American journal of respiratory and critical care medicine
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Am. J. Respir. Crit. Care Med. · Mar 2020
Observational StudyLung Microbiota Predict Clinical Outcomes in Critically Ill Patients.
Rationale: Recent studies have revealed that, in critically ill patients, lung microbiota are altered and correlate with alveolar inflammation. The clinical significance of altered lung bacteria in critical illness is unknown. Objectives: To determine if clinical outcomes of critically ill patients are predicted by features of the lung microbiome at the time of admission. ⋯ Detection of gut-associated bacteria was also associated with the presence of acute respiratory distress syndrome. Conclusions: Key features of the lung microbiome (bacterial burden and enrichment with gut-associated bacteria) predict outcomes in critically ill patients. The lung microbiome is an understudied source of clinical variation in critical illness and represents a novel therapeutic target for the prevention and treatment of acute respiratory failure.
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Am. J. Respir. Crit. Care Med. · Mar 2020
The Effects of Rare SERPINA1 Variants on Lung Function and Emphysema in SPIROMICS.
Rationale: The role of PI (protease inhibitor) type Z heterozygotes and additional rare variant genotypes in the gene encoding alpha-1 antitrypsin, SERPINA1 (serpin peptidase inhibitor, clade A, member 1), in determining chronic obstructive pulmonary disease risk and severity is controversial. Objectives: To comprehensively evaluate the effects of rare SERPINA1 variants on lung function and emphysema phenotypes in subjects with significant tobacco smoke exposure using deep gene resequencing and alpha-1 antitrypsin concentrations. Methods: DNA samples from 1,693 non-Hispanic white individuals, 385 African Americans, and 90 Hispanics with ≥20 pack-years smoking were resequenced for the identification of rare variants (allele frequency < 0.05) in 16.9 kB of SERPINA1. ⋯ In African Americans, a 5' untranslated region insertion (rs568223361) was associated with lower alpha-1 antitrypsin and functional small airway disease (P = 0.007). Conclusions: In this integrative deep sequencing study of SERPINA1 with alpha-1 antitrypsin concentrations in a heavy smoker and chronic obstructive pulmonary disease cohort, we confirmed the effects of PI Z heterozygote and compound heterozygote genotypes. We demonstrate the cumulative effects of multiple SERPINA1 variants on alpha-1 antitrypsin deficiency, lung function, and emphysema, thus significantly increasing the frequency of SERPINA1 variation associated with respiratory disease in at-risk smokers.
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Am. J. Respir. Crit. Care Med. · Mar 2020
Optimizing the Design of Latent Tuberculosis Treatment Trials: Insights from Mathematical Modeling.
Rationale: Noninferiority trials of treatment for latent tuberculosis infection (LTBI) are challenging because of imperfect LTBI diagnostic tests. Objectives: To assess the effect on study outcomes of different enrollment strategies for a noninferiority trial of LTBI treatment. Methods: We mathematically simulated a two-arm randomized clinical trial of LTBI in which the experimental therapy was 50% efficacious and the control was 80% efficacious, with an absolute 0.75% noninferiority margin. ⋯ Enrolling based on no test or regardless of test result led to falsely declaring noninferiority unless LTBI prevalence in the underlying population was higher than 45%. Enrolling based on a mix of TST and IGRA substantially reduced the likelihood of falsely declaring noninferiority over enrolling based on TST alone, even if as many as 70% of participants were enrolled based on positive TST. Conclusions: Noninferiority trials of LTBI should enroll based on the most specific diagnostic tests available (i.e., IGRAs) to avoid misclassifying inferior treatment regimens as noninferior.