American journal of respiratory and critical care medicine
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Am. J. Respir. Crit. Care Med. · Aug 2019
Identifying Novel Sepsis Subphenotypes Using Temperature Trajectories.
Rationale: Sepsis is a heterogeneous syndrome, and identifying clinically relevant subphenotypes is essential. Objectives: To identify novel subphenotypes in hospitalized patients with infection using longitudinal temperature trajectories. Methods: In the model development cohort, inpatient admissions meeting criteria for infection in the emergency department and receiving antibiotics within 24 hours of presentation were included. ⋯ The hyperthermic, fast resolvers had the lowest mortality rate (2.9%). Similar trajectory groups, patient characteristics, and outcomes were found in the validation cohort. Conclusions: We identified and validated four novel subphenotypes of patients with infection, with significant variability in inflammatory markers and outcomes.
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Am. J. Respir. Crit. Care Med. · Aug 2019
Clinical TrialThe Biological Effects of Double-Dose Alpha-1 Antitrypsin Augmentation Therapy: A Pilot Study.
Rationale: Augmentation therapy with intravenous AAT (alpha-1 antitrypsin) is the only specific therapy for individuals with pulmonary disease from AAT deficiency (AATD). The recommended standard dose (SD; 60 mg/kg/wk) elevates AAT trough serum levels to around 50% of normal; however, outside of slowing emphysema progression, its effects in other clinical outcomes have not been rigorously proven. Objectives: To evaluate the biological effects of normalizing AAT trough levels with double-dose (DD) therapy (120 mg/kg/wk) in subjects with AATD already receiving SD therapy. ⋯ Conclusions: Subjects with AATD on SD augmentation therapy still exhibit inflammation, protease activity, and elastin degradation that can be further improved by normalizing AAT levels. Higher AAT dosing than currently recommended may lead to enhanced clinical benefits and should be explored further. Clinical trial registered with www.clinicaltrials.gov (NCT01669421).
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Am. J. Respir. Crit. Care Med. · Aug 2019
Distinct Cancer-Promoting Stromal Gene Expression Depending on Lung Function.
Rationale: Chronic obstructive pulmonary disease is an independent risk factor for lung cancer, but the underlying molecular mechanisms are unknown. We hypothesized that lung stromal cells activate pathological gene expression programs that support oncogenesis. Objectives: To identify molecular mechanisms operating in the lung stroma that support the development of lung cancer. ⋯ Furthermore, an in situ examination of lung tissue showed that stromal fibroblasts expressed cancer-associated proteins from two procancer secretomes: one that included IL-6 (in cases of mild or no airflow obstruction), and one that included BMP1 (in cases of severe airflow obstruction). Conclusions: Two distinct stromal gene expression programs that promote cancer initiation are activated in patients with lung cancer depending on lung function. Our work has implications both for screening strategies and for personalized approaches to cancer treatment.
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Am. J. Respir. Crit. Care Med. · Aug 2019
Spatial Network Mapping of Pulmonary Multidrug-Resistant Tuberculosis Cavities Using RNA Sequencing.
Rationale: There is poor understanding about protective immunity and the pathogenesis of cavitation in patients with tuberculosis. Objectives: To map pathophysiological pathways at anatomically distinct positions within the human tuberculosis cavity. Methods: Biopsies were obtained from eight predetermined locations within lung cavities of patients with multidrug-resistant tuberculosis undergoing therapeutic surgical resection (n = 14) and healthy lung tissue from control subjects without tuberculosis (n = 10). ⋯ The mathematical model demonstrated that neuroendocrine, protein kinase C-θ, and triggering receptor expressed on myeloid cells-1 pathways, and macrophage and neutrophil numbers, had the highest correlation with bacterial burden (r > 0.6), whereas T-helper effector systems did not. Conclusions: These data provide novel insights into host immunity to Mycobacterium tuberculosis-related cavitation. The pathways defined may serve as useful targets for the design of host-directed therapies, and transmission prevention interventions.