Genomic epidemiology of Mycobacterium abscessus at an adult cystic fibrosis programme reveals low potential for healthcare-associated transmission.

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.

Clinical factors associated with racial differences in the prevalence of occult hypoxemia: a retrospective case-control study.

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.

Deep Learning Classification of Usual Interstitial Pneumonia Predicts Outcomes.

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.

FEV1/FVC Severity Stages for Chronic Obstructive Pulmonary Disease.

Rationale: The diagnosis of chronic obstructive pulmonary disease (COPD) is based on a low FEV1/FVC ratio, but the severity of COPD is classified using FEV1% predicted (ppFEV1). Objectives: To test a new severity classification scheme for COPD using FEV1/FVC ratio, a more robust measure of airflow obstruction than ppFEV1. 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 (ppFEV1 of ⩾80%, ⩾50-80%, ⩾30-50%, and <30%). A new severity classification (STaging of Airflow obstruction by Ratio; STAR) was tested in COPDGene-FEV1/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 FEV1/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 ppFEV1, and is less sensitive to race/ethnicity and other demographic characteristics.

Molecular Epidemiologic Investigation of Mycobacterium intracellulare Subspecies chimaera Lung Infections at an Adult Cystic Fibrosis Program.

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.

Molecular networks in atopic mothers impact the risk of infant atopy.

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.

Biology vs. ecology: a longitudinal examination of sleep, development, and a change in school start times.

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.

Longitudinal Association Between Muscle Loss and Mortality in Ever Smokers.

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-cm2 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.

Changing school start times: impact on sleep in primary and secondary school students.

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.

Efficacy and safety of reslizumab in the treatment of eosinophilic granulomatosis with polyangiitis.

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.

Benralizumab as a Steroid-Sparing Treatment Option in Eosinophilic Granulomatosis with Polyangiitis.

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.

Fleischner Society Visual Emphysema CT Patterns Help Predict Progression of Emphysema in Current and Former Smokers: Results from the COPDGene Study.

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.

Expression and activation of the steroidogenic enzyme CYP11A1 is associated with IL-13 production in T cells from peanut allergic children.

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.

Deep Learning Enables Automatic Classification of Emphysema Pattern at CT.

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, 2019Online supplemental material is available for this article.

Impact of sleep opportunity on asthma outcomes in adolescents.

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.

Corticosteroid use and increased CXCR2 levels on leukocytes are associated with lumacaftor/ivacaftor discontinuation in cystic fibrosis patients homozygous for the F508del CFTR mutation.

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.