoring system that predicts acute respiratory distress syndrome outcome with high probability. Our objective was to develop an outcome score that clinicians could easi

Objectives Overall mortality in patients with acute respiratory distress syndrome is a composite endpoint because it includes death from multiple causes. In most acute respiratory distress syndrome trials, it is unknown whether reported deaths are due to acute respiratory distress syndrome or the underlying disease, unrelated to the specific intervention tested. We investigated the causes of death after contracting acute respiratory distress syndrome in a large cohort. Design A secondary analysis from three prospective, multicenter, observational studies. Setting A network of multidisciplinary ICUs. Patients We studied 778 patients with moderate-to-severe acute respiratory distress syndrome treated with lung-protective ventilation. Interventions None. Measurements and main results We examined death in the ICU from individual causes. Overall ICU mortality was 38.8% (95% CI, 35.4-42.3). Causes of acute respiratory distress syndrome modified the risk of death. Twenty-three percent of deaths occurred from refractory hypoxemia due to nonresolving acute respiratory distress syndrome. Most patients died from causes unrelated to acute respiratory distress syndrome: 48.7% of nonsurvivors died from multisystem organ failure, and cancer or brain injury was involved in 37.1% of deaths. When quantifying the true burden of acute respiratory distress syndrome outcome, we identified 506 patients (65.0%) with one or more exclusion criteria for enrollment into current interventional trials. Overall ICU mortality of the "trial cohort" (21.3%) was markedly lower than the parent cohort (relative risk, 0.55; 95% CI, 0.43-0.70; p Conclusions Most deaths in acute respiratory distress syndrome patients are not directly related to lung damage but to extrapulmonary multisystem organ failure. It would be challenging to prove that specific lung-directed therapies have an effect on overall survival.

SummaryBackgroundThe only available score to assess the risk for fatal bleeding in patients with venous thromboembolism (VTE) has not been validated yet.MethodsWe used the RIETE database to validate the risk-score for fatal bleeding within the first 3months of anticoagulation in a new cohort of patients recruited after the end of the former study. Accuracy was measured using the ROC curve analysis.ResultsAs of December 2011, 39,284 patients were recruited in RIETE. Of these, 15,206 had not been included in the former study, and were considered to validate the score. Within the first 3months of anticoagulation, 52 patients (0.34%; 95% CI: 0.27-0.45) died of bleeding. Patients with a risk score of 4 points had a rate of 1.44%. The c-statistic for fatal bleeding was 0.775 (95% CI 0.720-0.830). The score performed better for predicting gastrointestinal (c-statistic, 0.869; 95% CI: 0.810-0.928) than intracranial (c-statistic, 0.687; 95% CI: 0.568-0.806) fatal bleeding. The score value with highest combined sensitivity and specificity was 1.75. The risk for fatal bleeding was significantly increased (odds ratio: 7.6; 95% CI 3.7-16.2) above this cut-off value.ConclusionsThe accuracy of the score in this validation cohort was similar to the accuracy found in the index study. Interestingly, it performed better for predicting gastrointestinal than intracranial fatal bleeding.

The mitochondria are critical for steroidogenesis since the ability of cholesterol to move into mitochondria to be available for cytochrome P450, CYP11A1, determines the efficacy of steroid production. Several proteins kinases, such as PKA, MEK and ERK which are essential to complete steroidogenesis, form a mitochondria-associated complex. The protein-protein interactions between kinases and key factors during the transport of cholesterol takes place in the contact sites between the two mitochondrial membranes; however, no mitochondrial targeting sequence has been described for these kinases. Here we discuss the possibility that mitochondrial reorganization may be mediating a compartmentalized cellular response. This reorganization could allow the physical interaction between the hormone-receptor complex and the enzymatic and lipidic machinery necessary for the complete steroid synthesis and release. The movement of organelles in specialized cells could impact on biological processes that include, but are not limited to, steroid synthesis. Fil: Poderoso, Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina Fil: Duarte, Alejandra Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina Fil: Cooke, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina Fil: Orlando, Ulises Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina Fil: Gottifredi, Vanesa. Fundación Instituto Leloir; Argentina Fil: Solano, Angela Rosario. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina Fil: Lemos, José R.. University Of Massachussets; Estados Unidos Fil: Podesta, Ernesto Jorge. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina

Introduccion La prevalencia de la incontinencia fecal (IF) en la poblacion atendida en las areas basicas de salud (ABS) de nuestro hospital y su impacto en la calidad de vida son elevados. Desconocemos si los sistemas de actuacion por este problema en estas ABS son adecuados. Objetivo Evaluar los sistemas de actuacion ante la IF en una ABS de Barcelona. En concreto, determinar los casos de IF detectados por el sistema de atencion primaria en el ABS de Ciutat Vella, de la que tenemos una estimacion de la prevalencia de la IF real. En los casos detectados, evaluar el tiempo de demora del diagnostico y tratamiento, tipo de tratamiento y respuesta al mismo. Metodologia Los casos de IF detectados por el sistema se obtuvieron del registro electronico de diagnosticos codificados del ABS de Ciutat Vella y mediante la revision de historias clinicas informatizadas de una muestra aleatoria (N=604) de la poblacion atendida en dicha ABS. El resto de variables se obtuvieron mediante una encuesta telefonica estructurada. Resultados En la poblacion evaluada (N=65.025) con una prevalencia de IF conocida del 13% (95%IC 10–17%), solo 72 (0,11% [95%IC 0,9–0,14]) casos habian sido detectados. De estos, 42 (58%) contestaron la encuesta, 26M/16H, edad 68±18 anos. La mediana de tiempo desde el diagnostico de IF fue de 2,3 anos (6m-5a), mientras que el 32,5% (13/42) de los casos referia sintomas desde hacia > 5-10a. El 45% (19/42) aun tenian IF en el momento de la encuesta, con un indice de severidad de 12±4/24 (escala de Vaizey) y consideraban que necesitaban mas asistencia por este motivo. De los pacientes aun con IF, 15/19 (80%) presentaban diarrea y 3/19 (16%) estrenimiento. Solo un paciente tenia indicado tratamiento con fibra i ninguno con opiaceos. Conclusion Los sistemas de actuacion en atencion primaria no son eficientes para la deteccion y el tratamiento de la incontinencia fecal. El diseno de estrategias y protocolos clinico-asistenciales dirigidos a corregir este problema parece necesario.

Introduccion Hasta un 20–40% de pacientes con incontinencia fecal (IF) no responden a las medidas terapeuticas estandar no invasivas. La continencia fecal depende del buen funcionamiento de diversas estructuras colonicas y anorrectales, cada una de ellas bajo control neurologico. La neuromodulacion central, por medio de la estimulacion electrica de las raices nerviosas sacras, se ha mostrado efectiva en la IF pero es un procedimiento costoso e invasivo. Objetivo Evaluar si la neuromodulacion periferica mediante estimulacion electrica percutanea del nervio tibial (EPNT), una tecnica minimamente invasiva y que puede realizarse de forma ambulatoria, puede tener un papel terapeutico en aquellos pacientes con IF en los que fracasan los tratamientos estandar no invasivos. Metodos Estudio piloto en pacientes con IF que no han respondido a las medidas estandar (fibra/opiaceos en caso necesario, consejo higienico-dietetico, soporte y rehabilitacion del suelo pelvico y anal) en la Unidad del suelo pelvico (USP) de nuestro hospital. Los pacientes recibieron 2 sesiones semanales de EPNT (Urgent ® PC. Pulsos 0.15–9 mA, de 200 μsecs, frec 20 Hz) de 30 minutos de duracion durante 6 semanas, para luego continuar con 1 sesion semanal hasta los 3 meses y quincenal hasta los 6meses. Se evaluaron el numero de escapes diarios, gravedad de la IF segun escala validada de Wexner y la percepcion subjetiva global del paciente antes y a los 6 meses post-inicio del tratamiento. Los datos descriptivos se dan como medianas [rangos intercuartiles]. La comparacion de las variables pre- y post-tratamiento se analizaron mediante el calculo de los IC95% de la diferencia y t-test para datos pareados. Resultados Se incluyeron cinco pacientes (4 M, 1 H. Edad mediana 68anos [47–70]). El tiempo medio desde el inicio de los sintomas fue 4 anos [2,5–5,5] y la gravedad de la IF pre-tratamiento fue de 10 [7,5–16] segun la escala de Wexner (0–20) con una mediana de escapes diarios de 2 [1–2]. Dos pacientes presentaban incontinencia urinaria (IU) asociada. Ninguno de los pacientes habia sufrido cirugia anorrectal. Una paciente habia sido previamente operada de prolapso vesical. El paciente varon habia sufrido una prostatectomia radical precediendo a la aparicion de la IF, y las mujeres tenian paridad 1-3. Tras 6meses de tratamiento el numero de escapes disminuyo −1,6 (IC95% −0,9, −2,3; p=0,003) y la escala de Wexner −8 (IC95% 0,7, −16,6; p=0,01) hasta 2 [1–6,6]. Tres de los 5 pacientes se consideraron completamente curados de la IF y los otros dos solo manifestaron haber mejorado. Las dos pacientes con IU asociada se declararon curadas post-tratamiento. No hubo efectos secundarios durante el seguimiento. Conclusion La EPTN parece ser un tratamiento seguro que podria ser eficaz en pacientes con IF en los que fallen los tratamientos estandar no invasivos.