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Yisha Li,1 Ran Dai,2 Yeongjin Gwon,2 Stephen I Rennard,3 Barry J Make,4 Dinah Foer,5 Matthew J Strand,4 Erin Austin,6 Kendra A Young,1 John E Hokanson,1 Katherine A Pratte,7 Rebecca Conway,1 Gregory L Kinney1 On behalf of COPDGene investigators1Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; 2Department of Biostatistics, School of Public Health, University of Nebraska Medical Center, Omaha, NE, USA; 3Division of Pulmonary, Critical Care and Sleep Medicine, University of Nebraska Medical Center, Omaha, NE, USA; 4Department of Medicine, National Jewish Health, Denver, CO, USA; 5Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA; 6Mathematical and Statistical Sciences, University of Colorado Denver, Denver, CO, USA; 7Department of Biostatistics, National Jewish Health, Denver, CO, USACorrespondence: Gregory L Kinney, Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA, Tel +1 303-724-4437, Email GREG.KINNEY@CUANSCHUTZ.EDU

Rationale: Among patients with nontuberculous mycobacterial lung disease is a subset of previously healthy women with a slender body morphotype, often with scoliosis and/or pectus excavatum. We hypothesize that unidentified factors predispose these individuals to pulmonary nontuberculous mycobacterial disease.Objectives: To compare body morphotype, serum adipokine levels, and whole-blood cytokine responses of patients with pulmonary nontuberculous mycobacteria (pNTM) with contemporary control subjects who are well matched demographically.Methods: We enrolled 103 patients with pNTM and 101 uninfected control subjects of similar demographics. Body mass index and body fat were quantified. All patients with pNTM and a subset of control subjects were evaluated for scoliosis and pectus excavatum. Serum leptin and adiponectin were measured. Specific cytokines important to host-defense against mycobacteria were measured in whole blood before and after stimulation.Measurements and Main Results: Patients with pNTM and control subjects were well matched for age, gender, and race. Patients with pNTM had significantly lower body mass index and body fat and were significantly taller than control subjects. Scoliosis and pectus excavatum were significantly more prevalent in patients with pNTM. The normal relationships between the adipokines and body fat were lost in the patients with pNTM, a novel finding. IFN-γ and IL-10 levels were significantly suppressed in stimulated whole blood of patients with pNTM.Conclusions: This is the first study to comprehensively compare body morphotype, adipokines, and cytokine responses between patients with NTM lung disease and demographically matched controls. Our findings suggest a novel, predisposing immunophenotype that should be mechanistically defined. [ABSTRACT FROM AUTHOR]

Background and Objective: Evaluations of the disease management (DM) programs for commercial health plans are widely published. However, publications of DM-program outcomes for the more at-risk Medicaid population are rare. This study evaluates the impact of DM efforts in a Medicaid congestive heart failure (CHF) program. The objective of this study is to use propensity score methods to evaluate the impact of CHF DM efforts on compliance to evidence-based guideline pharmacy drug use in a US Northwestern state Medicaid program.Methods: Two retrospective observational methods using propensity scores are considered: propensity-score matching and covariate adjustment by the propensity score. Data were collected between October 2000 and May 2005 for members of the Medicaid program who were eligible for the study. The DM intervention group included Medicaid participants identified with CHF and not enrolled in any other DM program prior to participating in the CHF DM program. The control group included Medicaid participants identified with CHF who could not be contacted for enrollment or chose not to participate in the program. A total of 162 matched-pairs were included in the propensity score matched analysis, while 250 DM intervention group participants and 232 controls were included in the covariate adjustment analysis. The main outcome measures were total number of pharmacy prescriptions, proportion of patients using ACE inhibitors, and proportion of patients using beta-adrenoceptor antagonists.Results: In both propensity score methods, the total number of pharmacy prescriptions and ACE inhibitor use were statistically significantly higher in the DM intervention group compared with the control group during the program period, with DM participants having 25% more total pharmacy prescriptions and a 20% higher rate of ACE inhibitor use.Conclusions: This analysis suggests that CHF DM programs can result in increased compliance to evidence-based guideline prescription drug use. The results of this study support the need for randomized controlled trials of DM programs to validate the positive pharmaceutical compliance results found in this study, and further to evaluate whether DM programs can reduce the use of medical services and cost of care while improving health status. [ABSTRACT FROM AUTHOR]

Rationale: Glucocorticoids (GCs) are highly effective in the treatment of asthma. However, some individuals have GC-insensitive asthma.Objectives: To evaluate the functional response to steroids of bronchoalveolar lavage (BAL) cells from sites of airway inflammation from patients with GC-insensitive versus GC-sensitive asthma. As well, to attempt to define the functional role of glucocorticoid receptor (GCR)beta (a splicing variant, and dominant negative inhibitor of, the classic GCRalpha) in controlling GCRalpha nuclear translocation and transactivation at a molecular level.Methods and Measurements: Fiberoptic bronchoscopy with collection of BAL fluid was performed on seven patients with GC-sensitive asthma and eight patients with GC-insensitive asthma. GCRalpha cellular shuttling in response to 10(-6) M dexamethasone treatment and GCRbeta expression were analyzed in BAL cells by immunofluorescence staining. The effects of overexpression and silencing of GCRbeta mRNA on GCRalpha function were assessed.Main Results: Significantly reduced nuclear translocation of GCRalpha in response to steroids was found in BAL cells from patients with GC-insensitive asthma. BAL macrophages from patients with GC-insensitive asthma had significantly increased levels of cytoplasmic and nuclear GCRbeta. It was demonstrated that GCRalpha nuclear translocation and its transactivation properties were proportionately reduced by level of viral transduction of the GCRbeta gene into the DO-11.10 cell line. RNA silencing of GCRbeta mRNA in human BAL macrophages from patients with GC-insensitive asthma resulted in enhanced dexamethasone-induced GCRalpha transactivation.Conclusions: GC insensitivity is associated with loss of GCRalpha nuclear translocation in BAL cells and elevated GCRbeta, which may inhibit GCRalpha transactivation in response to steroids. [ABSTRACT FROM AUTHOR]

Multidrug-resistant tuberculosis, a disease caused by Mycobacterium tuberculosis strains that are resistant at least to rifampin and isoniazid, entails extended treatment, expensive and toxic regimens, and higher rates of treatment failure and death. We retrospectively analyzed the outcomes in 205 patients treated at our center for multidrug-resistant tuberculosis, with strains resistant to a median of six drugs, and compared the results with those of our previous series. Logistic regression and survival analysis were used to evaluate short- and long-term outcomes, respectively. Initial favorable response, defined as at least three consecutive negative sputum cultures over a period of at least 3 months, was 85% compared with 65% in the prior cohort. The current cohort had greater long-term success rates, 75% versus 56%, and lower tuberculosis death rates, 12% versus 22%, than the earlier one. Surgical resection and fluoroquinolone therapy were associated with improved microbiological and clinical outcomes in the 205 patients studied after adjusting for other variables. The improvement was statistically significant for surgery and among older patients for fluoroquinolone therapy. [ABSTRACT FROM AUTHOR]

Rationale: Nontuberculous mycobacteria (NTM) has been reported to be transmitted between people with cystic fibrosis (CF) attending CF centres. A suspected Mycobacterium abscessus outbreak was investigated at the University of Texas Southwestern (UTSW) Adult CF Program using a combination of pathogen genomic sequencing and epidemiologic methods. The objectives of the present study were to apply the Healthcare-Associated Links in Transmission of NTM (HALT NTM) study to investigate the occurrence of potential healthcare-associated transmission and/or acquisition of NTM among people with CF infected with genetically similar NTM isolates., Methods: Whole-genome sequencing of respiratory M. abscessus isolates from 50 people with CF receiving care at UTSW was performed to identify genetically similar isolates. Epidemiologic investigation, comparison of respiratory and environmental isolates, and home residence watershed mapping were studied., Measurements and Main Results: Whole-genome sequencing analysis demonstrated seven clusters of genetically similar M. abscessus (four ssp . abscessus and three ssp. massiliense ). Epidemiologic investigation revealed potential opportunities for healthcare-associated transmission within three of these clusters. Healthcare environmental sampling did not recover M. abscessus , but did recover four human disease-causing species of NTM. No subjects having clustered infections lived in the same home residence watershed. Some subjects were infected with more than one M. abscessus genotype, both within and outside of the dominant circulating clones., Conclusions: Healthcare-associated person-to-person transmission of M. abscessus appears to be rare at this centre. However, polyclonal infections of M. abscessus species and subspecies, not originating from the endemic hospital environment, suggest multiple shared modes of acquisition outside the healthcare setting., Competing Interests: Conflict of interest: J.E. Gross reports support for the present manuscript from the Cystic Fibrosis (CF) Foundation and grants or contracts from CF Foundation outside the submitted work; and is a board member of the Rocky Mountain Chapter of the Cystic Fibrosis Foundation and Chair of the American Board of Pediatrics Pulmonology Subboard, disclosures made outside the submitted work. Conflict of interest: J.D. Finklea reports support for the present manuscript from a CF Foundation QI improvement grant, CF Foundation Success with Therapies Research Consortium. Conflict of interest: C.K. Vang reports support for the present manuscript from the CF Foundation. Conflict of interest: J.R. Honda reports support for the present manuscript from the Padosi Foundation and the University of Texas Health Science Center at Tyler; grants or contracts from the National Science Foundation, National Institutes of Health, CF Foundation and the John Chapman Endowed Professorship in Microbiology, outside the submitted work; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from the North American CF Foundation, Yale University, National Jewish Health, NTM Research Consortium and Albert Einstein College of Medicine, outside the submitted work; support for attending meetings and/or travel from the Padosi Foundation, National Science Foundation, National Jewish Health, NIH AGOLD-PRIDE, Albert Einstein College of Medicine, Sam Houston State University, American Thoracic Society, Texas Tech University, Colorado State University, NTM Research Consortium and North American CF Foundation, outside the submitted work; a leadership or fiduciary role for the American Thoracic Society, outside the submitted work; and receipt of equipment, materials, drugs, medical writing, gifts or other services from the University of Texas Health Science Center at Tyler, outside the submitted work. Conflict of interest: M. Strand reports support for the present manuscript from Effort from CF Foundation grant “Prospective Healthcare-Associated Transmission of Nontuberculous Mycobacteria”. Conflict of interest: C.L. Daley reports support for the present manuscript from CF Foundation; grants or contracts from AN2, Bugworks, Insmed, Juvabis and Paratek, outside the submitted work; consulting fees from Genentech and Pfizer, outside the submitted work; and participation on a data safety monitoring or advisory board for AN2, AstraZeneca, Hyfe, Insmed, MannKind, Matinas Biopharma, Nob Hill, Paratek, Spero and Zambon, outside the submitted work. Conflict of interest: The remaining authors have nothing to disclose., (Copyright ©The authors 2024.)

Rationale: Computed tomography (CT) enables noninvasive diagnosis of usual interstitial pneumonia (UIP), but enhanced image analyses are needed to overcome the limitations of visual assessment. Objectives: Apply multiple instance learning (MIL) to develop an explainable deep learning algorithm for prediction of UIP from CT and validate its performance in independent cohorts. Methods: We trained an MIL algorithm using a pooled dataset ( n  = 2,143) and tested it in three independent populations: data from a prior publication ( n  = 127), a single-institution clinical cohort ( n  = 239), and a national registry of patients with pulmonary fibrosis ( n  = 979). We tested UIP classification performance using receiver operating characteristic analysis, with histologic UIP as ground truth. Cox proportional hazards and linear mixed-effects models were used to examine associations between MIL predictions and survival or longitudinal FVC. Measurements and Main Results: In two cohorts with biopsy data, MIL improved accuracy for histologic UIP (area under the curve, 0.77 [ n  = 127] and 0.79 [ n  = 239]) compared with visual assessment (area under the curve, 0.65 and 0.71). In cohorts with survival data, MIL-UIP classifications were significant for mortality ( n  = 239, mortality to April 2021: unadjusted hazard ratio, 3.1; 95% confidence interval [CI], 1.96-4.91; P  < 0.001; and n  = 979, mortality to July 2022: unadjusted hazard ratio, 3.64; 95% CI, 2.66-4.97; P  < 0.001). Individuals classified as UIP positive by the algorithm had a significantly greater annual decline in FVC than those classified as UIP negative (-88 ml/yr vs. -45 ml/yr; n  = 979; P  < 0.01), adjusting for extent of lung fibrosis. Conclusions: Computerized assessment using MIL identifies clinically significant features of UIP on CT. Such a method could improve confidence in radiologic assessment of patients with interstitial lung disease, potentially enabling earlier and more precise diagnosis.

Background: Recent studies showed that Black patients more often have falsely normal oxygen saturation on pulse oximetry compared to White patients. However, whether the racial differences in occult hypoxemia are mediated by other clinical differences is unknown., Methods: We conducted a retrospective case-control study utilizing two large ICU databases (eICU and MIMIC-IV). We defined occult hypoxemia as oxygen saturation on pulse oximetry within 92-98% despite oxygen saturation on arterial blood gas below 90%. We assessed associations of commonly measured clinical factors with occult hypoxemia using multivariable logistic regression and conducted mediation analysis of the racial effect., Results: Among 24,641 patients, there were 1,855 occult hypoxemia cases and 23,786 controls. In both datasets, Black patients were more likely to have occult hypoxemia (unadjusted odds ratio 1.66 [95%-CI: 1.41-1.95] in eICU and 2.00 [95%-CI: 1.22-3.14] in MIMIC-IV). In multivariable models, higher respiratory rate, PaCO2 and creatinine as well as lower hemoglobin were associated with increased odds of occult hypoxemia. Differences in the commonly measured clinical markers accounted for 9.2% and 44.4% of the racial effect on occult hypoxemia in eICU and MIMIC-IV, respectively., Conclusion: Clinical differences, in addition to skin tone, might mediate some of the racial differences in occult hypoxemia., Competing Interests: Competing interests: BDH, MHC, and MM have received grant support from Bayer. BDH has received an honorarium from AstraZeneca for an educational lecture, unrelated to this work. MM has also received consulting fees from Sitka, TheaHealth, 2ndMD, TriNetX, and Verona Pharma, unrelated to this work. All other authors declare no conflict of interest.

Rationale: The diagnosis of chronic obstructive pulmonary disease (COPD) is based on a low FEV 1 /FVC ratio, but the severity of COPD is classified using FEV 1 % predicted (ppFEV 1 ). Objectives: To test a new severity classification scheme for COPD using FEV 1 /FVC ratio, a more robust measure of airflow obstruction than ppFEV 1 . Methods: In COPDGene (Genetic Epidemiology of COPD) ( N  = 10,132), the severity of airflow obstruction was categorized by Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages 1-4 (ppFEV 1 of ⩾80%, ⩾50-80%, ⩾30-50%, and <30%). A new severity classification (STaging of Airflow obstruction by Ratio; STAR) was tested in COPDGene-FEV 1 /FVC ⩾0.60 to <0.70, ⩾0.50 to <0.60, ⩾0.40 to <0.50, and <0.40, respectively, for stages 1-4-and applied to the combined Pittsburgh SCCOR and Emphysema COPD Research Registry for replication ( N  = 2,017). Measurements and Main Results: The agreements (weighted Bangdiwala B values) between GOLD and the new FEV 1 /FVC ratio severity stages were 0.89 in COPDGene and 0.88 in the Pittsburgh cohort. In COPDGene and the Pittsburgh cohort, compared with GOLD staging, STAR provided significant discrimination between the absence of airflow obstruction and stage 1 for all-cause mortality, respiratory quality of life, dyspnea, airway wall thickness, exacerbations, and lung function decline. No major differences were noted for emphysema, small airway disease, and 6-minute-walk distance. The STAR classification system identified a greater number of adults with stage 3/4 disease who would be eligible for lung transplantation and lung volume reduction procedure evaluations. Conclusions: The new STAR severity classification scheme provides discrimination for mortality that is similar to the GOLD classification but with a more uniform gradation of disease severity. STAR differentiates patients' symptoms, disease burden, and prognosis better than the existing scheme based on ppFEV 1 , and is less sensitive to race/ethnicity and other demographic characteristics.

Rationale: Outbreaks of nontuberculous mycobacteria (NTM) among people with cystic fibrosis (pwCF) have been reported at CF centers with conflicting conclusions. The occurrence of NTM at the UVMC (University of Vermont Medical Center) adult CF program was investigated. Objectives: Use the HALT NTM (Healthcare-associated Links in Transmission of NTM) toolkit to investigate the healthcare-associated transmission and/or acquisition of NTM among pwCF having genetically similar NTM isolates. Methods: Whole genome sequencing of NTM isolates from 23 pwCF was conducted to identify genetically similar NTM isolate clusters (30 or fewer single-nucleotide polymorphism differences). The epidemiological investigation, comparison of respiratory and healthcare environmental isolates, and home residence watershed mapping were analyzed. Results: Whole genome sequencing analysis revealed two clusters of NTM isolates ( Mycobacterium avium and M. intracellulare ssp. chimaera ) among pwCF. The epidemiologic investigation demonstrated opportunities for healthcare-associated transmission within both clusters. Healthcare environmental M. avium isolates revealed no genetic similarity to respiratory isolates. However, M. intracellulare ssp. chimaera respiratory isolates revealed greater genetic similarity to a hospital water biofilm isolate than to each other. Neither cluster had all subjects residing in the same watershed. Conclusions: This study suggests the healthcare-associated transmission of M. avium among pwCF is unlikely at UVMC but supports the healthcare-associated environmental acquisition of M. intracellulare ssp. chimaera . The presence of genetically similar isolates alone is insufficient to confirm healthcare-associated transmission and/or acquisition. The HALT NTM toolkit standardizes outbreak investigation with genetic analysis, epidemiologic investigation, healthcare environmental sampling, and home of residence watershed identification to test the frequency and nature of healthcare-associated NTM transmission among pwCF.

Background: The prevalence of atopic diseases has increased with atopic dermatitis (AD) as the earliest manifestation. We assessed if molecular risk factors in atopic mothers influence their infants' susceptibility to an atopic disease., Methods: Pregnant women and their infants with (n = 174, high-risk) or without (n = 126, low-risk) parental atopy were enrolled in a prospective birth cohort. Global differentially methylated regions (DMRs) were determined in atopic (n = 92) and non-atopic (n = 82) mothers. Principal component analysis was used to predict atopy risk in children dependent on maternal atopy. Genome-wide transcriptomic analyses were performed in paired atopic (n = 20) and non-atopic (n = 15) mothers and cord blood. Integrative genomic analyses were conducted to define methylation-gene expression relationships., Results: Atopic dermatitis was more prevalent in high-risk compared to low-risk children by age 2. Differential methylation analyses identified 165 DMRs distinguishing atopic from non-atopic mothers. Inclusion of DMRs in addition to maternal atopy significantly increased the odds ratio to develop AD in children from 2.56 to 4.26. In atopic compared to non-atopic mothers, 139 differentially expressed genes (DEGs) were identified significantly enriched of genes within the interferon signaling pathway. Expression quantitative trait methylation analyses dependent on maternal atopy identified 29 DEGs controlled by 136 trans-acting methylation marks, some located near transcription factors. Differential expression for the same nine genes, including MX1 and IFI6 within the interferon pathway, was identified in atopic and non-atopic mothers and high-risk and low-risk children., Conclusion: These data suggest that in utero epigenetic and transcriptomic mechanisms predominantly involving the interferon pathway may impact and predict the development of infant atopy., (© 2022 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Body composition measures, specifically low weight or reduced muscle mass, are associated with mortality in COPD, but the effect of longitudinal body composition changes is undefined., Research Question: Is the longitudinal loss of fat-free mass (FFM) associated with increased mortality, including in those with initially normal or elevated body composition metrics?, Study Design and Methods: Participants with complete data for at least one visit in the COPDGene study (n = 9,268) and the ECLIPSE study (n = 1,760) were included and monitored for 12 and 8 years, respectively. Pectoralis muscle area (PMA) was derived from thoracic CT scans and used as a proxy for FFM. A longitudinal mixed submodel for PMA and a Cox proportional hazards submodel for survival were fitted on a joint distribution, using a shared random intercept parameter and Markov chain Monte Carlo parameter estimation., Results: Both cohorts demonstrated a left-shifted distribution of baseline FFM, not reflected in BMI, and an increase in all-cause mortality risk associated with longitudinal loss of PMA. For each 1-cm 2 PMA loss, mortality increased 3.1% (95% CI, 2.4%-3.7%; P < .001) in COPDGene, and 2.4% (95% CI, 0.9%-4.0%; P < .001) in ECLIPSE. Increased mortality risk was independent of enrollment values for BMI and disease severity [BODE (body mass, airflow obstruction, dyspnea, and exercise capacity) index quartiles] and was significant even in participants with initially greater than average PMA., Interpretation: Longitudinal loss of PMA is associated with increased all-cause mortality, regardless of BMI or initial muscle mass. Consideration of novel screening tests and further research into mechanisms contributing to muscle decline may improve risk stratification and identify novel therapeutic targets in ever smokers., (Copyright © 2021 American College of Chest Physicians. All rights reserved.)

Background: Secondary school start times are associated with student sleep and daytime functioning; however, no study examining this association has included linked longitudinal data for both primary and secondary students. To understand the interplay between biology (ie, normal developmental changes in sleep) and ecology (ie, school start times), this study examined sleep and daytime functioning in elementary/primary and secondary school students over a three-year period that included changes to school start times., Methods: Students (grades 3-10, n = 6168) and parents (for student grades Kindergarten-2, n = 2772) completed annual surveys before (pre-change) and for two-years after (post-change, follow-up) implementation of new school start times (elementary/primary: 60 min earlier, secondary: 50-80 min later). Participants were 48.9% female, 65.5% White, and 16.2% qualified for free/reduced lunch., Results: With new school start times, significant changes were found for weekday wake times and sleep duration; elementary/primary students woke earlier (23 min) and obtained less sleep (14 min), while secondary students woke later (44 min) and obtained more sleep (31 min). Small changes in weekend sleep duration (<7 min) were found across levels. Secondary school students had significant improvements in daytime functioning post-change, due in part to changes in sleep duration. Minimal changes in elementary/primary students' daytime functioning was found, despite shorter sleep duration., Conclusions: School start times are a significant factor in weekday wake times for students across grade levels, while later bedtimes are more a factor of normal development. Later start times positively affected secondary students' daytime functioning, with non-significant findings for earlier elementary/primary start times., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Study Objectives: To examine the impact of changing school start times on sleep for primary (elementary school: ES) and secondary (middle and high school: MS/HS) students., Methods: Students (grades 3-12) and parents (grades K-12) were surveyed annually, before and for 2 years after school start time changes (ES: 60 min earlier, MS: 40-60 min later; HS: 70 min later). Student sleep and daytime sleepiness were measured with school-administered student surveys and parent-proxy online surveys., Results: Approximately 28,000 students annually completed surveys (~55% White, ~21% free/reduced lunch [FRL]). One-year post-change, weekday bedtimes and wake times were slightly earlier for ES students, with an 11-min decrease in sleep duration. MS and HS students reported slightly later weekday bedtimes, significantly later wake times, and significantly longer sleep duration (MS: 29 min; HS: 45 min). The percent of ES students reporting sufficient sleep duration, poor sleep quality, or daytime sleepiness did not change, but the percent of MS and HS students reporting sufficient sleep duration significantly increased and clinically significant daytime sleepiness decreased. All results were maintained at the 2-year follow-up. Benefits of later start times were similar across racial and free/reduced lunch groups., Conclusions: This is the first large scale, longitudinal, and representative study to concurrently examine the impact of changing school start times across students in primary/secondary school. Findings suggest a minimal impact of earlier start times on ES students' sleep or daytime sleepiness, while further supporting the significant benefits of delaying MS and HS start times on student sleep and daytime sleepiness., (© Sleep Research Society 2021. Published by Oxford University Press on behalf of the Sleep Research Society.)

Background: Eosinophilic granulomatosis with polyangiitis (EGPA), a rare vasculitis with substantial morbidity, is characterized by asthma, eosinophilia, sinusitis, pulmonary infiltrates, neuropathy, positivity for antineutrophil cytoplasmic antibody, and multiorgan vasculitis. Although treatment options previously included corticosteroids and immunosuppressants, anti-interleukin 5 therapies have gained interest in EGPA treatment. Mepolizumab was approved for and recently benralizumab was found to have safety and efficacy in EGPA., Objective: To determine the safety and efficacy of reslizumab in EGPA., Methods: In this open-label, pilot study, we evaluated the safety and efficacy of intravenous reslizumab (3 mg/kg) in EGPA in 10 subjects. Oral corticosteroid dose, adverse events, exacerbations, symptom control, disease activity, blood markers, and lung function were evaluated before, during, and after 7 monthly reslizumab treatments., Results: Reslizumab was tolerated and resulted in a significant reduction in daily oral corticosteroid (P < .05). Of the 10 subjects, 3 experienced an EGPA exacerbation during the treatment. One had a severe adverse event, requiring removal from the study., Conclusion: Yielding similar results to other anti-interleukin 5 biologic medications, reslizumab is generally a safe and effective treatment for EGPA that warrants further study., Trial Registration: ClinicalTrials.gov Identifier: NCT02947945., (Copyright © 2021 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Eosinophilic granulomatosis with polyangiitis (EGPA) is a vasculitis associated with significant morbidity and mortality that has historically been treated with systemic corticosteroids and immunosuppressants. The IL-5 antagonist mepolizumab was Food and Drug Administration approved in 2017 after demonstrating safety and efficacy in EGPA. We hypothesized that benralizumab, an IL-5 receptor antagonist approved for eosinophilic asthma, would demonstrate safety and efficacy in EGPA., Objectives: To determine the safety and efficacy of benralizumab in EGPA as measured by reduction in oral corticosteroid dose and EGPA exacerbations., Methods: We conducted a prospective 40-week open-label pilot study of benralizumab 30 mg administered subcutaneously in 10 patients with EGPA. Adverse events, oral corticosteroid dosing, exacerbations, and lung function were evaluated before, during, and after benralizumab treatment. Paired tests and tests derived from longitudinal models were used to compare outcome variables between phases or visits., Results: Benralizumab was well tolerated and resulted in reduction of median corticosteroid dose from 15 mg at the start to 2 mg at the end of treatment. Geometric mean corticosteroid dose was reduced from 11.6 mg during pretreatment to 6.3 mg during treatment phase. Five patients were able to achieve a dose of 0 mg. Mean annualized exacerbation rate was lowest during the treatment (1.5) compared with the pre- and posttreatment phases (4.6, P = .008 for treatment vs pre- and postphases combined)., Conclusions: Benralizumab was well tolerated, facilitated oral corticosteroid reduction, and reduced exacerbations in EGPA. Larger controlled trials are warranted to further evaluate the role of benralizumab in EGPA., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background The correlation between visual emphysema patterns and subsequent progression of disease may provide a way to enrich a study population for treatment trials of emphysema. Purpose To evaluate the potential relationship between emphysema visual subtypes and progression of emphysema and gas trapping. Materials and Methods Current and former smokers with and without chronic obstructive pulmonary disease (COPD) enrolled in the prospective Genetic Epidemiology of COPD (COPDGene) study (ClinicalTrials.gov identifier: NCT02445183) between 2008 and 2011 had their Fleischner Society visual CT scores assessed at baseline, quantitative inspiratory, and expiratory CT and at 5 years. They also underwent pulmonary function testing at baseline CT and at 5 years. The dependent variables were inspiratory lung density at 15th percentile (adjusted for lung volume) as a measure of emphysema and percentage of lung volume with attenuation less than -856 HU at expiratory CT as a measure of air trapping. Statistical analysis used a linear mixed model, adjusted for age, height, sex, race, smoking status, and scanner make. Results A total of 4166 participants (mean age, 60 years ± 9 [standard deviation]; 2091 [50%] men) were evaluated. In participants with COPD (1655 participants, 40%), those with visual presence of mild, moderate, and confluent emphysema at baseline CT showed a mean decline in lung density of 4.6 g/L ± 1.1 ( P < .001), 6.7 g/L ± 1.1 ( P < .001), and 6.4 g/L ± 1.2 ( P < .001), respectively, compared with 2.4 g/L ± 1.3 ( P < .001) for those with trace emphysema. For participants without COPD, those with visual presence of mild and moderate emphysema at baseline CT showed a mean decline in lung density of 3.6 g/L ± 1.0 ( P < .001) and 3.1 g/L ± 1.6 ( P < .001), respectively, compared with 1.8 g/L ± 1.0 ( P < .001) for those with trace emphysema. Conclusion The pattern of parenchymal emphysema at baseline CT was an independent predictor of subsequent progression of emphysema in participants who are current or former cigarette smokers with and without chronic obstructive pulmonary disease. © RSNA, 2020 Online supplemental material is available for this article.

Activation of the steroidogenic enzyme CYP11A1 was shown to be necessary for the development of peanut-induced intestinal anaphylaxis and IL-13 production in allergic mice. We determined if levels of CYP11A1 in peripheral blood T cells from peanut-allergic (PA) children compared to non-allergic controls were increased and if levels correlated to IL-13 production and oral challenge outcomes to peanut. CYP11A1 mRNA and protein levels were significantly increased in activated CD4+ T cells from PA patients. In parallel, IL-13 production was significantly increased; IFNγ levels were not different between groups. There were significant correlations between expression levels of CYP11A1 mRNA and levels of IL13 mRNA and protein, levels of serum IgE anti-Ara h 2 and to outcomes of peanut challenge. The importance of CYP11A1 on cytokine production was tested using a CYP11A1 CRISPR/Cas9 KO plasmid or an inhibitor of enzymatic CYP11A1 activity. Inhibition of CYP11A1 activation in patient cells treated with the inhibitor, aminoglutethimide, or CD4+ T cell line transfected with the CYP11A1 KO plasmid resulted in reduced IL-13 production. These data suggest that the CYP11A1-CD4+Tcell-IL-13 axis in activated CD4+ T cells from PA children is associated with development of PA reactions. CYP11A1 may represent a novel target for therapeutic intervention in PA children., Competing Interests: The authors have no conflicts of interest to declare.

BackgroundPattern of emphysema at chest CT, scored visually by using the Fleischner Society system, is associated with physiologic impairment and mortality risk.PurposeTo determine whether participant-level emphysema pattern could predict impairment and mortality when classified by using a deep learning method.Materials and MethodsThis retrospective analysis of Genetic Epidemiology of COPD (COPDGene) study participants enrolled between 2007 and 2011 included those with baseline CT, visual emphysema scores, and survival data through 2018. Participants were partitioned into nonoverlapping sets of 2407 for algorithm training, 100 for validation and parameter tuning, and 7143 for testing. A deep learning algorithm using convolutional neural network and long short-term memory architectures was trained to classify pattern of emphysema according to Fleischner criteria. Deep learning scores were compared with visual scores and clinical parameters including pulmonary function tests. Cox proportional hazard models were used to evaluate relationships between emphysema scores and survival. The algorithm was also tested by using CT and clinical data in 1962 participants enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) study.ResultsA total of 7143 COPDGene participants (mean age ± standard deviation, 59.8 years ± 8.9; 3734 men and 3409 women) were evaluated. Deep learning emphysema classifications were associated with impaired pulmonary function tests, 6-minute walk distance, and St George's Respiratory Questionnaire at univariate analysis ( P < .001 for each). Testing in the ECLIPSE cohort showed similar associations ( P < .001). In the COPDGene test cohort, deep learning emphysema classification improved the fit of linear mixed models in the prediction of these clinical parameters compared with visual scoring ( P < .001). Compared with participants without emphysema, mortality was greater in participants classified by the deep learning algorithm as having any grade of emphysema (adjusted hazard ratios were 1.5, 1.7, 2.9, 5.3, and 9.7, respectively, for trace, mild, moderate, confluent, and advanced destructive emphysema; P < .05).ConclusionDeep learning automation of the Fleischner grade of emphysema at chest CT is associated with clinical measures of pulmonary insufficiency and the risk of mortality.© RSNA, 2019 Online supplemental material is available for this article.

Rationale: Insufficient sleep is associated with a number of negative health outcomes; as most adolescents obtain <7 h of sleep per night, it is important to understand how sleep impacts asthma among adolescents., Objectives: To examine the impact of sleep opportunity on asthma in adolescents., Methods: In this study, 54 adolescents with asthma (12-17 years, 69% female, 65% Caucasian) participated in a randomized, cross-over sleep manipulation trial, including a sleep stabilization week, five nights of a "Short" sleep opportunity (time in bed: 6.5 h/night), and five nights of a "Long" sleep opportunity (time in bed: 9.5 h/night). Wake times were consistent across all three study weeks. Primary outcomes were lung function (daily peak expiratory flow rate, weekly spirometry) and functional asthma outcomes (daily asthma symptoms, Asthma Control Questionnaire, PROMIS Asthma Impact Scale). Markers of inflammation were also explored., Measurements and Main Results: Compared to the Long sleep week, during the Short sleep week, morning FEV1 was lower (p = 0.006), while asthma symptoms and albuterol use was higher (p < 0.05), and asthma showed a trend towards greater negative impact on daily life (p = 0.07). No differences were found for weekly measures of lung function or inflammation., Conclusions: An insufficient sleep opportunity negatively impacts objective and subjective daily symptoms of asthma in adolescents, as well as health related quality of life. As most adolescents are significantly sleep deprived, it is important to target sleep health in the treatment of asthma., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Chronic obstructive pulmonary disease (COPD) remains a major cause of morbidity and mortality. Present-day diagnostic criteria are largely based solely on spirometric criteria. Accumulating evidence has identified a substantial number of individuals without spirometric evidence of COPD who suffer from respiratory symptoms and/or increased morbidity and mortality. There is a clear need for an expanded definition of COPD that is linked to physiologic, structural (computed tomography [CT]) and clinical evidence of disease. Using data from the COPD Genetic Epidemiology study (COPDGene ® ), we hypothesized that an integrated approach that includes environmental exposure, clinical symptoms, chest CT imaging and spirometry better defines disease and captures the likelihood of progression of respiratory obstruction and mortality., Methods: Four key disease characteristics - environmental exposure (cigarette smoking), clinical symptoms (dyspnea and/or chronic bronchitis), chest CT imaging abnormalities (emphysema, gas trapping and/or airway wall thickening), and abnormal spirometry - were evaluated in a group of 8784 current and former smokers who were participants in COPDGene ® Phase 1. Using these 4 disease characteristics, 8 categories of participants were identified and evaluated for odds of spirometric disease progression (FEV 1 > 350 ml loss over 5 years), and the hazard ratio for all-cause mortality was examined., Results: Using smokers without symptoms, CT imaging abnormalities or airflow obstruction as the reference population, individuals were classified as Possible COPD, Probable COPD and Definite COPD. Current Global initiative for obstructive Lung Disease (GOLD) criteria would diagnose 4062 (46%) of the 8784 study participants with COPD. The proposed COPDGene ® 2019 diagnostic criteria would add an additional 3144 participants. Under the new criteria, 82% of the 8784 study participants would be diagnosed with Possible, Probable or Definite COPD. These COPD groups showed increased risk of disease progression and mortality. Mortality increased in patients as the number of their COPD characteristics increased, with a maximum hazard ratio for all cause-mortality of 5.18 (95% confidence interval [CI]: 4.15-6.48) in those with all 4 disease characteristics., Conclusions: A substantial portion of smokers with respiratory symptoms and imaging abnormalities do not manifest spirometric obstruction as defined by population normals. These individuals are at significant risk of death and spirometric disease progression. We propose to redefine the diagnosis of COPD through an integrated approach using environmental exposure, clinical symptoms, CT imaging and spirometric criteria. These expanded criteria offer the potential to stimulate both current and future interventions that could slow or halt disease progression in patients before disability or irreversible lung structural changes develop., Competing Interests: The COPDGene® study is funded by National Heart, Lung, and Blood Institute grants U01 HL089897 and U01 HL089856. The COPDGene® study (NCT00608764) is also supported by the COPD Foundation through contributions made to an Industry Advisory Committee comprised of AstraZeneca, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, Siemens, and Sunovion. While some individual authors of this manuscript were employed by one of the listed funders at the time the work of this study was conducted, these employment relationships did not constitute undue influence by funders. These funders have had no official role in the collection, management, analysis and interpretation of the data or design and conduct of the study. All authors have completed a Conflict of Interest form, disclosing any real or apparent financial relationships including receiving royalties, honoraria or fees for consulting, lectures, speakers’ bureaus, continuing education, medical advisory boards or expert testimony; receipt of grants; travel reimbursement; direct employment compensation. These disclosure forms have been filed with the Chronic Obstructive Pulmonary Diseases: Journal of the COPD Foundation Editorial Office and are available for review, upon request, at COPDC@njhealth.org., (JCOPDF © 2019.)

Cystic fibrosis (CF) is the most common life-shortening genetic disease and is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Several current therapies aim at improving availability and/or function of the mutant CFTR proteins. The combination therapeutic lumacaftor/ivacaftor (Orkambi, luma/iva) partially corrects folding and potentiates CFTR function impaired by the F508del mutation. Despite the potential for clinical benefit, a substantial number of patients discontinue treatment due to intolerable adverse effects. The aim of the present study is to identify differences between individuals who continued treatment and those who discontinued due to adverse respiratory effects to potentially inform treatment decisions. Clinical data from the year prior to treatment initiation were analyzed from 82 patients homozygous for the F508del mutation treated at the Colorado Adult CF Program. Blood samples were collected from 30 of these subjects before initiation of treatment to examine expression of circulating leukocyte surface antigens and cytokines. Clinical and demographic characteristics were analyzed along with inflammatory markers to determine biomarkers of drug discontinuation. The use of oral prednisone and/or nasal budesonide in the year prior to luma/iva initiation was more prevalent in CF subjects who did not tolerate luma/iva (82% vs. 43%). Increased age, but not gender or initial lung function, was associated with higher probability of discontinuing treatment due to side effects overall. Worse lung function (lower ppFEV1, ppFEF25-75 ≤ 60%) was associated with higher incidence of discontinuing treatment due to pulmonary adverse effects. In a nested cohort of patients, increased surface levels of CXCR2 on CD14+CD16- monocytes were associated with discontinuation. Overall, the patients who tolerated luma/iva were distinguishable from those who did not tolerate the drug based on clinical and cellular markers obtained prior to treatment initiation., Competing Interests: DPN has received grant funding from Vertex Pharmaceuticals. JLT has received grant funding from Vertex Pharmaceuticals, Gilead, Bayer, Proteostasis, and Novalis, reports personal fees from participation in advisory boards for Vertex Pharmaceuticals, Gilead, Novartis, Genentech and Proteostasis, and reports personal fees for speaking on behalf of Vertex Pharmaceuticals and Gilead. Commercial funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.

This paper describes a de-icing salt-frost scaling test method for analysis of the salt-frost scaling behaviour in high-performance concrete with various binders. The method was therefore designed to result in considerable scaling damage for the concrete considered to be salt-frost resistant. In addition, the experimental set-up was designed to avoid leakage, and to allow testing of a large number of samples. The method was validated by testing concrete with three different binders with a water-binder ratio of 0.40 with 5% air content. Various preconditioning procedures and freeze-thaw cycles were evaluated. The results show that the freeze-thaw cycle chosen results in a large mass of scaling and the salt-frost scaling behaviour agreed with the findings of previous studies. Thus, the method was considered suitable to study the salt-frost scaling behaviour in high-performance concrete. Three distinguishing features of the method are the following: •The freeze-thaw cycle result in a large mass of salt-frost scaling to enable study of high-performance concrete.•The concrete sample is above the salt solution to prevent leakage. The test surface is submerged 2 mm into the salt solution inside a cup.•Freezers with air as the thermal medium are used to allow a large number of samples.

Background: Previous investigations in adult smokers from the COPDGene Study have shown that early-life respiratory disease is associated with reduced lung function, COPD, and airway thickening. Using 5-year follow-up data, we assessed disease progression in subjects who had experienced early-life respiratory disease. We hypothesized that there are alternative pathways to reaching reduced FEV 1 and that subjects who had childhood pneumonia, childhood asthma, or asthma-COPD overlap (ACO) would have less lung function decline than subjects without these conditions., Methods: Subjects returning for 5-year follow-up were assessed. Childhood pneumonia was defined by self-reported pneumonia at < 16 years. Childhood asthma was defined as self-reported asthma diagnosed by a health professional at < 16 years. ACO was defined as subjects with COPD who self-reported asthma diagnosed by a health-professional at ≤ 40 years. Smokers with and those without these early-life respiratory diseases were compared on measures of disease progression., Results: Follow-up data from 4,915 subjects were examined, including 407 subjects who had childhood pneumonia, 323 subjects who had childhood asthma, and 242 subjects with ACO. History of childhood asthma or ACO was associated with an increased exacerbation frequency (childhood asthma, P < .001; ACO, P = .006) and odds of severe exacerbations (childhood asthma, OR, 1.41; ACO, OR, 1.42). History of childhood pneumonia was associated with increased exacerbations in subjects with COPD (absolute difference [β], 0.17; P = .04). None of these early-life respiratory diseases were associated with an increased rate of lung function decline or progression on CT scans., Conclusions: Subjects who had early-life asthma are at increased risk of developing COPD and of having more active disease with more frequent and severe respiratory exacerbations without an increased rate of lung function decline over a 5-year period., Trial Registry: ClinicalTrials.gov; No. NCT00608764; https://clinicaltrials.gov., (Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Prolonged cigarette smoking (CS) causes chronic obstructive pulmonary disease (COPD), a prevalent serious condition that may persist or progress after smoking cessation. To provide insight into how CS triggers COPD, we investigated temporal patterns of lung transcriptome expression and systemic metabolome changes induced by chronic CS exposure and smoking cessation. Whole lung RNA-seq data was analyzed at transcript and exon levels from C57Bl/6 mice exposed to CS for 1- or 7 days, for 3-, 6-, or 9 months, or for 6 months followed by 3 months of cessation using age-matched littermate controls. We identified previously unreported dysregulation of pyrimidine metabolism and phosphatidylinositol signaling pathways and confirmed alterations in glutathione metabolism and circadian gene pathways. Almost all dysregulated pathways demonstrated reversibility upon smoking cessation, except the lysosome pathway. Chronic CS exposure was significantly linked with alterations in pathways encoding for energy, phagocytosis, and DNA repair and triggered differential expression of genes or exons previously unreported to associate with CS or COPD, including Lox, involved in matrix remodeling, Gp2, linked to goblet cells, and Slc22a12 and Agpat3, involved in purine and glycerolipid metabolism, respectively. CS-induced lung metabolic pathways changes were validated using metabolomic profiles of matched plasma samples, indicating that dynamic metabolic gene regulation caused by CS is reflected in the plasma metabolome. Using advanced technologies, our study uncovered novel pathways and genes altered by chronic CS exposure, including those involved in pyrimidine metabolism, phosphatidylinositol signaling and lysosome function, highlighting their potential importance in the pathogenesis or diagnosis of CS-associated conditions.

Rationale: Acute exacerbations of chronic obstructive pulmonary disease (COPD) increase the risk of death and drive healthcare costs, but whether they accelerate loss of lung function remains controversial. Whether exacerbations in subjects with mild COPD or similar acute respiratory events in smokers without airflow obstruction affect lung function decline is unknown., Objectives: To determine the association between acute exacerbations of COPD (and acute respiratory events in smokers without COPD) and the change in lung function over 5 years of follow-up., Methods: We examined data on the first 2,000 subjects who returned for a second COPDGene visit 5 years after enrollment. Baseline data included demographics, smoking history, and computed tomography emphysema. We defined exacerbations (and acute respiratory events in those without established COPD) as acute respiratory symptoms requiring either antibiotics or systemic steroids, and severe events by the need for hospitalization. Throughout the 5-year follow-up period, we collected self-reported acute respiratory event data at 6-month intervals. We used linear mixed models to fit FEV 1 decline based on reported exacerbations or acute respiratory events., Measurements and Main Results: In subjects with COPD, exacerbations were associated with excess FEV 1 decline, with the greatest effect in Global Initiative for Chronic Obstructive Lung Disease stage 1, where each exacerbation was associated with an additional 23 ml/yr decline (95% confidence interval, 2-44; P = 0.03), and each severe exacerbation with an additional 87 ml/yr decline (95% confidence interval, 23-151; P = 0.008); statistically significant but smaller effects were observed in Global Initiative for Chronic Obstructive Lung Disease stage 2 and 3 subjects. In subjects without airflow obstruction, acute respiratory events were not associated with additional FEV 1 decline., Conclusions: Exacerbations are associated with accelerated lung function loss in subjects with established COPD, particularly those with mild disease. Trials are needed to test existing and novel therapies in subjects with early/mild COPD to potentially reduce the risk of progressing to more advanced lung disease. Clinical trial registered with www.clinicaltrials.gov (NCT 00608764).

Rationale: The small conducting airways are the major site of airflow obstruction in chronic obstructive pulmonary disease and may precede emphysema development., Objectives: We hypothesized a novel computed tomography (CT) biomarker of small airway disease predicts FEV1 decline., Methods: We analyzed 1,508 current and former smokers from COPDGene with linear regression to assess predictors of change in FEV1 (ml/yr) over 5 years. Separate models for subjects without and with airflow obstruction were generated using baseline clinical and physiologic predictors in addition to two novel CT metrics created by parametric response mapping (PRM), a technique pairing inspiratory and expiratory CT images to define emphysema (PRM(emph)) and functional small airways disease (PRM(fSAD)), a measure of nonemphysematous air trapping., Measurements and Main Results: Mean (SD) rate of FEV1 decline in ml/yr for GOLD (Global Initiative for Chronic Obstructive Lung Disease) 0-4 was as follows: 41.8 (47.7), 53.8 (57.1), 45.6 (61.1), 31.6 (43.6), and 5.1 (35.8), respectively (trend test for grades 1-4; P < 0.001). In multivariable linear regression, for participants without airflow obstruction, PRM(fSAD) but not PRM(emph) was associated with FEV1 decline (P < 0.001). In GOLD 1-4 participants, both PRM(fSAD) and PRM(emph) were associated with FEV1 decline (P < 0.001 and P = 0.001, respectively). Based on the model, the proportional contribution of the two CT metrics to FEV1 decline, relative to each other, was 87% versus 13% and 68% versus 32% for PRM(fSAD) and PRM(emph) in GOLD 1/2 and 3/4, respectively., Conclusions: CT-assessed functional small airway disease and emphysema are associated with FEV1 decline, but the association with functional small airway disease has greatest importance in mild-to-moderate stage chronic obstructive pulmonary disease where the rate of FEV1 decline is the greatest. Clinical trial registered with www.clinicaltrials.gov (NCT 00608764).

Background: Medical treatment for multidrug-resistant (MDR)-tuberculosis is complex, toxic, and associated with poor outcomes. Surgical lung resection may be used as an adjunct to medical therapy, with the intent of reducing bacterial burden and improving cure rates. We conducted an individual patient data metaanalysis to evaluate the effectiveness of surgery as adjunctive therapy for MDR-tuberculosis., Methods: Individual patient data, was obtained from the authors of 26 cohort studies, identified from 3 systematic reviews of MDR-tuberculosis treatment. Data included the clinical characteristics and medical and surgical therapy of each patient. Primary analyses compared treatment success (cure and completion) to a combined outcome of failure, relapse, or death. The effects of all forms of resection surgery, pneumonectomy, and partial lung resection were evaluated., Results: A total of 4238 patients from 18 surgical studies and 2193 patients from 8 nonsurgical studies were included. Pulmonary resection surgery was performed on 478 patients. Partial lung resection surgery was associated with improved treatment success (adjusted odds ratio [aOR], 3.0; 95% confidence interval [CI], 1.5-5.9; I(2)R, 11.8%), but pneumonectomy was not (aOR, 1.1; 95% CI, .6-2.3; I(2)R, 13.2%). Treatment success was more likely when surgery was performed after culture conversion than before conversion (aOR, 2.6; 95% CI, 0.9-7.1; I(2)R, 0.2%)., Conclusions: Partial lung resection, but not pneumonectomy, was associated with improved treatment success among patients with MDR-tuberculosis. Although improved outcomes may reflect patient selection, partial lung resection surgery after culture conversion may improve treatment outcomes in patients who receive optimal medical therapy., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

The geographic overlap between the prevalence of cigarette smoke (CS) exposure and tuberculosis (TB) in the world is striking. In recent years, relatively large number of studies has linked cigarette or biomass fuel smoke exposure and various aspects of TB. Our goals are to summarize the significance of the known published studies, graphically represent reports that quantified the association and discuss their potential limitations. PubMed searches were performed using the key words 'tuberculosis' with 'cigarette', 'tobacco', 'smoke' or 'biomass fuel smoke.' The references of relevant articles were examined for additional pertinent papers. A large number of mostly case-control and cross-sectional studies significantly associate both direct and second-hand smoke exposure with tuberculous infection, active TB, and/or more severe and lethal TB. Fewer link biomass fuel smoke exposure and TB. While a number of studies interpreted the association with multivariate analysis, other confounders are often not accounted for in these analyses. It is also important to emphasize that these retrospective studies can only show an association and not any causal link. We further explored the possibility that even if CS exposure is a risk factor for TB, several mechanisms may be responsible. Numerous studies associate cigarette and biomass smoke exposure with TB but the mechanism(s) remains largely unknown. While the associative link of these two health maladies is well established, more definitive, mechanistic studies are needed to cement the effect of smoke exposure on TB pathogenesis and to utilize this knowledge in empowering public health policies., (© 2015 Asian Pacific Society of Respirology.)

Background: The usual interstitial pneumonia (UIP) pattern of lung injury may occur in the setting of connective tissue disease (CTD), but it is most commonly found in the absence of a known cause, in the clinical context of idiopathic pulmonary fibrosis (IPF). Our objective was to observe and compare longitudinal changes in pulmonary function and survival between patients with biopsy-proven UIP found in the clinical context of either CTD or IPF., Methods: We used longitudinal data analytic models to compare groups (IPF [n = 321] and CTD-UIP [n = 56]) on % predicted FVC (FVC %) or % predicted diffusing capacity of the lung for carbon monoxide (Dlco %), and we used both unadjusted and multivariable techniques to compare survival between these groups., Results: There were no significant differences between groups in longitudinal changes in FVC % or Dlco % up to diagnosis, or from diagnosis to 10 years beyond (over which time, the mean decrease in FVC % per year [95% CI] was 4.1 [3.4, 4.9] for IPF and 3.5 [1.8, 5.1] for CTD-UIP, P = .49 for difference; and the mean decrease in Dlco % per year was 4.7 [4.0, 5.3] for IPF and 4.3 [3.0, 5.6] for CTD-UIP, P = .60 for difference). Despite the lack of differences in pulmonary function, subjects with IPF had worse survival in unadjusted (log-rank P = .003) and certain multivariable analyses., Conclusions: Despite no significant differences in changes in pulmonary function over time, patients with CTD-UIP (at least those with certain classifiable CTDs) live longer than patients with IPF--an observation that we suspect is due to an increased rate of mortal acute exacerbations in patients with IPF.

Nuclear factor-kappa B (NFκB) is a ubiquitous transcription factor that mediates pro-inflammatory responses required for host control of many microbial pathogens; on the other hand, NFκB has been implicated in the pathogenesis of other inflammatory and infectious diseases. Mice with genetic disruption of the p50 subunit of NFκB are more likely to succumb to Mycobacterium tuberculosis (MTB). However, the role of NFκB in host defense in humans is not fully understood. We sought to examine the role of NFκB activation in the immune response of human macrophages to MTB. Targeted pharmacologic inhibition of NFκB activation using BAY 11-7082 (BAY, an inhibitor of IκBα kinase) or an adenovirus construct with a dominant-negative IκBα significantly decreased the number of viable intracellular mycobacteria recovered from THP-1 macrophages four and eight days after infection. The results with BAY were confirmed in primary human monocyte-derived macrophages and alveolar macrophages. NFκB inhibition was associated with increased macrophage apoptosis and autophagy, which are well-established killing mechanisms of intracellular MTB. Inhibition of the executioner protease caspase-3 or of the autophagic pathway significantly abrogated the effects of BAY. We conclude that NFκB inhibition decreases viability of intracellular MTB in human macrophages via induction of apoptosis and autophagy.

Background: Treatment of multidrug resistant tuberculosis (MDR-TB) is lengthy, toxic, expensive, and has generally poor outcomes. We undertook an individual patient data meta-analysis to assess the impact on outcomes of the type, number, and duration of drugs used to treat MDR-TB., Methods and Findings: Three recent systematic reviews were used to identify studies reporting treatment outcomes of microbiologically confirmed MDR-TB. Study authors were contacted to solicit individual patient data including clinical characteristics, treatment given, and outcomes. Random effects multivariable logistic meta-regression was used to estimate adjusted odds of treatment success. Adequate treatment and outcome data were provided for 9,153 patients with MDR-TB from 32 observational studies. Treatment success, compared to failure/relapse, was associated with use of: later generation quinolones, (adjusted odds ratio [aOR]: 2.5 [95% CI 1.1-6.0]), ofloxacin (aOR: 2.5 [1.6-3.9]), ethionamide or prothionamide (aOR: 1.7 [1.3-2.3]), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.3 [1.3-3.9]), and three or more likely effective drugs in the continuation phase (aOR: 2.7 [1.7-4.1]). Similar results were seen for the association of treatment success compared to failure/relapse or death: later generation quinolones, (aOR: 2.7 [1.7-4.3]), ofloxacin (aOR: 2.3 [1.3-3.8]), ethionamide or prothionamide (aOR: 1.7 [1.4-2.1]), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.7 [1.9-3.9]), and three or more likely effective drugs in the continuation phase (aOR: 4.5 [3.4-6.0])., Conclusions: In this individual patient data meta-analysis of observational data, improved MDR-TB treatment success and survival were associated with use of certain fluoroquinolones, ethionamide, or prothionamide, and greater total number of effective drugs. However, randomized trials are urgently needed to optimize MDR-TB treatment. Please see later in the article for the Editors' Summary.

Multidrug-resistant tuberculosis (TB) strains resistant to the fluoroquinolones and streptomycin but susceptible to second-line injection treatment would not be defined as extensively drug-resistant TB. In a cohort of 174 patients with multidrug-resistant TB, we demonstrated that 12 patients with multidrug-resistant TB strains resistant to the fluoroquinolones and streptomycin had significantly better initial and long-term outcomes, compared with 10 patients with extensively drug-resistant TB.

Using exact, analytic results for the average power of the Benjamini-Hochberg (1995) procedure, we provide example power analyses useful for scientists planning studies involving multiple comparisons. The power results are based on the distribution of the p-value under the alternative for the Pearson's χ 2 , and for the Hotelling-Lawley trace, the Wilks' lambda, and the Pillai-Bartlett trace, all tests for the general linear multivariate model. Detailed example power analyses are given for a planned mammography experiment with categorical data and a study that tests the association of a single nucleotide polymorphism with insulin resistance and visceral adiposity.

Chronic inflammatory diseases often have residual CD8(+) T-cell infiltration despite treatment with systemic corticosteroids, which suggests divergent steroid responses between CD4(+) and CD8(+) cells. To examine steroid sensitivity, dexamethasone (DEX)-induced histone H4 lysine 5 (K5) acetylation and glucocorticoid receptor alpha (GCR alpha) translocation were evaluated. DEX treatment for 6 hours significantly induced histone H4 K5 acetylation in normal CD4(+) cells (P = .001) but not in CD8(+) cells. DEX responses were functionally impaired in CD8(+) compared with CD4(+) cells when using mitogen-activated protein kinase phosphatase (1 hour; P = .02) and interleukin 10 mRNA (24 hours; P = .004) induction as a readout of steroid-induced transactivation. Normal DEX-induced GCR alpha nuclear translocation and no significant difference in GCR alpha and GCR beta mRNA expression were observed in both T-cell types. In addition, no significant difference in SRC-1, p300, or TIP60 expression was found. However, activating transcription factor-2 (ATF2) expression was significantly lower in CD8(+) compared with CD4(+) cells (P = .009). Importantly, inhibition of ATF2 expression by small interfering RNA in CD4(+) cells resulted in inhibition of DEX-induced transactivation in CD4(+) cells. The data indicate refractory steroid-induced transactivation but similar steroid-induced transrepression of CD8(+) cells compared with CD4(+) cells caused by decreased levels of the histone acetyltransferase ATF2.

Rapidly growing mycobacteria (RGM) are ubiquitous in the environment but cause lung disease in only a fraction of exposed individuals. This variable susceptibility to disease implies vulnerability to RGM infection due to weakness in host defense. Since most persons who contract RGM lung disease have no known host defense defect, it is likely that uncharacterized host deficiencies exist that predispose to RGM infection. Alpha-1-antitrypsin (AAT) is a host factor that may protect individuals from respiratory infections. Therefore, we assessed AAT protein anomalies as a risk factor for RGM lung disease. In a cohort of 100 patients with RGM lung disease, Mycobacterium (M.) abscessus was the most prevalent organism, isolated in 64 (64%) subjects. Anomalous AAT proteins were present in 27% of the cohort, which is 1.6 times the estimated prevalence of anomalous AAT proteins in the United States population (p=0.008). In in vitro studies, both AAT and a synthetic inhibitor of serine proteases suppressed M. abscessus infection of monocyte-derived macrophages by up to 65% (p<0.01). AAT may be an anti-RGM host-defense factor, and anomalous AAT phenotypes or AAT deficiency may constitute risk factors for pulmonary disease due to RGM.

Ten dialysis patients were followed in a prospective study to determine the neurotoxicity of metabolites in the middle molecule (MM) molecular weight (mol wt) range of 500-200 daltons/molecule. In the absence of readily available direct serum measurements of MM concentrations, a theoretically calculated dialysis index, D1(MM), which included the combined effects of dialysis and residual glomerular filtration rate (GFR) on MM removal was used to estimate changes in their predialysis concentrations. The ten patients were dialyzed on protocols which yielded a D1(MM) less than 1.0. Evidence of uremic neuropathy developed in six of these ten patients, and five of these six also developed a progression in their anemia. Two additional patients with no signs of neuropathy developed a progression in their anemia. One patient developed pericarditis with tamponade. A total of eight patients developed complications. One additional patient developed increased weakness, tiredness and general malaise without change in objective findings. When the dialysis therapy to reduce MM concentrations by increasing the D1(MM) above 1.0 was instituted, the complications were reversed. Our data support the findings of others, namely, that there are toxic substances in the MM mol wt range of 500-2000 daltons/molecule. However, a synergism between elevated concentrations of small molecules and MM cannot be ruled out.