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151. Gene Expression Profiling Of Sepsis Patients Reveals Inflammasome-Mediated Susceptibility To Acute Respiratory Distress Syndrome Development

Author

Anthony F. Massaro, Rebecca M. Baron, Lee Gazourian, Tamas Dolinay, Roberto Lanazury, Augustine M.K. Choi, Laura E. Fredenburgh, and Judie A. Howrylak

Subjects
Gene expression profiling, Sepsis, medicine.medical_specialty, business.industry, Immunology, medicine, Inflammasome, Acute respiratory distress, Intensive care medicine, medicine.disease, business, medicine.drug
Published
2011

153. Airway Reactivity And Persistent Inflammation Is Associated With Antigen Presenting Cell Population Shifts In A Murine Model Of Chronic Inhalational Endotoxin Exposure

Author

Manuela Cernadas, Oliver Hofmann, Jennifer M. Austin, Miguel A. Pinilla, Alvaro Macias, Peggy S. Lai, Ronald D. Brown, Winston Hide, Joshua A. Englert, David C. Christiani, and Rebecca M. Baron

Subjects
Pathology, medicine.medical_specialty, education.field_of_study, business.industry, Population, Persistent inflammation, Murine model, Immunology, medicine, Reactivity (chemistry), education, Antigen-presenting cell, Airway, business
Published
2011

155. Cytokine Profile In Bronchiolitis Obliterans Syndrome Following Allogeneic Hematopoietic Stem Cell Transplantation

Author

Rebecca M. Baron, Gerald L. Weinhouse, Jerome Ritz, Ruby Ibanga, Joseph H. Antin, Angela J. Rogers, Lee Gazourian, Edwin K. Silverman, Robert J. Soiffer, Vincent T. Ho, and Augustine M.K. Choi

Subjects
business.industry, Cytokine profile, medicine.medical_treatment, Immunology, medicine, Bronchiolitis obliterans, Hematopoietic stem cell transplantation, medicine.disease, business
Published
2011

159. Distamycin A Inhibits HMGA1-Binding to the P-Selectin Promoter and Attenuates Lung and Liver Inflammation during Murine Endotoxemia

Author

Matthew D. Layne, Rebecca M. Baron, Raymond Reeves, Cailin Harris, Alvaro Macias, Su Wol Chung, Silvia Lopez-Guzman, Dario F. Riascos, Mark A. Perrella, Guiying Cheng, and Ulrich H. von Andrian

Subjects
Male, Neutrophils, Science, Endothelial cells, Plasma protein binding, Cell Communication, Lung injury, Biology, Transfection, DNA-binding protein, chemistry.chemical_compound, Mice, Critical Care and Emergency Medicine/Sepsis and Multiple Organ Failure, Transcription factors, Animals, Humans, HMGA1a Protein, Promoter Regions, Genetic, Gene, Transcription factor, Molecular Biology, Respiratory Medicine, Lung, Inflammation, Multidisciplinary, Distamycins, NF-kappa B, Endothelial Cells, NFKB1, Molecular biology, AT Rich Sequence, Endotoxemia, Gene regulation, DNA binding site, Endotoxins, Mice, Inbred C57BL, P-Selectin, chemistry, Liver, Medicine, Cytokines, Cattle, DNA, Radiolabeling, Research Article, Protein Binding
Abstract

BackgroundThe architectural transcription factor High Mobility Group-A1 (HMGA1) binds to the minor groove of AT-rich DNA and forms transcription factor complexes ("enhanceosomes") that upregulate expression of select genes within the inflammatory cascade during critical illness syndromes such as acute lung injury (ALI). AT-rich regions of DNA surround transcription factor binding sites in genes critical for the inflammatory response. Minor groove binding drugs (MGBs), such as Distamycin A (Dist A), interfere with AT-rich region DNA binding in a sequence and conformation-specific manner, and HMGA1 is one of the few transcription factors whose binding is inhibited by MGBs.ObjectivesTo determine whether MGBs exert beneficial effects during endotoxemia through attenuating tissue inflammation via interfering with HMGA1-DNA binding and modulating expression of adhesion molecules.Methodology/principal findingsAdministration of Dist A significantly decreased lung and liver inflammation during murine endotoxemia. In intravital microscopy studies, Dist A attenuated neutrophil-endothelial interactions in vivo following an inflammatory stimulus. Endotoxin induction of P-selectin expression in lung and liver tissue and promoter activity in endothelial cells was significantly reduced by Dist A, while E-selectin induction was not significantly affected. Moreover, Dist A disrupted formation of an inducible complex containing NF-kappaB that binds an AT-rich region of the P-selectin promoter. Transfection studies demonstrated a critical role for HMGA1 in facilitating cytokine and NF-kappaB induction of P-selectin promoter activity, and Dist A inhibited binding of HMGA1 to this AT-rich region of the P-selectin promoter in vivo.Conclusions/significanceWe describe a novel targeted approach in modulating lung and liver inflammation in vivo during murine endotoxemia through decreasing binding of HMGA1 to a distinct AT-rich region of the P-selectin promoter. These studies highlight the ability of MGBs to function as molecular tools for dissecting transcriptional mechanisms in vivo and suggest alternative treatment approaches for critical illness.

Published
2010

166. Inflammasome Mediators Predict Disease Severity and Mortality in Patients with Sepsis and Acute Respiratory Distress Syndrome

Author

Anthony F. Massaro, Rebecca M. Baron, Tamas Dolinay, Augustine M.K. Choi, Kiichi Nakahira, Laura E. Fredenburgh, and Roberto Lanazury

Subjects
Sepsis, medicine.medical_specialty, Disease severity, business.industry, medicine, In patient, Inflammasome, Acute respiratory distress, medicine.disease, Intensive care medicine, business, medicine.drug
Published
2009

167. Pathobiology of sepsis: are we still asking the same questions?

Author

Rebecca M. Baron, Mark A. Perrella, and Miriam J. Baron

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, Bacteriological Techniques, business.industry, Clinical Biochemistry, MEDLINE, Historical Article, History, 19th Century, Cell Biology, History, 20th Century, medicine.disease, Infections, Sepsis, Medicine, Animals, Humans, Female, business, Intensive care medicine, Molecular Biology
Published
2006

168. [Untitled]

Author

Robert L. Owens, Amar Vedamurthy, Jeremy R. Beitler, Rebecca M. Baron, Anthony F. Massaro, Gerald L. Weinhouse, Susan Lagambina, and Paul Nuccio

Subjects
medicine.medical_specialty, ARDS, business.industry, medicine, Acute respiratory distress, Pulmonary compliance, Critical Care and Intensive Care Medicine, Intensive care medicine, business, medicine.disease
Published
2014

169. [Untitled]

Author

Kenneth B. Christopher, Augusto A. Litonjua, Augustine M.K. Choi, Rebecca M. Baron, Lee Gazourian, Angela J. Rogers, Laura E. Fredenburgh, and Anthony F. Massaro

Subjects
business.industry, Critical illness, Metabolome, Vitamin D and neurology, Medicine, Physiology, Critical Care and Intensive Care Medicine, business
Published
2014

170. Reduction of nitric oxide synthase 2 expression by distamycin A improves survival from endotoxemia

Author

Irvith M. Carvajal, Xiaoli Liu, Rebecca M. Baron, Matthew D. Layne, Alvaro Macias, Yen-Hsu Chen, Laura E. Fredenburgh, Rachel Okabe, Mark A. Perrella, and Kuniaki Ejima

Subjects
Lipopolysaccharides, Male, Immunology, Nitric Oxide Synthase Type II, Cell Line, chemistry.chemical_compound, Interferon-gamma, Mice, In vivo, parasitic diseases, Immunology and Allergy, Animals, Enzyme Inhibitors, Enhancer, Overproduction, Promoter Regions, Genetic, Transcription factor, Cells, Cultured, Mice, Knockout, biology, Distamycins, Nitric oxide synthase 2, respiratory system, Phosphoproteins, Molecular biology, In vitro, Endotoxemia, DNA binding site, DNA-Binding Proteins, Mice, Inbred C57BL, Disease Models, Animal, chemistry, Gene Expression Regulation, Enzyme Induction, biology.protein, Macrophages, Peritoneal, Hypotension, Nitric Oxide Synthase, DNA, Interferon Regulatory Factor-1, Protein Binding
Abstract

NO synthase 2 (NOS2) plays an important role in endotoxemia through overproduction of NO. Distamycin A (Dist A) belongs to a class of drugs termed minor-groove DNA binders, which can inhibit transcription factor binding to AT-rich regions of DNA. We and others have previously shown that AT-rich regions of DNA surrounding transcription factor binding sites in the NOS2 promoter are critical for NOS2 induction by inflammatory stimuli in vitro. Therefore, we hypothesized that Dist A would attenuate NOS2 up-regulation in vivo during endotoxemia and improve animal survival. C57BL/6 wild-type (WT) mice treated with Dist A and LPS (endotoxin) showed significantly improved survival compared with animals treated with LPS alone. In contrast, LPS-treated C57BL/6 NOS2-deficient (NOS2−/−) mice did not benefit from the protective effect of Dist A on mortality from endotoxemia. Treatment with Dist A resulted in protection from hypotension in LPS-treated WT mice, but not in NOS2−/− mice. Furthermore, LPS-induced NOS2 expression was attenuated in vivo (WT murine tissues) and in vitro (primary peritoneal and RAW 264.7 murine macrophages) with addition of Dist A. Dist A selectively decreased IFN regulatory factor-1 DNA binding in the enhancer region of the NOS2 promoter, and this IFN regulatory factor-1 site is critical for the effect of Dist A in attenuating LPS induction of NOS2. Our data point to a novel approach in modulating NOS2 expression in vivo during endotoxemia and suggest the potential for alternative treatment approaches for critical illness.

Published
2004

171. Nitric oxide synthase-2 down-regulates surfactant protein-B expression and enhances endotoxin-induced lung injury in mice

Author

Mark A. Perrella, Irvith M. Carvajal, Larry A. Sonna, Edward P. Ingenito, George T. De Sanctis, Kathleen J. Haley, Laura E. Fredenburgh, Rebecca M. Baron, Yolanda Porrata, Michael L. Cullivan, and Xiaoli Liu

Subjects
Lipopolysaccharides, Transcription, Genetic, Nitric Oxide Synthase Type II, Inflammation, Lung injury, Nitric Oxide, Biochemistry, Nitric oxide, chemistry.chemical_compound, Leukocyte Count, Mice, parasitic diseases, Genetics, medicine, Animals, Surface Tension, RNA, Messenger, Molecular Biology, Lung, Bone Marrow Transplantation, Aerosols, Mice, Knockout, Respiratory Distress Syndrome, Pulmonary Surfactant-Associated Protein B, biology, Pulmonary Surfactant-Associated Protein A, Interleukin-6, Tumor Necrosis Factor-alpha, Surfactant dysfunction, Nitric oxide synthase 2, respiratory system, Pulmonary Surfactant-Associated Protein C, Epithelium, Surfactant protein B, Cell biology, Specific Pathogen-Free Organisms, Mice, Inbred C57BL, medicine.anatomical_structure, chemistry, Radiation Chimera, Immunology, Models, Animal, biology.protein, medicine.symptom, Nitric Oxide Synthase, Bronchoalveolar Lavage Fluid, Biotechnology
Abstract

Acute respiratory distress syndrome (ARDS) is a life-threatening ailment characterized by severe lung injury involving inflammatory cell recruitment to the lung, cytokine production, surfactant dysfunction, and up-regulation of nitric oxide synthase 2 (NOS2) resulting in nitric oxide (NO) production. We hypothesized that NO production from NOS2 expressed in lung parenchymal cells in a murine model of ARDS would correlate with abnormal surfactant function and reduced surfactant protein-B (SP-B) expression. Pulmonary responses to nebulized endotoxin (lipopolysaccharide, LPS) were evaluated in wild-type (WT) mice, NOS2 null (-/-) mice, and NOS2-chimeric animals derived from bone marrow transplantation. NOS2-/- animals exhibited significantly less physiologic lung dysfunction and loss of SP-B expression than did WT animals. However, lung neutrophil recruitment and bronchoalveolar lavage cytokine levels did not significantly differ between NOS2-/- and WT animals. Chimeric animals for NOS2 exhibited the phenotype of the recipient and therefore demonstrated that parenchymal production of NOS2 is critical for the development of LPS-induced lung injury. Furthermore, administration of NO donors, independent of cytokine stimulation, decreased SP-B promoter activity and mRNA expression in mouse lung epithelial cells. This study demonstrates that expression of NOS2 in lung epithelial cells is critical for the development of lung injury and mediates surfactant dysfunction independent of NOS2 inflammatory cell expression and cytokine production.

Published
2004

172. Elk-3 is a transcriptional repressor of nitric-oxide synthase 2

Author

Rebecca M. Baron, Matthew D. Layne, Su Wol Chung, Shaw-Fang Yet, Yen-Hsu Chen, Mark A. Perrella, and Kuniaki Ejima

Subjects
Lipopolysaccharides, Male, animal diseases, Molecular Sequence Data, Repressor, Nitric Oxide Synthase Type II, Endogeny, Biochemistry, Nitric oxide, Cell Line, Transforming Growth Factor beta1, chemistry.chemical_compound, Mice, fluids and secretions, Mediator, Transforming Growth Factor beta, parasitic diseases, Gene expression, Animals, Amino Acid Sequence, RNA, Messenger, Promoter Regions, Genetic, Molecular Biology, Transcription factor, Oncogene Proteins, Binding Sites, biology, Base Sequence, Proto-Oncogene Proteins c-ets, Nitric oxide synthase 2, Cell Biology, 3T3 Cells, DNA, respiratory system, Molecular biology, Mice, Inbred C57BL, Repressor Proteins, chemistry, biology.protein, Mutagenesis, Site-Directed, Nitric Oxide Synthase, Transforming growth factor, Transcription Factors
Abstract

The inducible isoform of nitric-oxide synthase (NOS2), a key enzyme catalyzing the dramatic increase in nitric oxide by lipopolysaccharide (LPS), plays an important role in the pathophysiology of endotoxemia and sepsis. Recent evidence suggests that Ets transcription factors may contribute to NOS2 induction by inflammatory stimuli. In this study, we investigated the role of Ets transcription factors in the regulation of NOS2 by LPS and transforming growth factor (TGF)-beta 1. Transient transfection assays in macrophages showed that Ets-2 produced an increase in NOS2 promoter activity, whereas the induction by Ets-1 was modest and NERF2 had no effect. Elk-3 (Net/Erp/Sap-2a) markedly repressed NOS2 promoter activity in a dose-dependent fashion, and overexpression of Elk-3 blunted the induction of endogenous NOS2 message. Mutation of the Net inhibitory domain of Elk-3, but not the C-terminal-binding protein interaction domain, partially alleviated this repressive effect. We also found that deletion of the Ets domain of Elk-3 completely abolished its repressive effect on the NOS2 promoter. LPS administration to macrophages led to a dose-dependent decrease in endogenous Elk-3 mRNA levels, and this decrease in Elk-3 preceded the induction of NOS2 mRNA. In a mouse model of endotoxemia, the expression of Elk-3 in kidney, lung, and heart was significantly down-regulated after systemic administration of LPS, and this down-regulation also preceded NOS2 induction. Moreover, TGF-beta 1 significantly increased endogenous Elk-3 mRNA levels that had been down-regulated by LPS in macrophages. This increase in Elk-3 correlated with a TGF-beta 1-induced down-regulation of NOS2. Taken together, our data suggest that Elk-3 is a strong repressor of NOS2 promoter activity and mRNA levels and that endogenous expression of Elk-3 inversely correlates with NOS2. Thus, Elk-3 may serve as an important mediator of NOS2 gene expression.

Published
2003

173. Cyclooxygenase-2-deficient mice are resistant to endotoxin-induced inflammation and death

Author

Kuniaki Ejima, Patricia A. Kritek, Bruce D. Levy, Irvith M. Carvajal, Jeffrey Vom Saal, Rebecca M. Baron, Matthew D. Layne, Yen-Hsu Chen, Mark A. Perrella, and Shaw-Fang Yet

Subjects
Lipopolysaccharides, Lipopolysaccharide, medicine.medical_treatment, Active Transport, Cell Nucleus, Nitric Oxide Synthase Type II, Inflammation, Biochemistry, Models, Biological, Gene Expression Regulation, Enzymologic, Sepsis, chemistry.chemical_compound, Mice, Genetics, medicine, Animals, Molecular Biology, Transcription factor, Escherichia coli Infections, Mice, Knockout, biology, business.industry, NF-kappa B, Nitric oxide synthase 2, Membrane Proteins, NF-κB, DNA, medicine.disease, Survival Analysis, Endotoxemia, Isoenzymes, Cytokine, chemistry, Cyclooxygenase 2, Prostaglandin-Endoperoxide Synthases, Immunology, Heme Oxygenase (Decyclizing), biology.protein, Cytokines, Cyclooxygenase, medicine.symptom, Nitric Oxide Synthase, business, Heme Oxygenase-1, Biotechnology, Transcription Factors
Abstract

Sepsis is a systemic inflammatory response to a blood-borne infection that is associated with an extremely high rate of morbidity and mortality. The present study investigates the role of cyclooxygenase (COX)-2 in host responses to bacterial endotoxemia. After administration of Escherichia coli lipopolysaccharide, 50% of wild-type mice die within 96 h. COX-2 deficient mice displayed a dramatic improvement in survival with reduced leukocyte infiltration into critical organs (kidneys and lungs) and a blunted and delayed induction of the cytokine inducible genes nitric oxide synthase 2 and heme oxygenase-1. Translocation and activation of transcription factors important for signaling events during an inflammatory response, such as nuclear factor (NF)-kappaB, were also markedly reduced. While the absence of COX-2 did not alter the induction of several pro-inflammatory cytokines in tissue macrophages, induction of the anti-inflammatory cytokine IL-10 was exaggerated. Administration of IL-10 to wild-type mice reduced NF-kappaB activation. Taken together, our data suggest that COX-2 deficient mice are resistant to many of the detrimental consequences of endotoxemia. These beneficial effects occur, in part, by a compensatory increase in IL-10 that counterbalances the pro-inflammatory host response to endotoxemia.

Published
2003

174. Rebuttal From Dr Baron

Author

Rebecca M. Baron

Subjects
Pulmonary and Respiratory Medicine, Activated Partial Thromboplastin Time measurement, business.industry, Rebuttal, Cardiac catheterization lab, Critical Care and Intensive Care Medicine, medicine.disease, Procedural complication, Critical illness, medicine, Medical emergency, Theology, Cardiology and Cardiovascular Medicine, business
Published
2012

175. Constitutive and cytokine-induced expression of the ETS transcription factor ESE-3 in the lung

Author

Rebecca M. Baron, Xuesong Gu, Towia A. Libermann, Scott T. Weiss, Matthew D. McKenna, Kathleen J. Haley, Richard J. Riese, Louis Le, Arlene Hallock, Jeffrey M. Drazen, Lyle J. Palmer, Eric S. Silverman, Stephanie A. Shore, Antonio Tugores, and Venkat Subramaniam

Subjects
Pulmonary and Respiratory Medicine, Transcription, Genetic, medicine.medical_treatment, Clinical Biochemistry, Molecular Sequence Data, Repressor, Gene Expression, Antineoplastic Agents, Bronchi, Respiratory Mucosa, Biology, Transfection, Mice, Transcription (biology), medicine, Animals, Humans, RNA, Messenger, Promoter Regions, Genetic, Molecular Biology, Gene, Messenger RNA, Proto-Oncogene Proteins c-ets, Activator (genetics), Tumor Necrosis Factor-alpha, ETS transcription factor family, Epithelial Cells, Muscle, Smooth, Cell Biology, 3T3 Cells, respiratory system, Fibroblasts, respiratory tract diseases, Cell biology, DNA-Binding Proteins, Cytokine, Cancer research, Tumor necrosis factor alpha, Matrix Metalloproteinase 1, Interleukin-1, Transcription Factors
Abstract

Family studies of asthma suggest that the genes ESE-2 and ESE-3 contain polymorphisms that contribute to disease susceptibility. Each gene codes for an ETS transcription factor that is characterized by epithelium-restricted constitutive expression and may function as a context-dependent activator or repressor of transcription; however, nothing is known about the role of these genes in lung homeostasis or the pathogenesis of airway disease. In this study, we show that ESE-3 mRNA and protein are constitutively expressed in bronchial and mucous gland epithelial cells. Consistent with these findings, ESE-3 mRNA is constitutively expressed in human bronchial epithelial cells grown in tissue culture. In contrast, ESE-2 mRNA could not be detected in the lung or cultured human bronchial epithelial cells. Human bronchial smooth muscle cells and fibroblasts do not constitutively express ESE-3; however, after stimulation with interleukin-1beta or tumor necrosis factor-alpha, levels of ESE-3 mRNA and protein increase dramatically by 24 h. This cytokine induction is dose-dependent and abrogated by specific inhibitors of the MEK1/2 (U0126) and p38 (SB03580) signal transduction pathways. Overexpression of ESE-3 protein in 3T3 cells and human bronchial smooth muscle cells inhibits MMP-1 promoter activity, suggesting that ESE-3 may function as a transcriptional repressor.

Published
2002

176. DNA sequence variants in epithelium-specific ETS-2 and ETS-3 are not associated with asthma

Author

Rebecca M. Baron, Towia A. Libermann, Scott T. Weiss, Louis Le, Jeffrey M. Drazen, Stacey Gabriel, Arlene Hallock, Lyle J. Palmer, Larry A. Sonna, Kelan G. Tantisira, and Eric S. Silverman

Subjects
Pulmonary and Respiratory Medicine, Adult, Genetic Markers, Male, Candidate gene, Adolescent, Genotype, Biology, Critical Care and Intensive Care Medicine, Population stratification, Polymorphism, Single Nucleotide, Genetic determinism, Linkage Disequilibrium, Gene Frequency, Polymorphism (computer science), Predictive Value of Tests, Forced Expiratory Volume, medicine, Humans, Genetic Predisposition to Disease, Asthma, Genetic association, Genetics, Autosome, Base Sequence, Proto-Oncogene Proteins c-ets, Genetic Variation, Odds ratio, Immunoglobulin E, Middle Aged, medicine.disease, United States, DNA-Binding Proteins, Case-Control Studies, Multivariate Analysis, Female, Transcription Factors
Abstract

Epithelium-specific ETS-2 and ETS-3 are transcription factors that have been proposed as asthma candidate genes. To investigate the association of sequence variants in these genes with asthma, we conducted a case-control association analysis in a sample of 311 white subjects with asthma and 177 white subjects without asthma. Common polymorphisms in these genes were detected by sequencing DNA from 32 cell lines obtained from Coriel (Camden, NJ). Seven noncoding or synonymous single-nucleotide polymorphisms were detected: three in epithelium-specific ETS-2 and four in epithelium-specific ETS-3. Subjects were genotyped at all loci by mass spectroscopy. To ensure the suitability of our control subjects, we also genotyped subjects at 49 unlinked polymorphisms evenly distributed throughout the autosomes and found no evidence of population stratification. Logistic regression adjusted for age and sex suggested a weak association of one epithelium-specific ETS-2 polymorphism with asthma diagnosis (odds ratio = 1.89, 95% confidence interval = 1.13-3.18, p = 0.02). Total serum immunoglobulin E and FEV1 predicted levels were not associated with any of the polymorphisms. Extended haplotyping indicated linkage disequilibrium in these genes; however, no association or epistatic interaction was found. This study suggests that epithelium-specific ETS-2 and ETS-3 genes are unlikely to contain polymorphic loci that have a major impact on asthma susceptibility in our population.

Published
2002

177. The pharmacogenetics of asthma: a candidate gene approach

Author

Rebecca M. Baron, Stephen B. Liggett, Eric S. Silverman, Jeffrey M. Drazen, Scott T. Weiss, S Bolk, L J Rosenwasser, and Erwin W. Gelfand

Subjects
Pharmacology, medicine.medical_specialty, business.industry, education, Medical school, Genetic variants, Adrenergic beta-Agonists, Beclometasone, humanities, Asthma, Genome research, Pharmacogenetics, Family medicine, Immunology, Genetics, medicine, Molecular Medicine, Humans, Leukotriene Antagonists, business, Glucocorticoids, health care economics and organizations, Research center
Abstract

Department of Medicine, Channing Laboratory, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA; 2Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH; Departments of Medicine and Pediatrics, National Jewish Medical and Research Center, University of Colorado Health Sciences Center, Denver, CO; 4Whitehead Institute for Genome Research, Massachusetts Institute of Technology, Boston, MA, USA

Published
2002

178. High-mobility group-I/Y proteins: Potential role in the pathophysiology of critical illnesses

Author

Irvith M, Carvajal, Rebecca M, Baron, and Mark A, Perrella

Subjects
Inflammation, Enhancer Elements, Genetic, Gene Expression Regulation, Sepsis, Models, Immunological, Animals, Humans, Nitric Oxide Synthase Type II, HMGA1a Protein, Nitric Oxide Synthase
Abstract

High-mobility group (HMG) proteins are architectural factors that have been shown to play a role in the transcriptional regulation of various mammalian genes. One family of HMG proteins, HMG-I/Y, is known to facilitate the initiation of gene transcription by modifying the conformation of DNA and recruiting transcription factors into an organized complex on transcriptional regulatory regions of specific genes. In many circumstances, the nuclear factor-kappa B family of transcription factors is involved in gene regulation that is mediated by HMG-I/Y. We will review the mechanisms by which HMG-I/Y proteins regulate gene transcription, give an overview of selected genes regulated by HMG-I/Y, summarize the potential roles of these genes in critical illnesses, and provide more detailed information about the role of HMG-I/Y in the regulation of nitric oxide synthase-2 during an inflammatory response, such as endotoxemia/sepsis.

Published
2002

179. Pulmonary Clinicopathological Correlation In Long Term Survivors Following Allogeneic Hematopoietic Stem Cell Transplantation: An Autopsy Series

Author

Laura Spring, Lee Gazourian, Lynette Sholl, Jyothi Jagannathan, Emily Meserve, Ami S. Bhatt, Gerald L. Weinhouse, Victor Pinto-Plata, Robert J. Soiffer, Joseph H. Antin, Vincent T. Ho, Rebecca M. Baron, and George R. Washko

Subjects
medicine.medical_specialty, education.field_of_study, Lung, business.industry, Vascular disease, medicine.medical_treatment, Immunology, Population, Bronchiolitis obliterans, Autopsy, Cell Biology, Hematology, Hematopoietic stem cell transplantation, medicine.disease, Biochemistry, Gastroenterology, Surgery, Transplantation, Graft-versus-host disease, medicine.anatomical_structure, Internal medicine, medicine, business, education
Abstract

Background Pulmonary complications are a significant cause of morbidity and mortality following Hematopoietic Stem Cell Transplantation (HSCT). It is estimated that they occur in 40-60% of patients, causing 10-40% of transplant-related deaths and resulting in diminished quality of life in those who survive. The wide spectrum of pulmonary complications is believed to be multifactorial, including pretransplant chemoradiation, infection, and graft-versus-host disease (GVHD). The histological spectrum of pulmonary GVHD features interstitial injury, airway injury (including bronchiolitis obliterans), and vascular disease (including veno-occlusive disease). The objective of this study was to compare ante mortem clinical suspicion of pulmonary complications and postmortem findings in a modern HSCT cohort. Methods All patients who underwent allogeneic HSCT at our institution (n=1854) between January 1, 2000 and June 30th 2010 were reviewed. To date we have completed the review of all autopsies (38) in patients who died of any cause greater than one year following HSCT. Presence of pulmonary GVHD was assessed by a pathologist blinded to the autopsy report, according to the categories of injury previously described by Yousem (1995). Lymphocytic infiltration and structural remodeling was scored separately for the airways, vasculature, and interstitium. Cases with extensive lung involvement by infection, malignancy, or other defined process (i.e. aspiration injury) were excluded from analysis. We evaluated the following clinical predictors for an association with development of airway disease and pulmonary vascular disease: patient gender, male patient with female donor, baseline FEV1%, peripheral blood stem cell source, myeloablative conditioning regimen, busulfan based conditioning regimen, patient CMV status, donor CMV status, related donor, matched donor, presence of acute GVHD, presence of chronic GVHD, and donor age. Each predictor was evaluated for significance between cases and controls. Two-sided Fisher’s exact test was used to compare categorical variables between groups, and a 2-sided Wilcoxon Rank-Sum test was used to compare continuous variables. All statistical analyses were performed using SAS9.3. Results A total of 35 (92%) patients had evaluable pathology and were reviewed. Pulmonary complications were felt to contribute to death in 17 (49%) cases, and 28 (80%) of the patients had a diagnosis of chronic GVHD prior to death. Airway disease, interstitial disease, and vascular disease were all clinically under recognized compared to the number of cases detected on autopsy (table 1). Varying degrees of pathological changes were detected (table 2); including 10 (28.6%) patients having bronchiolitis obliterans (BO) and 12 (34.3%) patients having pulmonary veno-oclussive disease (PVOD). Of the patients with PVOD, 12 (86%) also had airway disease (p=0.07). In a univariate analysis, a positive cytomegalovirus (CMV) serology status in the patient was associated with the presence of airway disease (p= Conclusions Pulmonary manifestations of chronic GVHD, particularly BO, were clinically under recognized in our allogeneic HSCT population. Our results also suggest that pulmonary VOD, which has traditionally been considered a rare complication, may be clinically and histologically under recognized. A positive CMV serology status in patients was associated with the occurrence of airway disease. Ablative conditioning and the presence of acute GVHD was associated with the occurrence of vascular disease. Disclosures: No relevant conflicts of interest to declare.

Published
2013

180. Airway Dilation in Bronchiolitis Obliterans After Allogeneic Hematopoietic Stem Cell Transplantation

Author

Robert J. Soiffer, Gerald L. Weinhouse, Jerome Ritz, Rebecca M. Baron, Anna Coronata, Vincent T. Ho, Joseph H. Antin, George R. Washko, Angela J. Rogers, and Lee Gazourian

Subjects
Male, Pathology, Vital capacity, medicine.medical_treatment, Vital Capacity, Hematopoietic stem cell transplantation, 030204 cardiovascular system & hematology, Biochemistry, Pulmonary function testing, 0302 clinical medicine, DLCO, Forced Expiratory Volume, Lung volumes, Bronchiolitis Obliterans, Computed tomography, COPD, 0303 health sciences, Hematopoietic Stem Cell Transplantation, Hematology, Bronchography, Middle Aged, respiratory system, humanities, 3. Good health, 030220 oncology & carcinogenesis, Airway Remodeling, Female, Radiology, Dilatation, Pathologic, Adult, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Bone marrow transplantation, Immunology, Bronchiolitis obliterans, Bronchi, Article, Young Adult, 03 medical and health sciences, FEV1/FVC ratio, Airway disease, medicine, Humans, Aged, 030304 developmental biology, business.industry, Bronchiolitis obliterans syndrome, Cell Biology, medicine.disease, respiratory tract diseases, Transplantation, Case-Control Studies, Tomography, X-Ray Computed, business, Airway, Nuclear medicine, 030215 immunology
Abstract

Abstract 3058 Rationale: Bronchiolitis obliterans syndrome (BOS) is a late, non-infectious pulmonary complication following hematopoietic stem cell transplantation (HSCT). The prevalence is estimated to be between 5–10% after allogeneic HSCT with a significant increase in morbidity and mortality. We were interested in assessing quantitative radiologic characterization of airway remodeling in these subjects. Objectives: To examine quantitative measurements of airway morphology and their correlation with lung function in a cohort of patients who underwent HSCT and developed BOS. Methods: All patients who underwent an allogeneic HSCT at the Dana-Farber Cancer Institute/Brigham and Women's Hospital (n=1854) between January 1st 2000 and June 30th2010 were screened for the development of BOS using modified NIH diagnostic criteria. Clinically acquired high resolution CT (HRCT) scans of the chest were collected. Discrete measures of airway wall area were performed in a total of 16 manually selected airways in the right and left upper and lower lobes using Airway Inspector ( www.airwayinspector.org ). From these measures, the square root of wall area of a 10-mm luminal perimeter (Pi10) was calculated. Spearman correlation was used to assess the relationship between square root of wall area at Pi10 and pulmonary function measures. Paired t-test was used for within group comparisons. Analyses were performed with SAS v. 9.2. Measurements and Main Results: Within our cohort 89 cases of BOS were identified of which 37 patients had HRCT scans available for analysis. 33 patients had pulmonary function tests within 30 days of the HRCT ( Table 1 ). Ten of the 37 BOS patients had a HRCT scan at or prior to transplantation and a HRCT scan available after the diagnosis of BOS. Square root of wall area at Pi10 correlated significantly with FEV1(r = 0.636, p Fig. 1 ), and when adjusted for age, sex and total lung capacity, the correlations remained significant (p Fig 2 ). Conclusions: On HRCT scan BOS is characterized by central airway dilation, the degree of which is correlated to decrements in lung function. Future studies will examine whether chest CT assessment of central airway dilation can be used as a sensitive and specific tool for diagnosis and staging of BOS. Table 1 . Correlation coefficients (r Values) of the univariate regression analysis for square root of wall area at Pi10 with pulmonary function tests. FVC indicates forced vital capacity; FEV1, 1-second forced expiratory volume; FEF25–75 %, forced expiratory flow between 25–75%; VC, vital capacity; IC, inspiratory capacity; ERV, end residual volume; TLC, total lung capacity; RV, residual volume; DLCO,carbon monoxide diffusion capacity PFT r value FVC % 0.546 0.001 FEV1 % 0.636 FEV1/FVC 0.343 NS FEF25–75 % 0.578 0.0004 VC % 0.595 0.002 IC % 0.602 0.002 ERV % −0.353 NS TLC % 0.219 NS RV % −0.561 0.002 RV/TLC % −0.736 DLCO % –0.175 NS Download : Download high-res image (127KB) Download : Download full-size image Figure 1 . A. Graphs of the relationship between Square root of wall area at Pi10 and FEV1 (r = 0.636, p Download : Download high-res image (187KB) Download : Download full-size image Figure 2 . A. Ten BOS patients with Pre BOS diagnosis HRCT scans (on or before transplant) and post diagnosis BOS HRCT scan. * Pre BOS vs. BOS p B. Representative image of pre-transplant CT scan and post diagnosis BOS CT scan demonstrating airway dilation. Disclosures: No relevant conflicts of interest to declare.

Published
2012

181. Low Dose Busulfan Is Associated with Bronchiolitis Obliterans Syndrome Following Allogeneic Hematopoietic Stem Cell Transplantation

Author

Gerald L. Weinhouse, Jerome Ritz, Lee Gazourian, Ruby Igbanga, Vincent T. Ho, George R. Washko, Joseph H. Antin, Robert J. Soiffer, Rebecca M. Baron, and Angela J. Rogers

Subjects
medicine.medical_specialty, Univariate analysis, business.industry, medicine.medical_treatment, Immunology, Respiratory infection, Bronchiolitis obliterans, Cell Biology, Hematology, Hematopoietic stem cell transplantation, medicine.disease, Biochemistry, humanities, Pulmonary function testing, Surgery, Transplantation, FEV1/FVC ratio, Internal medicine, medicine, business, Busulfan, medicine.drug
Abstract

Abstract 3128 Rationale: Bronchiolitis obliterans syndrome (BOS) is the most common late non-infectious pulmonary complication following hematopoietic stem cell transplantation (HSCT). The prevalence is estimated to be between 5–10% after allogeneic HSCT with a significant increase in morbidity and mortality. We conducted a retrospective case control study to evaluate the associations between patients with BOS and those who did not develop airflow obstruction or symptoms. Methods: Between January 1st 2000 and June 30th 2010 all patients who underwent an allogeneic HSCT at the Dana-Farber Cancer Institute/Brigham and Women's Hospital (n=1854) were screened for the development of BOS, using a modified NIH diagnostic criteria. BOS was defined as 1) new onset airflow obstruction, FEV1/FVC ratio ≤0.7 and FEV1 Results: We identified 89 subjects meeting our diagnostic criteria for BOS with a prevalence of 4.8%. The median time from transplantation to meeting criteria for BOS was 491 days (range: 48–2067). Univariate analysis demonstrated that BOS was significantly associated with previously reported risk factors including age, pre-transplantation PFT's, high risk disease, source of peripheral blood stem cells, unrelated donor, history of respiratory infection prior to day 100, and busulfan based conditioning regimens. (all p Conclusion: Our findings extend those from prior reports of risk factors associated with BOS. Our results demonstrate that busulfan, even when used at lower doses in reduced intensity conditioning transplantation, confers an increased risk for BOS. Future studies in prospective cohorts will be important to confirm these findings. Disclosures: No relevant conflicts of interest to declare.

Published
2012

183. Book Review: Preoperative Assessment

Author

Rebecca M. Baron

Subjects
medicine.medical_specialty, business.industry, General surgery, medicine, Critical Care and Intensive Care Medicine, business
Published
2002

184. Preoperative Assessment

Author

Rebecca M. Baron

Subjects
Critical Care and Intensive Care Medicine
Published
2002

185. The ITM2B (BRI2) gene is a target of BCL6 repression: Implications for lymphomas and neurodegenerative diseases

Author

Rebecca M. Baron, Joseph M. Baron, and Beverly W. Baron

Subjects
Lymphoma, ITM2B gene, Deafness, Mice, 0302 clinical medicine, immune system diseases, hemic and lymphatic diseases, 0303 health sciences, Gene knockdown, Membrane Glycoproteins, Neurodegenerative Diseases, Alzheimer's disease, BCL6, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, medicine.anatomical_structure, Proto-Oncogene Proteins c-bcl-6, Molecular Medicine, RNA Interference, Protein Binding, Lymphoma, B-Cell, Cerebellar Ataxia, Blotting, Western, BCL6 target, Biology, Cataract, Article, 03 medical and health sciences, Cell Line, Tumor, medicine, Animals, Humans, Immunoprecipitation, Familial British dementia, Gene, Psychological repression, Molecular Biology, B cell, Adaptor Proteins, Signal Transducing, 030304 developmental biology, Alternative splicing, Germinal center, Blotting, Northern, medicine.disease, Familial Danish dementia, NIH 3T3 Cells, Cancer research, Dementia, 030217 neurology & neurosurgery
Abstract

The human BCL6 gene encodes a transcriptional repressor that is crucial for germinal center B cell development and T follicular helper cell differentiation. It is involved in the pathogenesis of certain human lymphomas. In an effort to identify targets of BCL6 repression, we used a previously described cell system in which BCL6 repressive effects are inhibited, followed by subtractive hybridization, and identified the integral membrane 2B gene (ITM2B, formerly BRI2) as a potential target. Here we show that BCL6 can bind to its preferential consensus binding site within the first intron of ITM2B and represses its transcription. Knockdown of endogenous BCL6 in a human B cell lymphoma line increases ITM2B expression. Further, there is an inverse relationship between the expression levels of BCL6 and ITM2B proteins in 16 human B- and T-cell lymphomas studied by immunohistochemistry. Both the BCL6 and ITM2B proteins are expressed ubiquitously. Similar to some other targets of BCL6, a short form of the ITM2B protein generated by alternative splicing induces apoptosis in hematopoietic cell lines. Molecular alterations in the ITM2B gene are associated with two neurodegenerative diseases, Familial British and Familial Danish dementia. ITM2B dysfunction also may be relevant for the development of Alzheimer's disease. Our data confirm ITM2B as a target of BCL6 repression in lymphoma. A further understanding of the genes that function as regulators of the ITM2B protein may provide insights for the development of new molecular tools not only for targeted lymphoma therapy but also for the treatment of these dementias.

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186. 0474. Circulating mitochondrial dna and vitamin d in critical illness

Author

Amk Choi, Augusto A. Litonjua, Rebecca M. Baron, Lee Gazourian, Laura E. Fredenburgh, Kenneth B. Christopher, Kiichi Nakahira, and Anthony F. Massaro

Subjects
Vitamin, medicine.medical_specialty, Mitochondrial DNA, APACHE II, business.industry, Apache II score, Critical Care and Intensive Care Medicine, Gastroenterology, Surgery, chemistry.chemical_compound, chemistry, Internal medicine, Cohort, Critical illness, Vitamin D and neurology, Oral Presentation, Medicine, In patient, business
Abstract

Of the cohort patients studied, 37% were women and 84% were white. The mean age at critical care initiation was 53.5 years (SD 14.2). The mean APACHE II score was 24.5 (SD 8.3), while 100% of the cohort had SIRS, 71% had a source of infection identified and 18% had ARDS. The mean plasma 25(OH)D was 20.6 (SD 11.4) and 28.6% of the study cohort had plasma 25(OH)D ≤ 15 ng/mL. Gross unadjusted 30-day mortality was 26.5%. The mean (SD) plasma 25(OH)D was significantly higher in patients with mtDNA < 4000 copies/ml [25(OH)D 22.0 (11.2) ng/ml] relative to those with mtDNA ≥ 4000 copies/ml [25(OH)D 14.9 (10.9) ng/mL]; P < 0.001. When the cohort was analyzed with the exposure as plasma 25(OH)D and the outcome as plasma mtDNA ≥ 4000 copies/ml, we find that patients with plasma 25(OH)D < 15 ng/mL have a significantly higher odds of having plasma mtDNA ≥ 4000 copies/ml (unadjusted OR= 7.50, 95% CI 1.53-36.79; P=0.013). 25(OH)D in the cohort remains a significant predictor of plasma mtDNA ≥ 4000 copies/ml following adjustment for age, gender, race and APACHE II (adjusted OR= 13.19, 95% CI 1.69-103.34; P=0.014). Cox proportional hazard multivariable regression modeling, adjusting for ap rioridefined covariates comprising APACHE II score, age, sex, race, and plasma 25(OH)D, showed that mtDNA was predictive of all cause mortality following critical care (HR, 4.02; 95% CI, 1.14-14.20 ng/ml). Conclusions 25(OH)D levels are associated with circulating mtDNA levels. This study cannot determine a relationship between 25(OH)D and mtDNA beyond association but raises the question as to whether vitamin D-mediated pathways might play a role in linking autophagic and inflammasome processes.

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187. Timing of invasive mechanical ventilation and death in critically ill adults with COVID-19: A multicenter cohort study.

Author

Adam Green, Jean-Sebastien Rachoin, Christa Schorr, Phil Dellinger, Jonathan D Casey, Isabel Park, Shruti Gupta, Rebecca M Baron, Shahzad Shaefi, Krystal Hunter, David E Leaf, and STOP-COVID Investigators

Subjects
Medicine, Science
Abstract

PurposeTo investigate if the timing of initiation of invasive mechanical ventilation (IMV) for critically ill patients with COVID-19 is associated with mortality.Materials and methodsThe data for this study were derived from a multicenter cohort study of critically ill adults with COVID-19 admitted to ICUs at 68 hospitals across the US from March 1 to July 1, 2020. We examined the association between early (ICU days 1-2) versus late (ICU days 3-7) initiation of IMV and time-to-death. Patients were followed until the first of hospital discharge, death, or 90 days. We adjusted for confounding using a multivariable Cox model.ResultsAmong the 1879 patients included in this analysis (1199 male [63.8%]; median age, 63 [IQR, 53-72] years), 1526 (81.2%) initiated IMV early and 353 (18.8%) initiated IMV late. A total of 644 of the 1526 patients (42.2%) in the early IMV group died, and 180 of the 353 (51.0%) in the late IMV group died (adjusted HR 0.77 [95% CI, 0.65-0.93]).ConclusionsIn critically ill adults with respiratory failure from COVID-19, early compared to late initiation of IMV is associated with reduced mortality.

Published
2023
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188. Metabolomic derangements are associated with mortality in critically ill adult patients.

Author

Angela J Rogers, Michael McGeachie, Rebecca M Baron, Lee Gazourian, Jeffrey A Haspel, Kiichi Nakahira, Laura E Fredenburgh, Gary M Hunninghake, Benjamin A Raby, Michael A Matthay, Ronny M Otero, Vance G Fowler, Emanuel P Rivers, Christopher W Woods, Stephen Kingsmore, Ray J Langley, and Augustine M K Choi

Subjects
Medicine, Science
Abstract

To identify metabolomic biomarkers predictive of Intensive Care Unit (ICU) mortality in adults.Comprehensive metabolomic profiling of plasma at ICU admission to identify biomarkers associated with mortality has recently become feasible.We performed metabolomic profiling of plasma from 90 ICU subjects enrolled in the BWH Registry of Critical Illness (RoCI). We tested individual metabolites and a Bayesian Network of metabolites for association with 28-day mortality, using logistic regression in R, and the CGBayesNets Package in MATLAB. Both individual metabolites and the network were tested for replication in an independent cohort of 149 adults enrolled in the Community Acquired Pneumonia and Sepsis Outcome Diagnostics (CAPSOD) study.We tested variable metabolites for association with 28-day mortality. In RoCI, nearly one third of metabolites differed among ICU survivors versus those who died by day 28 (N = 57 metabolites, p

Published
2014
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189. Death in hospital following ICU discharge: insights from the LUNG SAFE study

Author

Madotto F., McNicholas B., Rezoagli E., Pham T., Laffey J. G., Bellani G., Pesenti A., Brochard L., Esteban A., Gattinoni L., van Haren F., Ranieri M., Rubenfeld G., Thompson B. T., Slutsky A. S., Rios F., Faruq M. O., Sottiaux T., Depuydt P., Lora F. S., Azevedo C. C., Fan E., Bugedo G., Qiu H., Gonzalez M., Silesky J., Cerny V., Nielsen J., Jibaja M., Wrigge H., Matamis D., Ranero J. L., Gomersall C., Amin P., Hashemian S. M., Clarkson K., Kurahashi K., Koh Y., Villagomez A., Zeggwagh A. A., Heunks L. M., Laake J. H., Kashif W., Synclair J., Palo J. E., do Vale Fernandes A., Sandesc D., Arabi Y., Bumbasierevic V., Nin N., Lorente J. A., Larsson A., Piquilloud L., Patjanasoontorn B., Abroug F., McAuley D. F., McNamee L., Hurtado J., Bajwa E., Dempaire G., Francois G. M., Rabboni F., Conti S., Sula H., Nunci L., Cani A., Zazu A., Dellera C., Insaurralde C. S., Alejandro R. V., Daldin J., Vinzio M., Fernandez R. O., Cardonnet L. P., Bettini L. R., Bisso M. C., Osman E. M., Setten M. G., Lovazzano P., Alvarez J., Villar V., Pozo N. C., Grubissich N., Plotnikow G. A., Vasquez D. N., Ilutovich S., Tiribelli N., Chena A., Pellegrini C. A., Saenz M. G., Estenssoro E., Brizuela M., Gianinetto H., Gomez P. E., Cerrato V. I., Bezzi M. G., Borello S. A., Loiacono F. A., Fernandez A. M., Knowles S., Reynolds C., Inskip D. M., Miller J. J., Kong J., Whitehead C., Bihari S., Seven A., Krstevski A., Rodgers H. J., Millar R. T., Mckenna T. E., Bailey I. M., Hanlon G. C., Aneman A., Lynch J. M., Azad R., Neal J., Woods P. W., Roberts B. L., Kol M. R., Wong H. S., Riss K. C., Staudinger T., Wittebole X., Berghe C., Bulpa P. A., Dive A. M., Verstraete R., Lebbinck H., Vermassen J., Meersseman P., Ceunen H., Rosa J. I., Beraldo D. O., Piras C., Rampinelli A. M., Nassar N. P., Mataloun S., Moock M., Thompson M. M., Goncalves C. H., Antonio A. C. P., Ascoli A., Biondi R. S., Fontenele D. C., Nobrega D., Sales V. M., Shindhe S., Aiman D. M., Ismail B. P. H., Laffey J., Beloncle F., Davies K. G., Cirone R., Manoharan V., Ismail M., Goligher E. C., Jassal M., Ferguson N. D., Nishikawa E., Javeed A., Curley G., Rittayamai N., Parotto M., Mehta S., Knoll J., Pronovost A., Canestrini S., Bruhn A. R., Garcia P. H., Aliaga F. A., Farias P. A., Yumha J. S., Ortiz C. A., Salas J. E., Saez A. A., Vega L. D., Labarca E. F., Martinez F. T., Carreno N. G., Lora P., Liu H., Liu L., Tang R., Luo X., An Y., Zhao H., Gao Y., Zhai Z., Ye Z. L., Wang W., Li W., Li Q., Zheng R., Yu W., Shen J., Li X., Yu T., Lu W., Wu Y. Q., Huang X. B., He Z., Lu Y., Han H., Zhang F., Sun R., Wang H. X., Qin S. H., Zhu B. H., Zhao J., Liu J., Li B., Liu J. L., Zhou F. C., Li Q. J., Zhang X. Y., Li-Xin Z., Xin-Hua Q., Jiang L., Gao Y. N., Zhao X. Y., Li Y. Y., Li X. L., Wang C., Yao Q., Yu R., Chen K., Shao H., Qin B., Huang Q. Q., Zhu W. H., Hang A. Y., Hua M. X., Li Y., Xu Y., Di Y. D., Ling L. L., Qin T. H., Wang S. H., Qin J., Han Y., Zhou S., Vargas M. P., Jimenez J. I. S., Rojas M. A. G., Solis-Quesada J. E., Ramirez-Alfaro C. M., Maca J., Sklienka P., Gjedsted J., Christiansen A., Villamagua B. G., Llano M., Burtin P., Buzancais G., Beuret P., Pelletier N., Mortaza S., Mercat A., Chelly J., Jochmans S., Terzi N., Daubin C., Carteaux G., de Prost N., Chiche J. -D., Daviaud F., Fartoukh M., Barberet G., Biehler J., Dellamonica J., Doyen D., Arnal J. -M., Briquet A., Klasen F., Papazian L., Follin A., Roux D., Messika J., Kalaitzis E., Dangers L., Combes A., Au S. -M., Beduneau G., Carpentier D., Zogheib E. H., Dupont H., Ricome S., Santoli F. L., Besset S. L., Michel P., Gelee B., Danin P. -E., Goubaux B., Crova P. J., Phan N. T., Berkelmans F., Badie J. C., Tapponnier R., Gally J., Khebbeb S., Herbrecht J. -E., Schneider F., Declercq P. -L. M., Rigaud J. -P., Duranteau J., Harrois A., Chabanne R., Marin J., Constantin J. -M., Thibault S., Ghazi M., Boukhazna M., Zein S. O., Richecoeur J. R., Combaux D. M., Grelon F., Le Moal C., Sauvadet E. P., Robine A., Lemiale V., Reuter D., Dres M., Demoule A., Goldgran-Toledano D., Baboi L., Guerin C., Lohner R., Krassler J., Schafer S., Zacharowski K. D., Meybohm P., Reske A. W., Simon P., Hopf H. -B. F., Schuetz M., Baltus T., Papanikolaou M. N., Papavasilopoulou T. G., Zacharas G. A., Ourailogloy V., Mouloudi E. K., Massa E. V., Nagy E. O., Stamou E. E., Kiourtzieva E. V., Oikonomou M. A., Avila L. E., Cortez C. A., Citalan J. E., Jog S. A., Sable S. D., Shah B., Gurjar M., Baronia A. K., Memon M., Muthuchellappan R., Ramesh V. J., Shenoy A., Unnikrishnan R., Dixit S. B., Rhayakar R. V., Ramakrishnan N., Bhardwaj V. K., Mahto H. L., Sagar S. V., Palaniswamy V., Ganesan D., Jamaati H., Heidari F., Meaney E. A., Nichol A., Knapman K. M., O'Croinin D., Dunne E. S., Breen D. M., Clarkson K. P., Jaafar R. F., Dwyer R., Amir F., Ajetunmobi O. O., O'Muircheartaigh A. C., Black C. S., Treanor N., Collins D. V., Altaf W., Zani G., Fusari M., Spadaro S., Volta C. A., Graziani R., Brunettini B., Palmese S., Formenti P., Umbrello M., Lombardo A., Pecci E., Botteri M., Savioli M., Protti A., Mattei A., Schiavoni L., Tinnirello A., Todeschini M., Giaccone P. P., Giarratano A., Cortegiani A., Sher S., Rossi A., Antonelli M. M., Montini L. M., Casalena P., Scafetti S., Panarello G., Occhipinti G., Patroniti N., Pozzi M., Biscione R. R., Poli M. M., Raimondi F., Albiero D., Crapelli G., Beck E., Pota V., Schiavone V., Molin A., Tarantino F., Monti G., Frati E., Mirabella L., Cinnella G., Fossali T., Colombo R., Pattarino P. T. I., Mojoli F., Braschi A., Borotto E. E., Cracchiolo A. N., Palma D. M., Raponi F., Foti G., Vascotto E. R., Coppadoro A., Brazzi L., Floris L., Iotti G. A., Venti A., Yamaguchi O., Takagi S., Maeyama H. N., Watanabe E., Yamaji Y., Shimizu K., Shiozaki K., Futami S., Ryosuke S., Saito K., Kameyama Y., Ueno K., Izawa M., Okuda N., Suzuki H., Harasawa T., Nasu M., Takada T., Ito F., Nunomiya S., Koyama K., Abe T., Andoh K., Kusumoto K., Hirata A., Takaba A., Kimura H., Matsumoto S., Higashijima U., Honda H., Aoki N., Imai H., Ogino Y., Mizuguchi I., Ichikado K., Nitta K., Mochizuki K., Hashida T., Tanaka H., Nakamura T., Niimi D., Ueda T., Kashiwa Y., Uchiyama A., Sabelnikovs O., Oss P., Haddad Y., Liew K. Y., Namendys-Silva S. A., Jarquin-Badiola Y. D., Sanchez-Hurtado L. A., Gomez-Flores S. S., Marin M. C., Villagomez A. J., Lemus J. S., Fierro J. M., Cervantes M. R., Mejia F. J. F., Dector D., Dector D. M., Gonzalez D. R., Estrella C. R., Sanchez-Medina J. R., Ramirez-Gutierrez A., George F. G., Aguirre J. S., Buensuseso J. A., Poblano M., University M. V., Dendane T., Balkhi H., Elkhayari M., Samkaoui N., Ezzouine H., Benslama A., Amor M., Maazouzi W., Cimic N., Beck O., Bruns M. M., Schouten J. A., Rinia M., Raaijmakers M., Van Wezel H. M., Heines S. J., Strauch U., Buise M. P., Simonis F. D., Schultz M. J., Goodson J. C., Browne T. S., Navarra L., Hunt A., Hutchison R. A., Bailey M. B., Newby L., Mcarthur C., Kalkoff M., Mcleod A., Casement J., Hacking D. J., Andersen F. H., Dolva M. S., Barratt-Due A., Noremark K. A. L., Soreide E., Sjobo B. A., Guttormsen A. B., Yoshido H. H. L., Aguilar R. Z., Oscanoa F. A. M., Alisasis A. U., Robles J. B., Pasanting-Lim R. A. B., Tan B. C., Andruszkiewicz P., Jakubowska K., Coxo C. M., Alvarez A. M., Oliveira B. S., Montanha G. M., Barros N. C., Pereira C. S., Messias A. M., Monteiro J. M., Araujo A. M., Catorze N. T., Marum S. M., Bouw M. J., Gomes R. M., Brito V. A., Castro S., Estilita J. M., Barros F. M., Serra I. M., Martinho A. M., Tomescu D. R., Marcu A., Bedreag O. H., Papurica M., Corneci D. E., Negoita S. I., Grigoriev E., Gritsan A. I., Gazenkampf A. A., Almekhlafi G., Albarrak M. M., Mustafa G. M., Maghrabi K. A., Salahuddin N., Aisa T. M., Al Jabbary A. S., Tabhan E., Arabi Y. M., Trinidad O. A., Al Dorzi H. M., Tabhan E. E., Bolon S., Smith O., Mancebo J., Aguirre-Bermeo H., Lopez-Delgado J. C., Esteve F., Rialp G., Forteza C., De Haro C., Artigas A., Albaiceta G. M., De Cima-Iglesias S., Seoane-Quiroga L., Ceniceros-Barros A., Ruiz-Aguilar A. L., Claraco-Vega L. M., Soler J. A., del Carmen Lorente M., Hermosa C., Gordo F., Prieto-Gonzalez M., Lopez-Messa J. B., Perez M. P., Perez C. P., Allue R. M., Roche-Campo F., Ibanez-Santacruz M., Temprano S., Pintado M. C., De Pablo R., Gomez P. R. A., Ruiz S. R., Moles S. I., Jurado M. ªT., Arizmendi A., Piacentini E. A., Franco N., Honrubia T., Cheng M. P., Losada E. P., Blanco J., Yuste L. J., Carbayo-Gorriz C., Cazorla-Barranquero F. G., Alonso J. G., Alda R. S., Algaba A., Navarro G., Cereijo E., Diaz-Rodriguez E., Marcos D. P., Montero L. A., Para L. H., Sanchez R. J., Navalpotro M. A. B., Abad R. D., lez R. M. G. A., Toribio D. P., Castro A. G., Artiga M. J. D., Penuelas O., Roser T. P., Olga M. F., Curto E. G., Sanchez R. M., Imma V. P., Elisabet G. M., Claverias L., Magret M., Pellicer A. M., Rodriguez L. L., Sanchez-Ballesteros J., Gonzalez-Salamanca A., Jimenez A. G., Huerta F. P., Diaz J. C. J. S., Lopez E. B., Moya D. D. L., Alfonso A. A. T., Luis P. S. E., Cesar P. S., Rafael S. I., Virgilio C. G., Recio N. N., Adamsson R. O., Rylander C. C., Holzgraefe B., Broman L. M., Wessbergh J., Persson L., Schioler F., Kedelv H., Tibblin A. O., Appelberg H., Hedlund L., Helleberg J., Eriksson K. E., Glietsch R., Larsson N., Nygren I., Nunes S. L., Morin A. -K., Kander T., Adolfsson A., Zender H. O., Leemann-Refondini C., Elatrous S., Bouchoucha S., Chouchene I., Ouanes I., Marsa L., Souissi A. B., Kamoun S., Demirkiran O., Aker M., Erbabacan E., Ceylan I., Girgin N. K., Ozcelik M., Unal N., Meco B. C., Akyol O. O., Derman S. 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J., Kitch, B. T., Cohen, J. E., Beegle, S. H., Gueret, R. M., Tulaimat, A., Choudry, S., Stigler, W., Batra, H., Huff, N. G., Lamb, K. D., Oetting, T. W., Mohr, N. M., Judy, C., Saito, S., Kheir, F. M., Kheir, F., Schlichting, A. B., Delsing, A., Crouch, D. R., Elmasri, M., Ismail, D., Dreyer, K. R., Blakeman, T. C., Baron, R. M., Grijalba, C. Q., Hou, P. C., Seethala, R., Aisiku, I., Henderson, G., Frendl, G., Hou, S. -K., Owens, R. L., Schomer, A., Bumbasirevic, V., Jovanovic, B., Surbatovic, M., Veljovic, M., UCL - SSS/IREC/MEDA - Pôle de médecine aiguë, UCL - (MGD) Services des soins intensifs, UCL - (SLuc) Service de soins intensifs, Investigators, LUNG SAFE, Group, ESICM Trials, Madotto, F, Mcnicholas, B, Rezoagli, E, Pham, T, Laffey, J, Bellani, G, Pesenti, A, Brochard, L, Esteban, A, Gattinoni, L, van Haren, F, Ranieri, M, Rubenfeld, G, Thompson, B, Slutsky, A, Rios, F, Faruq, M, Sottiaux, T, Depuydt, P, Lora, F, Azevedo, C, Fan, E, Bugedo, G, Qiu, H, Gonzalez, M, Silesky, J, Cerny, V, Nielsen, J, Jibaja, M, Wrigge, H, Matamis, D, Ranero, J, Gomersall, C, Amin, P, Hashemian, S, Clarkson, K, Kurahashi, K, Koh, Y, Villagomez, A, Zeggwagh, A, Heunks, L, Laake, J, Kashif, W, Synclair, J, Palo, J, do Vale Fernandes, A, Sandesc, D, Arabi, Y, Bumbasierevic, V, Nin, N, Lorente, J, Larsson, A, Piquilloud, L, Patjanasoontorn, B, Abroug, F, Mcauley, D, Mcnamee, L, Hurtado, J, Bajwa, E, Dempaire, G, Francois, G, 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Vladimir Cerny, Jonas Nielsen, Manuel Jibaja, Tài Pham, Hermann Wrigge, Dimitrios Matamis, Jorge Luis Ranero, Charles Gomersall, Pravin Amin, S M Hashemian, Kevin Clarkson, Giacomo Bellani, Kiyoyasu Kurahashi, Younsuck Koh, Asisclo Villagomez, Amine Ali Zeggwagh, Leo M Heunks, Jon Henrik Laake, Waqar Kashif, Jorge Synclair, Jose Emmanuel Palo, Antero do Vale Fernandes, Dorel Sandesc, Yaasen Arabi, Vesna Bumbasierevic, Nicolas Nin, Jose A Lorente, Anders Larsson, Lise Piquilloud, Boonsong Patjanasoontorn, Fekri Abroug, Daniel F McAuley, Lia McNamee, Javier Hurtado, Ed Bajwa, Gabriel Démpaire, Guy M Francois, Francesca Rabboni, Fabiana Madotto, Sara Conti, Hektor Sula, Lordian Nunci, Alma Cani, Alan Zazu, Christian Dellera, Carolina S Insaurralde, Risso V Alejandro, Julio Daldin, Mauricio Vinzio, Ruben O Fernandez, Luis P Cardonnet, Lisandro R Bettini, Mariano Carboni Bisso, Emilio M Osman, Mariano G Setten, Pablo Lovazzano, Javier Alvarez, Veronica Villar, Norberto C Pozo, Nicolas 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Gonçalves, Ana Carolina P Antônio, Aline Ascoli, Rodrigo S Biondi, Danielle C Fontenele, Danielle Nobrega, Vanessa M Sales, Suresh Shindhe, Dk Maizatul Aiman, BPg Hj Ismail, John Laffey, Francois Beloncle, Kyle G Davies, Rob Cirone, Venika Manoharan, Mehvish Ismail, Ewan C Goligher, Mandeep Jassal, Niall D Ferguson, Erin Nishikawa, Areej Javeed, Gerard Curley, Nuttapol Rittayamai, Matteo Parotto, Sangeeta Mehta, Jenny Knoll, Antoine Pronovost, Sergio Canestrini, Alejandro R Bruhn, Patricio H Garcia, Felipe A Aliaga, Pamela A Farías, Jacob S Yumha, Claudia A Ortiz, Javier E Salas, Alejandro A Saez, Luis D Vega, Eduardo F Labarca, Felipe T Martinez, Nicolás G Carreño, Pilar Lora, Haitao Liu, Haibo Qiu, Ling Liu, Rui Tang, Xiaoming Luo, Youzhong An, Huiying Zhao, Yan Gao, Zhe Zhai, Zheng L Ye, Wei Wang, Wenwen Li, Qingdong Li, Ruiqiang Zheng, Wenkui Yu, Juanhong Shen, Xinyu Li, Tao Yu, Weihua Lu, Ya Q Wu, Xiao B Huang, Zhenyang He, Yuanhua Lu, Hui Han, Fan Zhang, Renhua Sun, Hua X Wang, 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Zacharowski, Patrick Meybohm, Andreas W Reske, Philipp Simon, Hans-Bernd F Hopf, Michael Schuetz, Thomas Baltus, Metaxia N Papanikolaou, Theonymfi G Papavasilopoulou, Giannis A Zacharas, Vasilis Ourailogloy, Eleni K Mouloudi, Eleni V Massa, Eva O Nagy, Electra E Stamou, Ellada V Kiourtzieva, Marina A Oikonomou, Luis E Avila, Cesar A Cortez, Johanna E Citalán, Sameer A Jog, Safal D Sable, Bhagyesh Shah, Mohan Gurjar, Arvind K Baronia, Mohammedfaruk Memon, Radhakrishnan Muthuchellappan, Venkatapura J Ramesh, Anitha Shenoy, Ramesh Unnikrishnan, Subhal B Dixit, Rachana V Rhayakar, Nagarajan Ramakrishnan, Vallish K Bhardwaj, Heera L Mahto, Sudha V Sagar, Vijayanand Palaniswamy, Deeban Ganesan, Seyed Mohammadreza Hashemian, Hamidreza Jamaati, Farshad Heidari, Edel A Meaney, Alistair Nichol, Karl M Knapman, Donall O'Croinin, Eimhin S Dunne, Dorothy M Breen, Kevin P Clarkson, Rola F Jaafar, Rory Dwyer, Fahd Amir, Olaitan O Ajetunmobi, Aogan C O'Muircheartaigh, Colin S Black, Nuala Treanor, Daniel V Collins, Wahid Altaf, Gianluca Zani, Maurizio Fusari, Savino Spadaro, Carlo A Volta, Romano Graziani, Barbara Brunettini, Salvatore Palmese, Paolo Formenti, Michele Umbrello, Andrea Lombardo, Elisabetta Pecci, Marco Botteri, Monica Savioli, Alessandro Protti, Alessia Mattei, Lorenzo Schiavoni, Andrea Tinnirello, Manuel Todeschini, Antonino Giarratano, Andrea Cortegiani, Sara Sher, Anna Rossi, Massimo M Antonelli, Luca M Montini, Paolo Casalena, Sergio Scafetti, Giovanna Panarello, Giovanna Occhipinti, Nicolò Patroniti, Matteo Pozzi, Roberto R Biscione, Michela M Poli, Ferdinando Raimondi, Daniela Albiero, Giulia Crapelli, Eduardo Beck, Vincenzo Pota, Vincenzo Schiavone, Alexandre Molin, Fabio Tarantino, Giacomo Monti, Elena Frati, Lucia Mirabella, Gilda Cinnella, Tommaso Fossali, Riccardo Colombo, Pierpaolo Terragni Ilaria Pattarino, Francesco Mojoli, Antonio Braschi, Erika E Borotto, Andrea N Cracchiolo, Daniela M Palma, Francesco Raponi, Giuseppe Foti, Ettore R Vascotto, Andrea Coppadoro, Luca Brazzi, Leda Floris, Giorgio A Iotti, Aaron Venti, Osamu Yamaguchi, Shunsuke Takagi, Hiroki N Maeyama, Eizo Watanabe, Yoshihiro Yamaji, Kazuyoshi Shimizu, Kyoko Shiozaki, Satoru Futami, Sekine Ryosuke, Koji Saito, Yoshinobu Kameyama, Keiko Ueno, Masayo Izawa, Nao Okuda, Hiroyuki Suzuki, Tomofumi Harasawa, Michitaka Nasu, Tadaaki Takada, Fumihito Ito, Shin Nunomiya, Kansuke Koyama, Toshikazu Abe, Kohkichi Andoh, Kohei Kusumoto, Akira Hirata, Akihiro Takaba, Hiroyasu Kimura, Shuhei Matsumoto, Ushio Higashijima, Hiroyuki Honda, Nobumasa Aoki, Hiroshi Imai, Yasuaki Ogino, Ichiko Mizuguchi, Kazuya Ichikado, Kenichi Nitta, Katsunori Mochizuki, Tomoaki Hashida, Hiroyuki Tanaka, Tomoyuki Nakamura, Daisuke Niimi, Takeshi Ueda, Yozo Kashiwa, Akinori Uchiyama, Olegs Sabelnikovs, Peteris Oss, Youssef Haddad, Kong Y Liew, Silvio A Ñamendys-Silva, Yves D Jarquin-Badiola, Luis A Sanchez-Hurtado, Saira S Gomez-Flores, Maria C Marin, Asisclo J Villagomez, Jordana S Lemus, Jonathan M Fierro, Mavy Ramirez Cervantes, Francisco Javier Flores Mejia, Dulce Dector, Dulce M Dector, Daniel R Gonzalez, Claudia R Estrella, Jorge R Sanchez-Medina, Alvaro Ramirez-Gutierrez, Fernando G George, Janet S Aguirre, Juan A Buensuseso, Manuel Poblano, Mohammed V University, Tarek Dendane, Amine Ali Zeggwagh, Hicham Balkhi, Mina Elkhayari, Nacer Samkaoui, Hanane Ezzouine, Abdellatif Benslama, Mourad Amor, Wajdi Maazouzi, Nedim Cimic, Oliver Beck, Monique M Bruns, Jeroen A Schouten, Myra Rinia, Monique Raaijmakers, Leo M Heunks, Hellen M Van Wezel, Serge J Heines, Ulrich Strauch, Marc P Buise, Fabienne D Simonis, Marcus J Schultz, Jennifer C Goodson, Troy S Browne, Leanlove Navarra, Anna Hunt, Robyn A Hutchison, Mathew B Bailey, Lynette Newby, Colin Mcarthur, Michael Kalkoff, Alex Mcleod, Jonathan Casement, Danielle J Hacking, Finn H Andersen, Merete S Dolva, Jon H Laake, Andreas Barratt-Due, Kim Andre L Noremark, Eldar Søreide, Brit Å Sjøbø, Anne B Guttormsen, Hector H Leon Yoshido, Ronald Zumaran Aguilar, Fredy A Montes Oscanoa, Alain U Alisasis, Joanne B Robles, Rossini Abbie B Pasanting-Lim, Beatriz C Tan, Pawel Andruszkiewicz, Karina Jakubowska, Cristina M Coxo, António M Alvarez, Bruno S Oliveira, Gustavo M Montanha, Nelson C Barros, Carlos S Pereira, António M Messias, Jorge M Monteiro, Ana M Araujo, Nuno T Catorze, Susan M Marum, Maria J Bouw, Rui M Gomes, Vania A Brito, Silvia Castro, Joana M Estilita, Filipa M Barros, Isabel M Serra, Aurelia M Martinho, Dana R Tomescu, Alexandra Marcu, Ovidiu H Bedreag, Marius Papurica, Dan E Corneci, Silvius Ioan Negoita, Evgeny Grigoriev, Alexey I Gritsan, Andrey A Gazenkampf, Ghaleb Almekhlafi, Mohamad M Albarrak, Ghanem M Mustafa, Khalid A Maghrabi, Nawal Salahuddin, Tharwat M Aisa, Ahmed S Al Jabbary, Edgardo Tabhan, Yaseen M Arabi, Olivia A Trinidad, Hasan M Al Dorzi, Edgardo E Tabhan, Stefan Bolon, Oliver Smith, Jordi Mancebo, Hernan Aguirre-Bermeo, Juan C Lopez-Delgado, Francisco Esteve, Gemma Rialp, Catalina Forteza, Candelaria De Haro, Antonio Artigas, Guillermo M Albaiceta, Sara De Cima-Iglesias, Leticia Seoane-Quiroga, Alexandra Ceniceros-Barros, Antonio L Ruiz-Aguilar, Luis M Claraco-Vega, Juan Alfonso Soler, Maria Del Carmen Lorente, Cecilia Hermosa, Federico Gordo, Miryam Prieto-González, Juan B López-Messa, Manuel P Perez, Cesar P Perez, Raquel Montoiro Allue, Ferran Roche-Campo, Marcos Ibañez-Santacruz, Susana Temprano, Maria C Pintado, Raul De Pablo, Pilar Ricart Aroa Gómez, Silvia Rodriguez Ruiz, Silvia Iglesias Moles, Mª Teresa Jurado, Alfons Arizmendi, Enrique A Piacentini, Nieves Franco, Teresa Honrubia, Meisy Perez Cheng, Elena Perez Losada, Javier Blanco, Luis J Yuste, Cecilia Carbayo-Gorriz, Francisca G Cazorla-Barranquero, Javier G Alonso, Rosa S Alda, Ángela Algaba, Gonzalo Navarro, Enrique Cereijo, Esther Diaz-Rodriguez, Diego Pastor Marcos, Laura Alvarez Montero, Luis Herrera Para, Roberto Jimenez Sanchez, Miguel Angel Blasco Navalpotro, Ricardo Diaz Abad, Raquel Montiel Gonz Á Lez, Dácil Parrilla Toribio, Alejandro G Castro, Maria Jose D Artiga, Oscar Penuelas, Tomas P Roser, Moreno F Olga, Elena Gallego Curto, Rocío Manzano Sánchez, Vallverdu P Imma, Garcia M Elisabet, Laura Claverias, Monica Magret, Ana M Pellicer, Lucia L Rodriguez, Jesús Sánchez-Ballesteros, Ángela González-Salamanca, Antonio G Jimenez, Francisco P Huerta, Juan Carlos J Sotillo Diaz, Esther Bermejo Lopez, David D Llinares Moya, Alec A Tallet Alfonso, Palazon Sanchez Eugenio Luis, Palazon Sanchez Cesar, Sánchez I Rafael, Corcoles G Virgilio, Noelia N Recio, Richard O Adamsson, Christian C Rylander, Bernhard Holzgraefe, Lars M Broman, Joanna Wessbergh, Linnea Persson, Fredrik Schiöler, Hans Kedelv, Anna Oscarsson Tibblin, Henrik Appelberg, Lars Hedlund, Johan Helleberg, Karin E Eriksson, Rita Glietsch, Niklas Larsson, Ingela Nygren, Silvia L Nunes, Anna-Karin Morin, Thomas Kander, Anne Adolfsson, Lise Piquilloud, Hervé O Zender, Corinne Leemann-Refondini, Souheil Elatrous, Slaheddine Bouchoucha, Imed Chouchene, Islem Ouanes, La Marsa, Asma Ben Souissi, Salma Kamoun, Oktay Demirkiran, Mustafa Aker, Emre Erbabacan, Ilkay Ceylan, Nermin Kelebek Girgin, Menekse Ozcelik, Necmettin Ünal, Basak Ceyda Meco, Onat O Akyol, Suleyman S Derman, Barry Kennedy, Ken Parhar, Latha Srinivasa, Lia McNamee, Danny McAuley, Phil Hopkins, Clare Mellis, Vivek Kakar, Dan Hadfield, Andre Vercueil, Kaushik Bhowmick, Sally K Humphreys, Andrew Ferguson, Raymond Mckee, Ashok S Raj, Danielle A Fawkes, Philip Watt, Linda Twohey, Rajeev R JhaMatthew Thomas, Alex Morton, Varsha Kadaba, Mark J Smith, Anil P Hormis, Santhana G Kannan, Miriam Namih, Henrik Reschreiter, Julie Camsooksai, Alek Kumar, Szabolcs Rugonfalvi, Christopher Nutt, Orla Oneill, Colette Seasman, Ged Dempsey, Christopher J Scott, Helen E Ellis, Stuart Mckechnie, Paula J Hutton, Nora N Di Tomasso, Michela N Vitale, Ruth O Griffin, Michael N Dean, Julius H Cranshaw, Emma L Willett, Nicholas Ioannou, Sarah Gillis, Peter Csabi, Rosaleen Macfadyen, Heidi Dawson, Pieter D Preez, Alexandra J Williams, Owen Boyd, Laura Ortiz-Ruiz De Gordoa, Jon Bramall, Sophie Symmonds, Simon K Chau, Tim Wenham, Tamas Szakmany, Piroska Toth-Tarsoly, Katie H Mccalman, Peter Alexander, Lorraine Stephenson, Thomas Collyer, Rhiannon Chapman, Raphael Cooper, Russell M Allan, Malcolm Sim, David W Wrathall, Donald A Irvine, Kim S Zantua, John C Adams, Andrew J Burtenshaw, Gareth P Sellors, Ingeborg D Welters, Karen E Williams, Robert J Hessell, Matthew G Oldroyd, Ceri E Battle, Suresh Pillai, Istvan Kajtor, Mageswaran Sivashanmugavel, Sinead C Okane, Adrian Donnelly, Aniko D Frigyik, Jon P Careless, Martin M May, Richard Stewart, T John Trinder, Samantha J Hagan, Matt P Wise, Jade M Cole, Caroline C MacFie, Anna T Dowling, Javier Hurtado, Nicolás Nin, Javier Hurtado, Edgardo Nuñez, Gustavo Pittini, Ruben Rodriguez, María C Imperio, Cristina Santos, Alberto Deicas, Carolina Serra, Aditya Uppalapati, Ghassan Kamel, Valerie M Banner-Goodspeed, Jeremy R Beitler, Satyanarayana Reddy Mukkera, Shreedhar Kulkarni, Jarone Lee, Tomaz Mesar, John O Shinn Iii, Dina Gomaa, Christopher Tainter, Jarone Lee, Tomaz Mesar, Jarone Lee, Dale J Yeatts, Jessica Warren, Michael J Lanspa, Russel R Miller, Colin K Grissom, Samuel M Brown, Philippe R Bauer, Ryan J Gosselin, Barrett T Kitch, Jason E Cohen, Scott H Beegle, Renaud M Gueret, Aiman Tulaimat, Shazia Choudry, William Stigler, Hitesh Batra, Nidhi G Huff, Keith D Lamb, Trevor W Oetting, Nicholas M Mohr, Claine Judy, Shigeki Saito, Fayez M Kheir, Fayez Kheir, Adam B Schlichting, Angela Delsing, Daniel R Crouch, Mary Elmasri, Daniel R Crouch, Dina Ismail, Kyle R Dreyer, Thomas C Blakeman, Kyle R Dreyer, Dina Gomaa, Rebecca M Baron, Carolina Quintana Grijalba, Peter C Hou, Raghu Seethala, Imo Aisiku, Galen Henderson, Gyorgy Frendl, Sen-Kuang Hou, Robert L Owens, Ashley Schomer, Vesna Bumbasirevic, Bojan Jovanovic, Maja Surbatovic, Milic Veljovic, John G Laffey, Giacomo Bellani, Antonio Pesenti

Subjects
Male, ARDS, LUNG SAFE, health care facilities, manpower, and services, Acute hypoxemic respiratory failure, Acute respiratory distress syndrome, Hospital survival, ICU discharge, Kaplan-Meier Estimate, Critical Care and Intensive Care Medicine, 0302 clinical medicine, Risk Factors, 030212 general & internal medicine, Prospective Studies, Prospective cohort study, COPD, Medical emergencies. Critical care. Intensive care. First aid, Middle Aged, Patient Discharge, Intensive Care Units, medicine.anatomical_structure, Lung safe, SOFA score, Female, Respiratory Insufficiency, Adult, medicine.medical_specialty, NO, 03 medical and health sciences, Settore MED/41 - ANESTESIOLOGIA, medicine, Humans, ddc:610, Risk factor, Mortality, Aged, Lung, RC86-88.9, business.industry, Research, 030208 emergency & critical care medicine, medicine.disease, Logistic Models, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], Respiratory failure, Emergency medicine, Observational study, business
Abstract

Background To determine the frequency of, and factors associated with, death in hospital following ICU discharge to the ward. Methods The Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE study was an international, multicenter, prospective cohort study of patients with severe respiratory failure, conducted across 459 ICUs from 50 countries globally. This study aimed to understand the frequency and factors associated with death in hospital in patients who survived their ICU stay. We examined outcomes in the subpopulation discharged with no limitations of life sustaining treatments (‘treatment limitations’), and the subpopulations with treatment limitations. Results 2186 (94%) patients with no treatment limitations discharged from ICU survived, while 142 (6%) died in hospital. 118 (61%) of patients with treatment limitations survived while 77 (39%) patients died in hospital. Patients without treatment limitations that died in hospital after ICU discharge were older, more likely to have COPD, immunocompromise or chronic renal failure, less likely to have trauma as a risk factor for ARDS. Patients that died post ICU discharge were less likely to receive neuromuscular blockade, or to receive any adjunctive measure, and had a higher pre- ICU discharge non-pulmonary SOFA score. A similar pattern was seen in patients with treatment limitations that died in hospital following ICU discharge. Conclusions A significant proportion of patients die in hospital following discharge from ICU, with higher mortality in patients with limitations of life-sustaining treatments in place. Non-survivors had higher systemic illness severity scores at ICU discharge than survivors. Trial Registration: ClinicalTrials.gov NCT02010073.

Published
2021

190. Circulating mitochondrial DNA in patients in the ICU as a marker of mortality: derivation and validation.

Author

Kiichi Nakahira, Sun-Young Kyung, Angela J Rogers, Lee Gazourian, Sojung Youn, Anthony F Massaro, Carolina Quintana, Juan C Osorio, Zhaoxi Wang, Yang Zhao, Laurie A Lawler, Jason D Christie, Nuala J Meyer, Finnian R Mc Causland, Sushrut S Waikar, Aaron B Waxman, Raymond T Chung, Raphael Bueno, Ivan O Rosas, Laura E Fredenburgh, Rebecca M Baron, David C Christiani, Gary M Hunninghake, and Augustine M K Choi

Subjects
Medicine
Abstract

BackgroundMitochondrial DNA (mtDNA) is a critical activator of inflammation and the innate immune system. However, mtDNA level has not been tested for its role as a biomarker in the intensive care unit (ICU). We hypothesized that circulating cell-free mtDNA levels would be associated with mortality and improve risk prediction in ICU patients.Methods and findingsAnalyses of mtDNA levels were performed on blood samples obtained from two prospective observational cohort studies of ICU patients (the Brigham and Women's Hospital Registry of Critical Illness [BWH RoCI, n = 200] and Molecular Epidemiology of Acute Respiratory Distress Syndrome [ME ARDS, n = 243]). mtDNA levels in plasma were assessed by measuring the copy number of the NADH dehydrogenase 1 gene using quantitative real-time PCR. Medical ICU patients with an elevated mtDNA level (≥3,200 copies/µl plasma) had increased odds of dying within 28 d of ICU admission in both the BWH RoCI (odds ratio [OR] 7.5, 95% CI 3.6-15.8, p = 1×10(-7)) and ME ARDS (OR 8.4, 95% CI 2.9-24.2, p = 9×10(-5)) cohorts, while no evidence for association was noted in non-medical ICU patients. The addition of an elevated mtDNA level improved the net reclassification index (NRI) of 28-d mortality among medical ICU patients when added to clinical models in both the BWH RoCI (NRI 79%, standard error 14%, pConclusionsIncreased mtDNA levels are associated with ICU mortality, and inclusion of mtDNA level improves risk prediction in medical ICU patients. Our data suggest that mtDNA could serve as a viable plasma biomarker in medical ICU patients.

Published
2013
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191. Integrating murine gene expression studies to understand obstructive lung disease due to chronic inhaled endotoxin.

Author

Peggy S Lai, Oliver Hofmann, Rebecca M Baron, Manuela Cernadas, Quanxin Ryan Meng, Herbert S Bresler, David M Brass, Ivana V Yang, David A Schwartz, David C Christiani, and Winston Hide

Subjects
Medicine, Science
Abstract

Endotoxin is a near ubiquitous environmental exposure that that has been associated with both asthma and chronic obstructive pulmonary disease (COPD). These obstructive lung diseases have a complex pathophysiology, making them difficult to study comprehensively in the context of endotoxin. Genome-wide gene expression studies have been used to identify a molecular snapshot of the response to environmental exposures. Identification of differentially expressed genes shared across all published murine models of chronic inhaled endotoxin will provide insight into the biology underlying endotoxin-associated lung disease.We identified three published murine models with gene expression profiling after repeated low-dose inhaled endotoxin. All array data from these experiments were re-analyzed, annotated consistently, and tested for shared genes found to be differentially expressed. Additional functional comparison was conducted by testing for significant enrichment of differentially expressed genes in known pathways. The importance of this gene signature in smoking-related lung disease was assessed using hierarchical clustering in an independent experiment where mice were exposed to endotoxin, smoke, and endotoxin plus smoke.A 101-gene signature was detected in three murine models, more than expected by chance. The three model systems exhibit additional similarity beyond shared genes when compared at the pathway level, with increasing enrichment of inflammatory pathways associated with longer duration of endotoxin exposure. Genes and pathways important in both asthma and COPD were shared across all endotoxin models. Mice exposed to endotoxin, smoke, and smoke plus endotoxin were accurately classified with the endotoxin gene signature.Despite the differences in laboratory, duration of exposure, and strain of mouse used in three experimental models of chronic inhaled endotoxin, surprising similarities in gene expression were observed. The endotoxin component of tobacco smoke may play an important role in disease development.

Published
2013
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192. Distamycin A inhibits HMGA1-binding to the P-selectin promoter and attenuates lung and liver inflammation during murine endotoxemia.

Author

Rebecca M Baron, Silvia Lopez-Guzman, Dario F Riascos, Alvaro A Macias, Matthew D Layne, Guiying Cheng, Cailin Harris, Su Wol Chung, Raymond Reeves, Ulrich H von Andrian, and Mark A Perrella

Subjects
Medicine, Science
Abstract

BackgroundThe architectural transcription factor High Mobility Group-A1 (HMGA1) binds to the minor groove of AT-rich DNA and forms transcription factor complexes ("enhanceosomes") that upregulate expression of select genes within the inflammatory cascade during critical illness syndromes such as acute lung injury (ALI). AT-rich regions of DNA surround transcription factor binding sites in genes critical for the inflammatory response. Minor groove binding drugs (MGBs), such as Distamycin A (Dist A), interfere with AT-rich region DNA binding in a sequence and conformation-specific manner, and HMGA1 is one of the few transcription factors whose binding is inhibited by MGBs.ObjectivesTo determine whether MGBs exert beneficial effects during endotoxemia through attenuating tissue inflammation via interfering with HMGA1-DNA binding and modulating expression of adhesion molecules.Methodology/principal findingsAdministration of Dist A significantly decreased lung and liver inflammation during murine endotoxemia. In intravital microscopy studies, Dist A attenuated neutrophil-endothelial interactions in vivo following an inflammatory stimulus. Endotoxin induction of P-selectin expression in lung and liver tissue and promoter activity in endothelial cells was significantly reduced by Dist A, while E-selectin induction was not significantly affected. Moreover, Dist A disrupted formation of an inducible complex containing NF-kappaB that binds an AT-rich region of the P-selectin promoter. Transfection studies demonstrated a critical role for HMGA1 in facilitating cytokine and NF-kappaB induction of P-selectin promoter activity, and Dist A inhibited binding of HMGA1 to this AT-rich region of the P-selectin promoter in vivo.Conclusions/significanceWe describe a novel targeted approach in modulating lung and liver inflammation in vivo during murine endotoxemia through decreasing binding of HMGA1 to a distinct AT-rich region of the P-selectin promoter. These studies highlight the ability of MGBs to function as molecular tools for dissecting transcriptional mechanisms in vivo and suggest alternative treatment approaches for critical illness.

Published
2010
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193. Characteristics and Outcomes of US Patients Hospitalized With COVID-19.

Author

Peltan ID, Caldwell E, Admon AJ, Attia EF, Gundel SJ, Mathews KS, Nagrebetsky A, Sahetya SK, Ulysse C, Brown SM, Chang SY, Goodwin AJ, Hope AA, Iwashyna TJ, Johnson NJ, Lanspa MJ, Richardson LD, Vranas KC, Angus DC, Baron RM, Haaland BA, Hayden DL, Thompson BT, Rice TW, and Hough CL

Subjects
Aged, Female, Hospital Mortality, Hospitalization, Humans, Intensive Care Units, Male, Middle Aged, Pandemics, Respiration, Artificial, Retrospective Studies, SARS-CoV-2, COVID-19 therapy
Abstract

Background: Understanding COVID-19 epidemiology is crucial to clinical care and to clinical trial design and interpretation., Objective: To describe characteristics, treatment, and outcomes among patients hospitalized with COVID-19 early in the pandemic., Methods: A retrospective cohort study of consecutive adult patients with laboratory-confirmed, symptomatic SARS-CoV-2 infection admitted to 57 US hospitals from March 1 to April 1, 2020., Results: Of 1480 inpatients with COVID-19, median (IQR) age was 62.0 (49.4-72.9) years, 649 (43.9%) were female, and 822 of 1338 (61.4%) were non-White or Hispanic/Latino. Intensive care unit admission occurred in 575 patients (38.9%), mostly within 4 days of hospital presentation. Respiratory failure affected 583 patients (39.4%), including 284 (19.2%) within 24 hours of hospital presentation and 413 (27.9%) who received invasive mechanical ventilation. Median (IQR) hospital stay was 8 (5-15) days overall and 15 (9-24) days among intensive care unit patients. Hospital mortality was 17.7% (n = 262). Risk factors for hospital death identified by penalized multivariable regression included older age; male sex; comorbidity burden; symptoms-to-admission interval; hypotension; hypoxemia; and higher white blood cell count, creatinine level, respiratory rate, and heart rate. Of 1218 survivors, 221 (18.1%) required new respiratory support at discharge and 259 of 1153 (22.5%) admitted from home required new health care services., Conclusions: In a geographically diverse early-pandemic COVID-19 cohort with complete hospital folllow-up, hospital mortality was associated with older age, comorbidity burden, and male sex. Intensive care unit admissions occurred early and were associated with protracted hospital stays. Survivors often required new health care services or respiratory support at discharge., (©2022 American Association of Critical-Care Nurses.)

Published
2022
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