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1. 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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2. Plasma renin as a novel prognostic biomarker of sepsis-associated acute respiratory distress syndrome

Author

Anjali Chakradhar, Rebecca M. Baron, Mayra Pinilla Vera, Prasad Devarajan, Lakhmir Chawla, and Peter C. Hou

Subjects
Renin, Sepsis, Acute respiratory distress syndrome (ARDS), Septic shock, Mortality, Critical care, Medicine, Science
Abstract

Abstract Sepsis-associated acute respiratory distress syndrome (ARDS) is a life-threatening condition in critical care medicine for which there is a substantial need for early prognostic biomarkers of outcome. The present study seeks to link plasma renin levels and 30-day mortality in sepsis-associated ARDS patients treated at our institution. The Registry of Critical Illness (RoCI) prospectively enrolled patients from the intensive care units (ICU) within a single academic medical center, and a convenience sample of patients with sepsis-associated ARDS was analyzed from this cohort. This study was approved by the Mass General Brigham Institutional Review Boards (IRB) as part of the RoCI, and all procedures performed were in accordance with the ethical standards of the institutional board. From April 2012 to February 2019, a cohort of 32 adult sepsis-associated ARDS patients with 500 µL of plasma samples available on Day 0 and Day 3 of their ICU stay were enrolled. Renin levels were measured twice, on Day 0 and Day 3 via the direct renin enzyme-linked immunosorbent assay (ELISA EIA-525) by DRG diagnostics. Day 0 and Day 3 renin were statistically evaluated via logistic regression to predict 30-day mortality. Direct renin levels of 64 samples were assayed from 32 sepsis-associated ARDS patients (50% male; mean ± SD, 55 ± 13.8 years old). The 30-day hospital mortality rate was 59.4%. Patients who died within 30 days of admission were more likely to have an elevated Day 3 Renin (Odds ratio [OR] = 6, 95% CI 1.25–28.84) and have received vasopressors (OR = 13.33, 95% CI 1.43–123.95). Adjusting for vasopressor use as a proxy for septic shock status, patients with an Elevated Day 3 Renin had a 6.85 (95% CI 1.07–43.75) greater odds of death than those with Low-Normal Day 3 Renin. Patients with sustained Elevated Renin levels from Day 0 to Day 3 had the highest risk of death in a 30-day window. In this study, we found that renin may be a novel biomarker that has prognostic value for patients with sepsis-associated ARDS. Future studies evaluating renin levels in patients with sepsis-associated ARDS are needed to validate these findings.

Published
2024
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3. 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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4. 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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5. 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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6. 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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7. Investigating the Association Between Dynamic Driving Pressure and Mortality in COVID-19-Related Acute Respiratory Distress Syndrome: A Joint Modeling Approach Using Real-Time Continuously-Monitored Ventilation Data

Author

Daniel J. Tan, MBI, Joseph M. Plasek, PhD, Peter C. Hou, MD, Rebecca M. Baron, MD, Benjamin J. Atkinson, MD, and Li Zhou, MD, PhD

Subjects
Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

IMPORTANCE AND OBJECTIVES:. COVID-19-related acute respiratory distress syndrome (ARDS) is associated with high mortality and often necessitates invasive mechanical ventilation (IMV). Previous studies on non-COVID-19 ARDS have shown driving pressure to be robustly associated with ICU mortality; however, those studies relied on “static” driving pressure measured periodically and manually. As “continuous” automatically monitored driving pressure is becoming increasingly available and reliable with more advanced mechanical ventilators, we aimed to examine the effect of this “dynamic” driving pressure in COVID-19 ARDS throughout the entire ventilation period. DESIGN, SETTING, AND PARTICIPANTS:. This retrospective, observational study cohort study evaluates the association between driving pressure and ICU mortality in patients with concurrent COVID-19 and ARDS using multivariate joint modeling. The study cohort (n = 544) included all adult patients (≥ 18 yr) with COVID-19 ARDS between March 1, 2020, and April 30, 2021, on volume-control mode IMV for 12 hours or more in a Mass General Brigham, Boston, MA ICU. MEASUREMENTS AND MAIN RESULTS:. Of 544 included patients, 171 (31.4%) died in the ICU. Increased dynamic ΔP was associated with increased risk in the hazard of ICU mortality (hazard ratio [HR] 1.035; 95% credible interval, 1.004–1.069) after adjusting for other relevant dynamic respiratory biomarkers. A significant increase in risk in the hazard of death was found for every hour of exposure to high intensities of driving pressure (≥ 15 cm H2O) (HR 1.002; 95% credible interval 1.001–1.003). CONCLUSIONS:. Limiting patients’ exposure to high intensities of driving pressure even while under lung-protective ventilation may represent a critical step in improving ICU survival in patients with COVID-19 ARDS. Time-series IMV data could be leveraged to enhance real-time monitoring and decision support to optimize ventilation strategies at the bedside.

Published
2024
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8. A targetable ‘rogue’ neutrophil-subset, [CD11b+DEspR+] immunotype, is associated with severity and mortality in acute respiratory distress syndrome (ARDS) and COVID-19-ARDS

Author

Victoria L. M. Herrera, Allan J. Walkey, Mai Q. Nguyen, Christopher M. Gromisch, Julie Z. Mosaddhegi, Matthew S. Gromisch, Bakr Jundi, Soeren Lukassen, Saskia Carstensen, Ridiane Denis, Anna C. Belkina, Rebecca M. Baron, Mayra Pinilla-Vera, Meike Mueller, W. Taylor Kimberly, Joshua N. Goldstein, Irina Lehmann, Angela R. Shih, Roland Eils, Bruce D. Levy, and Nelson Ruiz-Opazo

Subjects
Medicine, Science
Abstract

Abstract Neutrophil-mediated secondary tissue injury underlies acute respiratory distress syndrome (ARDS) and progression to multi-organ-failure (MOF) and death, processes linked to COVID-19-ARDS. This secondary tissue injury arises from dysregulated neutrophils and neutrophil extracellular traps (NETs) intended to kill pathogens, but instead cause cell-injury. Insufficiency of pleiotropic therapeutic approaches delineate the need for inhibitors of dysregulated neutrophil-subset(s) that induce subset-specific apoptosis critical for neutrophil function-shutdown. We hypothesized that neutrophils expressing the pro-survival dual endothelin-1/VEGF-signal peptide receptor, DEspR, are apoptosis-resistant like DEspR+ cancer-cells, hence comprise a consequential pathogenic neutrophil-subset in ARDS and COVID-19-ARDS. Here, we report the significant association of increased peripheral DEspR+CD11b+ neutrophil-counts with severity and mortality in ARDS and COVID-19-ARDS, and intravascular NET-formation, in contrast to DEspR[-] neutrophils. We detect DEspR+ neutrophils and monocytes in lung tissue patients in ARDS and COVID-19-ARDS, and increased neutrophil RNA-levels of DEspR ligands and modulators in COVID-19-ARDS scRNA-seq data-files. Unlike DEspR[-] neutrophils, DEspR+CD11b+ neutrophils exhibit delayed apoptosis, which is blocked by humanized anti-DEspR-IgG4S228P antibody, hu6g8, in ex vivo assays. Ex vivo live-cell imaging of Rhesus-derived DEspR+CD11b+ neutrophils showed hu6g8 target-engagement, internalization, and induction of apoptosis. Altogether, data identify DEspR+CD11b+ neutrophils as a targetable ‘rogue’ neutrophil-subset associated with severity and mortality in ARDS and COVID-19-ARDS.

Published
2022
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9. Surfactant Protein D Influences Mortality During Abdominal Sepsis by Facilitating Escherichia coli Colonization in the Gut

Author

Jack Varon, MD, MBA, Antonio Arciniegas Rubio, MD, Diana Amador-Munoz, MD, Alexis Corcoran, BA, Joseph A. DeCorte, BS, Colleen Isabelle, BA, Miguel Pinilla Vera, MD, Katherine Walker, MD, MSc, Luke Brown, BSc, Manuela Cernadas, MD, Lynn Bry, MD, PhD, Haopu Yang, Georgios D. Kitsios, MD, PhD, Bryan J. McVerry, MD, Alison Morris, MD, MS, Hyunwook Lee, BA, Judie Howrylak, MD, PhD, Joshua A. Englert, MD, and Rebecca M. Baron, MD

Subjects
Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

OBJECTIVES:. Determine the role of surfactant protein D (SPD) in sepsis. DESIGN:. Murine in vivo study. SETTING:. Research laboratory at an academic medical center. PATIENTS:. SPD knockout (SPD−/−) and wild-type (SPD+/+) mice. INTERVENTIONS:. SPD−/− and SPD+/+ mice were subjected to cecal ligation and puncture (CLP). After CLP, Escherichia coli bacteremia was assessed in both groups. Cecal contents from both groups were cultured to assess for colonization by E. coli. To control for parental effects on the microbiome, SPD−/− and SPD+/+ mice were bred from heterozygous parents, and levels of E. coli in their ceca were measured. Gut segments were harvested from mice, and SPD protein expression was measured by Western blot. SPD−/− mice were gavaged with green fluorescent protein, expressing E. coli and recombinant SPD (rSPD). MEASUREMENTS AND MAIN RESULTS:. SPD−/− mice had decreased mortality and decreased E. coli bacteremia compared with SPD+/+ mice following CLP. At baseline, SPD−/− mice had decreased E. coli in their cecal flora. When SPD−/− and SPD+/+ mice were bred from heterozygous parents and then separated after weaning, less E. coli was cultured from the ceca of SPD−/− mice. E. coli gut colonization was increased by gavage of rSPD in SPD−/− mice. The source of enteric SPD in SPD+/+ mice was the gallbladder. CONCLUSIONS:. Enteral SPD exacerbates mortality after CLP by facilitating colonization of the mouse gut with E. coli.

Published
2022
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10. Machine Learning Prediction of Death in Critically Ill Patients With Coronavirus Disease 2019

Author

Matthew M. Churpek, MD, MPH, PhD, Shruti Gupta, MD, MPH, Alexandra B. Spicer, MS, Salim S. Hayek, MD, Anand Srivastava, MD, MPH, Lili Chan, MD, MSCR, Michal L. Melamed, MD, MHS, Samantha K. Brenner, MD, MPH, Jared Radbel, MD, Farah Madhani-Lovely, MD, Pavan K. Bhatraju, MD, MSc, Anip Bansal, MD, Adam Green, MD, MBA, Nitender Goyal, MD, Shahzad Shaefi, MD, MPH, Chirag R. Parikh, MD, PhD, Matthew W. Semler, MD, David E. Leaf, MD, MMSc, Carl P. Walther, Samaya J. Anumudu, Justin Arunthamakun, Kathleen F. Kopecky, Gregory P. Milligan, Peter A. McCullough, ThuyDuyen Nguyen, Shahzad Shaefi, Megan L. Krajewski, Sidharth Shankar, Ameeka Pannu, Juan D. Valencia, Sushrut S. Waikar, Zoe A. Kibbelaar, Ambarish M. Athavale, Peter Hart, Oyintayo Ajiboye, Matthew Itteera, Adam Green, Jean-Sebastien Rachoin, Christa A. Schorr, Lisa Shea, Daniel L. Edmonston, Christopher L. Mosher, Alexandre M. Shehata, Zaza Cohen, Valerie Allusson, Gabriela Bambrick-Santoyo, Noor ul aain Bhatti, Bijal Metha, Aquino Williams, Samantha K. Brenner, Patricia Walters, Ronaldo C. Go, Keith M. Rose, Miguel A. Hernán, Amy M. Zhou, Ethan C. Kim, Rebecca Lisk, Lili Chan, Kusum S. Mathews, Steven G. Coca, Deena R. Altman, Aparna Saha, Howard Soh, Huei Hsun Wen, Sonali Bose, Emily Leven, Jing G. Wang, Gohar Mosoyan, Girish N. Nadkarni, Allon N. Friedman, John Guirguis, Rajat Kapoor, Christopher Meshberger, Chirag R. Parikh, Brian T. Garibaldi, Celia P. Corona-Villalobos, Yumeng Wen, Steven Menez, Rubab F. Malik, Carmen Elena Cervantes, Samir C. Gautam, Crystal Chang, H. Bryant Nguyen, Afshin Ahoubim, Leslie F. Thomas, Pramod K. Guru, Paul A. Bergl, Yan Zhou, Jesus Rodriguez, Jatan A. Shah, Mrigank S. Gupta, Princy N. Kumar, Deepa G. Lazarous, Seble G. Kassaye, Michal L. Melamed, Tanya S. Johns, Ryan Mocerino, Kalyan Prudhvi, Denzel Zhu, Rebecca V. Levy, Yorg Azzi, Molly Fisher, Milagros Yunes, Kaltrina Sedaliu, Ladan Golestaneh, Maureen Brogan, Jyotsana Thakkar, Neelja Kumar, Michael J. Ross, Michael Chang, Ritesh Raichoudhury, Edward J. Schenck, Soo Jung Cho, Maria Plataki, Sergio L. Alvarez-Mulett, Luis G. Gomez-Escobar, Di Pan, Stefi Lee, Jamuna Krishnan, William Whalen, David Charytan, Ashley Macina, Daniel W. Ross, Anand Srivastava, Alexander S. Leidner, Carlos Martinez, Jacqueline M. Kruser, Richard G. Wunderink, Alexander J. Hodakowski, Juan Carlos Q. Velez, Eboni G. Price-Haywood, Luis A. Matute-Trochez, Anna E. Hasty, Muner MB. Mohamed, Rupali S. Avasare, David Zonies, David E. Leaf, Shruti Gupta, Rebecca M. Baron, Meghan E. Sise, Erik T. Newman, Samah Abu Omar, Kapil K. Pokharel, Shreyak Sharma, Harkarandeep Singh, Simon Correa Gaviria, Tanveer Shaukat, Omer Kamal, Wei Wang, Heather Yang, Jeffery O. Boateng, Meghan Lee, Ian A. Strohbehn, Jiahua Li, Saif A. Muhsin, Ernest I. Mandel, Ariel L. Mueller, Nicholas S. Cairl, Farah Madhani-Lovely, Chris Rowan, Farah Madhai-Lovely, Vasil Peev, Jochen Reiser, John J. Byun, Andrew Vissing, Esha M. Kapania, Zoe Post, Nilam P. Patel, Joy-Marie Hermes, Anne K. Sutherland, Amee Patrawalla, Diana G. Finkel, Barbara A. Danek, Sowminya Arikapudi, Jeffrey M. Paer, Jared Radbel, Sonika Puri, Jag Sunderram, Matthew T. Scharf, Ayesha Ahmed, Ilya Berim, Jayanth Vatson, Shuchi Anand, Joseph E. Levitt, Pablo Garcia, Suzanne M. Boyle, Rui Song, Jingjing Zhang, Moh’d A. Sharshir, Vadym V. Rusnak, Anip Bansal, Amber S. Podoll, Michel Chonchol, Sunita Sharma, Ellen L. Burnham, Arash Rashidi, Rana Hejal, Eric Judd, Laura Latta, Ashita Tolwani, Timothy E. Albertson, Jason Y. Adams, Steven Y. Chang, Rebecca M. Beutler, Carl E. Schulze, Etienne Macedo, Harin Rhee, Kathleen D. Liu, Vasantha K. Jotwani, Jay L. Koyner, Chintan V. Shah, Vishal Jaikaransingh, Stephanie M. Toth-Manikowski, Min J. Joo, James P. Lash, Javier A. Neyra, Nourhan Chaaban, Alfredo Iardino, Elizabeth H. Au, Jill H. Sharma, Marie Anne Sosa, Sabrina Taldone, Gabriel Contreras, David De La Zerda, Hayley B. Gershengorn, Salim S. Hayek, Pennelope Blakely, Hanna Berlin, Tariq U. Azam, Husam Shadid, Michael Pan, Patrick O’ Hayer, Chelsea Meloche, Rafey Feroze, Kishan J. Padalia, Jeff Leya, John P. Donnelly, Andrew J. Admon, Jennifer E. Flythe, Matthew J. Tugman, Brent R. Brown, Amanda K. Leonberg-Yoo, Ryan C. Spiardi, Todd A. Miano, Meaghan S. Roche, Charles R. Vasquez, Amar D. Bansal, Natalie C. Ernecoff, Csaba P. Kovesdy, Miklos Z. Molnar, S. Susan Hedayati, Mridula V. Nadamuni, Sadaf S. Khan, Duwayne L. Willett, Samuel A.P. Short, Amanda D. Renaghan, Pavan Bhatraju, A. Bilal Malik, Matthew W. Semler, Anitha Vijayan, Christina Mariyam Joy, Tingting Li, Seth Goldberg, Patricia F. Kao, Greg L. Schumaker, Nitender Goyal, Anthony J. Faugno, Caroline M. Hsu, Asma Tariq, Leah Meyer, Marta Christov, Francis P. Wilson, Tanima Arora, and Ugochukwu Ugwuowo

Subjects
Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

OBJECTIVES:. Critically ill patients with coronavirus disease 2019 have variable mortality. Risk scores could improve care and be used for prognostic enrichment in trials. We aimed to compare machine learning algorithms and develop a simple tool for predicting 28-day mortality in ICU patients with coronavirus disease 2019. DESIGN:. This was an observational study of adult patients with coronavirus disease 2019. The primary outcome was 28-day inhospital mortality. Machine learning models and a simple tool were derived using variables from the first 48 hours of ICU admission and validated externally in independent sites and temporally with more recent admissions. Models were compared with a modified Sequential Organ Failure Assessment score, National Early Warning Score, and CURB-65 using the area under the receiver operating characteristic curve and calibration. SETTING:. Sixty-eight U.S. ICUs. PATIENTS:. Adults with coronavirus disease 2019 admitted to 68 ICUs in the United States between March 4, 2020, and June 29, 2020. INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. The study included 5,075 patients, 1,846 (36.4%) of whom died by day 28. eXtreme Gradient Boosting had the highest area under the receiver operating characteristic curve in external validation (0.81) and was well-calibrated, while k-nearest neighbors were the lowest performing machine learning algorithm (area under the receiver operating characteristic curve 0.69). Findings were similar with temporal validation. The simple tool, which was created using the most important features from the eXtreme Gradient Boosting model, had a significantly higher area under the receiver operating characteristic curve in external validation (0.78) than the Sequential Organ Failure Assessment score (0.69), National Early Warning Score (0.60), and CURB-65 (0.65; p < 0.05 for all comparisons). Age, number of ICU beds, creatinine, lactate, arterial pH, and Pao2/Fio2 ratio were the most important predictors in the eXtreme Gradient Boosting model. CONCLUSIONS:. eXtreme Gradient Boosting had the highest discrimination overall, and our simple tool had higher discrimination than a modified Sequential Organ Failure Assessment score, National Early Warning Score, and CURB-65 on external validation. These models could be used to improve triage decisions and clinical trial enrichment.

Published
2021
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11. Whole blood RNA sequencing reveals a unique transcriptomic profile in patients with ARDS following hematopoietic stem cell transplantation

Author

Joshua A. Englert, Michael H. Cho, Andrew E. Lamb, Maya Shumyatcher, Diana Barragan-Bradford, Maria C. Basil, Angelica Higuera, Colleen Isabelle, Mayra Pinilla Vera, Paul B. Dieffenbach, Laura E. Fredenburgh, Joyce B. Kang, Ami S. Bhatt, Joseph H. Antin, Vincent T. Ho, Robert J. Soiffer, Judie A. Howrylak, Blanca E. Himes, and Rebecca M. Baron

Subjects
Acute respiratory distress syndrome (ARDS), RNA sequencing, RNA-Seq, Transcriptome profiling, Hematopoietic stem cell transplantation, Respiratory failure, Diseases of the respiratory system, RC705-779
Abstract

Abstract Background The acute respiratory distress syndrome (ARDS) is characterized by the acute onset of hypoxemia and bilateral lung infiltrates in response to an inciting event, and is associated with high morbidity and mortality. Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) are at increased risk for ARDS. We hypothesized that HSCT patients with ARDS would have a unique transcriptomic profile identifiable in peripheral blood compared to those that did not undergo HSCT. Methods We isolated RNA from banked peripheral blood samples from a biorepository of critically ill ICU patients. RNA-Seq was performed on 11 patients with ARDS (5 that had undergone HSCT and 6 that had not) and 12 patients with sepsis without ARDS (5 that that had undergone HCST and 7 that had not). Results We identified 687 differentially expressed genes between ARDS and ARDS-HSCT (adjusted p-value

Published
2019
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12. Metabolome alterations in severe critical illness and vitamin D status

Author

Jessica Lasky-Su, Amber Dahlin, Augusto A. Litonjua, Angela J. Rogers, Michael J. McGeachie, Rebecca M. Baron, Lee Gazourian, Diana Barragan-Bradford, Laura E. Fredenburgh, Augustine M. K. Choi, Kris M. Mogensen, Sadeq A. Quraishi, Karin Amrein, and Kenneth B. Christopher

Subjects
Vitamin D, Metabolite, Metabolomics, Homeostasis, Critical illness, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

Abstract Background Metabolic homeostasis is substantially disrupted in critical illness. Given the pleiotropic effects of vitamin D, we hypothesized that metabolic profiles differ between critically ill patients relative to their vitamin D status. Methods We performed a metabolomics study on biorepository samples collected from a single academic medical center on 65 adults with systemic inflammatory response syndrome or sepsis treated in a 20-bed medical ICU between 2008 and 2010. To identify key metabolites and metabolic pathways related to vitamin D status in critical illness, we first generated metabolomic data using gas and liquid chromatography mass spectroscopy. We followed this by partial least squares-discriminant analysis to identify individual metabolites that were significant. We then interrogated the entire metabolomics profile using metabolite set enrichment analysis to identify groups of metabolites and pathways that were differentiates of vitamin D status. Finally we performed logistic regression to construct a network model of chemical-protein target interactions important in vitamin D status. Results Metabolomic profiles significantly differed in critically ill patients with 25(OH)D ≤ 15 ng/ml relative to those with levels >15 ng/ml. In particular, increased 1,5-anhydroglucitol, tryptophan betaine, and 3-hydroxyoctanoate as well as decreased 2-arachidonoyl-glycerophosphocholine and N-6-trimethyllysine were strong predictors of 25(OH)D >15 ng/ml. The combination of these five metabolites led to an area under the curve for discrimination for 25(OH)D > 15 ng/ml of 0.82 (95% CI 0.71–0.93). The metabolite pathways related to glutathione metabolism and glutamate metabolism are significantly enriched with regard to vitamin D status. Conclusion Vitamin D status is associated with differential metabolic profiles during critical illness. Glutathione and glutamate pathway metabolism, which play principal roles in redox regulation and immunomodulation, respectively, were significantly altered with vitamin D status.

Published
2017
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13. Organization of Outpatient Care After COVID-19 Hospitalization

Author

Thomas S. Valley, Amanda Schutz, Ithan D. Peltan, Kelly C. Vranas, Kusum S. Mathews, Sarah E. Jolley, Jessica A. Palakshappa, Catherine L. Hough, Jay S. Steingrub, Mark A. Tidswell, Lori-Ann Kozikowski, Cynthia Kardos, Lesley DeSouza, Rebecca M. Baron, Mayra Pinilla-Vera, David M. Rubins, Antonio Arciniegas, Richard Riker, Christine Lord, Marie-Carmelle Elie, Daniel Talmor, Nathan Shapiro, Valerie Banner-Goodspeed, Kathryn A. Hibbert, Kelsey Brait, Natalie Pulido, Alan Jones, James Galbraith, Utsav Nandi, Rebekah Peacock, Jenna Davis, Matthew Prekker, Michael Puskarich, Seth Jones, Anne Roerhl, Audrey Hendrickson, Michael Matthay, Kirsten Kangelaris, Kathleen Liu, Kimberly Yee, Hanjing Zhuo, Gregory Hendey, Steven Chang, Nida Qadir, Andrea Tam, Rebecca Beutler, Trisha Agarwal, Joseph Levitt, Jennifer G. Wilson, Angela Rogers, Jonasel Roque, Rosemary Vojnik, Timothy E. Albertson, James A. Chenoweth, Jason Y. Adams, Brian M. Morrissey, Skyler J. Pearson, Eyad Almasri, Alyssa Hughes, Marc Moss, Adit Ginde, Jeffrey McKeehan, Lani Finck, Michelle Howell, Carrie Higgins, Jason Haukoos, Stephanie Gravitz, Carolynn Lyle, Ivor S. Douglas, Terra Hiller, Audrey Goold, James Finigan, Robert Hyzy, Pauline Park, Michael Sjoding, Stephen Kay, Kristine Nelson, Kelli McDonough, Namita Jayaprakash, Emanuel P. Rivers, Jennifer Swiderek, Jasreen Kaur Gill, Jacqueline Day, Robert Sherwin, James Wooden, Thomas Mazzoco, Michelle Ng Gong, Michael Aboodi, Ayesha Asghar, Omowunmi Amosu, Hiwet Tzehaie, Aluko A. Hope, Jen-Ting Chen, Rahul Nair, Brenda Lopez, Obiageli Offor, Jarrod M. Mosier, Cameron D. Hypes, Elizabeth Salvagio, Christian Bime, Elaine Cristan, Lynne D. Richardson, Neha Goel, Patrick Maher, Samuel Acquah, Donald Cardone, Gary Oldenburg, Andrew Dunn, Duncan Hite, Kristin Hudock, Jose Gomez Arroyo, Tammy Roads, Abhijit Duggal, Eduardo Mireles-Cabodevila, Bryce R.H. Robinson, Nicholas J. Johnson, Stephanie Gundel, Laura Evans, D. Shane O'Mahony, Julie A. Wallick, Isabel Pedraza, Akram Khan, Olivia Krol, Milad Karami Jouzestani, Kelly Vranas, Donald M. Yealy, Derek C. Angus, Alexandra Weissman, David T. Huang, Aimee Boeltz-Skrtich, Steven Moore, Derek Isenberg, D. Clark Files, Chadwick Miller, Kevin Gibbs, Lori Flores, Mary LaRose, Lauren Koehler, Leigha Landreth, Peter Morris, Evan Cassity, Jamie Sturgill, Kirby Mayer, Ashley Montgomery-Yates, Marjolein de Wit, Jessica Mason, Andrew Goodwin, Abigail Grady, Patterson Burch, Kyle B. Enfield, Jeffrey M. Sturek, Mary Marshall, Joseph R. Bledsoe, Samuel M. Brown, Colin K. Grissom, Brent Armbruster, Estelle Harris, John Eppensteiner, Bria Johnston Hall, Grace L. Hall, Lauren McGowan, Andrew Bouffler, Erica Walker, Samuel Francis, Tedra Porter, Bennett P. deBoisblanc, Matthew R. Lammi, David R. Janz, Paula Lauto, Connie Romaine, Marie Sandi, Todd W. Rice, Wesley H. Self, Nancy Ringwood, Alexander Nagrebetsky, Laura Fitzgerald, Roy G. Brower, Lora A. Reineck, Neil R. Aggarwal, and Karen Bienstock

Subjects
Hospitalization, Pulmonary and Respiratory Medicine, Ambulatory Care, COVID-19, Humans, Cardiology and Cardiovascular Medicine, Critical Care and Intensive Care Medicine
Published
2022

14. Effect of total cholesterol and statin therapy on mortality in ARDS patients: a secondary analysis of the SAILS and HARP-2 trials

Author

Shaun M. Pienkos, Andrew R. Moore, Jiazhen Guan, Joseph E. Levitt, Michael A. Matthay, Rebecca M. Baron, John Conlon, Daniel F. McAuley, Cecilia M. O’Kane, and Angela J. Rogers

Subjects
Critical care, Cholesterol, Acute respiratory distress syndrome, Research, Sepsis, Statins, Critical Care and Intensive Care Medicine
Abstract

Background Two acute respiratory distress syndrome (ARDS) trials showed no benefit for statin therapy, though secondary analyses suggest inflammatory subphenotypes may have a differential response to simvastatin. Statin medications decrease cholesterol levels, and low cholesterol has been associated with increased mortality in critical illness. We hypothesized that patients with ARDS and sepsis with low cholesterol could be harmed by statins. Methods Secondary analysis of patients with ARDS and sepsis from two multicenter trials. We measured total cholesterol from frozen plasma samples obtained at enrollment in Statins for Acutely Injured Lungs from Sepsis (SAILS) and Simvastatin in the Acute Respiratory Distress Syndrome (HARP-2) trials, which randomized subjects with ARDS to rosuvastatin versus placebo and simvastatin versus placebo, respectively, for up to 28 days. We compared the lowest cholesterol quartile ( Results There were 678 subjects with cholesterol measured in SAILS and 509 subjects in HARP-2, of whom 384 had sepsis. Median cholesterol at enrollment was 97 mg/dL in both SAILS and HARP-2. Low cholesterol was associated with higher APACHE III and shock prevalence in SAILS, and higher Sequential Organ Failure Assessment score and vasopressor use in HARP-2. Importantly, the effect of statins differed in these trials. In SAILS, patients with low cholesterol who received rosuvastatin were more likely to die (odds ratio (OR) 2.23, 95% confidence interval (95% CI) 1.06–4.77, p = 0.02; interaction p = 0.02). In contrast, in HARP-2, low cholesterol patients had lower mortality if randomized to simvastatin, though this did not reach statistical significance in the smaller cohort (OR 0.44, 95% CI 0.17–1.07, p = 0.06; interaction p = 0.22). Conclusions Cholesterol levels are low in two cohorts with sepsis-related ARDS, and those in the lowest cholesterol quartile are sicker. Despite the very low levels of cholesterol, simvastatin therapy seems safe and may reduce mortality in this group, though rosuvastatin was associated with harm. Graphical abstract

Published
2023

15. Inflammasome activation in neutrophils of patients with severe COVID-19

Author

Karen Aymonnier, Julie Ng, Laura E. Fredenburgh, Katherin Zambrano-Vera, Patrick Münzer, Sarah Gutch, Shoichi Fukui, Michael Desjardins, Meera Subramaniam, Rebecca M Baron, Benjamin A. Raby, Mark A. Perrella, James A. Lederer, and Denisa D. Wagner

Subjects
Inflammasomes, Neutrophils, SARS-CoV-2, neutrophil, COVID-19, Regular Article, NETs, Hematology, ASC, Extracellular Traps, Mice, MTOC, inflammasome, Animals, Humans
Abstract

Neutrophils with intact multilobulated nuclei show ASC speck formation and high histone H3 citrullination in patients with severe COVID-19. In murine neutrophils, ASC speck forms transiently at the microtubule organizing center, before nuclear rounding, early in NETosis. Abstract Infection by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) engages the inflammasome in monocytes and macrophages and leads to the cytokine storm in COVID-19. Neutrophils, the most abundant leukocytes, release neutrophil extracellular traps (NETs), which have been implicated in the pathogenesis of COVID-19. Our recent study shows that activation of the NLRP3 inflammasome is important for NET release in sterile inflammation. However, the role of neutrophil inflammasome formation in human disease is unknown. We hypothesized that SARS-COV-2 infection may induce inflammasome activation in neutrophils. We also aimed to assess the localization of inflammasome formation, (i.e. ASC speck assembly), and timing relative to NETosis in stimulated neutrophils by real time video microscopy. Neutrophils isolated from severe COVID-19 patients demonstrated that approximately 2% of neutrophils in both the peripheral blood and tracheal aspirates presented ASC speck. ASC speck was observed in neutrophils with an intact poly-lobulated nucleus, suggesting early formation during neutrophil activation. Additionally, 40% of nuclei were positive for citrullinated histone H3, and there was a significant correlation between speck formation and nuclear histone citrullination. Time-lapse microscopy in LPS-stimulated neutrophils from fluorescent ASC reporter mice showed that ASC speck formed transiently and at the microtubule organizing center, long before NET release. Our study shows that ASC speck is present in neutrophils from COVID-19 patients with respiratory failure and that it forms early in NETosis. Our findings suggest that inhibition of neutrophil inflammasomes may be beneficial in COVID-19.

Published
2022

16. Characteristics and Outcomes of US Patients Hospitalized With COVID-19

Author

Theodore J. Iwashyna, Michael J. Lanspa, Engi F. Attia, Alexander Nagrebetsky, Aluko A. Hope, Douglas Hayden, Lynne D. Richardson, Kusum S. Mathews, Ithan D. Peltan, Rebecca M. Baron, Todd W. Rice, Nicholas J. Johnson, Stephanie J. Gundel, Christine A. Ulysse, Steven Y. Chang, Kelly C. Vranas, Samuel M. Brown, Derek C. Angus, Catherine L. Hough, Sarina K. Sahetya, B. Taylor Thompson, Andrew J. Goodwin, Benjamin Haaland, Ellen Caldwell, and Andrew J Admon

Subjects
Male, medicine.medical_specialty, medicine.medical_treatment, Critical Care Nursing, Article, law.invention, law, Health care, Epidemiology, medicine, Humans, Hospital Mortality, Pandemics, Aged, Retrospective Studies, Mechanical ventilation, SARS-CoV-2, business.industry, COVID-19, Retrospective cohort study, General Medicine, Middle Aged, medicine.disease, Respiration, Artificial, Intensive care unit, Comorbidity, Hospitalization, Intensive Care Units, Respiratory failure, Emergency medicine, Cohort, Female, business
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.

Published
2022

17. Advancing precision medicine for acute respiratory distress syndrome

Author

Theodore J. Standiford, Roger J. Lewis, Jeremy R. Beitler, Eric P. Schmidt, Loren C. Denlinger, Rebecca M. Baron, Hector R. Wong, Carolyn S. Calfee, Julie A. Bastarache, Laura J. Esserman, Neil R. Aggarwal, Thomas R. Martin, John C. Marshall, Eileen Rubin, Marc Moss, Lorraine B. Ware, Nuala J. Meyer, Lisa M. LaVange, Daniel F. McAuley, Lora A. Reineck, B. Taylor Thompson, and Michelle N. Gong

Subjects
Pulmonary and Respiratory Medicine, ARDS, medicine.medical_specialty, Clinical Sciences, MEDLINE, Lung injury, Rare Diseases, SDG 3 - Good Health and Well-being, Pandemic, medicine, Humans, Precision Medicine, Intensive care medicine, Acute Respiratory Distress Syndrome, Lung, Respiratory Distress Syndrome, Other Medical and Health Sciences, business.industry, COVID-19, medicine.disease, Precision medicine, Clinical trial, Orphan Drug, Good Health and Well Being, Respiratory, Public Health and Health Services, Position paper, Position Paper, business, Cohort study
Abstract

Acute respiratory distress syndrome (ARDS) is a heterogeneous clinical syndrome. Understanding of the complex pathways involved in lung injury pathogenesis, resolution, and repair has grown considerably in recent decades. Nevertheless, to date, only therapies targeting ventilation-induced lung injury have consistently proven beneficial, and despite these gains, ARDS morbidity and mortality remain high. Many candidate therapies with promise in preclinical studies have been ineffective in human trials, probably at least in part due to clinical and biological heterogeneity that modifies treatment responsiveness in human ARDS. A precision medicine approach to ARDS seeks to better account for this heterogeneity by matching therapies to subgroups of patients that are anticipated to be most likely to benefit, which initially might be identified in part by assessing for heterogeneity of treatment effect in clinical trials. In October 2019, the US National Heart, Lung, and Blood Institute convened a workshop of multidisciplinary experts to explore research opportunities and challenges for accelerating precision medicine in ARDS. Topics of discussion included the rationale and challenges for a precision medicine approach in ARDS, the roles of preclinical ARDS models in precision medicine, essential features of cohort studies to advance precision medicine, and novel approaches to clinical trials to support development and validation of a precision medicine strategy. In this Position Paper, we summarise workshop discussions, recommendations, and unresolved questions for advancing precision medicine in ARDS. Although the workshop took place before the COVID-19 pandemic began, the pandemic has highlighted the urgent need for precision therapies for ARDS as the global scientific community grapples with many of the key concepts, innovations, and challenges discussed at this workshop.

Published
2022

18. Therapeutic hypothermia for intracerebral hemorrhage: Systematic review and meta-analysis of the experimental and clinical literature

Author

Luis Ascanio-Cortez, Stephan A. Mayer, Patrick D. Lyden, Turner S. Baker, Christopher P. Kellner, Fred Rincon, John R. Durbin, Anthony Costa, Frederick Colbourne, Zachary Troiani, and Rebecca M. Baron

Subjects
Intracerebral hemorrhage, Hematoma, medicine.medical_specialty, Rehabilitation, business.industry, medicine.medical_treatment, Brain Edema, Hypothermia, Clinical literature, medicine.disease, Neuroprotection, Stroke, Neurology, Hypothermia, Induced, Meta-analysis, medicine, Humans, medicine.symptom, Intensive care medicine, business, Cerebral Hemorrhage
Abstract

Background Intracerebral hemorrhage remains the deadliest form of stroke worldwide, inducing neuronal death through a wide variety of pathways. Therapeutic hypothermia is a robust and well-studied neuroprotectant widely used across a variety of specialties. Aims This review summarizes results from preclinical and clinical studies to highlight the overall effectiveness of therapeutic hypothermia to improve long-term intracerebral hemorrhage outcomes while also elucidating optimal protocol regimens to maximize therapeutic effect. Summary of review A systematic review was conducted across three databases to identify trials investigating the use of therapeutic hypothermia to treat intracerebral hemorrhage. A random-effects meta-analysis was conducted on preclinical studies, looking at neurobehavioral outcomes, blood brain barrier breakdown, cerebral edema, hematoma volume, and tissue loss. Several mixed-methods meta-regression models were also performed to adjust for variance and variations in hypothermia induction procedures. Twwenty-one preclinical studies and five human studies were identified. The meta-analysis of preclinical studies demonstrated a significant benefit in behavioral scores (ES = −0.43, p = 0.02), cerebral edema (ES = 1.32, p = 0.0001), and blood brain barrier (ES = 2.73, p ≤ 0.00001). Therapeutic hypothermia was not found to significantly affect hematoma expansion (ES = −0.24, p = 0.12) or tissue loss (ES = 0.06, p = 0.68). Clinical study outcome reporting was heterogeneous; however, there was recurring evidence of therapeutic hypothermia-induced edema reduction. Conclusions The combined preclinical evidence demonstrates that therapeutic hypothermia reduced multiple cell death mechanisms initiated by intracerebral hemorrhage; yet, there is no definitive evidence in clinical studies. The cooling strategies employed in both preclinical and clinical studies were highly diverse, and focused refinement of cooling protocols should be developed in future preclinical studies. The current data for therapeutic hypothermia in intracerebral hemorrhage remains questionable despite the highly promising indications in preclinical studies. Definitive randomized controlled studies are still required to answer this therapeutic question.

Published
2021

19. High plasma IL-18 identifies high-risk ARDS patients not identified by latent class analysis sub-phenotyping: a secondary analysis of the SAILS and HARP-2 studies

Author

Andrew R Moore, Shaun M Pienkos, Pratik Sinha, Jiazhen Guan, Cecilia M O’Kane, Joseph E Levitt, Jennifer G Wilson, Manu Shankar-Hari, Michael A Matthay, Carolyn S Calfee, Rebecca M Baron, Daniel F McAuley, and Angela J Rogers

Abstract

Background: Both latent class analysis (LCA) assignment based upon a panel of plasma biomarkers and interleukin-18 (IL-18) plasma level have been shown to predict prognosis and treatment response in Acute Respiratory Distress Syndrome (ARDS). Interleukin-18 is a measure of inflammasome activation and plays a distinct role in inflammation that is not captured by the biomarkers used in LCA assignments. We hypothesized that elevated IL-18 would provide additive prognostic and therapeutic information to previously published LCA assignments in ARDS, identifying additional “high-risk” patients not captured by LCA who could be eligible for inclusion in future precision medicine-focused trials. Methods: IL-18 and a panel of protein markers used for LCA had been previously measured in plasma from 683/745 patients in the Statins for Acutely Injured Lungs from Sepsis (SAILS) and 511/540 patients in the Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction (HARP-2) trials. We tested the association between high IL-18 (>800 pg/mL) and LCA class assignment using McNemar’s test and evaluated the association of each subgrouping as well as treatment with 60-day mortality using Fisher’s exact test. We assessed 60-day mortality in each combination (high/low IL-18, hypo-/hyper-inflammatory LCA class, and treatment/placebo) using Kaplan-Meier survival analysis. We evaluated the correlation between the log2 transformed IL-18 level and LCA biomarkers using Pearson’s correlation coefficient. Results: 33% of patients in SAILS and HARP-2 were discordant by IL-18 level and LCA class. Elevated IL-18 identified a high-risk group of individuals previously classified as hypo-inflammatory by LCA in both SAILS (OR 3.3, 95% CI 1.8-6.1, p of 0.17-0.47. Conclusions: High Plasma IL-18 level provides additional prognostic information to LCA sub-phenotypes in two large ARDS cohorts.

Published
2022

20. Thrombosis-Related Loss of Arterial Lines in the First Wave of COVID-19 and Non-COVID-19 Intensive Care Unit Patients

Author

Rebecca L. Zon, Lauren E. Merz, Kara G. Fields, Jessica Grandoni, Jessica C. Stuart, Rachel H. Occhiogrosso, Linda Li, Rebecca M. Baron, Laura E. Fredenburgh, Ann E. Woolley, Jean M. Connors, and Gyorgy Frendl

Subjects
Anesthesiology and Pain Medicine
Abstract

Patients with coronavirus disease 2019 (COVID-19) can present with severe respiratory distress requiring intensive care unit (ICU)-level care. Such care often requires placement of an arterial line for monitoring of pulmonary disease progression, hemodynamics, and laboratory tests. During the first wave of the COVID-19 pandemic in March 2020, experienced physicians anecdotally reported multiple attempts, decreased insertion durations, and greater need for replacement of arterial lines in patients with COVID-19 due to persistent thrombosis. Because invasive procedures in patients with COVID-19 may increase the risk for caregiver infection, better defining difficulties in maintaining arterial lines in COVID-19 patients is important. We sought to explore the association between COVID-19 infection and arterial line thrombosis in critically ill patients.In this primary exploratory analysis, a multivariable Fine-Gray subdistribution hazard model was used to retrospectively estimate the association between critically ill COVID-19 (versus sepsis/acute respiratory distress syndrome [ARDS]) patients and the risk of arterial line removal for thrombosis (with arterial line removal for any other reason treated as a competing risk). As a sensitivity analysis, we compared the number of arterial line clots per 1000 arterial line days between critically ill COVID-19 and sepsis/ARDS patients using multivariable negative binomial regression.We retrospectively identified 119 patients and 200 arterial line insertions in patients with COVID-19 and 54 patients and 68 arterial line insertions with non-COVID ARDS. Using a Fine-Gray subdistribution hazard model, we found the adjusted subdistribution hazard ratio (95% confidence interval [CI]) for arterial line clot to be 2.18 (1.06-4.46) for arterial lines placed in COVID-19 patients versus non-COVID-19 sepsis/ARDS patients (P = .034). Patients with COVID-19 had 36.3 arterial line clots per 1000 arterial line days compared to 19.1 arterial line clots per 1000 arterial line days in patients without COVID-19 (adjusted incidence rate ratio [IRR] [95% CI], 1.78 [0.94-3.39]; P = .078).Our study suggests that arterial line complications due to thrombosis are more likely in COVID-19 patients and supports the need for further research on the association between COVID-19 and arterial line dysfunction requiring replacement.

Published
2022

21. The upper and lower respiratory tract microbiome in severe aspiration pneumonia

Author

Georgios D. Kitsios, Vi D. Nguyen, Khaled Sayed, Nameer Al-Yousif, Caitlin Schaefer, Faraaz A. Shah, William Bain, Haopu Yang, Adam Fitch, Kelvin Li, Xiaohong Wang, Shulin Qin, Heather Gentry, Yingze Zhang, Jack Varon, Antonio Arciniegas Rubio, Joshua A. Englert, Rebecca M. Baron, Janet S. Lee, Barbara Methé, Panayiotis V. Benos, Alison Morris, and Bryan J. McVerry

Subjects
Multidisciplinary
Published
2023

22. Machine learning approaches to the human metabolome in sepsis identify metabolic links with survival

Author

Leah B. Kosyakovsky, Emily Somerset, Angela J. Rogers, Michael Sklar, Jared R. Mayers, Augustin Toma, Yishay Szekely, Sabri Soussi, Bo Wang, Chun-Po S. Fan, Rebecca M. Baron, and Patrick R. Lawler

Subjects
Critical Care and Intensive Care Medicine
Abstract

Background Metabolic predictors and potential mediators of survival in sepsis have been incompletely characterized. We examined whether machine learning (ML) tools applied to the human plasma metabolome could consistently identify and prioritize metabolites implicated in sepsis survivorship, and whether these methods improved upon conventional statistical approaches. Methods Plasma gas chromatography–liquid chromatography mass spectrometry quantified 411 metabolites measured ≤ 72 h of ICU admission in 60 patients with sepsis at a single center (Brigham and Women’s Hospital, Boston, USA). Seven ML approaches were trained to differentiate survivors from non-survivors. Model performance predicting 28 day mortality was assessed through internal cross-validation, and innate top-feature (metabolite) selection and rankings were compared across the 7 ML approaches and with conventional statistical methods (logistic regression). Metabolites were consensus ranked by a summary, ensemble ML ranking procedure weighing their contribution to mortality risk prediction across multiple ML models. Results Median (IQR) patient age was 58 (47, 62) years, 45% were women, and median (IQR) SOFA score was 9 (6, 12). Mortality at 28 days was 42%. The models’ specificity ranged from 0.619 to 0.821. Partial least squares regression-discriminant analysis and nearest shrunken centroids prioritized the greatest number of metabolites identified by at least one other method. Penalized logistic regression demonstrated top-feature results that were consistent with many ML methods. Across the plasma metabolome, the 13 metabolites with the strongest linkage to mortality defined through an ensemble ML importance score included lactate, bilirubin, kynurenine, glycochenodeoxycholate, phenylalanine, and others. Four of these top 13 metabolites (3-hydroxyisobutyrate, indoleacetate, fucose, and glycolithocholate sulfate) have not been previously associated with sepsis survival. Many of the prioritized metabolites are constituents of the tryptophan, pyruvate, phenylalanine, pentose phosphate, and bile acid pathways. Conclusions We identified metabolites linked with sepsis survival, some confirming prior observations, and others representing new associations. The application of ensemble ML feature-ranking tools to metabolomic data may represent a promising statistical platform to support biologic target discovery.

Published
2022

23. COVID‐19‐induced endotheliitis: emerging evidence and possible therapeutic strategies

Author

Robert J. Soiffer, Eleonora Calabretta, Rebecca M. Baron, Israel Vlodavsky, José M. Moraleda, Massimo Iacobelli, Jawed Fareed, Paul G. Richardson, Ruben Jara, Alessio Aghemo, Peter O'Gorman, Carmelo Carlo-Stella, Clifton C. Mo, and Antonio Pagliuca

Subjects
Vasculitis, medicine.medical_specialty, ARDS, Multiple Organ Failure, medicine.medical_treatment, Hepatic Veno-Occlusive Disease, Graft vs Host Disease, Apoptosis, Context (language use), Anemia, Sickle Cell, Disease, Asymptomatic, 03 medical and health sciences, Polydeoxyribonucleotides, 0302 clinical medicine, Intensive care, Humans, Thrombophilia, Medicine, Idiopathic Interstitial Pneumonias, Intensive care medicine, Pandemics, Bone Marrow Transplantation, Glucuronidase, Covid‐19, Mechanical ventilation, Heparin, Interleukin-6, SARS-CoV-2, Thrombotic Microangiopathies, business.industry, Mortality rate, Organ dysfunction, Anticoagulants, COVID-19, Endothelial Cells, Hematology, medicine.disease, Viral Tropism, Organ Specificity, 030220 oncology & carcinogenesis, Commentary, Endothelium, Vascular, medicine.symptom, business, Stem Cell Transplantation, 030215 immunology
Abstract

The coronavirus disease 2019 (COVID‐19) pandemic, a viral illness caused by the severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), 1 has produced at the time of this writing nearly 33 million cases of infection, with over a million deaths in 235 countries, 2 causing an unprecedented burden on healthcare systems and a severe global socioeconomic crisis. As the pandemic spreads, knowledge on the disease course, as well as potential risk factors and predictors of severity is increasing daily, and initial data from randomised controlled studies have allowed care providers to refine therapeutic strategies. Nonetheless, mortality is markedly elevated among those presenting with severe disease, long‐term sequelae among survivors are unknown, and vaccine‐based therapies currently remain at early stages of development. Most reported cases are asymptomatic or present with mild symptoms; however, 7–26% of hospitalised patients experience severe disease, often requiring admission to intensive care units (ICUs), with progressive multiple organ dysfunction and high mortality. 3 , 4 , 5 Such differences in clinical outcomes have led physicians to initiate diverse pharmacological therapies at various stages of the disease, generating challenges as to the most appropriate therapeutic choice for COVID‐19. In this context, the use of dexamethasone has significantly reduced mortality rates in critically ill patients requiring supplemental oxygen or mechanical ventilation, 6 and remdesivir has demonstrated clinical benefit in hospitalised patients, but with unknown survival benefit to date 7 ; additional effective treatment options are therefore urgently needed. In an initial attempt to provide a uniform and widely reproducible methodology to guide systematic treatment strategies, a three‐stage classification of COVID‐19 has been proposed. 8 The Stage I or ‘early infection’ occurs at the initial establishment of disease with high viral replication, and commonly presents with a range of complaints that can include mild and often non‐specific influenza‐like signs and symptoms. Stage II is the ‘pulmonary phase’, with preferential viral‐mediated injury of the lung parenchyma and this is characterised by shortness of breath, hypoxia and pulmonary infiltrates with some degree of lung inflammation. Stage III is characterised by an exaggerated host immune‐inflammatory response to the virus, leading to acute respiratory distress syndrome (ARDS) and multi‐organ failure (MOF).

Published
2021

24. Recent advances in understanding and treating ARDS [version 1; referees: 2 approved]

Author

Rebecca M. Baron and Bruce D. Levy

Subjects
Review, Articles, Airway/Respiratory Physiology, Respiratory Pharmacology, Respiratory Problems in Critical Care, Adjunctive therapy, Berlin criteria, Low Tidal Volume Ventilation, Prone Positioning, Neuromuscular Blockade
Abstract

Acute respiratory distress syndrome represents a complex syndrome with considerable morbidity and mortality, for which there exist no targeted treatment strategies. However, recent advances in clinical care have improved outcomes, and we will review a number of these approaches here, as well as explore the mechanisms underlying the benefit of intervention that might point us in the direction toward future treatment and preventive strategies for this devastating syndrome.

Published
2016
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25. Increased Odds of Death for Patients with Interstitial Lung Disease and COVID-19: A Case–Control Study

Author

Anthony J. Esposito, Gary M. Hunninghake, Souheil El-Chemaly, Laura E. Fredenburgh, Tracy J. Doyle, Hilary J. Goldberg, Aravind A. Menon, Rebecca M. Baron, Rachel K. Putman, and Auyon J. Ghosh

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Interstitial lung disease, MEDLINE, Case-control study, Critical Care and Intensive Care Medicine, medicine.disease, Odds, Internal medicine, Correspondence, medicine, business
Published
2020

26. Redefining critical illness

Author

David M. Maslove, Benjamin Tang, Manu Shankar-Hari, Patrick R. Lawler, Derek C. Angus, J. Kenneth Baillie, Rebecca M. Baron, Michael Bauer, Timothy G. Buchman, Carolyn S. Calfee, Claudia C. dos Santos, Evangelos J. Giamarellos-Bourboulis, Anthony C. Gordon, John A. Kellum, Julian C. Knight, Aleksandra Leligdowicz, Daniel F. McAuley, Anthony S. McLean, David K. Menon, Nuala J. Meyer, Lyle L. Moldawer, Kiran Reddy, John P. Reilly, James A. Russell, Jonathan E. Sevransky, Christopher W. Seymour, Nathan I. Shapiro, Mervyn Singer, Charlotte Summers, Timothy E. Sweeney, B. Taylor Thompson, Tom van der Poll, Balasubramanian Venkatesh, Keith R. Walley, Timothy S. Walsh, Lorraine B. Ware, Hector R. Wong, Zsolt E. Zador, John C. Marshall, Maslove, David M [0000-0002-0765-7158], Tang, Benjamin [0000-0002-1469-9540], Shankar-Hari, Manu [0000-0002-5338-2538], Baillie, J Kenneth [0000-0001-5258-793X], Bauer, Michael [0000-0002-1521-3514], Buchman, Timothy G [0000-0001-7350-5921], Giamarellos-Bourboulis, Evangelos J [0000-0003-4713-3911], Gordon, Anthony C [0000-0002-0419-547X], Kellum, John A [0000-0003-1995-2653], Leligdowicz, Aleksandra [0000-0001-6055-4644], McAuley, Daniel F [0000-0002-3283-1947], Menon, David K [0000-0002-3228-9692], Meyer, Nuala J [0000-0003-4597-5584], Reddy, Kiran [0000-0002-1621-1481], Reilly, John P [0000-0003-3937-5320], Singer, Mervyn [0000-0002-1042-6350], Summers, Charlotte [0000-0002-7269-2873], van der Poll, Tom [0000-0002-9199-5079], Wong, Hector R [0000-0001-7989-1173], Apollo - University of Cambridge Repository, NIHR, Center of Experimental and Molecular Medicine, and Infectious diseases

Subjects
Critical Care, SARS-CoV-2, Critical Illness, Immunology, COVID-19, Humans, General Medicine, Syndrome, 11 Medical and Health Sciences, General Biochemistry, Genetics and Molecular Biology
Abstract

Both research and practice in critical care medicine have long been defined by syndromes. Though clinically recognizable entities, these are in fact loose amalgams of heterogeneous states, within which responses to therapy may vary. Mounting translational evidence suggests the current syndrome-based framework of critical illness should be reconsidered. Moreover, research done during the COVID-19 pandemic illustrates how the study of a more biologically homogeneous condition – respiratory failure due to SARS-CoV-2 infection – can increase the efficiency with which actionable results are generated. We discuss recent findings from basic science and clinical research in critical care, and explore how these might inform a new conceptual model of critical illness. De-emphasizing syndromes, we focus instead on the underlying biological changes that underpin critical illness states, and that may be amenable to treatment. We hypothesize that such an approach will accelerate translational critical care research, leading to a richer understanding of the pathobiology of critical illness, and of the proximate determinants of ICU outcomes. The specificity and granularity gained will support the design of more effective clinical trials, and inform a more precise, effective practice at the bedside.

Published
2022
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27. SARS-CoV-2 viral load is associated with increased disease severity and mortality

Author

Daniel R. Kuritzkes, Katrina Armstrong, Michael Dougan, Colline Wong, Rebecca M. Baron, Kathryn T. Hall, Edward T. Ryan, Alicja Piechocka-Trocha, Kendyll Coxen, Dusan Hanidziar, Caroline Atyeo, Stephanie Fischinger, Jonathan Z. Li, Athe M. N. Tsibris, Bruce D. Walker, Xu G. Yu, Andrew T. Chan, Lindsey R. Baden, Nikolaus Jilg, Yijia Li, Elizabeth Gillespie, Daniel P Worrall, Galit Alter, Francoise Giguel, Rida Chishti, Keith T. Flaherty, Heather Corry, James Regan, Alexandra Rosenthal, and Jesse Fajnzylber

Subjects
0301 basic medicine, Lymphocyte, viruses, General Physics and Astronomy, Antibodies, Viral, Severity of Illness Index, Prognostic markers, 0302 clinical medicine, Medicine, Longitudinal Studies, skin and connective tissue diseases, lcsh:Science, Multidisciplinary, biology, Respiratory disease, virus diseases, Middle Aged, Viral Load, Hospitalization, medicine.anatomical_structure, C-Reactive Protein, Massachusetts, 030220 oncology & carcinogenesis, RNA, Viral, Female, medicine.symptom, Antibody, Coronavirus Infections, Viral load, Adult, medicine.medical_specialty, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Science, Pneumonia, Viral, Inflammation, Viremia, macromolecular substances, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Betacoronavirus, Disease severity, Internal medicine, Severity of illness, Humans, Interleukin 6, Pandemics, Aged, business.industry, Interleukin-6, SARS-CoV-2, C-reactive protein, fungi, COVID-19, General Chemistry, medicine.disease, body regions, Pneumonia, Increased risk, 030104 developmental biology, Viral infection, biology.protein, lcsh:Q, business, Biomarkers
Abstract

The relationship between SARS-CoV-2 viral load and risk of disease progression remains largely undefined in coronavirus disease 2019 (COVID-19). Here, we quantify SARS-CoV-2 viral load from participants with a diverse range of COVID-19 disease severity, including those requiring hospitalization, outpatients with mild disease, and individuals with resolved infection. We detected SARS-CoV-2 plasma RNA in 27% of hospitalized participants, and 13% of outpatients diagnosed with COVID-19. Amongst the participants hospitalized with COVID-19, we report that a higher prevalence of detectable SARS-CoV-2 plasma viral load is associated with worse respiratory disease severity, lower absolute lymphocyte counts, and increased markers of inflammation, including C-reactive protein and IL-6. SARS-CoV-2 viral loads, especially plasma viremia, are associated with increased risk of mortality. Our data show that SARS-CoV-2 viral loads may aid in the risk stratification of patients with COVID-19, and therefore its role in disease pathogenesis should be further explored., In this study, Massachusetts Consortium for Pathogen Readiness (MassCPR) investigators assess the relationship between SARS-CoV-2 viral load and COVID-19 disease severity and report that the levels of detectable viral RNA, especially in plasma, correlates with severity of respiratory disease, inflammatory markers and predicted risk of death.

Published
2020

28. Soluble Urokinase Receptor and Acute Kidney Injury

Author

Jochen Reiser, Ranadheer R. Dande, Xuexiang Wang, Jenny Szu-Chin Pan, David Sheikh-Hamad, Mehmet M. Altintas, Rebecca M. Baron, James L. Januzzi, Ayman Samman Tahhan, Shreyak Sharma, Sanja Sever, Changli Wei, Mohamad Raad, Michael W. Holliday, David E. Leaf, Alexander Camacho, Nasrien E. Ibrahim, Sushrut S. Waikar, Salim S. Hayek, Arshed A. Quyyumi, and Steven D. Weisbord

Subjects
Male, Critical Illness, Transgene, Mice, Transgenic, 030204 cardiovascular system & hematology, Pharmacology, Coronary Angiography, Risk Assessment, Article, Receptors, Urokinase Plasminogen Activator, Mice, 03 medical and health sciences, Postoperative Complications, 0302 clinical medicine, Odds Ratio, medicine, Animals, Humans, 030212 general & internal medicine, Cardiac Surgical Procedures, Receptor, Aged, chemistry.chemical_classification, biology, Podocytes, business.industry, Acute kidney injury, Antibodies, Monoclonal, General Medicine, Odds ratio, Acute Kidney Injury, Middle Aged, medicine.disease, Urokinase-Type Plasminogen Activator, Urokinase receptor, Disease Models, Animal, Intensive Care Units, Kidney Tubules, chemistry, SuPAR, biology.protein, Female, Antibody, Glycoprotein, business, Biomarkers
Abstract

BACKGROUND: Acute kidney injury is common, with a major effect on morbidity and health care utilization. Soluble urokinase plasminogen activator receptor (suPAR) is a signaling glycoprotein thought to be involved in the pathogenesis of kidney disease. We investigated whether a high level of suPAR predisposed patients to acute kidney injury in multiple clinical contexts, and we used experimental models to identify mechanisms by which suPAR acts and to assess it as a therapeutic target. METHODS: We measured plasma levels of suPAR preprocedurally in patients who underwent coronary angiography and patients who underwent cardiac surgery and at the time of admission to the intensive care unit in critically ill patients. We assessed the risk of acute kidney injury at 7 days as the primary outcome and acute kidney injury or death at 90 days as a secondary outcome, according to quartile of suPAR level. In experimental studies, we used a monoclonal antibody to urokinase plasminogen activator receptor (uPAR) as a therapeutic strategy to attenuate acute kidney injury in transgenic mice receiving contrast material. We also assessed cellular bioenergetics and generation of reactive oxygen species in human kidney proximal tubular (HK-2) cells that were exposed to recombinant suPAR. RESULTS: The suPAR level was assessed in 3827 patients who were undergoing coronary angiography, 250 who were undergoing cardiac surgery, and 692 who were critically ill. Acute kidney injury developed in 318 patients (8%) who had undergone coronary angiography. The highest suPAR quartile (vs. the lowest) had an adjusted odds ratio of 2.66 (95% confidence interval [CI], 1.77 to 3.99) for acute kidney injury and 2.29 (95% CI, 1.71 to 3.06) for acute kidney injury or death at 90 days. Findings were similar in the surgical and critically ill cohorts. The suPAR-overexpressing mice that were given contrast material had greater functional and histologic evidence of acute kidney injury than wild-type mice. The suPAR-treated HK-2 cells showed heightened energetic demand and mitochondrial superoxide generation. Pretreatment with a uPAR monoclonal antibody attenuated kidney injury in suPAR-overexpressing mice and normalized bioenergetic changes in HK-2 cells. CONCLUSIONS: High suPAR levels were associated with acute kidney injury in various clinical and experimental contexts. (Funded by the National Institutes of Health and others.)

Published
2020

29. Circulating N-formylmethionine and metabolic shift in critical illness: a multicohort metabolomics study

Author

Martin Ingi Sigurdsson, Hirotada Kobayashi, Karin Amrein, Kiichi Nakahira, Angela J. Rogers, Mayra Pinilla-Vera, Rebecca M. Baron, Laura E. Fredenburgh, Jessica A. Lasky-Su, and Kenneth B. Christopher

Subjects
Adult, Intensive Care Units, Clinical Trials as Topic, N-Formylmethionine, Critical Illness, Fatty Acids, Humans, Metabolomics, Female, Hospital Mortality, Critical Care and Intensive Care Medicine, Amino Acids, Branched-Chain, Kynurenine
Abstract

Background Cell stress promotes degradation of mitochondria which release danger-associated molecular patterns that are catabolized to N-formylmethionine. We hypothesized that in critically ill adults, the response to N-formylmethionine is associated with increases in metabolomic shift-related metabolites and increases in 28-day mortality. Methods We performed metabolomics analyses on plasma from the 428-subject Correction of Vitamin D Deficiency in Critically Ill Patients trial (VITdAL-ICU) cohort and the 90-subject Brigham and Women’s Hospital Registry of Critical Illness (RoCI) cohort. In the VITdAL-ICU cohort, we analyzed 983 metabolites at Intensive Care Unit (ICU) admission, day 3, and 7. In the RoCI cohort, we analyzed 411 metabolites at ICU admission. The association between N-formylmethionine and mortality was determined by adjusted logistic regression. The relationship between individual metabolites and N-formylmethionine abundance was assessed with false discovery rate correction via linear regression, linear mixed-effects, and Gaussian graphical models. Results Patients with the top quartile of N-formylmethionine abundance at ICU admission had a significantly higher adjusted odds of 28-day mortality in the VITdAL-ICU (OR, 2.4; 95%CI 1.5–4.0; P = 0.001) and RoCI cohorts (OR, 5.1; 95%CI 1.4–18.7; P = 0.015). Adjusted linear regression shows that with increases in N-formylmethionine abundance at ICU admission, 55 metabolites have significant differences common to both the VITdAL-ICU and RoCI cohorts. With increased N-formylmethionine abundance, both cohorts had elevations in individual short-chain acylcarnitine, branched chain amino acid, kynurenine pathway, and pentose phosphate pathway metabolites. Conclusions The results indicate that circulating N-formylmethionine promotes a metabolic shift with heightened mortality that involves incomplete mitochondrial fatty acid oxidation, increased branched chain amino acid metabolism, and activation of the pentose phosphate pathway. Graphic Abstract

Published
2022

30. Dynamic Monitoring of Systemic Biomarkers with Gastric Sensors

Author

Christoph Steiger, Daniel Reker, Alison Hayward, Hen-Wei Huang, Joy Collins, Rebecca M. Baron, Nhi V Phan, Aaron Lopes, Declan Gwynne, Siddartha Tamang, Rebecca McManus, Edy Y. Kim, Giovanni Traverso, Haoying Sun, and Jacqueline N. Chu

Subjects
medicine.medical_specialty, Analyte, Swine, General Chemical Engineering, Science, General Physics and Astronomy, Medicine (miscellaneous), Biochemistry, Genetics and Molecular Biology (miscellaneous), 03 medical and health sciences, 0302 clinical medicine, Dynamic monitoring, biomarker monitoring, In vivo, Intensive care, medicine, Animals, gastric sensors, General Materials Science, Intensive care medicine, Intubation, Gastrointestinal, Research Articles, 030304 developmental biology, Oxygen saturation (medicine), Transdermal, Monitoring, Physiologic, 0303 health sciences, nasogastric tubes, Gastric Juice, Isoflurane, business.industry, Continuous monitoring, Stomach, General Engineering, Acute Kidney Injury, Ketones, continuous monitoring, 3. Good health, Disease Models, Animal, 030220 oncology & carcinogenesis, Anesthetics, Inhalation, business, Biomarkers, medicine.drug, Research Article
Abstract

Continuous monitoring in the intensive care setting has transformed the capacity to rapidly respond with interventions for patients in extremis. Noninvasive monitoring has generally been limited to transdermal or intravascular systems coupled to transducers including oxygen saturation or pressure. Here it is hypothesized that gastric fluid (GF) and gases, accessible through nasogastric (NG) tubes, commonly found in intensive care settings, can provide continuous access to a broad range of biomarkers. A broad characterization of biomarkers in swine GF coupled to time‐matched serum is conducted . The relationship and kinetics of GF‐derived analyte level dynamics is established by correlating these to serum levels in an acute renal failure and an inducible stress model performed in swine. The ability to monitor ketone levels and an inhaled anaesthetic agent (isoflurane) in vivo is demonstrated with novel NG‐compatible sensor systems in swine. Gastric access remains a main stay in the care of the critically ill patient, and here the potential is established to harness this establishes route for analyte evaluation for clinical management., Nasogastric tube placement in intensive care settings is a mainstay in the management of critical conditions. The authors demonstrate that systemic biomarkers are present in gastric fluid and that nasogastric tubes can be leveraged to monitor systemic disturbances through evaluation of these biomarkers. Real‐time biomarker monitoring can help improve responsiveness of clinical teams and improve critical care.

Published
2021

31. Steady-state visual evoked potentials are unchanged following physical and cognitive exertion paradigms

Author

Femi Oyewole, Ted Obi, Dylan Mahony, David Putrino, Rebecca M. Baron, Sophia I Salazar, Anna Kropelnicki, Adam Fry, and Adrian Cohen

Subjects
medicine.medical_specialty, Steady state (electronics), genetic structures, business.industry, Cognition, Neurosciences. Biological psychiatry. Neuropsychiatry, Visual evoked potentials, Audiology, Sports medicine, medicine, Exertion, business, RC1200-1245, RC321-571
Abstract

Background There is a need for objective biomarkers of sports-related concussion that are unaffected by physical and cognitive exertion. Electroencephalography-based biomarkers such as steady-state visually evoked potentials (SSVEPs) have been proposed as one such biomarker. The aim of this study was to investigate the effects of cognitive and physical exertion on SSVEP signal-to-noise ratio (SNR). Methods This study involved two experiments. The first experiment was performed in a controlled laboratory environment and involved a treadmill run designed to induce physical fatigue and a Stroop task designed to induce mental fatigue, completed in a randomized order on two separate visits. SSVEPs were evoked using a 15-Hz strobe using a Nurochek headset before and after each task. Changes in the 15-Hz SSVEP SNR and self-reported fatigue (visual analog scales) were assessed. In the second experiment, SSVEP SNR was measured before and after real-world boxing matches. Paired t-tests compared pre- and post-task SSVEP SNR and fatigue scores. Results Eighteen participants were recruited for experiment 1. Following the treadmill run, participants reported higher physical fatigue, mental fatigue, and overall fatigue ( p ≤ 0.005; d ≥ 0.90). Following the Stroop task, participants reported higher mental fatigue and overall fatigue ( p Conclusions The results of both experiments demonstrate that SSVEP SNR scores were not different following the treadmill run, Stroop task or amateur boxing match. These findings provide preliminary evidence that SSVEP fidelity may not be significantly affected by physical and cognitive exertion paradigms.

Published
2021

32. A woman presenting with an unusual cause of fulminant liver failure and sepsis

Author

Rebecca M. Baron, James M. Cleary, Alan Cubre, Jonathan H Young, Andrew H. Lichtman, Yannis K. Valtis, Trevor Barlowe, Jason L. Hornick, Nikroo Hashemi, and Lei Zhao

Subjects
medicine.medical_specialty, Right upper quadrant pain, Hepatology, Intravascular Spread, business.industry, Gastroenterology, Autopsy, Liver Failure, Acute, Middle Aged, medicine.disease, Surgery, Sepsis, Cholangiocarcinoma, Bacteremia, Medicine, Humans, Female, business, Clinical syndrome, Fulminant liver failure, Intrahepatic Cholangiocarcinoma
Abstract

We present the case of a 61-year-old woman who presented with acutely worsening right upper quadrant pain and was found to be in acute liver failure with Klebsiella pneumoniae bacteremia. Despite aggressive intensive care management, the patient ultimately died of refractory shock attributed to sepsis and fulminant liver failure. On autopsy, she was found unexpectedly to have diffuse intrahepatic cholangiocarcinoma with metastases to regional lymph nodes and intravascular spread to the lungs. The case highlights a rare instance where intrahepatic cholangiocarcinoma presents with acute liver failure and discusses key intensive care management principles of this clinical syndrome.

Published
2021

33. Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome: Insights from the LUNG SAFE study

Author

Madotto F, Rezoagli E, Pham T, Schmidt M, McNicholas B, Protti A, Panwar R, Bellani G, Fan E, van Haren F, Brochard L, Laffey JG, Antonio Pesenti, John G Laffey, Laurent Brochard, Andres Esteban, Luciano Gattinoni, Frank van Haren, Anders Larsson, Daniel F McAuley, Marco Ranieri, Gordon Rubenfeld, B Taylor Thompson, Hermann Wrigge, Arthur S Slutsky, Fernando Rios, T Sottiaux, P Depuydt, Fredy S Lora, Luciano Cesar Azevedo, Eddy Fan, Guillermo Bugedo, Haibo Qiu, Marcos Gonzalez, Juan Silesky, Vladimir Cerny, Jonas Nielsen, Manuel Jibaja, Tài Pham, Dimitrios Matamis, Jorge Luis Ranero, Pravin Amin, S M Hashemian, Kevin Clarkson, Giacomo Bellani, Kiyoyasu Kurahashi, Asisclo Villagomez, Amine Ali Zeggwagh, Leo M Heunks, Jon Henrik Laake, Jose Emmanuel Palo, Antero do Vale Fernandes, Dorel Sandesc, Yaasen Arabi, Vesna Bumbasierevic, Nicolas Nin, Jose A Lorente, Lise Piquilloud, Fekri Abroug, Lia McNamee, Javier Hurtado, Ed Bajwa, Gabriel Démpaire, Uhc Mother Theresa, Hektor Sula, Lordian Nunci, Alma Cani, Villa Maria, 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 Grubissich, Gustavo A Plotnikow, Daniela N Vasquez, Santiago Ilutovich, Norberto Tiribelli, Ariel Chena, Carlos A Pellegrini, María G Saenz, Elisa Estenssoro, Matias Brizuela, Hernan Gianinetto, Pablo E Gomez, Valeria I Cerrato, Marco G Bezzi, Silvina A Borello, Flavia A Loiacono, Adriana M Fernandez, Serena Knowles, Claire Reynolds, Deborah M Inskip, Jennene J Miller, Jing Kong, Christina Whitehead, Shailesh Bihari, Aylin Seven, Amanda Krstevski, Helen J Rodgers, Rebecca T Millar, Toni E Mckenna, Irene M Bailey, Gabrielle C Hanlon, Anders Aneman, Joan M Lynch, Raman Azad, John Neal, Paul W Woods, Brigit L Roberts, Mark R Kol, Helen S Wong, Katharina C Riss, Thomas Staudinger, Xavier Wittebole, Caroline Berghe, Pierre A Bulpa, Alain M Dive, Rik Verstraete, Herve Lebbinck, Pieter Depuydt, Joris Vermassen, Philippe Meersseman, Helga Ceunen, Jonas I Rosa, Daniel O Beraldo, Claudio Piras, Adenilton M Rampinelli, Antonio P Nassar Jr, Sergio Mataloun, Marcelo Moock, Marlus M Thompson, Claudio H Gonçalves, Ana Carolina P Antônio, Aline Ascoli, Rodrigo S Biondi, Danielle C Fontenele, Danielle Nobrega, Vanessa M Sales, Suresh Shindhe, Dk Maizatul Aiman B Pg Hj Ismail, John Laffey, Francois Beloncle, Kyle G Davies, Rob Cirone, Venika Manoharan, Mehvish Ismail, Ewan C Goligher, Mandeep Jassal, Erin Nishikawa, Areej Javeed, Gerard Curley, Nuttapol Rittayamai, Matteo Parotto, Niall D Ferguson, 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, 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, Shu H Qin, Bao H Zhu, Jun Zhao, Jian Liu, Bin Li, Jing L Liu, Fa C Zhou, Qiong J Li, Xing Y Zhang, Zhou Li-Xin, Qiang Xin-Hua, Liangyan Jiang, Yuan N Gao, Xian Y Zhao, Yuan Y Li, Xiao L Li, Chunting Wang, Qingchun Yao, Rongguo Yu, Kai Chen, Huanzhang Shao, Bingyu Qin, Qing Q Huang, Wei H Zhu, Ai Y Hang, Ma X Hua, Yimin Li, Yonghao Xu, Yu D Di, Long L Ling, Tie H Qin, Shou H Wang, Junping Qin, Yi Han, Suming Zhou, Monica P Vargas, Juan I Silesky Jimenez, Manuel A González Rojas, Jaime E Solis-Quesada, Christian M Ramirez-Alfaro, Jan Máca, Peter Sklienka, Jakob Gjedsted, Aage Christiansen, Boris G Villamagua, Miguel Llano, Philippe Burtin, Gautier Buzancais, Pascal Beuret, Nicolas Pelletier, Satar Mortaza, Alain Mercat, Jonathan Chelly, Sébastien Jochmans, Nicolas Terzi, Cédric Daubin, Guillaume Carteaux, Nicolas de Prost, Jean-Daniel Chiche, Fabrice Daviaud, Tai Pham, Muriel Fartoukh, Guillaume Barberet, Jerome Biehler, Jean Dellamonica, Denis Doyen, Jean-Michel Arnal, Anais Briquet, Sami Hraiech, Laurent Papazian, Arnaud Follin, Damien Roux, Jonathan Messika, Evangelos Kalaitzis, Laurence Dangers, Alain Combes, Siu-Ming Au, Gaetan Béduneau, Dorothée Carpentier, Elie H Zogheib, Herve Dupont, Sylvie Ricome, Francesco L Santoli, Sebastien L Besset, Philippe Michel, Bruno Gelée, Pierre-Eric Danin, Bernard Goubaux, Philippe J Crova, Nga T Phan, Frantz Berkelmans, Julio C Badie, Romain Tapponnier, Josette Gally, Samy Khebbeb, Jean-Etienne Herbrecht, Francis Schneider, Pierre-Louis M Declercq, Jean-Philippe Rigaud, Jacques Duranteau, Anatole Harrois, Russell Chabanne, Julien Marin, Charlene Bigot, Sandrine Thibault, Mohammed Ghazi, Messabi Boukhazna, Salem Ould Zein, Jack R Richecoeur, Daniele M Combaux, Fabien Grelon, Charlene Le Moal, Elise P Sauvadet, Adrien Robine, Virginie Lemiale, Danielle Reuter, Martin Dres, Alexandre Demoule, Dany Goldgran-Toledano, Loredana Baboi, Claude Guérin, Ralph Lohner, Jens Kraßler, Susanne Schäfer, Kai D 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, Tarek Dendane, 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, 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, D Á Cil 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, Hervé O Zender, Corinne Leemann-Refondini, Souheil Elatrous, Slaheddine Bouchoucha, Imed Chouchene, Islem Ouanes, 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, 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 O'Neill, Colette Seasman, Ged Dempsey, 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M., Rigaud, J. -P., Duranteau, J., Harrois, A., Chabanne, R., Marin, J., Bigot, C., 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., Mattei, A., Schiavoni, L., Tinnirello, A., Todeschini, M., 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., Shin-Nunomiya, Andoh, K., Kusumoto, K., Hirata, A., Takaba, A., Kimura, H., Kansuke-Koyama, Abe, T., 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., Dendane, T., Balkhi, H., Elkhayari, M., Samkaoui, N., Ezzouine, H., Amor, A. B. M., Maazouzi, W., Cimic, N., Beck, O., Bruns, M. M., Schouten, J. A., Myra-Rinia, Van Wezel, H. M., Heines, S. J., Strauch, U., Buise, M. P., Simonis, F. D., Schultz, M. J., Goodson, J. C., Browne, T. S., Raaijmakers, M., 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., Leon Yoshido, H. H., Aguilar, R. Z., Montes Oscanoa, F. A., 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. 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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, Graduate School, Intensive Care Medicine, ACS - Heart failure & arrhythmias, ACS - Diabetes & metabolism, ACS - Pulmonary hypertension & thrombosis, ACS - Microcirculation, Madotto, F, Rezoagli, E, Pham, T, Schmidt, M, Mcnicholas, B, Protti, A, Panwar, R, Bellani, G, Fan, E, Van Haren, F, Brochard, L, Laffey, J, Pesenti, A, Esteban, A, Gattinoni, L, Larsson, A, Mcauley, D, Ranieri, M, Rubenfeld, G, Thompson, B, Wrigge, H, Slutsky, A, Rios, F, Sottiaux, T, Depuydt, P, Lora, F, Azevedo, L, Bugedo, G, Qiu, H, Gonzalez, M, Silesky, J, Cerny, V, Nielsen, J, Jibaja, M, Matamis, D, Ranero, J, Amin, P, Hashemian, S, Clarkson, K, Kurahashi, K, Villagomez, A, Zeggwagh, A, Heunks, L, Laake, J, Palo, J, Do Vale Fernandes, A, Sandesc, D, Arabi, Y, Bumbasierevic, V, Nin, N, Lorente, J, 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Bugedo, Haibo Qiu, Marcos Gonzalez, Juan Silesky, Vladimir Cerny, Jonas Nielsen, Manuel Jibaja, Tài Pham, Dimitrios Matamis, Jorge Luis Ranero, Pravin Amin, S M Hashemian, Kevin Clarkson, Giacomo Bellani, Kiyoyasu Kurahashi, Asisclo Villagomez, Amine Ali Zeggwagh, Leo M Heunks, Jon Henrik Laake, Jose Emmanuel Palo, Antero do Vale Fernandes, Dorel Sandesc, Yaasen Arabi, Vesna Bumbasierevic, Nicolas Nin, Jose A Lorente, Lise Piquilloud, Fekri Abroug, Daniel F McAuley, Lia McNamee, Javier Hurtado, Ed Bajwa, Gabriel Démpaire, Uhc Mother Theresa, Hektor Sula, Lordian Nunci, Alma Cani, Villa Maria, 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 Grubissich, Gustavo A Plotnikow, Daniela N Vasquez, Santiago Ilutovich, Norberto Tiribelli, Ariel Chena, Carlos A Pellegrini, María G Saenz, Elisa Estenssoro, Matias Brizuela, Hernan Gianinetto, Pablo E Gomez, Valeria I Cerrato, Marco G Bezzi, Silvina A Borello, Flavia A Loiacono, Adriana M Fernandez, Serena Knowles, Claire Reynolds, Deborah M Inskip, Jennene J Miller, Jing Kong, Christina Whitehead, Shailesh Bihari, Aylin Seven, Amanda Krstevski, Helen J Rodgers, Rebecca T Millar, Toni E Mckenna, Irene M Bailey, Gabrielle C Hanlon, Anders Aneman, Joan M Lynch, Raman Azad, John Neal, Paul W Woods, Brigit L Roberts, Mark R Kol, Helen S Wong, Katharina C Riss, Thomas Staudinger, Xavier Wittebole, Caroline Berghe, Pierre A Bulpa, Alain M Dive, Rik Verstraete, Herve Lebbinck, Pieter Depuydt, Joris Vermassen, Philippe Meersseman, Helga Ceunen, Jonas I Rosa, Daniel O Beraldo, Claudio Piras, Adenilton M Rampinelli, Antonio P Nassar Jr, Sergio Mataloun, Marcelo Moock, Marlus M Thompson, Claudio H Gonçalves, Ana Carolina P Antônio, Aline Ascoli, Rodrigo S Biondi, Danielle C Fontenele, Danielle Nobrega, Vanessa M Sales, Suresh Shindhe, Dk Maizatul Aiman B Pg Hj Ismail, John Laffey, Francois Beloncle, Kyle G Davies, Rob Cirone, Venika Manoharan, Mehvish Ismail, Ewan C Goligher, Mandeep Jassal, Erin Nishikawa, Areej Javeed, Gerard Curley, Nuttapol Rittayamai, Matteo Parotto, Niall D Ferguson, 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, 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, Shu H Qin, Bao H Zhu, Jun Zhao, Jian Liu, Bin Li, Jing L Liu, Fa C Zhou, Qiong J Li, Xing Y Zhang, Zhou Li-Xin, Qiang Xin-Hua, Liangyan Jiang, Yuan N Gao, Xian Y Zhao, Yuan Y Li, Xiao L Li, Chunting Wang, Qingchun Yao, Rongguo Yu, Kai Chen, Huanzhang Shao, Bingyu Qin, Qing Q Huang, Wei H Zhu, Ai Y Hang, Ma X Hua, Yimin Li, Yonghao Xu, Yu D Di, Long L Ling, Tie H Qin, Shou H Wang, Junping Qin, Yi Han, Suming Zhou, Monica P Vargas, Juan I Silesky Jimenez, Manuel A González Rojas, Jaime E Solis-Quesada, Christian M Ramirez-Alfaro, Jan Máca, Peter Sklienka, Jakob Gjedsted, Aage Christiansen, Boris G Villamagua, Miguel Llano, Philippe Burtin, Gautier Buzancais, Pascal Beuret, Nicolas Pelletier, Satar Mortaza, Alain Mercat, Jonathan Chelly, Sébastien Jochmans, Nicolas Terzi, Cédric Daubin, Guillaume Carteaux, Nicolas de Prost, Jean-Daniel Chiche, Fabrice Daviaud, Tai Pham, Muriel Fartoukh, Guillaume Barberet, Jerome Biehler, Jean Dellamonica, Denis Doyen, Jean-Michel Arnal, Anais Briquet, Sami Hraiech, Laurent Papazian, Arnaud Follin, Damien Roux, Jonathan Messika, Evangelos Kalaitzis, Laurence Dangers, Alain Combes, Siu-Ming Au, Gaetan Béduneau, Dorothée Carpentier, Elie H Zogheib, Herve Dupont, Sylvie Ricome, Francesco L Santoli, Sebastien L Besset, Philippe Michel, Bruno Gelée, Pierre-Eric Danin, Bernard Goubaux, Philippe J Crova, Nga T Phan, Frantz Berkelmans, Julio C Badie, Romain Tapponnier, Josette Gally, Samy Khebbeb, Jean-Etienne Herbrecht, Francis Schneider, Pierre-Louis M Declercq, Jean-Philippe Rigaud, Jacques Duranteau, Anatole Harrois, Russell Chabanne, Julien Marin, Charlene Bigot, Sandrine Thibault, Mohammed Ghazi, Messabi Boukhazna, Salem Ould Zein, Jack R Richecoeur, Daniele M Combaux, Fabien Grelon, Charlene Le Moal, Elise P Sauvadet, Adrien Robine, Virginie Lemiale, Danielle Reuter, Martin Dres, Alexandre Demoule, Dany Goldgran-Toledano, Loredana Baboi, Claude Guérin, Ralph Lohner, Jens Kraßler, Susanne Schäfer, Kai D 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, Tarek Dendane, 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, 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, D Á Cil 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, Hervé O Zender, Corinne Leemann-Refondini, Souheil Elatrous, Slaheddine Bouchoucha, Imed Chouchene, Islem Ouanes, 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, 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 O'Neill, 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 O'Kane, 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, Nicolás Nin, Edgardo Nuñez, Gustavo Pittini, Ruben Rodriguez, María C Imperio, Cristina Santos, Ana G França, Alejandro Ebeid, 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 3rd, Dina Gomaa, Christopher Tainter, Dale J Yeatts, Jessica Warren, Michael J Lanspa, Russel R Miller, Colin K Grissom, Madotto F, Rezoagli E, Pham T, Schmidt M, McNicholas B, Protti A, Panwar R, Bellani G, Fan E, van Haren F, Brochard L, Laffey JG, and LUNG SAFE Investigators and the ESICM Trials Group, 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, Dina Ismail, Kyle R Dreyer, Thomas C Blakeman, 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

Subjects
ARDS, medicine.medical_treatment, 030204 cardiovascular system & hematology, Critical Care and Intensive Care Medicine, Hyperoxemia, Hypoxemia, law.invention, 0302 clinical medicine, law, Fraction of inspired oxygen, Oxygen therapy, Prevalence, Medicine, Hypoxia, Acute respiratory distress syndrome, Hyperoxia, Invasive mechanical ventilation, Mortality, Respiratory Distress Syndrome, Hyperbaric Oxygenation, Respiration, lcsh:Medical emergencies. Critical care. Intensive care. First aid, Intensive care unit, Intensive Care Units, Anesthesia, Artificial, medicine.symptom, Human, Artificial ventilation, Intensive Care Unit, NO, 03 medical and health sciences, Intensive care, Settore MED/41 - ANESTESIOLOGIA, Humans, business.industry, Research, Respiratory Distress Syndrome, Adult, lcsh:RC86-88.9, medicine.disease, Respiration, Artificial, respiratory tract diseases, Oxygen, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], 030228 respiratory system, business
Abstract

Background Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55–100 mmHg) patients (P = 0.47). Conclusions Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073

Published
2020

34. Initial antimicrobial management of sepsis

Author

Jeffrey Lipman, Jan DeWaele, Lila Bouadma, Girish B. Nair, Rebecca M. Baron, Thierry Calandra, Nick Daneman, Michael S. Niederman, and Marin H. Kollef

Subjects
Fungal infection, medicine.medical_specialty, Emergency Medical Services, INFECTIOUS-DISEASES SOCIETY, Urinary system, Bacteremia, Review, Critical Care and Intensive Care Medicine, Procalcitonin, CARE-ASSOCIATED PNEUMONIA, Antimicrobial therapy, Sepsis, Intra-abdominal infection, Medicine and Health Sciences, Medicine, Antimicrobial stewardship, Humans, Pharmacokinetics, Intensive care medicine, VENTILATOR-ASSOCIATED PNEUMONIA, CLINICAL-PRACTICE GUIDELINE, RC86-88.9, business.industry, Abdominal Infection, RESISTANT STAPHYLOCOCCUS-AUREUS, food and beverages, Medical emergencies. Critical care. Intensive care. First aid, COMMUNITY-ACQUIRED PNEUMONIA, Pneumonia, Antibiotic therapy, Antimicrobial, medicine.disease, Anti-Bacterial Agents, CAMPAIGN INTERNATIONAL GUIDELINES, Emergency Medical Technicians, Lactates, BETA-LACTAM ANTIBIOTICS, business, BLOOD-STREAM INFECTIONS, CRITICALLY-ILL PATIENTS, Biomarkers
Abstract

Sepsis is a common consequence of infection, associated with a mortality rate > 25%. Although community-acquired sepsis is more common, hospital-acquired infection is more lethal. The most common site of infection is the lung, followed by abdominal infection, catheter-associated blood steam infection and urinary tract infection. Gram-negative sepsis is more common than gram-positive infection, but sepsis can also be due to fungal and viral pathogens. To reduce mortality, it is necessary to give immediate, empiric, broad-spectrum therapy to those with severe sepsis and/or shock, but this approach can drive antimicrobial overuse and resistance and should be accompanied by a commitment to de-escalation and antimicrobial stewardship. Biomarkers such a procalcitonin can provide decision support for antibiotic use, and may identify patients with a low likelihood of infection, and in some settings, can guide duration of antibiotic therapy. Sepsis can involve drug-resistant pathogens, and this often necessitates consideration of newer antimicrobial agents.

Published
2021

35. Empirical Assessment of U.S. Coronavirus Disease 2019 Crisis Standards of Care Guidelines

Author

William Feldman, Rebecca M. Baron, Hibah Haider, Maheetha Bharadwaj, Bradford Diephus, Mayra Pinilla-Vera, Sandeep P. Kishore, Marisa Winkler, Julia L. Jezmir, Conor P. Crowley, Jack Varon, and Edy Y. Kim

Subjects
medicine.medical_specialty, Psychological intervention, Observational Study, intensive care unit, Article, law.invention, ethical triage, law, Intensive care, Health care, Pandemic, Medicine, Medical diagnosis, intensive care, business.industry, RC86-88.9, Medical emergencies. Critical care. Intensive care. First aid, General Medicine, Intensive care unit, Triage, crisis triage, medical ethics, Cohort, Emergency medicine, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, business
Abstract

Supplemental Digital Content is available in the text., OBJECTIVES: To establish the feasibility of empirically testing crisis standards of care guidelines. DESIGN: Retrospective single-center study. SETTING: ICUs at a large academic medical center in the United States. SUBJECTS: Adult, critically ill patients admitted to ICU, with 27 patients admitted for acute respiratory failure due to coronavirus disease 2019 and 37 patients admitted for diagnoses other than coronavirus disease 2019. INTERVENTIONS: Review of electronic health record. MEASUREMENTS AND MAIN RESULTS: Many U.S. states released crisis standards of care guidelines with algorithms to allocate scarce healthcare resources during the coronavirus disease 2019 pandemic. We compared state guidelines that represent different approaches to incorporating disease severity and comorbidities: New York, Maryland, Pennsylvania, and Colorado. Following each algorithm, we calculated priority scores at the time of ICU admission for a cohort of patients with primary diagnoses of coronavirus disease 2019 and diseases other than coronavirus disease 2019 (n = 64). We assessed discrimination of 28-day mortality by area under the receiver operating characteristic curve. We simulated real-time decision-making by applying the triage algorithms to groups of two, five, or 10 patients. For prediction of 28-day mortality by priority scores, area under the receiver operating characteristic curve was 0.56, 0.49, 0.53, 0.66, and 0.69 for New York, Maryland, Pennsylvania, Colorado, and raw Sequential Organ Failure Assessment score algorithms, respectively. For groups of five patients, the percentage of decisions made without deferring to a lottery were 1%, 57%, 80%, 88%, and 95% for New York, Maryland, Pennsylvania, Colorado, and raw Sequential Organ Failure Assessment score algorithms, respectively. The percentage of decisions made without lottery was higher in the subcohort without coronavirus disease 2019, compared with the subcohort with coronavirus disease 2019. CONCLUSIONS: Inclusion of comorbidities does not consistently improve an algorithm’s performance in predicting 28-day mortality. Crisis standards of care algorithms result in a substantial percentage of tied priority scores. Crisis standards of care algorithms operate differently in cohorts with and without coronavirus disease 2019. This proof-of-principle study demonstrates the feasibility and importance of empirical testing of crisis standards of care guidelines to understand whether they meet their goals.

Published
2021

36. Defibrotide: potential for treating endothelial dysfunction related to viral and post-infectious syndromes

Author

Ruben Jara, Carmelo Carlo-Stella, Israel Vlodavsky, José M. Moraleda, Marta Palomo, Maribel Diaz-Ricart, Paul G. Richardson, Rebecca M. Baron, Edward Richardson, Eleonora Calabretta, Jawed Fareed, David García-Bernal, Gregory A. Yanik, and Massimo Iacobelli

Subjects
0301 basic medicine, Endothelium, viruses, Clinical Biochemistry, Dengue virus, Defibrotide, medicine.disease_cause, Viral hemorrhagic fever, 03 medical and health sciences, 0302 clinical medicine, Polydeoxyribonucleotides, Post-Acute COVID-19 Syndrome, Drug Discovery, medicine, Humans, Endothelial dysfunction, Coronavirus, Pharmacology, Ebola virus, business.industry, SARS-CoV-2, COVID-19, Blood Coagulation Disorders, medicine.disease, Hemorrhagic Fevers, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Immunology, Molecular Medicine, Endothelium, Vascular, business, medicine.drug
Abstract

Introduction Defibrotide (DF) is a polyribonucleotide with antithrombotic, pro-fibrinolytic, and anti-inflammatory effects on endothelium. These effects and the established safety of DF present DF as a strong candidate to treat viral and post-infectious syndromes involving endothelial dysfunction. Areas covered We discuss DF and other therapeutic agents that have the potential to target endothelial components of pathogenesis in viral and post-infectious syndromes. We introduce defibrotide (DF), describe its mechanisms of action, and explore its established pleiotropic effects on the endothelium. We describe the established pathophysiology of Coronavirus Disease 2019 (COVID-19) and highlight the processes specific to COVID-19 potentially modulated by DF. We also present influenza A and viral hemorrhagic fevers, especially those caused by hantavirus, Ebola virus, and dengue virus, as viral syndromes in which DF might serve therapeutic benefit. Finally, we offer our opinion on novel treatment strategies targeting endothelial dysfunction in viral infections and their severe manifestations. Expert opinion Given the critical role of endothelial dysfunction in numerous infectious syndromes, in particular COVID-19, therapeutic pharmacology for these conditions should increasingly prioritize endothelial stabilization. Several agents with endothelial protective properties should be further studied as treatments for severe viral infections and vasculitides, especially where other therapeutic modalities have failed.

Published
2021

37. Inflammation resolution circuits are uncoupled in acute sepsis and correlate with clinical severity

Author

Joel Voldman, Bruce D. Levy, Raja-Elie E. Abdulnour, Jongyoon Han, Mayra Pinilla-Vera, Do-Hyun Lee, Rebecca M. Baron, Hyungkook Jeon, Julie Nijmeh, Melody G. Duvall, and Bakr Jundi

Subjects
Male, Pulmonology, Docosahexaenoic Acids, Neutrophils, Receptor expression, Inflammation, Immunologic Tests, In Vitro Techniques, Monocytes, Neutrophil Activation, Flow cytometry, Sepsis, chemistry.chemical_compound, Inflammation resolution, Bacterial infections, Humans, Medicine, Clinical severity, Immunity, Cellular, Principal Component Analysis, medicine.diagnostic_test, business.industry, Cellular immune response, General Medicine, Middle Aged, medicine.disease, chemistry, Immunology, Female, Inflammation Mediators, medicine.symptom, business, Resolvin, Ex vivo, Research Article, Signal Transduction
Abstract

Sepsis is a critical illness characterized by dysregulated inflammatory responses lacking counter-regulation. Specialized proresolving mediators are agonists for antiinflammation and for promoting resolution, and they are protective in preclinical sepsis models. Here, in human sepsis, we mapped resolution circuits for the specialized proresolving mediators resolvin D1 and resolvin D2 in peripheral blood neutrophils and monocytes, their regulation of leukocyte activation and function ex vivo, and their relationships to measures of clinical severity. Neutrophils and monocytes were isolated from healthy subjects and patients with sepsis by inertial microfluidics and resolvin D1 and resolvin D2 receptor expression determined by flow cytometry. The impact of these resolvins on leukocyte activation was determined by isodielectric separation and leukocyte function by stimulated phagolysosome formation. Leukocyte proresolving receptor expression was significantly higher in sepsis. In nanomolar concentrations, resolvin D1 and resolvin D2 partially reversed sepsis-induced changes in leukocyte activation and function. Principal component analyses of leukocyte resolvin receptor expression and responses differentiated sepsis from health and were associated with measures of sepsis severity. These findings indicate that resolvin D1 and resolvin D2 signaling for antiinflammation and resolution are uncoupled from leukocyte activation in early sepsis and suggest that indicators of diminished resolution signaling correlate with clinical disease severity.

Published
2021

38. Fluorescence-Guided Surgery: A Review on Timing and Use in Brain Tumor Surgery

Author

Manasa Rao, Constantinos G. Hadjipanayis, Rebecca M. Baron, Nicki Mohammadi, John Y K Lee, Francesco Acerbi, and Alexander J. Schupper

Subjects
medicine.medical_specialty, Fluorophore, fluorescein, Brain tumor, Review, Resection, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Glioma, timing, medicine, 5-ALA, Fluorescein, RC346-429, Brain tumor surgery, ICG, business.industry, medicine.disease, extent of resection, Fluorescence, Surgery, Neurology, chemistry, 030220 oncology & carcinogenesis, Neurology. Diseases of the nervous system, Neurology (clinical), business, Indocyanine green, fluorescence-guided surgery, 030217 neurology & neurosurgery
Abstract

Fluorescence-guided surgery (FGS) allows surgeons to have improved visualization of tumor tissue in the operating room, enabling maximal safe resection of malignant brain tumors. Over the past two decades, multiple fluorescent agents have been studied for FGS, including 5-aminolevulinic acid (5-ALA), fluorescein sodium, and indocyanine green (ICG). Both non-targeted and targeted fluorescent agents are currently being used in clinical practice, as well as under investigation, for glioma visualization and resection. While the efficacy of intraoperative fluorescence in studied fluorophores has been well established in the literature, the effect of timing on fluorophore administration in glioma surgery has not been as well depicted. In the past year, recent studies of 5-ALA use have shown that intraoperative fluorescence may persist beyond the previously studied window used in prior multicenter trials. Additionally, the use of fluorophores for different brain tumor types is discussed in detail, including a discussion of choosing the right fluorophore based on tumor etiology. In the following review, the authors will describe the temporal nature of the various fluorophores used in glioma surgery, what remains uncertain in FGS, and provide a guide for using fluorescence as a surgical adjunct in brain tumor surgery.

Published
2021

39. Defibrotide for the Treatment of Endotheliitis Complicating Sars-Cov-2 Infection: Rationale and Ongoing Studies As Part of the International Defacovid Study Group

Author

Rebecca M. Baron, Carmelo Carlo-Stella, Kenneth R. Cooke, Robert J. Soiffer, Maribel Diaz-Ricart, Pedro Castro, Peter O'Gorman, Israel Vlodavsky, Ruben Jara Rubio, Eleonora Calabretta, David García-Bernal, Alessio Aghemo, Gerald L. Weinhouse, Marta Palomo, Gregory A. Yanik, Clifton C. Mo, Enriqueta Andreu, Paul G. Richardson, Enric Carreras, Sara Fernández, Antonio Pagliuca, Massimo Iacobelli, Jawed Fareed, and José M. Moraleda

Subjects
ARDS, Endothelium, business.industry, Immunology, 332.Anticoagulation and Antithrombotic Therapy, Cell Biology, Hematology, Thrombomodulin, medicine.disease, Biochemistry, Proinflammatory cytokine, Endothelial stem cell, medicine.anatomical_structure, medicine, Cancer research, Tumor necrosis factor alpha, Cell adhesion, business, Macrophage inflammatory protein
Abstract

Coronavirus disease 2019 (COVID-19) is a heterogeneous clinical condition caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The initial stage of infection occurs at the time of respiratory viral invasion through angiotensin-converting enzyme 2 (ACE2) receptors in alveolar pneumocytes and macrophages. In the second stage of established pulmonary disease without and with hypoxia, viral multiplication and localized inflammation occurs. The third stage COVID-19 is the most severe, characterized by systemic hyperinflammation, acute respiratory distress syndrome (ARDS) and generalized microangiopathy, with significantly elevated biomarkers including IL-2, IL-6, IL-7, granulocyte-colony stimulating factor, macrophage inflammatory protein 1α, tumor necrosis factor-α, C-reactive protein, ferritin, D-dimer, von Willebrand factor (vWF) and thrombomodulin (TM). Evidence suggests that endothelial damage and activation play a key role in the pathobiology of the disease, and thus protecting endothelium and reversing endotheliitis may be a key therapeutic goal (Teuwen et al,Nat Rev Immunol2020). Defibrotide (DF), a complex mixture of poly-deoxyribonucleotides extracted from porcine mucosa, modulates expression of thrombogenic and inflammatory mediators produced in response to endothelial cell injury and/or leukocyte activation. DF increases tissue plasminogen activator (t-PA) and TM expression, thereby enhancing the enzymatic activity of plasmin to hydrolyze fibrin clot, while also decreasing vWF and plasminogen activator inhibitor-1 (PAI-1). Platelet adhesion is inhibited via increases in nitric oxide (NO), prostaglandin I2 (PGI2), and prostaglandin E2 (PGE2) (Falanga A et al,Leukemia 2003). Anti-inflammatory properties via inhibition of p38 MAPK pathway have been demonstrated with DF, attenuating the release of inflammatory mediators including IL-6, thromboxane A2, leukotriene B4, tumor necrosis factor-alpha, and reactive oxygen species (Mitsiades et al,Clin Cancer Res2009). Additionally, DF inhibits both the expression and activity of heparanase, which in turn modulates heparan sulfate, a vital moiety for viral infection (Richardson et al,Blood Adv2018; Koganti et al,Cell Mol Life Sci2020). DF also modulates endothelial cell injury in murine models by down-regulating the expression of endothelial cell adhesion molecules such as E-selectin, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), that are critical to leukocyte adhesion and migration, and by increasing the endothelial cell release of anti-inflammatory cytokines, conferring survival benefit (Garcia-Bernal et al,J Cell Mol Med2020). DF is approved for the treatment of severe veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) complicating stem cell transplantation and has demonstrated efficacy and safety in critically ill patients with multi-organ failure, underpinned by vasculopathy, endotheliitis, immune activation and hemorrhagic risk (Richardson et al,Blood2016). This multi-target and pleiotropic approach makes DF an attractive candidate for the treatment of advanced stage COVID 19 and the systemic endothelial complications underpinning both its pathobiology and ensuing mortality (Figure 1). Various clinical studies in Spain, Italy, Ireland, the UK and USA are underway, with the larger randomized placebo-controlled prospective phase 2 study in Spain (clinicaltrials.gov: NCT04348383) leading in accrual with promising early results, demonstrating safety to date with potential efficacy, as reflected by favorable outcome in a subset of intubated patients as part of an ongoing multi-center trial. Other studies within the group have focused on safety and particularly the therapeutic role of DF in advanced disease, including those patients requiring extracorporeal membrane oxygenation (ECMO) and full dose systemic anticoagulation. These trials include common in-depth biological correlatives, assessing biomarkers including heparanase, inflammatory cytokines, immune cell sub-populations, vWF and soluble TM, as well as other novel markers and pharmacokinetics. In aggregate, these studies will hopefully help demonstrate the effects of DF on the proposed targets in COVID-19 and successfully correlate these effects with improved clinical outcome. Disclosures Moraleda: Jazz Pharmaceuticals:Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Novartis, Sandoz, Takeda:Honoraria;Gilead:Honoraria, Other: Travel expenses.Carlo-Stella:Servier, Novartis, Genenta Science srl, ADC Therapeutics, F. Hoffmann-La Roche, Karyopharm, Jazz Pharmaceuticals:Membership on an entity's Board of Directors or advisory committees;Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen Oncology, AstraZeneca:Honoraria;Boehringer Ingelheim and Sanofi:Consultancy;ADC Therapeutics and Rhizen Pharmaceuticals:Research Funding.Jara Rubio:Edwards Lifesciences, Getinge:Honoraria.Diaz-Ricart:Jazz Pharmaceuticals:Honoraria, Research Funding;German Jose Carreras Leukaemia Foundation:Research Funding.Carreras:Jazz Pharmaceuticals:Research Funding, Speakers Bureau;German Jose´ Carreras Leukaemia Foundation:Research Funding.Mo:Celgene/BMS:Membership on an entity's Board of Directors or advisory committees.Cooke:Jazz Pharmaceuticals:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.Soiffer:Be the Match/ National Marrow Donor Program:Membership on an entity's Board of Directors or advisory committees;alexion:Consultancy;Celgene:Membership on an entity's Board of Directors or advisory committees;Juno:Membership on an entity's Board of Directors or advisory committees;Novartis:Consultancy;VOR Biopharma:Consultancy;Mana Therapeutics:Consultancy;Precision Bioscience:Consultancy;Cugene:Consultancy;Rheos Therapeutics:Consultancy;Gilead:Consultancy;Kiadis:Membership on an entity's Board of Directors or advisory committees.Baron:Genetech:Consultancy;Merck:Consultancy.Pagliuca:Jazz Pharmaceuticals:Membership on an entity's Board of Directors or advisory committees.Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm:Research Funding. OffLabel Disclosure: Defibrotide used for the treatment of endotheliitis complicating SARS-Cov-2 infection

Published
2020

40. Monitoring Research Blood Sampling in Critically Ill Patients: Avoiding Iatrogenic Anemia

Author

Nancy Ringwood, Bryan J. McVerry, Robert Paine, Eric P. Schmidt, Nathan I. Shapiro, Mark M. Wurfel, Wesley H. Self, R. Duncan Hite, John W. Christman, Kathleen D. Liu, Michael A. Matthay, Rebecca M. Baron, and Peter W. Adams

Subjects
Adult, Male, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Anemia, Critical Illness, Iatrogenic Disease, MEDLINE, Critical Care and Intensive Care Medicine, Correspondence, medicine, Humans, Intensive care medicine, Aged, Aged, 80 and over, Blood Specimen Collection, business.industry, Critically ill, Middle Aged, medicine.disease, Practice Guidelines as Topic, Critical illness, Female, business, Biological Monitoring, Blood sampling
Published
2020

41. Uric Acid and Acute Kidney Injury in the Critically Ill

Author

Rebecca M. Baron, David E. Leaf, Andrew N. Hoofnagle, Ragnar Palsson, Anand Srivastava, Polly Palacios, Venkata S. Sabbisetti, Sucheta M. Vaingankar, Margaret E. Chen, Angelica Higuera, Sushrut S. Waikar, and Paul M. Palevsky

Subjects
medicine.medical_specialty, medicine.medical_treatment, lcsh:RC870-923, urologic and male genital diseases, RRT, law.invention, chemistry.chemical_compound, AKI, uric acid, Interquartile range, law, Internal medicine, Internal Medicine, medicine, Renal replacement therapy, Dialysis, Original Research, business.industry, Acute kidney injury, lcsh:Diseases of the genitourinary system. Urology, medicine.disease, Intensive care unit, female genital diseases and pregnancy complications, chemistry, Nephrology, ICU, Cohort, dialysis, Uric acid, business, Cohort study
Abstract

Rationale & Objective Uric acid is excreted by the kidney and accumulates in acute kidney injury (AKI). Whether higher plasma uric acid level predisposes to AKI or its complications is not known. Study Design Prospective observational cohort study. Setting & Participants 2 independent cohorts of critically ill patients: (1) 208 patients without AKI admitted to the intensive care unit (ICU) at Brigham & Women’s Hospital between October 2008 and December 2016; and (2) 250 participants with AKI requiring renal replacement therapy (RRT) who had not yet initiated RRT enrolled in the Acute Renal Failure Trial Network (ATN) Study. Exposure Plasma uric acid level upon ICU admission and before RRT initiation in the ICU and ATN Study cohorts, respectively. Outcomes Incident AKI and 60-day mortality in the ICU and ATN Study cohorts, respectively. Analytical Approach Logistic regression models were used to test the association of plasma uric acid level with incident AKI and 60-day mortality. Results In the ICU cohort, median plasma uric acid level was 4.7 (interquartile range [IQR], 3.6-6.4) mg/dL, and 40 patients (19.2%) developed AKI. Higher plasma uric acid levels associated with incident AKI, but this association was confounded by serum creatinine level and was not significant after multivariable adjustment (adjusted OR per doubling of uric acid, 1.50; 95% CI, 0.80-2.81). In the ATN Study cohort, median plasma uric acid level was 11.1 (IQR, 8.6–14.2) mg/dL, and 125 participants (50.0%) died within 60 days. There was no statistically significant association between plasma uric acid levels and 60-day mortality in either unadjusted models or after multivariable adjustment for demographic, severity-of-illness, and kidney-specific covariates (adjusted OR per doubling of uric acid, 1.15; 95% CI, 0.71-1.86). Limitations Heterogeneity of ICU patients. Conclusions Plasma uric acid levels upon ICU admission or before RRT initiation are not independently associated with adverse clinical outcomes in critically ill patients., Graphical abstract

Published
2019

42. Network medicine framework for identifying drug-repurposing opportunities for COVID-19

Author

Xiao Gan, Italo Faria do Valle, Marinka Zitnik, Asher Ameli, Rebecca M. Baron, Helia N. Sanchez, Dina Ghiassian, Albert-László Barabási, Joseph Loscalzo, Deisy Morselli Gysi, and Onur Varol

Subjects
0301 basic medicine, Network medicine, FOS: Computer and information sciences, Computer Science - Machine Learning, Databases, Pharmaceutical, Molecular Networks (q-bio.MN), MEDLINE, Machine Learning (stat.ML), Computational biology, infectious diseases, Quantitative Biology - Quantitative Methods, Antiviral Agents, Article, Machine Learning (cs.LG), 03 medical and health sciences, Viral Proteins, 0302 clinical medicine, Pharmacotherapy, Statistics - Machine Learning, Chlorocebus aethiops, Medicine, Animals, Humans, Quantitative Biology - Molecular Networks, Vero Cells, Quantitative Methods (q-bio.QM), network medicine, Multidisciplinary, drug repurposing, business.industry, Systems Biology, Drug Repositioning, Timeline, Biological Sciences, COVID-19 Drug Treatment, Clinical trial, Drug repositioning, 030104 developmental biology, Drug development, FOS: Biological sciences, Hit rate, Neural Networks, Computer, business, 030217 neurology & neurosurgery, Protein Binding
Abstract

Significance The COVID-19 pandemic has highlighted the importance of prioritizing approved drugs to treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Here, we deployed algorithms relying on artificial intelligence, network diffusion, and network proximity to rank 6,340 drugs for their expected efficacy against SARS-CoV-2. We experimentally screened 918 drugs, allowing us to evaluate the performance of the existing drug-repurposing methodologies, and used a consensus algorithm to increase the accuracy of the predictions. Finally, we screened in human cells the top-ranked drugs, identifying six drugs that reduced viral infection, four of which could be repurposed to treat COVID-19. The developed strategy has significance beyond COVID-19, allowing us to identify drug-repurposing candidates for neglected diseases., The COVID-19 pandemic has highlighted the need to quickly and reliably prioritize clinically approved compounds for their potential effectiveness for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Here, we deployed algorithms relying on artificial intelligence, network diffusion, and network proximity, tasking each of them to rank 6,340 drugs for their expected efficacy against SARS-CoV-2. To test the predictions, we used as ground truth 918 drugs experimentally screened in VeroE6 cells, as well as the list of drugs in clinical trials that capture the medical community’s assessment of drugs with potential COVID-19 efficacy. We find that no single predictive algorithm offers consistently reliable outcomes across all datasets and metrics. This outcome prompted us to develop a multimodal technology that fuses the predictions of all algorithms, finding that a consensus among the different predictive methods consistently exceeds the performance of the best individual pipelines. We screened in human cells the top-ranked drugs, obtaining a 62% success rate, in contrast to the 0.8% hit rate of nonguided screenings. Of the six drugs that reduced viral infection, four could be directly repurposed to treat COVID-19, proposing novel treatments for COVID-19. We also found that 76 of the 77 drugs that successfully reduced viral infection do not bind the proteins targeted by SARS-CoV-2, indicating that these network drugs rely on network-based mechanisms that cannot be identified using docking-based strategies. These advances offer a methodological pathway to identify repurposable drugs for future pathogens and neglected diseases underserved by the costs and extended timeline of de novo drug development.

Published
2021

43. Attributable mortality of acute respiratory distress syndrome: A systematic review, meta-analysis, and survival analysis using targeted minimum loss-based estimation

Author

Mayra Pinilla Vera, David R. Price, Augustine M.K. Choi, Jin Won Huh, Katherine Hoffman, Lisa K. Torres, John Harrington, Rebecca M. Baron, Ilias I. Siempos, Clara Oromendia, Edward J. Schenck, Iván Díaz, Angelica Higuera, Laura E. Fredenburgh, and Luis Gomez-Escobar

Subjects
Pulmonary and Respiratory Medicine, ARDS, medicine.medical_specialty, Critical Illness, Article, law.invention, 03 medical and health sciences, 0302 clinical medicine, law, Medicine, Humans, 030212 general & internal medicine, Hospital Mortality, Risk factor, Survival analysis, Respiratory Distress Syndrome, business.industry, 030208 emergency & critical care medicine, medicine.disease, Intensive care unit, Survival Analysis, Intensive Care Units, Relative risk, Meta-analysis, Causal inference, Emergency medicine, Observational study, business
Abstract

BackgroundAlthough acute respiratory distress syndrome (ARDS) is associated with high mortality, its direct causal link with death is unclear. Clarifying this link is important to justify costly research on prevention of ARDS.ObjectiveTo estimate the attributable mortality, if any, of ARDS.DesignFirst, we performed a systematic review and meta-analysis of observational studies reporting mortality of critically ill patients with and without ARDS matched for underlying risk factor. Next, we conducted a survival analysis of prospectively collected patient-level data from subjects enrolled in three intensive care unit (ICU) cohorts to estimate the attributable mortality of critically ill septic patients with and without ARDS using a novel causal inference method.ResultsIn the meta-analysis, 44 studies (47 cohorts) involving 56 081 critically ill patients were included. Mortality was higher in patients with versus without ARDS (risk ratio 2.48, 95% CI 1.86 to 3.30; pConclusionsARDS has a direct causal link with mortality. Our findings provide information about the extent to which continued funding of ARDS prevention trials has potential to impart survival benefit.PROSPERO Registration NumberCRD42017078313

Published
2021

44. Fluorescence-Guided High-Grade Glioma Surgery More Than Four Hours After 5-Aminolevulinic Acid Administration

Author

Georgios A Maragkos, Panagiotis A. Sideras, Constantinos G. Hadjipanayis, Gabrielle Price, Nikita Lakomkin, Alexander J. Schupper, Adam M. Robin, Travis Hamilton, Ian Lee, Sameah Haider, and Rebecca M. Baron

Subjects
medicine.medical_specialty, Contrast enhancement, intraoperative imaging, Radiography, lcsh:RC346-429, Eloquent cortex, Oral administration, Glioma, glioma, medicine, 5-ALA, lcsh:Neurology. Diseases of the nervous system, High-Grade Glioma, Original Research, business.industry, Modified rankin score, medicine.disease, Surgery, Neurology, brain tumors, Karnofsky score, Neurology (clinical), fluorescence, glioblastomas, business, neuro-oncology
Abstract

Background: Fluorescence-guided surgery (FGS) using 5-aminolevulic acid (5-ALA) is a widely used strategy for delineating tumor tissue from surrounding brain intraoperatively during high-grade glioma (HGG) resection. 5-ALA reaches peak plasma levels ~4 h after oral administration and is currently approved by the FDA for use 2–4 h prior to induction to anesthesia.Objective: To demonstrate that there is adequate intraoperative fluorescence in cases undergoing surgery more than 4 h after 5-ALA administration and compare survival and radiological recurrence to previous data.Methods: Retrospective analysis of HGG patients undergoing FGS more than 4 h after 5-ALA administration was performed at two institutions. Clinical, operative, and radiographic pre- and post-operative characteristics are presented.Results: Sixteen patients were identified, 6 of them female (37.5%), with mean (SD) age of 59.3 ± 11.5 years. Preoperative mean modified Rankin score (mRS) was 2 ± 1. All patients were dosed with 20 mg/kg 5-ALA the morning of surgery. Mean time to anesthesia induction was 425 ± 334 min. All cases had adequate intraoperative fluorescence. Eloquent cortex was involved in 12 cases (75%), and 13 cases (81.3%) had residual contrast enhancement on postoperative MRI. Mean progression-free survival was 5 ± 3 months. In the study period, 6 patients died (37.5%), mean mRS was 2.3 ± 1.3, Karnofsky score 71.9 ± 22.1, and NIHSS 3.9 ± 2.4.Conclusion: Here we demonstrate that 5-ALA-guided HGG resection can be performed safely more than 4 h after administration, with clinical results largely similar to previous reports. Relaxation of timing restrictions could improve procedure workflow in busy neurosurgical centers, without additional risk to patients.

Published
2021

45. Circulating BMP9 Protects the Pulmonary Endothelium during Inflammation-induced Lung Injury in Mice

Author

Rebecca M. Baron, Lu Long, Kim Hoenderdos, Charlotte Summers, Paola Caruso, Nicholas W. Morrell, Ross D. King, Ivana Nikolic, Mark Southwood, Xudong Yang, Richard M. Salmon, Paul B. Yu, Geoffrey A. Bocobo, Sussan Nourshargh, Angelica Higuera, Wei Li, Katharine M Lodge, Zhen Tong, Alison M. Condliffe, Paul D. Upton, He Jiang, Edwin R. Chilvers, Peiran Yang, Li, Wei [0000-0002-1924-3120], Upton, Paul [0000-0003-2716-4921], Summers, Charlotte [0000-0002-7269-2873], Morrell, Nicholas [0000-0001-5700-9792], and Apollo - University of Cambridge Repository

Subjects
Pulmonary and Respiratory Medicine, Male, Pathology, medicine.medical_specialty, Endothelial permeability, Respiratory System, Acute Lung Injury, Inflammation, Pulmonary Edema, Acute respiratory distress, Lung injury, Critical Care and Intensive Care Medicine, BMP9, 03 medical and health sciences, Mice, 0302 clinical medicine, Sepsis, Growth Differentiation Factor 2, Medicine, Animals, Humans, Pulmonary endothelium, 030212 general & internal medicine, Endothelium, lung injury, 11 Medical and Health Sciences, business.industry, Editorials, Endothelial Cells, Pulmonary edema, medicine.disease, Endotoxemia, 030228 respiratory system, pulmonary endothelium, Case-Control Studies, Female, medicine.symptom, business, BMP signaling in endothelial cells
Abstract

Rationale: Pulmonary endothelial permeability contributes to the high-permeability pulmonary edema that characterizes acute respiratory distress syndrome. Circulating BMP9 (bone morphogenetic protein 9) is emerging as an important regulator of pulmonary vascular homeostasis. Objectives:To determine whether endogenous BMP9 plays a role in preserving pulmonary endothelial integrity and whether loss of endogenous BMP9 occurs during LPS challenge. Methods: A BMP9-neutralizing antibody was administrated to healthy adult mice, and lung vasculature was examined. Potential mechanisms were delineated by transcript analysis in human lung endothelial cells. The impact of BMP9 administration was evaluated in a murine acute lung injury model induced by inhaled LPS. Levels of BMP9 were measured in plasma from patients with sepsis and from endotoxemic mice. Measurements and Main Results: Subacute neutralization of endogenous BMP9 in mice (N = 12) resulted in increased lung vascular permeability (P = 0.022), interstitial edema (P = 0.0047), and neutrophil extravasation (P = 0.029) compared with IgG control treatment (N = 6). In pulmonary endothelial cells, BMP9 regulated transcriptome pathways implicated in vascular permeability and cell-membrane integrity. Augmentation of BMP9 signaling in mice (N = 8) prevented inhaled LPS-induced lung injury (P = 0.0027) and edema (P < 0.0001). In endotoxemic mice (N = 12), endogenous circulating BMP9 concentrations were markedly reduced, the causes of which include a transient reduction in hepatic BMP9 mRNA expression and increased elastase activity in plasma. In human patients with sepsis (N = 10), circulating concentratons of BMP9 were also markedly reduced (P < 0.0001). Conclusions: Endogenous circulating BMP9 is a pulmonary endothelial-protective factor, downregulated during inflammation. Exogenous BMP9 offers a potential therapy to prevent increased pulmonary endothelial permeability in lung injury.

Published
2020

46. Lung atelectasis promotes immune and barrier dysfunction as revealed by transcriptome sequencing in female sheep

Author

Rebecca M. Baron, Nathan M Kingston, Lynette M. Sholl, John N. Hutchinson, Tilo Winkler, Gabriel Casulari Motta-Ribeiro, Marcos F. Vidal Melo, K. S. Grogg, Matthew D. Layne, M.A. Lessa, T. Hinoshita, Xiangming Fang, Xaralabos Varelas, and Congli Zeng

Subjects
Pulmonary Atelectasis, Inflammation, Atelectasis, Lung injury, Systemic inflammation, Article, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Immune system, Exome Sequencing, medicine, Animals, Barrier function, 030304 developmental biology, Immunity, Cellular, 0303 health sciences, Sheep, Lung, business.industry, Sequence Analysis, RNA, medicine.disease, Anesthesiology and Pain Medicine, medicine.anatomical_structure, Immunology, Female, medicine.symptom, Lung Volume Measurements, business, 030217 neurology & neurosurgery
Abstract

Background Pulmonary atelectasis is frequent in clinical settings. Yet there is limited mechanistic understanding and substantial clinical and biologic controversy on its consequences. The authors hypothesize that atelectasis produces local transcriptomic changes related to immunity and alveolar–capillary barrier function conducive to lung injury and further exacerbated by systemic inflammation. Methods Female sheep underwent unilateral lung atelectasis using a left bronchial blocker and thoracotomy while the right lung was ventilated, with (n = 6) or without (n = 6) systemic lipopolysaccharide infusion. Computed tomography guided samples were harvested for NextGen RNA sequencing from atelectatic and aerated lung regions. The Wald test was used to detect differential gene expression as an absolute fold change greater than 1.5 and adjusted P value (Benjamini–Hochberg) less than 0.05. Functional analysis was performed by gene set enrichment analysis. Results Lipopolysaccharide-unexposed atelectatic versus aerated regions presented 2,363 differentially expressed genes. Lipopolysaccharide exposure induced 3,767 differentially expressed genes in atelectatic lungs but only 1,197 genes in aerated lungs relative to the corresponding lipopolysaccharide-unexposed tissues. Gene set enrichment for immune response in atelectasis versus aerated tissues yielded negative normalized enrichment scores without lipopolysaccharide (less than –1.23, adjusted P value less than 0.05) but positive scores with lipopolysaccharide (greater than 1.33, adjusted P value less than 0.05). Leukocyte-related processes (e.g., leukocyte migration, activation, and mediated immunity) were enhanced in lipopolysaccharide-exposed atelectasis partly through interferon-stimulated genes. Furthermore, atelectasis was associated with negatively enriched gene sets involving alveolar–capillary barrier function irrespective of lipopolysaccharide (normalized enrichment scores less than –1.35, adjusted P value less than 0.05). Yes-associated protein signaling was dysregulated with lower nuclear distribution in atelectatic versus aerated lung (lipopolysaccharide-unexposed: 10.0 ± 4.2 versus 13.4 ± 4.2 arbitrary units, lipopolysaccharide-exposed: 8.1 ± 2.0 versus 11.3 ± 2.4 arbitrary units, effect of lung aeration, P = 0.003). Conclusions Atelectasis dysregulates the local pulmonary transcriptome with negatively enriched immune response and alveolar–capillary barrier function. Systemic lipopolysaccharide converts the transcriptomic immune response into positive enrichment but does not affect local barrier function transcriptomics. Interferon-stimulated genes and Yes-associated protein might be novel candidate targets for atelectasis-associated injury. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Published
2020

47. Plasma from patients with bacterial sepsis or severe COVID-19 induces suppressive myeloid cell production from hematopoietic progenitors in vitro

Author

Rebecca M. Baron, Kianna Billman, Roby P. Bhattacharyya, Moshe Sade-Feldman, Miguel Reyes, Alexandra-Chloé Villani, Michael R. Filbin, Kyle R. Kays, Marcia B. Goldberg, Lisa A. Cosimi, Nir Hacohen, Deborah T. Hung, Abraham Sonny, Mayra Pinilla-Vera, Paul C. Blainey, Arnav Mehta, Bruce D. Levy, and Maura E. Benson

Subjects
Myeloid, SARS-CoV-2, Monocyte, CD14, Hematopoietic Stem Cell Transplantation, COVID-19, General Medicine, Biology, medicine.disease, Article, Sepsis, Haematopoiesis, medicine.anatomical_structure, Immunology, medicine, Humans, Myeloid Cells, Myelopoiesis, Bone marrow, Progenitor cell
Abstract

A recent estimate suggests that one in five deaths globally are associated with sepsis (1) . To date, no targeted treatment is available for this syndrome, likely due to substantial patient heterogeneity (2,3) and our lack of insight into sepsis immunopathology (4) . These issues are highlighted by the current COVID-19 pandemic, wherein many clinical manifestations of severe SARS-CoV-2 infection parallel bacterial sepsis (5–8) . We previously reported an expanded CD14+ monocyte state, MS1, in patients with bacterial sepsis or non-infectious critical illness, and validated its expansion in sepsis across thousands of patients using public transcriptomic data (9) . Despite its marked expansion in the circulation of bacterial sepsis patients, its relevance to viral sepsis and association with disease outcomes have not been examined. In addition, the ontogeny and function of this monocyte state remain poorly characterized. Using public transcriptomic data, we show that the expression of the MS1 program is associated with sepsis mortality and is up-regulated in monocytes from patients with severe COVID-19. We found that blood plasma from bacterial sepsis or COVID-19 patients with severe disease induces emergency myelopoiesis and expression of the MS1 program, which are dependent on the cytokines IL-6 and IL-10. Finally, we demonstrate that MS1 cells are broadly immunosuppressive, similar to monocytic myeloid-derived suppressor cells (MDSCs), and have decreased responsiveness to stimulation. Our findings highlight the utility of regulatory myeloid cells in sepsis prognosis, and the role of systemic cytokines in inducing emergency myelopoiesis during severe bacterial and SARS-CoV-2 infections.

Published
2020

48. Induction of a regulatory myeloid program in bacterial sepsis and severe COVID-19

Author

Maura E. Benson, Alexandra-Chloé Villani, Moshe Sade-Feldman, Paul C. Blainey, Kianna Billman, Arnav Mehta, Lisa A. Cosimi, Roby P. Bhattacharyya, Rebecca M. Baron, Deborah T. Hung, Miguel Reyes, Abraham Sonny, Nir Hacohen, Bruce D. Levy, Kyle R. Kays, Marcia B. Goldberg, Michael R. Filbin, and Mayra Pinilla-Vera

Subjects
Myeloid, business.industry, CD14, Monocyte, macromolecular substances, medicine.disease, STM r-articles, Transcriptome, Sepsis, Coronavirus, medicine.anatomical_structure, Immunopathology, Blood plasma, Immunology, medicine, Medicine, Myelopoiesis, business, Research Articles, Research Article
Abstract

Cytokines in plasma from sepsis or severe COVID-19 patients induce production of suppressive myeloid cells from hematopoietic progenitors in vitro., Myeloid suppressive cells enter the arena Patients with bacterial sepsis or severe COVID-19 have increased numbers of suppressive myeloid cells in their blood. Reyes et al. now show that similar cells can be induced by treatment of healthy human bone marrow progenitor cells in culture with plasma from patients with bacterial sepsis or severe COVID-19. The differentiation of suppressive myeloid cells in this cell model depended on the cytokines IL-6 and IL-10, indicating a role for systemic factors in inducing myeloid dysregulation in patients with severe infections., Bacterial sepsis and severe COVID-19 share similar clinical manifestations and are both associated with dysregulation of the myeloid cell compartment. We previously reported an expanded CD14+ monocyte state, MS1, in patients with bacterial sepsis and validated expansion of this cell subpopulation in publicly available transcriptomics data. Here, using published datasets, we show that the gene expression program associated with MS1 correlated with sepsis severity and was up-regulated in monocytes from patients with severe COVID-19. To examine the ontogeny and function of MS1 cells, we developed a cellular model for inducing CD14+ MS1 monocytes from healthy bone marrow hematopoietic stem and progenitor cells (HSPCs). We found that plasma from patients with bacterial sepsis or COVID-19 induced myelopoiesis in HSPCs in vitro and expression of the MS1 gene program in monocytes and neutrophils that differentiated from these HSPCs. Furthermore, we found that plasma concentrations of IL-6, and to a lesser extent IL-10, correlated with increased myeloid cell output from HSPCs in vitro and enhanced expression of the MS1 gene program. We validated the requirement for these two cytokines to induce the MS1 gene program through CRISPR-Cas9 editing of their receptors in HSPCs. Using this cellular model system, we demonstrated that induced MS1 cells were broadly immunosuppressive and showed decreased responsiveness to stimulation with a synthetic RNA analog. Our in vitro study suggests a potential role for systemic cytokines in inducing myelopoiesis during severe bacterial or SARS-CoV-2 infection.

Published
2020

49. VTE in ICU Patients With COVID-19

Author

Katelyn W. Sylvester, Matthew Moll, Rebecca M. Baron, Vivien Cheng, Evan C. Chen, Nathan T. Connell, Ann E. Woolley, Michael H. Cho, Laura E. Fredenburgh, Jean M. Connors, and Rebecca L. Zon

Subjects
Pulmonary and Respiratory Medicine, Adult, Male, medicine.medical_specialty, 2019-20 coronavirus outbreak, Icu patients, Coronavirus disease 2019 (COVID-19), Computed Tomography Angiography, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Pneumonia, Viral, L-Lactate dehydrogenase, Critical Care and Intensive Care Medicine, Severity of Illness Index, Fibrin Fibrinogen Degradation Products, Betacoronavirus, Medicine, Viral therapy, Humans, Enoxaparin, Pulmonary and Cardiovascular: Research Letter, Pandemics, Aged, Ultrasonography, Venous Thrombosis, L-Lactate Dehydrogenase, business.industry, Extramural, Heparin, SARS-CoV-2, Incidence, Anticoagulants, COVID-19, Fibrinogen, Venous Thromboembolism, Middle Aged, Intensive Care Units, C-Reactive Protein, Emergency medicine, Ferritins, Prothrombin Time, Female, Partial Thromboplastin Time, Cardiology and Cardiovascular Medicine, business, Coronavirus Infections, Pulmonary Embolism
Published
2020

50. A rapidly deployable individualized system for augmenting ventilator capacity

Author

Rebecca M. Baron, David Lagier, Khalil B. Ramadi, Joseph J. Frassica, Alison Hayward, Declan Gwynne, Robert Langer, Giovanni Traverso, Francesco Vicario, Shriya Srinivasan, Massachusetts Institute of Technology. Department of Mechanical Engineering, Massachusetts Institute of Technology. Department of Chemical Engineering, Massachusetts Institute of Technology. Institute for Medical Engineering & Science, and Koch Institute for Integrative Cancer Research at MIT

Subjects
medicine.medical_specialty, 2019-20 coronavirus outbreak, Swine, Computer science, Economic shortage, law.invention, 03 medical and health sciences, 0302 clinical medicine, law, Report, medicine, Animals, Humans, In patient, 030212 general & internal medicine, Intensive care medicine, Lung, Pandemics, Pulmonary mechanics, Ventilators, Mechanical, Pressure control, General Medicine, STM reports, Emergency situations, Respiratory status, Coronavirus, 030228 respiratory system, Ventilation (architecture), Reports
Abstract

Strategies to split ventilators to support multiple patients requiring ventilatory support have been proposed and used in emergency cases in which shortages of ventilators cannot otherwise be remedied by production or procurement strategies. However, the current approaches to ventilator sharing lack the ability to individualize ventilation to each patient, measure pulmonary mechanics, and accommodate rebalancing of the airflow when one patient improves or deteriorates, posing safety concerns to patients. Potential cross-contamination, lack of alarms, insufficient monitoring, and inability to adapt to sudden changes in patient status have prevented widespread acceptance of ventilator sharing. We have developed an individualized system for augmenting ventilator efficacy (iSAVE) as a rapidly deployable platform that uses a single ventilator to simultaneously and more safely support two individuals. The iSAVE enables individual-specific volume and pressure control and the rebalancing of ventilation in response to improvement or deterioration in an individual's respiratory status. The iSAVE incorporates mechanisms to measure pulmonary mechanics, mitigate cross-contamination and backflow, and accommodate sudden flow changes due to individual interdependencies within the respiratory circuit. We demonstrate these capacities through validation using closed- and open-circuit ventilators on linear test lungs. We show that the iSAVE can temporarily ventilate two pigs on one ventilator as efficaciously as each pig on its own ventilator. By leveraging off-the-shelf medical components, the iSAVE could rapidly expand the ventilation capacity of health care facilities during emergency situations such as pandemics.

Published
2020
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