American journal of respiratory and critical care medicine
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Am. J. Respir. Crit. Care Med. · Aug 2024
Randomized Controlled TrialHigh-Dose Isoniazid Lacks EARLY Bactericidal Activity Against Isoniazid-resistant Tuberculosis Mediated by katG Mutations: A Randomized, Phase 2 Clinical Trial.
Rationale: Observational studies suggest that high-dose isoniazid may be efficacious in treating multidrug-resistant tuberculosis. However, its activity against Mycobacterium tuberculosis (M.tb) with katG mutations (which typically confer high-level resistance) is not established. Objectives: To characterize the early bactericidal activity (EBA) of high-dose isoniazid in patients with tuberculosis caused by katG-mutated M.tb. ⋯ There were no grade 3 or higher drug-related adverse events. Conclusions: This study found negligible bactericidal activity of high-dose isoniazid (15-20 mg/kg) in the majority of participants with tuberculosis caused by katG-mutated M.tb. Clinical trial registered with www.clinicaltrials.gov (NCT01936831).
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Am. J. Respir. Crit. Care Med. · Aug 2024
Shift-Level Team Familiarity Is Associated with Improved Outcomes in Mechanically Ventilated Adults.
Rationale: Organizing ICU interprofessional teams is a high priority because of workforce needs, but the role of interprofessional familiarity remains unexplored. Objectives: Determine if mechanically ventilated patients cared for by teams with greater familiarity have improved outcomes, such as lower mortality, shorter duration of mechanical ventilation (MV), and greater spontaneous breathing trial (SBT) implementation. Methods: We used electronic health records data of five ICUs in an academic medical center to map interprofessional teams and their ICU networks, measuring team familiarity as network coreness and mean team value. ⋯ A 1-SD increase in team coreness was significantly associated with a 4.5% greater probability of SBT implementation, 23% shorter MV duration, and 3.8% lower probability of dying; the mean team value was significantly associated with lower mortality. Split-sample results were attenuated but congruent in direction and interpretation. Conclusions: Interprofessional familiarity was associated with improved outcomes; assignment models that prioritize familiarity might be a novel solution.
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Am. J. Respir. Crit. Care Med. · Aug 2024
Digital Spatial Profiling Identifies Distinct Molecular Signatures of Vascular Lesions in Pulmonary Arterial Hypertension.
Rationale: Idiopathic pulmonary arterial hypertension (IPAH) is characterized by extensive pulmonary vascular remodeling caused by plexiform and obliterative lesions, media hypertrophy, inflammatory cell infiltration, and alterations of the adventitia. Objective: We sought to test the hypothesis that microscopic IPAH vascular lesions express unique molecular profiles, which collectively are different from control pulmonary arteries. Methods: We used digital spatial transcriptomics to profile the genomewide differential transcriptomic signature of key pathological lesions (plexiform, obliterative, intima+media hypertrophy, and adventitia) in IPAH lungs (n = 11) and compared these data with the intima+media hypertrophy and adventitia of control pulmonary artery (n = 5). ⋯ Cellular deconvolution indicated variability in the number of vascular and inflammatory cells between IPAH lesions, which underlies the differential transcript profiling. Conclusions: IPAH lesions express unique molecular transcript profiles enriched for pathways involving pathogenetic pathways, including genetic disease drivers, innate and acquired immunity, hypoxia sensing, and angiogenesis signaling. These data provide a rich molecular-structural framework in IPAH vascular lesions that inform novel biomarkers and therapeutic targets in this highly morbid disease.
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Am. J. Respir. Crit. Care Med. · Aug 2024
Patent Ductus Arteriosus and Lung MRI Phenotype in Moderate and Severe Bronchopulmonary Dysplasia-Pulmonary Hypertension.
Rationale: Hemodynamically significant patent ductus arteriosus (hsPDA) in premature infants has been associated with bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH). However, these associations remain incompletely understood. Objectives: To assess the associations between hsPDA duration and clinical outcomes, PH, and phenotypic differences on lung magnetic resonance imaging (MRI). ⋯ Measurements and Main Results: In total, 133 infants born at 26.2 ± 1.9 weeks, weighing 776 ± 276 g, were reviewed (47 with no hsPDA, 44 with hsPDA 1-60 days, and 42 with hsPDA >60 d). hsPDA duration > 60 days was associated with BPD severity (P < 0.01), PH at 36 weeks' PMA (adjusted odds ratio [aOR], 9.7 [95% confidence interval (CI), 3.3-28.4]), PH-PVD (aOR, 6.5 [95% CI, 2.3-18.3]), and tracheostomy or death (aOR, 3.0 [95% CI, 1.0-8.8]). Duration of hsPDA > 60 days was associated with higher Ochiai score (P = 0.03) and indexed total lung volume (P = 0.01) but not whole-lung hyperdensity (P = 0.91). Conclusions: In infants with moderate or severe BPD, prolonged exposure to hsPDA is associated with BPD severity, PH-PVD, and increased parenchymal lung disease by MRI.