American journal of respiratory and critical care medicine
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Am. J. Respir. Crit. Care Med. · May 2023
Temperature Trajectory Subphenotypes in Oncology Patients with Neutropenia and Suspected Infection.
Rationale: Despite etiologic and severity heterogeneity in neutropenic sepsis, management is often uniform. Understanding host response clinical subphenotypes might inform treatment strategies for neutropenic sepsis. Objectives: In this retrospective two-hospital study, we analyzed whether temperature trajectory modeling could identify distinct, clinically relevant subphenotypes among oncology patients with neutropenia and suspected infection. ⋯ Bloodstream infections were more common among hyperthermic slow resolvers (n = 248 [21.8%]) and hyperthermic fast resolvers (n = 240 [18.3%]) than among hypothermic (n = 188 [11.7%]) or normothermic (n = 418 [11.5%]) encounters (P < 0.001). Adjusted for confounders, hyperthermic slow resolvers had increased adjusted odds for mortality (primary cohort odds ratio, 1.91 [P = 0.03]; validation cohort odds ratio, 2.19 [P < 0.001]) and bloodstream infection (primary odds ratio, 1.54 [P = 0.04]; validation cohort odds ratio, 2.15 [P < 0.001]). Conclusions: Temperature trajectory subphenotypes were independently associated with important outcomes among hospitalized patients with neutropenia in two independent cohorts.
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Rationale and Objectives: Up to 20% of idiopathic interstitial lung disease is familial, referred to as familial pulmonary fibrosis (FPF). An integrated analysis of FPF genetic risk was performed by comprehensively evaluating for genetic rare variants (RVs) in a large cohort of FPF kindreds. Methods: Whole-exome sequencing and/or candidate gene sequencing from affected individuals in 569 FPF kindreds was performed, followed by cosegregation analysis in large kindreds, gene burden analysis, gene-based risk scoring, cell-type enrichment analysis, and coexpression network construction. ⋯ By combining single-cell transcriptomics with prioritized candidate genes, expression of RV-containing genes was discovered to be enriched in smooth muscle cells, type II alveolar epithelial cells, and endothelial cells. Conclusions: In the most comprehensive FPF genetic study to date, the prevalence of RVs in known FPF-related genes was defined, and new candidate genes and pathways relevant to FPF were identified. However, new RV-containing genes shared across multiple kindreds were not identified, thereby suggesting that heterogeneous genetic variants involving a variety of genes and pathways mediate genetic risk in most FPF kindreds.
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Am. J. Respir. Crit. Care Med. · May 2023
Clinical TrialA Standardized Approach for Collection of Objective Data to Support Outcome Determination for Late-Phase TB Trials.
Rationale: We developed a standardized method, possible poor treatment response (PPTR), to help ascertain efficacy endpoints in Study S31/A5349 (NCT02410772), an open-label trial comparing two 4-month rifapentine-based regimens with a standard 6-month regimen for the treatment of pulmonary tuberculosis (TB). Objectives: We describe the use of the PPTR process and evaluate whether the goals of minimizing bias in efficacy endpoint assessment and attainment of relevant data to determine outcomes for all participants were achieved. Methods: A PPTR event was defined as the occurrence of one or more prespecified triggers. ⋯ At least one PPTR event was experienced by 92.4% (133 of 144) of participants with TB-related unfavorable outcome and between 13.8% and 14.7% of participants with favorable and not-assessable outcomes. A total of 75% of participants with TB-related unfavorable outcomes had microbiological confirmation of failure to achieve a disease-free cure. Conclusions: Standardized methodologies, such as our PPTR approach, could facilitate unbiased efficacy outcome determinations, improve discrimination between outcomes that are related and unrelated to regimen efficacy, and enhance the ability to conduct pooled analyses of contemporary trials.
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Am. J. Respir. Crit. Care Med. · May 2023
Single-Cell Analysis Reveals Distinct Immune and Smooth Muscle Cell Populations that Contribute to Chronic Thromboembolic Pulmonary Hypertension.
Rationale: Chronic thromboembolic pulmonary hypertension (CTEPH) is a sequela of acute pulmonary embolism (PE) in which the PE remodels into a chronic scar in the pulmonary arteries. This results in vascular obstruction, pulmonary microvasculopathy, and pulmonary hypertension. Objectives: Our current understanding of CTEPH pathobiology is primarily derived from cell-based studies limited by the use of specific cell markers or phenotypic modulation in cell culture. ⋯ Additionally, cultured endothelial, smooth muscle, and myofibroblast cells isolated from CTEPH fibrothrombotic material have distinct phenotypes from control cells with regard to angiogenic potential and rates of proliferation and apoptosis. Last, our analysis identified PAR1 (protease-activated receptor 1) as a potential therapeutic target that links thrombosis to chronic PE in CTEPH, with PAR1 inhibition decreasing SMC and myofibroblast proliferation and migration. Conclusions: These findings suggest a model for CTEPH similar to atherosclerosis, with chronic inflammation promoted by macrophages and T cells driving vascular remodeling through SMC modulation, and suggest new approaches for pharmacologically targeting this disease.