JDP2 and ATF3 deficiencies dampen maladaptive cardiac remodeling and preserve cardiac function.

c-Jun dimerization protein (JDP2) and Activating Transcription Factor 3 (ATF3) are closely related basic leucine zipper proteins. Transgenic mice with cardiac expression of either JDP2 or ATF3 showed maladaptive remodeling and cardiac dysfunction. Surprisingly, JDP2 knockout (KO) did not protect the heart following transverse aortic constriction (TAC). Instead, the JDP2 KO mice performed worse than their wild type (WT) counterparts. To test whether the maladaptive cardiac remodeling observed in the JDP2 KO mice is due to ATF3, ATF3 was removed in the context of JDP2 deficiency, referred as double KO mice (dKO). Mice were challenged by TAC, and followed by detailed physiological, pathological and molecular analyses. dKO mice displayed no apparent differences from WT mice under unstressed condition, except a moderate better performance in dKO male mice. Importantly, following TAC the dKO hearts showed low fibrosis levels, reduced inflammatory and hypertrophic gene expression and a significantly preserved cardiac function as compared with their WT counterparts in both genders. Consistent with these data, removing ATF3 resumed p38 activation in the JDP2 KO mice which correlates with the beneficial cardiac function. Collectively, mice with JDP2 and ATF3 double deficiency had reduced maladaptive cardiac remodeling and lower hypertrophy following TAC. As such, the worsening of the cardiac outcome found in the JDP2 KO mice is due to the elevated ATF3 expression. Simultaneous suppression of both ATF3 and JDP2 activity is highly beneficial for cardiac function in health and disease

Observational cohort study of IP-10's potential as a biomarker to aid in inflammation regulation within a clinical decision support protocol for patients with severe COVID-19.

BackgroundTreatment of severely ill COVID-19 patients requires simultaneous management of oxygenation and inflammation without compromising viral clearance. While multiple tools are available to aid oxygenation, data supporting immune biomarkers for monitoring the host-pathogen interaction across disease stages and for titrating immunomodulatory therapy is lacking.MethodsIn this single-center cohort study, we used an immunoassay platform that enables rapid and quantitative measurement of interferon γ-induced protein 10 (IP-10), a host protein involved in lung injury from virus-induced hyperinflammation. A dynamic clinical decision support protocol was followed to manage patients infected with severe acute respiratory syndrome coronavirus 2 and examine the potential utility of timely and serial measurements of IP-10 as tool in regulating inflammation.ResultsOverall, 502 IP-10 measurements were performed on 52 patients between 7 April and 10 May 2020, with 12 patients admitted to the intensive care unit. IP-10 levels correlated with COVID-19 severity scores and admission to the intensive care unit. Among patients in the intensive care unit, the number of days with IP-10 levels exceeding 1,000 pg/mL was associated with mortality. Administration of corticosteroid immunomodulatory therapy decreased IP-10 levels significantly. Only two patients presented with subsequent IP-10 flare-ups exceeding 1,000 pg/mL and died of COVID-19-related complications.ConclusionsSerial and readily available IP-10 measurements potentially represent an actionable aid in managing inflammation in COVID-19 patients and therapeutic decision-making.Trial registrationClinicaltrials.gov, NCT04389645, retrospectively registered on May 15, 2020

Influence of socio-economic status on functional recovery after ARDS caused by SARS-CoV-2: the multicentre, observational RECOVIDS study

International audiencePurpose: Survivors after acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19) are at high risk of developing respiratory sequelae and functional impairment. The healthcare crisis caused by the pandemic hit socially disadvantaged populations. We aimed to evaluate the influence of socio-economic status on respiratory sequelae after COVID-19 ARDS.Methods: We carried out a prospective multicenter study in 30 French intensive care units (ICUs), where ARDS survivors were pre-enrolled if they fulfilled the Berlin ARDS criteria. For patients receiving high flow oxygen therapy, a flow ≥ 50 l/min and an FiO2 ≥ 50% were required for enrollment. Socio-economic deprivation was defined by an EPICES (Evaluation de la Précarité et des Inégalités de santé dans les Centres d'Examens de Santé - Evaluation of Deprivation and Inequalities in Health Examination Centres) score ≥ 30.17 and patients were included if they performed the 6-month evaluation. The primary outcome was respiratory sequelae 6 months after ICU discharge, defined by at least one of the following criteria: forced vital capacity < 80% of theoretical value, diffusing capacity of the lung for carbon monoxide < 80% of theoretical value, oxygen desaturation during a 6-min walk test and fibrotic-like findings on chest computed tomography.Results: Among 401 analyzable patients, 160 (40%) were socio-economically deprived and 241 (60%) non-deprived; 319 (80%) patients had respiratory sequelae 6 months after ICU discharge (81% vs 78%, deprived vs non-deprived, respectively). No significant effect of socio-economic status was identified on lung sequelae (odds ratio (OR), 1.19 [95% confidence interval (CI), 0.72-1.97]), even after adjustment for age, sex, most invasive respiratory support, obesity, most severe P/F ratio (adjusted OR, 1.02 [95% CI 0.57-1.83]).Conclusions: In COVID-19 ARDS survivors, socio-economic status had no significant influence on respiratory sequelae 6 months after ICU discharge

Correction: Influence of socio-economic status on functional recovery after ARDS caused by SARS-CoV-2: the multicentre, observational RECOVIDS study

International audienc

Clinical practice guidelines for evidence-based management of sedoanalgesia in critically ill adult patients

El óptimo manejo de la sedación, analgesia y delirium ofrece al paciente crítico comodidad y seguridad, facilita el buen desarrollo de medidas de soporte y manejo integral y disminuye complicaciones, impactando en un mejor desenlace. Actualizar la Guía de práctica clínica basada en la evidencia para el manejo de la sedoanalgesia en el paciente adulto críticamente enfermo publicada en Medicina Intensiva en el 2007 y dar recomendaciones para el manejo de la sedación, analgesia y delirium. Se reunió un grupo de 21 intensivistas procedentes de 9 países de la Federación Panamericana e Ibérica de Sociedades de Medicina Crítica y Terapia Intensiva, 3 de ellos además especialistas en epidemiología clínica y metodología para elaboración de guías. Se acogió la propuesta del Grading of Recommendations Assessment, Development and Evaluation Working Group para emitir el grado de recomendación y evaluar la calidad de la evidencia. La fuerza de las recomendaciones fue calificada como 1 = fuerte, o 2 = débil, y la calidad de la evidencia como A = alta, B = moderada, o C = baja. Expertos en búsqueda de literatura apoyaron con esta estrategia de búsqueda: MEDLINE a través de PUBMED, bases de datos de la biblioteca Cochrane a través de The Cochrane Library y la base de datos Literatura Latinoamericana y del Caribe en Ciencias de la Salud. Los miembros asignados a las 11 secciones de la guía, basándose en la revisión de la literatura, presentaron las recomendaciones, sustentadas y discutidas en sesiones plenarias, aprobando aquellas que superaron el 80% del consenso. La elaboración de las guías contó con el soporte de la Asociación Colombiana de Medicina Crítica y Cuidado Intensivo. Para la elaboración de la guía fueron finalmente seleccionadas 467 referencias, observándose un importante aumento en el número y calidad de los estudios, permitiendo realizar 64 fuertes recomendaciones con evidencia alta y moderada, contrastando con las 28 de la edición anterior. Esta guía contiene recomendaciones y sugerencias basadas en la mejor evidencia para el manejo de la sedación, analgesia y delirium del paciente crítico, incluyendo un paquete de medidas (bundle). Se destacan: evaluación del dolor y la agitación/sedación mediante escalas; usar inicialmente opioides para el control de la analgesia, adicionando técnicas multimodales para disminuir consumo de opioides; promover el menor nivel de sedación necesario, evitando la sobresedación; en caso de requerir medicamentos sedantes, escoger el más apropiado, evitando el uso rutinario de benzodiazepinas; por último, identificar factores de riesgo para delirium, prevenirlo, diagnosticarlo y manejarlo, con el medicamento más conveniente, ya sea haloperidol, antipsicóticos atípicos o dexmedetomidina, evitando el uso de benzodiazepinas y disminuyendo el uso de opioides.Optimal management of sedation, analgesia and delirium offers comfort and security for the critical care patient, allows support measures to be applied more easily and enables an integral approach of medical care, at the same time that lowers the incidence of complications, wich translates in better patient outcomes. To update the Guía de práctica clínica basada en la evidencia para el manejo de la sedoanalgesia en el paciente adulto críticamente enfermo published in Medicina Intensiva in 2007, and give recommendations for the management of sedation, analgesia, and delirium. A group of 21 intensivists from 9 countries of the Federación Panamericana e Ibérica de Sociedades de Medicina Crítica y Terapia Intensiva, 3 of them also specialists in clinical epidemiology and methodology, gathered for the development of guidelines. Assessment of evidence quality and recommendations were made based on the Grading of Recommendations Assessment, Development and Evaluation system. Strength of recommendations was classified as 1 = strong, or 2 = weak, and quality of evidence as A = high, B = moderate, or C = low. Two authors searched the following databases: MEDLINE through PUBMED, The Cochrane Library and Literatura Latinoamericana y del Caribe en Ciencias de la Salud and retrieved pertinent information. Members assigned to the 11 sections of the guidelines, based on the literature review, formulated the recommendations, that were discussed in plenary sessions. Only those recommendations that achieved more than 80% of consensus were approved for the final document. The Colombian Association of Critical Medicine and Intensive Care (AMCI) supported the elaboration of this guidelines. Four hundred sixty-seven articles were included for review. An increase in number and quality of publications was observed. This allowed to generate 64 strong recommendations with high and moderate quality of evidence in contrast to the 28 recommendations of the previous edition. This Guidelines contains recommendations and suggestions based on the best evidence available for the management of sedation, analgesia and delirium of the critically ill patient, including a bundle of strategies that serves this purpose. We highlight the assessment of pain and agitation/sedation through validated scales, the use of opioids initially to apropiate analgesic control, associated with multimodal strategies in order to reduce opioide consumption; to promote the lowest level of sedation necessary avoiding over-sedation. Also, in case of the need of sedatives, choose the most appropiate for the patient needs, avoiding the use of benzodiazepines and identify risk factors for delirium, in order to prevent its occurrence, diagnose delirium and treat it with the most suitable pharmacological agent, whether it is haloperidol, atypical antipsychotics or dexmedetomidine, once again, avoiding the use of benzodiazepines and decreasing the use of opioids