Pub Date : 2024-08-27DOI: 10.1164/rccm.202406-1128RL
Sarah J Morgan, David P Nichols, Wendy Ni, Gina Hong, Stephen J Salipante, George M Solomon, Steven M Rowe, John P Clancy, Robert A Cramer, Pradeep K Singh
{"title":"Elexacaftor/Tezacaftor/Ivacaftor Markedly Reduces <i>Aspergillus fumigatus</i> in Cystic Fibrosis.","authors":"Sarah J Morgan, David P Nichols, Wendy Ni, Gina Hong, Stephen J Salipante, George M Solomon, Steven M Rowe, John P Clancy, Robert A Cramer, Pradeep K Singh","doi":"10.1164/rccm.202406-1128RL","DOIUrl":"https://doi.org/10.1164/rccm.202406-1128RL","url":null,"abstract":"","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":null,"pages":null},"PeriodicalIF":19.3,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142071823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-27DOI: 10.1164/rccm.202401-0065OC
Glenda Trujillo, Alicia Regueiro-Ren, Chunjian Liu, Buqu Hu, Ying Sun, Farida Ahangari, Vitoria Fiorini, Genta Ishikawa, Karam Al Jumaily, Johad Khoury, John McGovern, Chris J Lee, Xue Yan Peng, Taylor Pivarnik, Huanxing Sun, Anjali Walia, Samuel Woo, Sheeline Yu, Danielle E Antin-Ozerkis, Maor Sauler, Naftali Kaminski, Erica L Herzog, Changwan Ryu
Rationale: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease for which current treatment options only slow clinical progression. Previously, we identified a subset of patients with IPF with an accelerated disease course associated with fibroblast expression of Toll-Like Receptor 9 (TLR9) mediated by interactions with its ligand mitochondrial DNA (mtDNA).
Objectives: We aimed to show that TLR9 activation induces fibroproliferative responses that are abrogated by its antagonism by using two commercially-available indirect inhibitors and a proprietary, selective direct small molecule inhibitor.
Methods: We employed two independent cohorts of patients with IPF, multiple in vitro fibroblast cell culture platforms, an in vivo mouse model, and an ex vivo human precision cut lung slices system to investigate the clinical and biologic significance of TLR9 in this disease.
Measurements and main results: In two independent IPF cohorts, plasma mtDNA activates TLR9 in a manner associated with the expression of MCP-1, IL-6, TNFα, and IP-10 and worsened transplant-free survival. Our cell culture platform showed that TLR9 mediates fibroblast activation via TGFβ1 and stiff substrates, and that its antagonism, particularly direct inhibition, ameliorates this process, including production of these TLR9 associated pharmacodynamic endpoints. We further demonstrated that direct TLR9 inhibition mitigates these fibroproliferative responses in our in vivo and ex vivo models of pulmonary fibrosis.
Conclusions: In this novel study, we found that direct TLR9 inhibition mitigates fibroproliferative responses in preclinical models of pulmonary fibrosis. Our work demonstrates the therapeutic potential of direct TLR9 antagonism in IPF and related fibrotic lung diseases.
{"title":"Toll-like Receptor 9 Inhibition Mitigates Fibroproliferative Responses in Translational Models of Pulmonary Fibrosis.","authors":"Glenda Trujillo, Alicia Regueiro-Ren, Chunjian Liu, Buqu Hu, Ying Sun, Farida Ahangari, Vitoria Fiorini, Genta Ishikawa, Karam Al Jumaily, Johad Khoury, John McGovern, Chris J Lee, Xue Yan Peng, Taylor Pivarnik, Huanxing Sun, Anjali Walia, Samuel Woo, Sheeline Yu, Danielle E Antin-Ozerkis, Maor Sauler, Naftali Kaminski, Erica L Herzog, Changwan Ryu","doi":"10.1164/rccm.202401-0065OC","DOIUrl":"10.1164/rccm.202401-0065OC","url":null,"abstract":"<p><strong>Rationale: </strong>Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease for which current treatment options only slow clinical progression. Previously, we identified a subset of patients with IPF with an accelerated disease course associated with fibroblast expression of Toll-Like Receptor 9 (TLR9) mediated by interactions with its ligand mitochondrial DNA (mtDNA).</p><p><strong>Objectives: </strong>We aimed to show that TLR9 activation induces fibroproliferative responses that are abrogated by its antagonism by using two commercially-available indirect inhibitors and a proprietary, selective direct small molecule inhibitor.</p><p><strong>Methods: </strong>We employed two independent cohorts of patients with IPF, multiple <i>in vitro</i> fibroblast cell culture platforms, an <i>in vivo</i> mouse model, and an <i>ex vivo</i> human precision cut lung slices system to investigate the clinical and biologic significance of TLR9 in this disease.</p><p><strong>Measurements and main results: </strong>In two independent IPF cohorts, plasma mtDNA activates TLR9 in a manner associated with the expression of MCP-1, IL-6, TNFα, and IP-10 and worsened transplant-free survival. Our cell culture platform showed that TLR9 mediates fibroblast activation via TGFβ1 and stiff substrates, and that its antagonism, particularly direct inhibition, ameliorates this process, including production of these TLR9 associated pharmacodynamic endpoints. We further demonstrated that direct TLR9 inhibition mitigates these fibroproliferative responses in our <i>in vivo</i> and <i>ex vivo</i> models of pulmonary fibrosis.</p><p><strong>Conclusions: </strong>In this novel study, we found that direct TLR9 inhibition mitigates fibroproliferative responses in preclinical models of pulmonary fibrosis. Our work demonstrates the therapeutic potential of direct TLR9 antagonism in IPF and related fibrotic lung diseases.</p>","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":null,"pages":null},"PeriodicalIF":19.3,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142071824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-22DOI: 10.1164/rccm.202404-0813OC
Hannah Wunsch, Nicholas A Bosch, Anica C Law, Emily A Vail, May Hua, Burton H Shen, Peter K Lindenauer, David N Juurlink, Allan J Walkey, Hayley B Gershengorn
Rationale: Uncertainty remains regarding the risks associated with single dose use of etomidate.
Objectives: To assess use of etomidate in critically ill patients and compare outcomes for patients who received etomidate versus ketamine.
Methods: We assessed patients who received invasive mechanical ventilation (IMV), admitted to an ICU in the Premier Healthcare Database, 2008-2021. The exposure was receipt of etomidate on the day of IMV initiation and the main outcome was hospital mortality. Using multivariable regression we compared patients who received IMV within the first two days of hospitalization who received etomidate with propensity-score matched patients who received ketamine. We also assessed whether receipt of corticosteroids in the days after intubation modified the association between etomidate and mortality.
Measurements and main results: Of 1,689,945 patients who received IMV, nearly half (738,855; 43.7%) received etomidate. Among those who received IMV in the first two days of hospitalization, we established 22,273 matched pairs given either etomidate or ketamine. In the primary analysis, receipt of etomidate was associated with greater hospital mortality relative to ketamine (21.6% vs 18.7%; absolute risk difference: 2.8%, 95% CI 2.1%, 3.6%; adjusted odds ratio: 1.28, 95% CI 1.21,1.34). This was consistent across subgroups and sensitivity analyses. We found no attenuation of the association with mortality with receipt of corticosteroids in the days following etomidate use.
Conclusions: Use of etomidate on the day of IMV initiation is common and associated with a higher odds of hospital mortality compared with ketamine. This finding is independent of subsequent treatment with corticosteroids.
理论依据单剂量使用依托咪酯的相关风险仍存在不确定性:评估依托咪酯在重症患者中的使用情况,并比较接受依托咪酯与氯胺酮治疗的患者的预后:我们评估了2008-2021年Premier医疗保健数据库中入住重症监护病房、接受有创机械通气(IMV)的患者。暴露是指在开始 IMV 的当天接受了依托咪酯治疗,主要结果是住院死亡率。通过多变量回归,我们比较了在住院头两天内接受 IMV 的依托咪酯患者与接受氯胺酮的倾向分数匹配患者。我们还评估了插管后几天内使用皮质类固醇是否会改变依托咪酯与死亡率之间的关系:在1,689,945名接受IMV的患者中,近一半(738,855人;43.7%)接受了依托咪酯治疗。在住院头两天接受 IMV 的患者中,我们建立了 22,273 对配对,分别给予依托咪酯或氯胺酮。在主要分析中,与氯胺酮相比,接受依托咪酯治疗与更高的住院死亡率相关(21.6% vs 18.7%;绝对风险差异:2.8%,95% CI 2.1%,3.6%;调整后的几率比:1.28,95% CI 1.21,1.34)。这一点在亚组和敏感性分析中都是一致的。我们发现,在使用依托咪酯后的几天内接受皮质类固醇治疗与死亡率的关系没有减弱:结论:与氯胺酮相比,在开始使用 IMV 的当天使用依托咪酯很常见,而且与较高的住院死亡率相关。这一发现与随后的皮质类固醇治疗无关。
{"title":"Evaluation of Etomidate Use and Association with Mortality Compared with Ketamine Among Critically Ill Patients.","authors":"Hannah Wunsch, Nicholas A Bosch, Anica C Law, Emily A Vail, May Hua, Burton H Shen, Peter K Lindenauer, David N Juurlink, Allan J Walkey, Hayley B Gershengorn","doi":"10.1164/rccm.202404-0813OC","DOIUrl":"https://doi.org/10.1164/rccm.202404-0813OC","url":null,"abstract":"<p><strong>Rationale: </strong>Uncertainty remains regarding the risks associated with single dose use of etomidate.</p><p><strong>Objectives: </strong>To assess use of etomidate in critically ill patients and compare outcomes for patients who received etomidate versus ketamine.</p><p><strong>Methods: </strong>We assessed patients who received invasive mechanical ventilation (IMV), admitted to an ICU in the Premier Healthcare Database, 2008-2021. The exposure was receipt of etomidate on the day of IMV initiation and the main outcome was hospital mortality. Using multivariable regression we compared patients who received IMV within the first two days of hospitalization who received etomidate with propensity-score matched patients who received ketamine. We also assessed whether receipt of corticosteroids in the days after intubation modified the association between etomidate and mortality.</p><p><strong>Measurements and main results: </strong>Of 1,689,945 patients who received IMV, nearly half (738,855; 43.7%) received etomidate. Among those who received IMV in the first two days of hospitalization, we established 22,273 matched pairs given either etomidate or ketamine. In the primary analysis, receipt of etomidate was associated with greater hospital mortality relative to ketamine (21.6% vs 18.7%; absolute risk difference: 2.8%, 95% CI 2.1%, 3.6%; adjusted odds ratio: 1.28, 95% CI 1.21,1.34). This was consistent across subgroups and sensitivity analyses. We found no attenuation of the association with mortality with receipt of corticosteroids in the days following etomidate use.</p><p><strong>Conclusions: </strong>Use of etomidate on the day of IMV initiation is common and associated with a higher odds of hospital mortality compared with ketamine. This finding is independent of subsequent treatment with corticosteroids.</p>","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":null,"pages":null},"PeriodicalIF":19.3,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142034894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-22DOI: 10.1164/rccm.202406-1262ED
Sofia Zavala, Jason E Stout
{"title":"A Balancing Act: Finding the Right Dose of Pyrazinamide to Treat Tuberculosis.","authors":"Sofia Zavala, Jason E Stout","doi":"10.1164/rccm.202406-1262ED","DOIUrl":"https://doi.org/10.1164/rccm.202406-1262ED","url":null,"abstract":"","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":null,"pages":null},"PeriodicalIF":19.3,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142034893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-21DOI: 10.1164/rccm.202406-1139LE
Michael B Keller, Xin Tian, Sean Agbor-Enoh
{"title":"Reply to Glanville: The Emperor's New Clothes Revisited.","authors":"Michael B Keller, Xin Tian, Sean Agbor-Enoh","doi":"10.1164/rccm.202406-1139LE","DOIUrl":"https://doi.org/10.1164/rccm.202406-1139LE","url":null,"abstract":"","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":null,"pages":null},"PeriodicalIF":19.3,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-21DOI: 10.1164/rccm.202405-1014LE
Allan R Glanville
{"title":"The Emperor's New Clothes Revisited.","authors":"Allan R Glanville","doi":"10.1164/rccm.202405-1014LE","DOIUrl":"https://doi.org/10.1164/rccm.202405-1014LE","url":null,"abstract":"","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":null,"pages":null},"PeriodicalIF":19.3,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-21DOI: 10.1164/rccm.202407-1414ED
Michael R Pinsky, Alain Mercat
{"title":"Is Pulmonary Vascular Resistance in ARDS the Judge Defining Recruitment versus Overdistention with PEEP?","authors":"Michael R Pinsky, Alain Mercat","doi":"10.1164/rccm.202407-1414ED","DOIUrl":"https://doi.org/10.1164/rccm.202407-1414ED","url":null,"abstract":"","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":null,"pages":null},"PeriodicalIF":19.3,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-15DOI: 10.1164/rccm.202402-0272LE
Emiel R Marges, Iris G van der Sar, Jeska K de Vries-Bouwstra, Tom W J Huizinga, Paul L A van Daele, Marlies S Wijsenbeek, Catharina C Moor, J J Miranda Geelhoed
{"title":"Detection of Systemic Sclerosis-associated Interstitial Lung Disease by Exhaled Breath Analysis Using Electronic Nose Technology.","authors":"Emiel R Marges, Iris G van der Sar, Jeska K de Vries-Bouwstra, Tom W J Huizinga, Paul L A van Daele, Marlies S Wijsenbeek, Catharina C Moor, J J Miranda Geelhoed","doi":"10.1164/rccm.202402-0272LE","DOIUrl":"10.1164/rccm.202402-0272LE","url":null,"abstract":"","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":null,"pages":null},"PeriodicalIF":19.3,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141282739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-15DOI: 10.1164/rccm.202310-1899LE
Hajime Fujimoto, Corina N D'Alessandro-Gabazza, Taro Yasuma, Esteban C Gabazza, Osamu Hataji, Tetsu Kobayashi
{"title":"Leveraging Microbiome Composition Variability for Precision Medicine in Idiopathic Pulmonary Fibrosis.","authors":"Hajime Fujimoto, Corina N D'Alessandro-Gabazza, Taro Yasuma, Esteban C Gabazza, Osamu Hataji, Tetsu Kobayashi","doi":"10.1164/rccm.202310-1899LE","DOIUrl":"10.1164/rccm.202310-1899LE","url":null,"abstract":"","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":null,"pages":null},"PeriodicalIF":19.3,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11351789/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139563176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-15DOI: 10.1164/rccm.202312-2262LE
David N O'Dwyer, Imre Noth, Justin M Oldham
{"title":"Reply to Fujimoto <i>et al.</i>: Leveraging Microbiome Composition Variability for Precision Medicine in Idiopathic Pulmonary Fibrosis.","authors":"David N O'Dwyer, Imre Noth, Justin M Oldham","doi":"10.1164/rccm.202312-2262LE","DOIUrl":"10.1164/rccm.202312-2262LE","url":null,"abstract":"","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":null,"pages":null},"PeriodicalIF":19.3,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11351812/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139563182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}