American journal of respiratory and critical care medicine最新文献

{"title":"Zinc-mediated Inhibition of Soluble Epoxide Hydrolase Promotes Pulmonary Hypertension.","authors":"Daniel Simoes de Jesus, Stanley Buffonge, Giancarlo Abis, Roberto Buccafusca, Reshma Baliga, Helen R Warren, Adrian Hobbs, Clemens Ruppert, Astrid Weiss, Ralph T Schermuly, Philip Eaton, Rebecca L Charles","doi":"","DOIUrl":"","url":null,"abstract":"<p><strong>Rationale: </strong>Pulmonary hypertension (PH) and vascular remodeling involve complex molecular mechanisms, with zinc and epoxyeicosatrienoic acids playing key roles.</p><p><strong>Objectives: </strong>To investigate whether zinc-mediated inhibition of soluble epoxide hydrolase contributes to the development of PH and vascular remodeling under hypoxic conditions.</p><p><strong>Methods: </strong>Activity assays measured zinc-mediated soluble epoxide hydrolase inhibition, with mutagenesis and inductively coupled mass spectrometry identifying key cysteines. Pulmonary arteries and HPASMCs were used to measure vasoconstriction in response to epoxyeicosatrienoic acid, zinc, soluble epoxide hydrolase inhibition, or hypoxia treatment. A C230A knock-in mouse was generated to elucidate the mechanism <i>in vivo</i> in acute and chronic hypoxia. Hydrolase expression was assessed in patients with idiopathic pulmonary artery hypertension or chronic obstructive pulmonary disease. Using UK Biobank data, soluble epoxide hydrolase mutations were assessed for a link to increased PH risk.</p><p><strong>Measurements and main results: </strong>Zinc inhibited soluble epoxide hydrolase by binding to C232/C230 and C423. C230A mice, resistant to zinc binding, were protected from acute hypoxia-induced soluble epoxide hydrolase inhibition, epoxyeicosatrienoic acids accumulation, and increased pulmonary pressure. C230A mice were also resistant to chronic hypoxia-induced pulmonary hypertension, the associated remodeling and loss of hydrolase expression. Patient lung samples showed decreased soluble epoxide hydrolase expression echoing our mice findings. UK Biobank participants with loss-of-function mutations in soluble epoxide hydrolase exhibited a higher risk of developing PH.</p><p><strong>Conclusions: </strong>Loss of sEH activity, whether due to genetics, acute zinc-dependent inhibition or chronic zinc-dependent loss of hydrolase protein, ultimately results in PH and targeting this pathway may offer new therapeutic opportunities.</p>","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":" ","pages":"None"},"PeriodicalIF":19.3,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144281987","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}

{"title":"The 4-Month HPMZ Treatment Regimen for Drug-Susceptible Pulmonary Tuberculosis - A Word of Caution.","authors":"John W Wilson, Zelalem Temesgen, James G Gaensbauer","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":" ","pages":"None"},"PeriodicalIF":19.3,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144281986","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}

{"title":"Detection and Evaluation of Drug-associated Pulmonary Arterial Hypertension.","authors":"Clément Jambon-Barbara, Alex Hlavaty, Julien Grynblat, Fabrice Antigny, Marie-Camille Chaumais, Marc Humbert, Jean-Luc Cracowski, David Montani, Charles Khouri","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":" ","pages":"None"},"PeriodicalIF":19.3,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144281982","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}

{"title":"An Alarming Loss of Pulmonary Rehabilitation Programs: Example from the U.S. Veterans Administration.","authors":"Marilyn L Moy, Linda Nici","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":" ","pages":"None"},"PeriodicalIF":19.3,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144281980","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}

{"title":"Reply to Wilson <i>et al.</i>: The 4-Month HPMZ Treatment Regimen for Drug-Susceptible Pulmonary Tuberculosis - A Word of Caution.","authors":"Jussi Saukkonen, Sonal Munsiff, Carla Winston, Raquel Duarte, Manoj Mammen","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":" ","pages":"None"},"PeriodicalIF":19.3,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144281985","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}

{"title":"Aging Gracefully: Does Elexacaftor/Tezacaftor/Ivacaftor Safety and Efficacy Stand the Test of Time?","authors":"Gemma Wilson, Dominic Hughes","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":" ","pages":"None"},"PeriodicalIF":19.3,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144281979","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}

{"title":"Post-COPD: Can Emphysema Be Repaired?","authors":"J Michael Wells, Jerry A Krishnan, R Chad Wade, Greg Kinney, Robert A Wise, Enid Neptune, Francesca Polverino, Nicola A Hanania, Matthew Moll, Melanie Königshoff, Divay Chandra, Frank Sciurba, Nathaniel Marchetti, Raúl San José Estépar, Alejandro A Diaz, Karim El-Kersh, Mario Castro, Ying Zhang, Janet T Holbrook, Elizabeth A Sugar, Monica Kraft, Robert J Kaner, Barry Make, Stephen Rennard","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Clinical and translational observations suggest that repair or new growth of alveolar structures in humans is feasible. The pathways and mechanisms for repairing damaged alveoli have been characterized in <i>in vivo</i> and <i>ex vivo</i> models, and many of these major biological pathways involved in facilitating lung repair have been validated in adult human lung tissue. Improvements in imaging, functional studies, and biomarkers have led to sensitive measures of treatment effects and clinical outcomes that can be used to study emphysema repair in humans with emphysema. Additionally, the development of innovative platform clinical trial designs now allows for the simultaneous testing of multiple drugs and treatment response biomarkers within a heterogenous population, helping to distinguish responders from non-responders. Several approved medications targeting pathways involved in lung repair could be tested to treat emphysema (e.g., all-trans retinoic acid, thiazolidinediones, metformin, non-steroidal anti-inflammatory drugs, and lithium). These advances enable feasible assessment of the scientific premise of lung repair in human emphysema in clinical trials.</p>","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":" ","pages":"None"},"PeriodicalIF":19.3,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274018","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}

{"title":"Temporary Transvenous Diaphragm Neurostimulation for Weaning from Mechanical Ventilation (RESCUE-3).","authors":"Martin Dres, Ralf Ewert, Steven A Conrad, Ali Ataya, Joseph Shrager, Satar Mortaza, Flora Delamaire, Georg Nilius, Alexander Heine, Nawzer Mehta, Judy Ways, Doug Evans, Giorgio Paulon, Farah Khandwala, Nick Berry, Kert Viele, Teresa Nelson, Miranda Gilbertson, Thomas Similowski, Marcelo Gama de Abreu, Ewan C Goligher","doi":"","DOIUrl":"","url":null,"abstract":"<p><strong>Background: </strong>Diaphragm dysfunction impedes weaning from mechanical ventilation. Transvenous diaphragm neurostimulation can increase diaphragm strength but its impact on patient outcomes is uncertain.</p><p><strong>Methods: </strong>This international, multicenter, open-label, randomized clinical trial (RESCUE-3) included adult patients requiring mechanical ventilation for ≥96 hours who met readiness-to-wean criteria and failed ≥2 weaning attempts. Patients were randomized to twice-daily transvenous diaphragm neurostimulation (Treatment) or standard of care (Control). The primary outcome was successful weaning at Day 30. Secondary outcomes included duration of ventilation to Day 30 and mortality at Day 30. The pre-specified primary analysis utilized a Bayesian approach with borrowing of prior information from a previous phase II randomized trial, downweighted to account for possible differences in trials.</p><p><strong>Results: </strong>Due to slow enrolment and financial considerations, the trial was halted at the first interim analysis after 200 patients were randomized. Overall, 216 patients were randomized in the modified intent-to-treat population (Treatment, 102; Control 114). At Day 30, 71 (70%) Treatment patients and 69 (61%) Control patients were successfully weaned (adjusted hazard ratio 1.34, 95% credible interval 1.01-1.78, posterior probability of superiority, 97.9%). Treatment reduced the duration of ventilation (adjusted difference -2.5 days, 95% credible interval -5.0 to 0.1, posterior probability of superiority, 97.1%). Serious adverse events were reported in 36% of Treatment patients and 24% of Control patients; 9.8% of Treatment patients and 10.5% of Control patients died (adjusted hazard ratio 0.74, 95% credible interval 0.37-1.46, posterior probability of superiority 80.6%).</p><p><strong>Conclusion: </strong>Although the trial was stopped early due to slow enrollment, transvenous diaphragm neurostimulation showed a high probability of potential benefit for weaning success but with a possible increase in serious adverse events. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/). Clinical trial registration available at www.</p><p><strong>Clinicaltrials: </strong>gov, ID: NCT03783884.</p>","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":" ","pages":"None"},"PeriodicalIF":19.3,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144265047","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}

{"title":"Refining Pulmonary Embolism Management: Balancing Innovation with Accuracy.","authors":"Amrit K Deol, John J Ryan","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":" ","pages":"None"},"PeriodicalIF":19.3,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144265046","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}

{"title":"Biologic Mechanisms Underlying the Heterogeneous Response to Tight Glycemic Control among Differentially Inflamed Patients in the HALF-PINT Trial.","authors":"Matt S Zinter, Clove S Taylor, Daniela Markovic, Matteo Pellegrini, Kayley Wong, Brunilda Balliu, Kinisha P Gala, Lisa A Asaro, Vinay M Nadkarni, Patrick S McQuillen, Sitaram S Vangala, Pratik Sinha, Michael A Matthay, Michael S D Agus, Anil Sapru","doi":"","DOIUrl":"","url":null,"abstract":"<p><strong>Rationale: </strong>Tight glycemic control with insulin (TGC) has not consistently shown benefit in critically ill patients. We previously reported that the subset of children with a hyperinflammatory subphenotype benefitted from TGC in the HALF-PINT study of hyperglycemic children with heart and lung failure and the IIT-SBPP study in severely burned pediatric patients. However, whether this effect was mediated through a reduction in inflammation or some other biological process is not fully understood.</p><p><strong>Objectives: </strong>To deepen the understanding of inflammatory subphenotypes and explore the biological mechanisms underlying heterogeneous response to TGC.</p><p><strong>Methods: </strong>Plasma cytokine measurements and whole blood transcriptomics from 740 blood samples collected on pre- and post- treatment study days 0, 2, and 4 from 293 HALF-PINT participants (n=250 hypoinflammatory and n=43 hyperinflammatory) were used to identify cytokine and gene expression signatures of differential responses to TGC.</p><p><strong>Measurements and results: </strong>Patients with hyperinflammatory subphenotype had greater baseline expression of genes relating to inflammation, cell cycle activity, and immunometabolism. Hyperinflammatory patients treated to a target glucose range of 80-110 mg/dL experienced greater reduction in inflammatory cytokines, innate immune gene expression, and heme metabolism gene expression, as well as an increase in lymphocyte gene expression, compared to those treated to a target range of 150-180 mg/dL. Causal mediation testing indicated that these changes partly explained the observed mortality benefit of TGC in the hyperinflammatory subgroup of patients.</p><p><strong>Conclusions: </strong>These findings expand our understanding of the biology underlying inflammatory subphenotypes, and provide biological insight into the mortality benefit of TGC in hyperinflammatory children.</p>","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":" ","pages":"None"},"PeriodicalIF":19.3,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144265045","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}