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Article ; Online: Assessing the entire landscape of antifungal immune response to COVID-19-associated pulmonary aspergillosis.

Reizine, Florian / Tadié, Jean-Marc / Grégoire, Murielle / Tarte, Karin / Gangneux, Jean-Pierre

The Lancet. Microbe

2024

Language	English
Publishing date	2024-04-23
Publishing country	England
Document type	Letter
ISSN	2666-5247
ISSN (online)	2666-5247
DOI	10.1016/S2666-5247(24)00076-4
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Article ; Online: Citrulline enteral administration markedly reduces immunosuppressive extrafollicular plasma cell differentiation in a preclinical model of sepsis.

Gauthier, Juliette / Grégoire, Murielle / Reizine, Florian / Lesouhaitier, Mathieu / Desvois, Yoni / Ghukasyan, Gevorg / Moreau, Caroline / Amé, Patricia / Tarte, Karin / Tadié, Jean-Marc / Delaloy, Céline

European journal of immunology

2023 Volume 53, Issue 3, Page(s) e2250154

Abstract: The sustained immunosuppression associated with severe sepsis favors an increased susceptibility to secondary infections and remains incompletely understood. Plasmablast and plasma cell subsets, whose primary function is to secrete antibodies, have ... ...

Abstract	The sustained immunosuppression associated with severe sepsis favors an increased susceptibility to secondary infections and remains incompletely understood. Plasmablast and plasma cell subsets, whose primary function is to secrete antibodies, have emerged as important suppressive populations that expand during sepsis. In particular, sepsis supports CD39
MeSH term(s)	Mice ; Animals ; Citrulline/metabolism ; Coinfection ; Sepsis ; Arginine ; Immunosuppressive Agents ; Cell Differentiation
Chemical Substances	Citrulline (29VT07BGDA) ; Arginine (94ZLA3W45F) ; Immunosuppressive Agents
Language	English
Publishing date	2023-01-10
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.202250154
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Zs.A 489: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: AMPK activates Parkin independent autophagy and improves post sepsis immune defense against secondary bacterial lung infections.

Bone, Nathaniel B / Becker, Eugene J / Husain, Maroof / Jiang, Shaoning / Zmijewska, Anna A / Park, Dae-Won / Chacko, Balu / Darley-Usmar, Victor / Grégoire, Murielle / Tadie, Jean-Marc / Thannickal, Victor J / Zmijewski, Jaroslaw W

Scientific reports

2021 Volume 11, Issue 1, Page(s) 12387

Abstract: Metabolic and bioenergetic plasticity of immune cells is essential for optimal responses to bacterial infections. AMPK and Parkin ubiquitin ligase are known to regulate mitochondrial quality control mitophagy that prevents unwanted inflammatory responses. ...

Abstract	Metabolic and bioenergetic plasticity of immune cells is essential for optimal responses to bacterial infections. AMPK and Parkin ubiquitin ligase are known to regulate mitochondrial quality control mitophagy that prevents unwanted inflammatory responses. However, it is not known if this evolutionarily conserved mechanism has been coopted by the host immune defense to eradicate bacterial pathogens and influence post-sepsis immunosuppression. Parkin, AMPK levels, and the effects of AMPK activators were investigated in human leukocytes from sepsis survivors as well as wild type and Park2
MeSH term(s)	AMP-Activated Protein Kinases/metabolism ; Animals ; Autophagy ; Bacterial Infections/immunology ; Humans ; Lung Diseases/immunology ; Mice ; Mice, Inbred C57BL ; Sepsis/immunology ; Ubiquitin-Protein Ligases/metabolism
Chemical Substances	Ubiquitin-Protein Ligases (EC 2.3.2.27) ; parkin protein (EC 2.3.2.27) ; AMP-Activated Protein Kinases (EC 2.7.11.31)
Language	English
Publishing date	2021-06-11
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-90573-0
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Article ; Online: Enteral citrulline supplementation versus placebo on SOFA score on day 7 in mechanically ventilated critically ill patients: the IMMUNOCITRE randomized clinical trial.

Critical care (London, England)

2023 Volume 27, Issue 1, Page(s) 381

Abstract: Background: Restoring plasma arginine levels through enteral administration of L-citrulline in critically ill patients may improve outcomes. We aimed to evaluate whether enteral L-citrulline administration reduced organ dysfunction based on the ... ...

Abstract	Background: Restoring plasma arginine levels through enteral administration of L-citrulline in critically ill patients may improve outcomes. We aimed to evaluate whether enteral L-citrulline administration reduced organ dysfunction based on the Sequential Organ Failure Assessment (SOFA) score and affected selected immune parameters in mechanically ventilated medical intensive care unit (ICU) patients. Methods: A randomized, double-blind, multicenter clinical trial of enteral administration of L-citrulline versus placebo for critically ill adult patients under invasive mechanical ventilation without sepsis or septic shock was conducted in four ICUs in France between September 2016 and February 2019. Patients were randomly assigned to receive enteral L-citrulline (5 g) every 12 h for 5 days or isonitrogenous, isocaloric placebo. The primary outcome was the SOFA score on day 7. Secondary outcomes included SOFA score improvement (defined as a decrease in total SOFA score by 2 points or more between day 1 and day 7), secondary infection acquisition, ICU length of stay, plasma amino acid levels, and immune biomarkers on day 3 and day 7 (HLA-DR expression on monocytes and interleukin-6). Results: Of 120 randomized patients (mean age, 60 ± 17 years; 44 [36.7%] women; ICU stay 10 days [IQR, 7-16]; incidence of secondary infections 25 patients (20.8%)), 60 were allocated to L-citrulline and 60 were allocated to placebo. Overall, there was no significant difference in organ dysfunction as assessed by the SOFA score on day 7 after enrollment (4 [IQR, 2-6] in the L-citrulline group vs. 4 [IQR, 2-7] in the placebo group; Mann‒Whitney U test, p = 0.9). Plasma arginine was significantly increased on day 3 in the treatment group, while immune parameters remained unaffected. Conclusion: Among mechanically ventilated ICU patients without sepsis or septic shock, enteral L-citrulline administration did not result in a significant difference in SOFA score on day 7 compared to placebo. Trial registration: ClinicalTrials.gov Identifier NCT02864017 (date of registration: 11 August 2016).
MeSH term(s)	Adult ; Humans ; Female ; Middle Aged ; Aged ; Male ; Organ Dysfunction Scores ; Shock, Septic/complications ; Citrulline/pharmacology ; Citrulline/therapeutic use ; Multiple Organ Failure/etiology ; Critical Illness/therapy ; Respiration, Artificial/adverse effects ; Sepsis/drug therapy ; Sepsis/complications ; Intensive Care Units ; Dietary Supplements ; Arginine/therapeutic use
Chemical Substances	Citrulline (29VT07BGDA) ; Arginine (94ZLA3W45F)
Language	English
Publishing date	2023-10-03
Publishing country	England
Document type	Randomized Controlled Trial ; Multicenter Study ; Journal Article
ZDB-ID	2041406-7
ISSN	1466-609X ; 1364-8535
ISSN (online)	1466-609X
ISSN	1364-8535
DOI	10.1186/s13054-023-04651-y
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Zs.A 5517: Show issues

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Article: Short-term survival of acute respiratory distress syndrome patients due to influenza virus infection alone: a cohort study.

Gacouin, Arnaud / Lesouhaitier, Mathieu / Reizine, Florian / Pronier, Charlotte / Grégoire, Murielle / Painvin, Benoit / Maamar, Adel / Thibault, Vincent / Le Tulzo, Yves / Tadié, Jean Marc

ERJ open research

2020 Volume 6, Issue 4

Abstract: Background: Influenza virus (IV)-related pathophysiology suggests that the prognosis of acute respiratory distress syndrome (ARDS) due to IV could be different from the prognosis of ARDS due to other causes. However, the impact of IV infection alone on ... ...

Abstract	Background: Influenza virus (IV)-related pathophysiology suggests that the prognosis of acute respiratory distress syndrome (ARDS) due to IV could be different from the prognosis of ARDS due to other causes. However, the impact of IV infection alone on the prognosis of ARDS patients compared to that of patients with other causes of ARDS has been poorly assessed. Methods: We compared the 28-day survival from the diagnosis of ARDS with an arterial oxygen tension/inspiratory oxygen fraction ratio ≤150 mmHg between patients with and without IV infection alone. Data were collected prospectively and analysed retrospectively. We first performed survival analysis on the whole population; second, patients with IV infection alone were compared with matched pairs using propensity score matching. Results: The cohort admitted from October 2009 to March 2020 consisted of 572 patients, including 73 patients (13%) with IV alone. On the first 3 days of mechanical ventilation, nonpulmonary Sequential Organ Failure Assessment scores were significantly lower in patients with IV infection than in the other patients. After the adjusted analysis, IV infection alone remained independently associated with lower mortality at day 28 (hazard ratio 0.51, 95% CI 0.26-0.99, p=0.047). Mortality at day 28 was significantly lower in patients with IV infection alone than in other patients when propensity score matching was used (20% Conclusions: Our results suggest that patients with ARDS following IV infection alone have a significantly better prognosis at day 28 and less severe nonpulmonary organ dysfunction than do those with ARDS from causes other than IV infection alone.
Language	English
Publishing date	2020-11-10
Publishing country	England
Document type	Journal Article
ZDB-ID	2827830-6
ISSN	2312-0541
ISSN	2312-0541
DOI	10.1183/23120541.00587-2020
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Article ; Online: Venoarterial extracorporeal membrane oxygenation induces early immune alterations.

Frerou, Aurélien / Lesouhaitier, Mathieu / Gregoire, Murielle / Uhel, Fabrice / Gacouin, Arnaud / Reizine, Florian / Moreau, Caroline / Loirat, Aurélie / Maamar, Adel / Nesseler, Nicolas / Anselmi, Amedeo / Flecher, Erwan / Verhoye, Jean-Philippe / Le Tulzo, Yves / Cogné, Michel / Roussel, Mikael / Tarte, Karin / Tadié, Jean-Marc

Critical care (London, England)

2021 Volume 25, Issue 1, Page(s) 9

Abstract: Background: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) provides heart mechanical support in critically ill patients with cardiogenic shock. Despite important progresses in the management of patients under VA-ECMO, acquired infections ... ...

Abstract	Background: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) provides heart mechanical support in critically ill patients with cardiogenic shock. Despite important progresses in the management of patients under VA-ECMO, acquired infections remain extremely frequent and increase mortality rate. Since immune dysfunctions have been described in both critically ill patients and after surgery with cardiopulmonary bypass, VA-ECMO initiation may be responsible for immune alterations that may expose patients to nosocomial infections (NI). Therefore, in this prospective study, we aimed to study immune alterations induced within the first days by VA-ECMO initiation. Methods: We studied immune alterations induced by VA-ECMO initiation using cytometry analysis to characterize immune cell changes and enzyme-linked immunosorbent assay (ELISA) to explore plasma cytokine levels. To analyze specific changes induced by VA-ECMO initiation, nine patients under VA-ECMO (VA-ECMO patients) were compared to nine patients with cardiogenic shock (control patients). Results: Baseline immune parameters were similar between the two groups. VA-ECMO was associated with a significant increase in circulating immature neutrophils with a significant decrease in C5a receptor expression. Furthermore, we found that VA-ECMO initiation was followed by lymphocyte dysfunction along with myeloid-derived suppressor cells (MDSC) expansion. ELISA analysis revealed that VA-ECMO initiation was followed by an increase in pro-inflammatory cytokines such as IL-6, IL-8 and TNF-α along with IL-10, a highly immunosuppressive cytokine. Conclusion: VA-ECMO is associated with early immune changes that may be responsible for innate and adaptive immune alterations that could confer an increased risk of infection.
MeSH term(s)	Aged ; Chi-Square Distribution ; Cytokines/analysis ; Cytokines/blood ; Extracorporeal Membrane Oxygenation/adverse effects ; Extracorporeal Membrane Oxygenation/methods ; Female ; Humans ; Immune System Diseases/enzymology ; Immune System Diseases/etiology ; Immune System Diseases/physiopathology ; Male ; Middle Aged ; Prospective Studies ; Shock, Cardiogenic/physiopathology ; Shock, Cardiogenic/therapy ; Statistics, Nonparametric
Chemical Substances	Cytokines
Language	English
Publishing date	2021-01-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2041406-7
ISSN	1466-609X ; 1364-8535
ISSN (online)	1466-609X
ISSN	1364-8535
DOI	10.1186/s13054-020-03444-x
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Zs.A 5517: Show issues

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Article ; Online: Neutrophil function and bactericidal activity against Staphylococcus aureus after cardiac surgery with cardiopulmonary bypass.

Lesouhaitier, Mathieu / Gregoire, Murielle / Gacouin, Arnaud / Coirier, Valentin / Frerou, Aurélien / Piau, Caroline / Cattoir, Vincent / Dumontet, Erwan / Revest, Matthieu / Tattevin, Pierre / Roisne, Antoine / Verhoye, Jean-Philippe / Flecher, Erwan / Le Tulzo, Yves / Tarte, Karin / Tadié, Jean-Marc

Journal of leukocyte biology

2021 Volume 111, Issue 4, Page(s) 867–876

Abstract: Staphylococcus aureus is the main bacterial pathogen encountered in mediastinitis after cardiac surgical procedures; it remains a devastating complication with a high mortality rate. As neutrophils have a primordial role in the defense against ... ...

Abstract	Staphylococcus aureus is the main bacterial pathogen encountered in mediastinitis after cardiac surgical procedures; it remains a devastating complication with a high mortality rate. As neutrophils have a primordial role in the defense against staphylococcus infection and cardiopulmonary bypass (CPB) is known to induce immunosuppression, the aim of this study was to investigate CPB impact on neutrophil functions. Patients without known immunosuppression scheduled for cardiac surgery with CPB were included. Bone marrow and blood samples were harvested before, during, and after surgery. Neutrophil phenotypic maturation and functions (migration, adhesion, neutrophil extracellular trap [NET] release, reactive oxygen species (ROS) production, phagocytosis, and bacteria killing) were investigated. Two types of Staphylococcus aureus strains (one from asymptomatic nasal carriage and another from mediastinitis infected tissues) were used to assess in vitro bacterial direct impact on neutrophils. We found that CPB induced a systemic inflammation with an increase in circulating mature neutrophils after surgery. Bone marrow sample analysis did not reveal any modification of neutrophil maturation during CPB. Neutrophil lifespan was significantly increased and functions such as NET release and ROS production were enhanced after CPB whereas bacteria killing and phagocytosis were not impacted. Results were similar with the two different isolates of Staphylococcus aureus. These data suggest that CPB induces a recruitment of mature neutrophils via a demargination process rather than impacting their maturation in the bone marrow. In addition, neutrophils are fully efficient after CPB and do not contribute to postoperative immunosuppression.
MeSH term(s)	Cardiac Surgical Procedures ; Cardiopulmonary Bypass/adverse effects ; Cardiopulmonary Bypass/methods ; Humans ; Mediastinitis ; Neutrophils ; Reactive Oxygen Species ; Staphylococcal Infections ; Staphylococcus aureus
Chemical Substances	Reactive Oxygen Species
Language	English
Publishing date	2021-08-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	605722-6
ISSN	1938-3673 ; 0741-5400
ISSN (online)	1938-3673
ISSN	0741-5400
DOI	10.1002/JLB.5AB1219-737RR
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Zs.A 603: Show issues

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Article ; Online: Comparative immune profiling of acute respiratory distress syndrome patients with or without SARS-CoV-2 infection.

Roussel, Mikael / Ferrant, Juliette / Reizine, Florian / Le Gallou, Simon / Dulong, Joelle / Carl, Sarah / Lesouhaitier, Matheiu / Gregoire, Murielle / Bescher, Nadège / Verdy, Clotilde / Latour, Maelle / Bézier, Isabelle / Cornic, Marie / Vinit, Angélique / Monvoisin, Céline / Sawitzki, Birgit / Leonard, Simon / Paul, Stéphane / Feuillard, Jean /

Jeannet, Robin / Daix, Thomas / Tiwari, Vijay K / Tadié, Jean Marc / Cogné, Michel / Tarte, Karin

Cell reports. Medicine

2021 Volume 2, Issue 6, Page(s) 100291

Abstract: Acute respiratory distress syndrome (ARDS) is the main complication of coronavirus disease 2019 (COVID-19), requiring admission to the intensive care unit (ICU). Despite extensive immune profiling of COVID-19 patients, to what extent COVID-19-associated ... ...

Abstract	Acute respiratory distress syndrome (ARDS) is the main complication of coronavirus disease 2019 (COVID-19), requiring admission to the intensive care unit (ICU). Despite extensive immune profiling of COVID-19 patients, to what extent COVID-19-associated ARDS differs from other causes of ARDS remains unknown. To address this question, here, we build 3 cohorts of patients categorized in COVID-19
MeSH term(s)	Aged ; COVID-19/complications ; COVID-19/pathology ; COVID-19/virology ; Cohort Studies ; Evolution, Molecular ; Female ; HLA-DR Antigens/metabolism ; Humans ; Intensive Care Units ; Leukocytes, Mononuclear/cytology ; Leukocytes, Mononuclear/immunology ; Leukocytes, Mononuclear/metabolism ; Lipopolysaccharide Receptors/metabolism ; Machine Learning ; Male ; Middle Aged ; Monocytes/cytology ; Monocytes/immunology ; Monocytes/metabolism ; Respiratory Distress Syndrome/etiology ; Respiratory Distress Syndrome/immunology ; Respiratory Distress Syndrome/pathology ; SARS-CoV-2/isolation & purification ; Sialic Acid Binding Ig-like Lectin 1/metabolism ; Th1 Cells/cytology ; Th1 Cells/immunology ; Th1 Cells/metabolism
Chemical Substances	HLA-DR Antigens ; Lipopolysaccharide Receptors ; Sialic Acid Binding Ig-like Lectin 1
Language	English
Publishing date	2021-05-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2666-3791
ISSN (online)	2666-3791
DOI	10.1016/j.xcrm.2021.100291
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Article ; Online: Beneficial effects of citrulline enteral administration on sepsis-induced T cell mitochondrial dysfunction.

Reizine, Florian / Grégoire, Murielle / Lesouhaitier, Mathieu / Coirier, Valentin / Gauthier, Juliette / Delaloy, Céline / Dessauge, Elise / Creusat, Florent / Uhel, Fabrice / Gacouin, Arnaud / Dessauge, Frédéric / Le Naoures, Cécile / Moreau, Caroline / Bendavid, Claude / Daniel, Yoann / Petitjean, Kilian / Bordeau, Valérie / Lamaison, Claire / Piau, Caroline /

Cattoir, Vincent / Roussel, Mikael / Fromenty, Bernard / Michelet, Christian / Le Tulzo, Yves / Zmijewski, Jaroslaw / Thibault, Ronan / Cogné, Michel / Tarte, Karin / Tadié, Jean-Marc

Proceedings of the National Academy of Sciences of the United States of America

2022 Volume 119, Issue 8

Abstract: Severe sepsis induces a sustained immune dysfunction associated with poor clinical behavior. In particular, lymphopenia along with increased lymphocyte apoptosis and decreased lymphocyte proliferation, enhanced circulating regulatory T cells (Treg), and ... ...

Abstract	Severe sepsis induces a sustained immune dysfunction associated with poor clinical behavior. In particular, lymphopenia along with increased lymphocyte apoptosis and decreased lymphocyte proliferation, enhanced circulating regulatory T cells (Treg), and the emergence of myeloid-derived suppressor cells (MDSCs) have all been associated with persistent organ dysfunction, secondary infections, and late mortality. The mechanisms involved in MDSC-mediated T cell dysfunction during sepsis share some features with those described in malignancies such as arginine deprivation. We hypothesized that increasing arginine availability would restore T cell function and decrease sepsis-induced immunosuppression. Using a mouse model of sepsis based on cecal ligation and puncture and secondary pneumonia triggered by methicillin-resistant
MeSH term(s)	Animals ; Arginine/deficiency ; Arginine/metabolism ; Biological Availability ; Citrulline/metabolism ; Citrulline/pharmacology ; Cytokines/metabolism ; Disease Models, Animal ; Female ; Immune Tolerance/immunology ; Immunosuppression Therapy/methods ; Lymphocyte Activation/drug effects ; Lymphocyte Activation/immunology ; Mice ; Mice, Inbred C57BL ; Mitochondria/drug effects ; Mitochondria/metabolism ; Myeloid-Derived Suppressor Cells/immunology ; Sepsis/drug therapy ; Sepsis/metabolism ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; T-Lymphocytes, Regulatory/immunology
Chemical Substances	Cytokines ; Citrulline (29VT07BGDA) ; Arginine (94ZLA3W45F)
Language	English
Publishing date	2022-02-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2115139119
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Zs.A 1148: Show issues

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Article ; Online: Early Expansion of Circulating Granulocytic Myeloid-derived Suppressor Cells Predicts Development of Nosocomial Infections in Patients with Sepsis.

Uhel, Fabrice / Azzaoui, Imane / Grégoire, Murielle / Pangault, Céline / Dulong, Joelle / Tadié, Jean-Marc / Gacouin, Arnaud / Camus, Christophe / Cynober, Luc / Fest, Thierry / Le Tulzo, Yves / Roussel, Mikael / Tarte, Karin

American journal of respiratory and critical care medicine

2017 Volume 196, Issue 3, Page(s) 315–327

Abstract: Rationale: Sepsis induces a sustained immune dysfunction responsible for poor outcome and nosocomial infections. Myeloid-derived suppressor cells (MDSCs) described in cancer and inflammatory processes may be involved in sepsis-induced immune suppression, ...

Abstract	Rationale: Sepsis induces a sustained immune dysfunction responsible for poor outcome and nosocomial infections. Myeloid-derived suppressor cells (MDSCs) described in cancer and inflammatory processes may be involved in sepsis-induced immune suppression, but their clinical impact remains poorly defined. Objectives: To clarify phenotype, suppressive activity, origin, and clinical impact of MDSCs in patients with sepsis. Methods: Peripheral blood transcriptomic analysis was performed on 29 patients with sepsis and 15 healthy donors. A second cohort of 94 consecutive patients with sepsis, 11 severity-matched intensive care patients, and 67 healthy donors was prospectively enrolled for flow cytometry and functional experiments. Measurements and main results: Genes involved in MDSC suppressive functions, including S100A12, S100A9, MMP8, and ARG1, were up-regulated in the peripheral blood of patients with sepsis. CD14 Conclusions: M-MDSCs and G-MDSCs strongly contribute to T-cell dysfunction in patients with sepsis. More specifically, G-MDSCs producing arginase 1 are associated with a higher incidence of nosocomial infections and seem to be major actors of sepsis-induced immune suppression.
MeSH term(s)	Adult ; Aged ; Cell Proliferation ; Cross Infection/blood ; Cross Infection/immunology ; Female ; Flow Cytometry ; Granulocytes/immunology ; Humans ; Male ; Middle Aged ; Myeloid-Derived Suppressor Cells/immunology ; Prospective Studies ; Sepsis/blood ; Sepsis/immunology
Language	English
Publishing date	2017-02-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1180953-x
ISSN	1535-4970 ; 0003-0805 ; 1073-449X
ISSN (online)	1535-4970
ISSN	0003-0805 ; 1073-449X
DOI	10.1164/rccm.201606-1143OC
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