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Context: No consensus exists for adjusting inhaled corticosteroid therapy in patients with asthma. Approaches include adjustment at outpatient visits guided by physician assessment of asthma control (symptoms, rescue therapy, pulmonary function), based on exhaled nitric oxide, or on a day-to-day basis guided by symptoms.Objective: To determine if adjustment of inhaled corticosteroid therapy based on exhaled nitric oxide or day-to-day symptoms is superior to guideline-informed, physician assessment-based adjustment in preventing treatment failure in adults with mild to moderate asthma.Design, Setting, and Participants: A randomized, parallel, 3-group, placebo-controlled, multiply-blinded trial of 342 adults with mild to moderate asthma controlled by low-dose inhaled corticosteroid therapy (n = 114 assigned to physician assessment-based adjustment [101 completed], n = 115 to biomarker-based [exhaled nitric oxide] adjustment [92 completed], and n = 113 to symptom-based adjustment [97 completed]), the Best Adjustment Strategy for Asthma in the Long Term (BASALT) trial was conducted by the Asthma Clinical Research Network at 10 academic medical centers in the United States for 9 months between June 2007 and July 2010.Interventions: For physician assessment-based adjustment and biomarker-based (exhaled nitric oxide) adjustment, the dose of inhaled corticosteroids was adjusted every 6 weeks; for symptom-based adjustment, inhaled corticosteroids were taken with each albuterol rescue use.Main Outcome Measure: The primary outcome was time to treatment failure.Results: There were no significant differences in time to treatment failure. The 9-month Kaplan-Meier failure rates were 22% (97.5% CI, 14%-33%; 24 events) for physician assessment-based adjustment, 20% (97.5% CI, 13%-30%; 21 events) for biomarker-based adjustment, and 15% (97.5% CI, 9%-25%; 16 events) for symptom-based adjustment. The hazard ratio for physician assessment-based adjustment vs biomarker-based adjustment was 1.2 (97.5% CI, 0.6-2.3). The hazard ratio for physician assessment-based adjustment vs symptom-based adjustment was 1.6 (97.5% CI, 0.8-3.3).Conclusion: Among adults with mild to moderate persistent asthma controlled with low-dose inhaled corticosteroid therapy, the use of either biomarker-based or symptom-based adjustment of inhaled corticosteroids was not superior to physician assessment-based adjustment of inhaled corticosteroids in time to treatment failure.Trial Registration: clinicaltrials.gov Identifier: NCT00495157. [ABSTRACT FROM AUTHOR]

Background: Although guidelines recommend daily therapy for patients with mild persistent asthma, prescription patterns suggest that most such patients use these so-called controller therapies intermittently. In patients with mild persistent asthma, we evaluated the efficacy of intermittent short-course corticosteroid treatment guided by a symptom-based action plan alone or in addition to daily treatment with either inhaled budesonide or oral zafirlukast over a one-year period.Methods: In a double-blind trial, 225 adults underwent randomization. The primary outcome was morning peak expiratory flow (PEF). Other outcomes included the forced expiratory volume in one second (FEV1) before and after bronchodilator treatment, the frequency of exacerbations, the degree of asthma control, the number of symptom-free days, and the quality of life.Results: The three treatments produced similar increases in morning PEF (7.1 to 8.3 percent; approximately 32 liters per minute; P=0.90) and similar rates of asthma exacerbations (P=0.24), even though the intermittent-treatment group took budesonide, on average, for only 0.5 week of the year. As compared with intermittent therapy or daily zafirlukast therapy, daily budesonide therapy produced greater improvements in pre-bronchodilator FEV1 (P=0.005), bronchial reactivity (P<0.001), the percentage of eosinophils in sputum (P=0.007), exhaled nitric oxide levels (P=0.006), scores for asthma control (P<0.001), and the number of symptom-free days (P=0.03), but not in post-bronchodilator FEV1 (P=0.29) or in the quality of life (P=0.18). Daily zafirlukast therapy did not differ significantly from intermittent treatment in any outcome measured.Conclusions: It may be possible to treat mild persistent asthma with short, intermittent courses of inhaled or oral corticosteroids taken when symptoms worsen. Further studies are required to determine whether this novel approach to treatment should be recommended. [ABSTRACT FROM AUTHOR]

Introduction: Olfactory dysfunction (OD) is common among people with cystic fibrosis (PwCF). The Questionnaire of Olfactory Disorders (QOD) is a validated instrument that evaluates olfactory-specific quality-of-life. The QOD minimal clinically important difference (MCID) and factors associated with olfactory improvement after elexacaftor/tezacaftor/ivacaftor have not been determined for PwCF., Methods: Prospective observational data were pooled from three studies that enrolled adult PwCF with chronic rhinosinusitis (CRS). QOD scores and disease characteristics were assessed. To evaluate internal consistency and calculate the QOD MCID, Cronbach's alpha and four distribution-based methods were employed. For participants who enrolled prior to elexacaftor/tezacaftor/ivacaftor, QOD scores were obtained at baseline and after elexacaftor/tezacaftor/ivacaftor initiation. Multivariable regression was used to identify factors associated with QOD improvement., Results: Of 129 PwCF included, 65 had QOD scores before and 3-6 months after starting elexacaftor/tezacaftor/ivacaftor. Mean baseline QOD score was 6.5 ± 7.9. Mean Cronbach's alpha was ≥0.85. The MCID estimates were as follows: Cohen's effect size = 1.6, standard error of measurement = 2.5, ½ baseline standard deviation = 4.0, and minimal detectable change = 6.9. Mean MCID was 3.7. Of those with pre/post elexacaftor/tezacaftor/ivacaftor QOD scores, the mean change in QOD was -1.3 ± 5.4. After elexacaftor/tezacaftor/ivacaftor, QOD improvement surpassed the MCID in 22% of participants (14/65). Worse baseline QOD scores and nasal polyps were associated with improved QOD scores after elexacaftor/tezacaftor/ivacaftor (both p < 0.04)., Conclusion: The QOD MCID in PwCF was estimated to be 3.7. Elexacaftor/tezacaftor/ivacaftor led to qualitative but not clinically meaningful improvements in QOD score for most PwCF; PwCF with worse baseline QOD scores and nasal polyps improved in a clinically significant manner., (© 2023 ARS‐AAOA, LLC.)

Background: Peripherally inserted central catheters (PICCs) are used commonly to administer antibiotics to people with cystic fibrosis (CF), but their use can be complicated by venous thrombosis and catheter occlusion., Research Question: Which participant-, catheter-, and catheter management-level attributes are associated with increased risk of complications of PICCs among people with CF?, Study Design and Methods: This was a prospective observational study of adults and children with CF who received PICCs at 10 CF care centers in the United States. The primary end point was defined as occlusion of the catheter resulting in unplanned removal, symptomatic venous thrombosis in the extremity containing the catheter, or both. Three categories of composite secondary outcomes were identified: difficult line placement, local soft tissue or skin reactions, and catheter malfunction. Data specific to the participant, catheter placement, and catheter management were collected in a centralized database. Risk factors for primary and secondary outcomes were analyzed by multivariate logistic regression., Results: Between June 2018 and July 2021, 157 adults and 103 children older than 6 years with CF had 375 PICCs placed. Patients underwent 4,828 catheter-days of observation. Of the 375 PICCs, 334 (89%) were ≤ 4.5 F, 342 (91%) were single lumen, and 366 (98%) were placed using ultrasound guidance. The primary outcome occurred in 15 PICCs for an event rate of 3.11 per 1,000 catheter-days. No cases of catheter-related bloodstream infection occurred. Other secondary outcomes developed in 147 of 375 catheters (39%). Despite evidence of practice variation, no risk factors for the primary outcome and few risk factors for secondary outcomes were identified., Interpretation: This study affirmed the safety of contemporary approaches to inserting and using PICCs in people with CF. Given the low rate of complications in this study, observations may reflect a widespread shift to selecting smaller-diameter PICCs and using ultrasound to guide their placement., Competing Interests: Financial/Nonfinancial Disclosures None declared., (Copyright © 2023 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Adults with cystic fibrosis (CF) are at increased risk for colon cancer. CF patients have reductions in intestinal bacteria that produce short chain fatty acids (SCFAs), although it is unclear whether this corresponds with intestinal SCFA levels and the presence of colonic neoplasia. The aim of this study was to compare gut microbiome and SCFA composition in patients with and without CF, and to assess associations with colonic adenomas., Methods: Colonic aspirates were obtained from adults with and without CF undergoing colon cancer screening or surveillance colonoscopy. Microbiome characterization was performed by 16S rRNA V3-V4 sequencing. Targeted profiling of SCFAs and related metabolites was performed by LC-MS., Results: 42 patients (21 CF, 21 control) were enrolled. CF patients had significantly reduced alpha diversity and decreased relative abundance of many SCFA-producing taxa. There were no significant differences in SCFA levels in CF patients, although there were reduced levels of branched chain fatty acids (BCFAs) and related metabolites. CF patients with adenomas, but not controls with adenomas, had significantly increased relative abundance of Bacteroides fragilis. CF microbiome composition was significantly associated with isovalerate concentration and the presence of adenomas., Conclusions: CF patients have marked disturbances in the gut microbiome, and CF patients with adenomas had notably increased relative abundance of B. fragilis, a pathogen known to promote colon cancer. Reductions in BCFAs but not SCFAs were found in CF. Further studies are warranted to evaluate the role of B. fragilis as well the biological significance of reductions in BCFAs in CF., Competing Interests: Declaration of Competing Interest There are no conflicts of interest to report for all authors., (Copyright © 2023. Published by Elsevier B.V.)

Objective: To characterize current trends and outcomes in pregnancies complicated by cystic fibrosis (CF) that resulted in delivery., Methods: This repeated cross-sectional study used the U.S. National Inpatient Sample to identify delivery hospitalizations of patients with CF between 2000 and 2019. Trends in delivery hospitalizations of patients with CF were assessed using joinpoint regression to determine the average annual percent change (AAPC). The risk of adverse maternal and obstetric outcomes was compared between patients with and without CF using adjusted logistic regression models accounting for demographic, clinical, and hospital characteristics, with adjusted odds ratios (aORs) with 95% CIs as measures of association. The proportion of patients with CF and other chronic conditions such as pregestational diabetes was analyzed over time., Results: From 2000 to 2019, the prevalence of CF at delivery increased from 2.1 to 10.4 per 100,000 deliveries (AAPC 6.7%, 95% CI 5.7-8.2%). The proportion of patients with CF and other chronic conditions increased from 18.0% to 37.3% (AAPC 3.1%, 95% CI 1.0-5.3%). Patients with CF were more likely to experience severe maternal morbidity (aOR 2.61, 95% CI 1.71-3.97), respiratory complications (aOR 17.45, 95% CI 11.85-25.68), venous thromboembolism (aOR 3.59, 95% CI 1.33-9.69), preterm delivery (aOR 2.15, 95% CI 1.79-2.59), abruption and antepartum hemorrhage (aOR 1.63, 95% CI 1.10-2.41), and gestational diabetes (aOR 2.47, 95% CI 2.47-3.70)., Conclusion: Although still infrequent (approximately 1 in 10,000), deliveries complicated by CF increased approximately fivefold over the study period. The proportion of patients with CF and other chronic conditions is increasing. Patients with CF are at increased risk for a broad range of adverse outcomes., Competing Interests: Financial Disclosure : Mary D'Alton had a senior leadership role in ACOG II's Safe Motherhood Initiative, which received unrestricted funding from Merck for Mothers. Timothy Wen serves as a consultant on the medical advisory board for Delfina Care Inc. The other authors did not report any potential conflicts of interest., (Copyright © 2022 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Asthma is a heterogeneous disease, with multiple underlying inflammatory pathways and structural airway abnormalities that impact disease persistence and severity. Recent progress has been made in developing targeted asthma therapeutics, especially for subjects with eosinophilic asthma. However, there is an unmet need for new approaches to treat patients with severe and exacerbation-prone asthma, who contribute disproportionately to disease burden. Extensive deep phenotyping has revealed the heterogeneous nature of severe asthma and identified distinct disease subtypes. A current challenge in the field is to translate new and emerging knowledge about different pathobiologic mechanisms in asthma into patient-specific therapies, with the ultimate goal of modifying the natural history of disease. Here, we describe the Precision Interventions for Severe and/or Exacerbation-Prone Asthma (PrecISE) Network, a groundbreaking collaborative effort of asthma researchers and biostatisticians from around the United States. The PrecISE Network was designed to conduct phase II/proof-of-concept clinical trials of precision interventions in the population with severe asthma, and is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Using an innovative adaptive platform trial design, the PrecISE Network will evaluate up to 6 interventions simultaneously in biomarker-defined subgroups of subjects. We review the development and organizational structure of the PrecISE Network, and choice of interventions being studied. We hope that the PrecISE Network will enhance our understanding of asthma subtypes and accelerate the development of therapeutics for severe asthma., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To characterize asthma prevalence and outcomes during U.S. delivery hospitalizations., Methods: For this repeated cross-sectional analysis, deliveries to women aged 15-54 years with asthma were identified in the 2000-2018 National Inpatient Sample, which approximates a 20% stratified sample of all hospitalizations nationally. Temporal trends in asthma were analyzed using joinpoint regression to estimate the average annual percent change with 95% CIs. The association of asthma with other comorbid conditions was analyzed. The relationship between asthma and several adverse maternal outcomes was analyzed with unadjusted and adjusted logistic regression models, with unadjusted odds ratios and adjusted odds ratios (aORs) as measures of effect. Risk for and trends in a composite of rare, but severe, respiratory complications also were analyzed., Results: An estimated 73,109,790 delivery hospitalizations from 2000 to 2018 were included in the analysis, of which 2,221,644 (3.0%) had a diagnosis of asthma. (Unweighted, the study sample included 15,213,024 deliveries, of which 462,276 [3.0%] had a diagnosis of asthma.) Asthma diagnoses rose from 1.2% in 2000 to 5.3% in 2018, representing an average annual percent change of 8.3% (95% CI 7.4-9.2%). Asthma was more common among women with obesity and chronic hypertension. In adjusted analyses, asthma was associated with severe maternal morbidity (aOR 1.50, 95% CI 1.45-1.55), preeclampsia and gestational hypertension (aOR 1.29, 95% CI 1.26-1.30), postpartum hemorrhage (aOR 1.21, 95% CI 1.19-1.24), cesarean delivery (aOR 1.16, 95% CI 1.15-1.18), gestational diabetes (aOR 1.20, 95% CI 1.18-1.21), venous thromboembolism (aOR 1.79, 95% CI 1.65-1.95), and preterm delivery (aOR 1.27, 95% CI 1.25-1.29). From 2000 to 2018, severe respiratory complications decreased from 72 per 10,000 deliveries with asthma to 14 per 10,000 deliveries with asthma (average annual percent change -9.4%, 95% CI -13.3% to -5.3%). This decreasing risk was offset on a population level by an increase in the risk of asthma., Conclusion: Asthma is increasing during deliveries, is associated with adverse maternal outcomes, and is associated with comorbid conditions. Severe respiratory complications are decreasing proportionately among deliveries with asthma, but are stable on a population basis., Competing Interests: Financial Disclosure Dr. D'Alton had a senior leadership role in ACOG II's Safe Motherhood Initiative, which received unrestricted funding from Merck for Mothers. Dr. Wright disclosed that he received royalties from UpToDate for writing/review of chapters related to cervical dysplasia, human papillomavirus, and cervical cancer. He served as a consultant for Clovis Oncology and participated in their advisory board (March 2019). He performed medicolegal review of malpractice cases related to delayed diagnosis of gynecologic cancer and intraoperative complications during gynecologic surgery. He is currently serving on the SGO Board of Directors (no monetary compensation) from 2019 to 2022. He conducted epidemiologic research trials examining patterns of care for ovarian, uterine, and cervical cancer for Merck. Lastly, he has also performed analysis of and provided education on clinical trials data for Otsuka Pharmacovigilance. The other authors did not report any potential conflicts of interest., (Copyright © 2021 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Few treatment options are available for oseltamivir-resistant influenza. It has been proposed that baloxavir can be effective in this setting due to its distinct mechanism of action but clinical experience is lacking for immunocompromised patients. We report two such cases treated with baloxavir after failure of oseltamivir and detection of oseltamivir resistance mutations. Baloxavir/zanamivir combination therapy was effective in one patient, but persistent viral shedding was noted with baloxavir monotherapy in the other patient., (© 2020 Wiley Periodicals LLC.)

Objective: There is a high prevalence of obesity in people with asthma, and obesity is associated with poorly controlled asthma. Significant weight loss might improve asthma control: the purpose of this study was to investigate patient characteristics and factors that might affect implementation of a weight loss and/or roflumilast intervention, to target both obesity and asthma., Methods: A cross-sectional study of people with obesity and poorly controlled asthma performed at 13 sites across the United States., Results: One hundred and two people participated in this study. Median BMI was 37 (IQR 35-42). The majority, 55%, were African American and 76% were female. Fifty two percent had very poorly controlled asthma. Most participants were quite sedentary (70% reported being inactive or participating only in light-intensity activities according to the Stanford Brief Activity Survey). Participants reported significant impairments related to physical function on the Impact of Weight on Quality of Life-Lite questionnaire (median score 67 [IQR 41-84]). Thirty-five percent of participants reported mild, and 2 % moderate, depressive symptoms as assessed by the Patient Health Questionnaire-9., Conclusions: Poorly controlled asthma and obesity often affect minority populations and are associated with significant impairments in health related to physical function and low levels of physical activity that might complicate efforts to lose weight. Interventions targeted at poorly controlled asthma associated with obesity in the United States need to address factors complicating health in underserved communities, such as increasing opportunities for physical activity, while also managing activity limitations related to the combination of asthma and obesity., Competing Interests: Anne E. Dixon reports grants from the NIH and ALA, and personal fees from UpToDate and Springer. Kathryn V. Blake reports grants from NIH, ALA, and Propeller Health. Emily A. DiMango reports no conflicts. Mark T. Dransfield reports grants from NIH, ALA, Departments of Defense and Veterans Affairs, and research support or consulting fees from Boehringer‐Ingelheim, GlaxoSmithKline, AstraZeneca, Yungjin, PneumRx/BTG, Pulmonx, Boston Scientific, Quark Pharmaceuticals, Mereo, Nuvaira, and Teva and CSA Medical. Robert A. Wise has received financial support over the past 5 years in the form of research support or consulting fees from the following companies that provide products or services for asthma or related lung diseases: AstraZeneca, Boehringer‐Ingelheim, Contrafect, GlaxoSmithKline, Merck, Verona, Mylan, Theravance, Novartis, ChimeRix, FSD Pharma, AbbVie, Bristol Myers Squibb, Kiniksa, Kinevant, Puretech, Galderma, Chiesi, Pulmonx, Roche‐Genentech, Pfizer, and Circassia. Emily A. DiMango, Laura C. Feemster, Olivia Johnson, Gem Roy, Heather Hazucha, Jean Harvey, Meredith C. McCormack, and Janet T. Holbrook report no conflicts., (© 2021 The Authors. Obesity Science & Practice published by World Obesity and The Obesity Society and John Wiley & Sons Ltd.)

Severe asthma accounts for almost half the cost associated with asthma. Severe asthma is driven by heterogeneous molecular mechanisms. Conventional clinical trial design often lacks the power and efficiency to target subgroups with specific pathobiological mechanisms. Furthermore, the validation and approval of new asthma therapies is a lengthy process. A large proportion of that time is taken by clinical trials to validate asthma interventions. The National Institutes of Health Precision Medicine in Severe and/or Exacerbation Prone Asthma (PrecISE) program was established with the goal of designing and executing a trial that uses adaptive design techniques to rapidly evaluate novel interventions in biomarker-defined subgroups of severe asthma, while seeking to refine these biomarker subgroups, and to identify early markers of response to therapy. The novel trial design is an adaptive platform trial conducted under a single master protocol that incorporates precision medicine components. Furthermore, it includes innovative applications of futility analysis, cross-over design with use of shared placebo groups, and early futility analysis to permit more rapid identification of effective interventions. The development and rationale behind the study design are described. The interventions chosen for the initial investigation and the criteria used to identify these interventions are enumerated. The biomarker-based adaptive design and analytic scheme are detailed as well as special considerations involved in the final trial design., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Tezacaftor (TEZ)/ivacaftor (IVA) is an approved CFTR modulator shown to be efficacious and generally safe and well tolerated in people ≥12 years of age with cystic fibrosis (CF) homozygous for the F508del-CFTR mutation or heterozygous for the F508del-CFTR mutation and a residual function mutation. Although previous studies with IVA alone showed clinical benefits in people with CFTR gating mutations, TEZ/IVA has not yet been evaluated in a Phase 3 study of participants heterozygous for F508del-CFTR and a gating mutation (F/gating genotypes). Here, we present results from a randomized, double-blind, IVA-controlled, parallel-group, Phase 3 study assessing the efficacy, safety, and pharmacokinetics (PK) of TEZ/IVA in participants ≥12 years of age with F/gating genotypes., Methods: Enrolled participants entered a 4-week IVA run-in period to create a stable IVA baseline. Participants were then randomized to receive IVA or TEZ/IVA for 8 weeks in an active comparator treatment period (ACTP). The primary endpoint was absolute change in percent predicted forced expiratory volume in 1 second (ppFEV 1 ). Key secondary endpoints were relative change in ppFEV 1 and absolute change in CF Questionnaire-Revised respiratory domain score. Secondary endpoints included absolute change in sweat chloride (SwCl) concentration, PK parameters, and safety. All endpoints except PK parameters and safety were assessed from baseline through Week 8., Results: Sixty-nine participants (92.0%) in the IVA group and 75 participants (98.7%) in the TEZ/IVA group completed treatment. No improvements were seen in efficacy endpoints from baseline at the end of the IVA run-in period through the end of the ACTP in the IVA group. No significant differences in ppFEV 1 or any key secondary endpoint were observed between the IVA and TEZ/IVA groups. SwCl concentrations decreased more in the TEZ/IVA versus IVA group during the ACTP. The safety profile and PK parameters of TEZ/IVA were consistent with those of previous studies in participants ≥12 years of age with CF., Conclusions: This Phase 3 study showed that the dual-combination regimen of TEZ/IVA demonstrated clinical efficacy but did not have significantly greater clinical efficacy than IVA alone in participants ≥12 years of age with F/gating genotypes. However, as reported in other studies, TEZ/IVA was generally safe and well tolerated (NCT02412111)., Competing Interests: Declaration of Competing Interest All authors received nonfinancial support (assistance with manuscript preparation) from ArticulateScience LLC, which received funding from Vertex Pharmaceuticals Incorporated. Additional disclosures are as follows: CAO, DC, and NA are employees of Vertex Pharmaceuticals Incorporated and may own stock or stock options in that company. EAD: grants from Vertex Pharmaceuticals Incorporated during the conduct of the study. EFM: grants and personal fees from Vertex Pharmaceuticals Incorporated during the conduct of the study; personal fees from Proteostasis Therapeutics Incorporated, other from A. Menarini, and grants from Gilead outside the submitted work. ET: grant from Vertex Pharmaceuticals Incorporated (paid to institution for conduct of clinical trials) during the conduct of the study; grants from Bayer, Boehringer Ingelheim, Celtaxsys Incorporated, Vertex Pharmaceuticals Incorporated, Corbus, and Aridigm Corporation outside the submitted work; personal fees from Proteostasis Therapeutics Incorporated (scientific advisory board), Horizon (advisory board), and Vertex Pharmaceuticals Incorporated (consulting related to scientific advisory board; honoraria for speaking) outside the submitted work. MH is an employee of Vertex Pharmaceuticals (Europe) Limited and may own stock or stock options in that company. SS: grants from Galapagos, Proteostasis Therapeutics Incorporated, Celtaxsys Incorporated, Flatley, and Vertex Pharmaceuticals Incorporated outside the submitted work; personal fees from Proteostasis Therapeutics Incorporated, Novartis Pharma GmbH, Vertex Pharmaceuticals Incorporated, Teva GmbH, and Chiesi GmbH outside the submitted work. TLB: personal fees from Respirtech Technologies outside the submitted work., (Copyright © 2020. Published by Elsevier B.V.)

Purpose: The purpose of this study was to pilot a home-based pulmonary rehabilitation (PR) program administered via a telemedicine approach using a combination of fitness application and self-selected activity in lung transplant candidates with cystic fibrosis (CF)., Methods: We recruited adult patients with CF. The main outcome was adherence, measured by number of sessions completed in 12 weeks. Secondary outcomes were adverse events, six-minute walk distance (6MWD), and dyspnea. Participants were provided a personalized exercise program and equipment including a fitness application that provided exercise videos, recorded exercise time, and corresponding heart rate. We reviewed data daily and provided text messages with feedback. We compared our study outcomes to a retrospective data set of CF patients who participated in a 24-session outpatient hospital-based PR program. Data presented as mean ± standard deviation., Results: Eleven patients participated in the home PR program, 45% female, age 33 ± 7 years, FEV1 27 ± 5% predicted. Sessions completed were 19 ± 12 home-based PR vs. 9 ± 4 hospital-based PR, p = .03. Fifty percent of the home-based group completed ≥24 sessions in 12 weeks versus 0% of the hospital-based patients ( p = .03). There were no adverse events during exercise. Completers of the home-based program demonstrated a clinically meaningful lower decline in 6 MWD than noncompleters (6MWD -7 ± 15 vs. -86 ± 108 meters). Only one participant performed a post 6 MWD in the hospital-based PR., Conclusion: Patients with severe CF demonstrated adherence to home PR delivered using fitness application and self-selected activity with no adverse events. This program style may be a viable solution for telerehabilitation in severe CF and is particularly relevant in the COVID era., Competing Interests: Dr. Layton is on a health and advisory council for Peloton Interactive, Inc. She receives no financial compensation from the company. Peloton Interactive, Inc. did not sponsor this project. There are no conflicts of interests to report for the other authors., (Copyright © 2021 Aimee M. Layton et al.)

The Precision Interventions for Severe and/or Exacerbation-prone Asthma (PrecISE) study is an adaptive platform trial designed to investigate novel interventions to severe asthma. The study is conducted under a master protocol and utilizes a crossover design with each participant receiving up to five interventions and at least one placebo. Treatment assignments are based on the patients' biomarker profiles and precision health methods are incorporated into the interim and final analyses. We describe key elements of the PrecISE study including the multistage adaptive enrichment strategy, early stopping of an intervention for futility, power calculations, and the primary analysis strategy.

Individuals with cystic fibrosis (CF) have lower bone mineral density (BMD) by DXA and are at higher risk of fracture than healthy controls. However, the 2-dimensional measurement of areal BMD (aBMD) provided by DXA is influenced by bone size and the true extent of the bone deficit is unclear. Our objective was to use high-resolution peripheral quantitative computed tomography (HR-pQCT) and individual trabecula segmentation (ITS) analysis to compare volumetric BMD (vBMD), microarchitecture and estimated strength at the distal radius and tibia in 26 young adults with CF and 26 controls matched for age, gender, and race. To assess the effect of limb length and minimize the confounding effects of size on HR-pQCT outcomes, we scanned participants at both the standard fixed HR-pQCT measurement sites and at a subject-specific relative site that varied according to limb length. CF participants did not differ significantly in age, height, weight, or BMI from controls. Ulnar and tibial lengths were 9mm shorter in CF patients, though differences were not significant. CF patients had significantly lower BMI-adjusted aBMD by DXA at the lumbar spine (8.9%, p<0.01), total hip (11.5%, p<0.01) and femoral neck (14.5%, p<0.01), but not at the forearm. At the fixed radius site, thickness of trabecular plates and torsional stiffness were significantly lower in CF participants than controls. At the relative radius site, only torsional stiffness was significantly lower in CF participants. At the tibia, total, trabecular and cortical vBMD were significantly lower at both fixed and relative sites in CF participants, with fewer, more widely-spaced trabecular plates, lower trabecular connectivity, and lower axial and torsional stiffness. Our results confirm that aBMD is lower at the spine and hip in young adults with CF, independent of BMI and body size. We also conclude that vBMD and stiffness are lower at the weight-bearing tibia. The pathogenesis of these differences in bone density and strength at the tibia appear to be related to trabecular drop-out and reduced trabecular connectivity and to be independent of differences in limb length, as assessed by scanning participants at both standard and relative sites. We concluded that significant deficits in bone structure and strength persist in young adults with CF, despite advances in care that permit them to attain relatively normal height and weight., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Tiotropium has activity as an asthma controller. However, predictors of a positive response to tiotropium have not been described., Objective: We sought to describe individual and differential responses of asthmatic patients to salmeterol and tiotropium when added to an inhaled corticosteroid, as well as predictors of a positive clinical response., Methods: Data from the double-blind, 3-way, crossover National Heart, Lung, and Blood Institute's Asthma Clinical Research Network's Tiotropium Bromide as an Alternative to Increased Inhaled Glucocorticoid in Patients Inadequately Controlled on a Lower Dose of Inhaled Corticosteroid (ClinicalTrials.gov number, NCT00565266) trial were analyzed for individual and differential treatment responses to salmeterol and tiotropium and predictors of a positive response to the end points FEV1, morning peak expiratory flow (PEF), and asthma control days (ACDs)., Results: Although approximately equal numbers of patients showed a differential response to salmeterol and tiotropium in terms of morning PEF (n = 90 and 78, respectively) and ACDs (n = 49 and 53, respectively), more showed a differential response to tiotropium for FEV1 (n = 104) than salmeterol (n = 62). An acute response to a short-acting bronchodilator, especially albuterol, predicted a positive clinical response to tiotropium for FEV1 (odds ratio, 4.08; 95% CI, 2.00-8.31; P < .001) and morning PEF (odds ratio, 2.12; 95% CI, 1.12-4.01; P = 0.021), as did a decreased FEV1/forced vital capacity ratio (FEV1 response increased 0.39% of baseline for every 1% decrease in FEV1/forced vital capacity ratio). Higher cholinergic tone was also a predictor, whereas ethnicity, sex, atopy, IgE level, sputum eosinophil count, fraction of exhaled nitric oxide, asthma duration, and body mass index were not., Conclusion: Although these results require confirmation, predictors of a positive clinical response to tiotropium include a positive response to albuterol and airway obstruction, factors that could help identify appropriate patients for this therapy., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Purpose: To report a case of sequential bilateral central retinal vein occlusions in a cystic fibrosis patient with hyperhomocysteinemia and hypergamma-globulinemia over 6 years of follow up., Methods: Observational case report of one patient., Results: A 31 year-old male with a history of cystic fibrosis presented with a central retinal vein occlusion (CRVO) in his left eye, followed by a CRVO in his right eye 4 years later. His medical workup was significant for elevated levels of homocysteine and gamma-globulins, which coincided with initiation of intravenous immunoglobulin (IVIG) proceeding his second CRVO., Conclusions: We describe a case of sequential bilateral central retinal vein occlusions in a cystic fibrosis patient with hyperhomocysteinemia and hypergamma-globulinemia over 6 years of follow up and discuss the important role of these risk factors in retinal venous occlusive disease.

Background: Long-acting beta-agonist (LABA) therapy improves symptoms in patients whose asthma is poorly controlled by an inhaled glucocorticoid alone. Alternative treatments for adults with uncontrolled asthma are needed., Methods: In a three-way, double-blind, triple-dummy crossover trial involving 210 patients with asthma, we evaluated the addition of tiotropium bromide (a long-acting anticholinergic agent approved for the treatment of chronic obstructive pulmonary disease but not asthma) to an inhaled glucocorticoid, as compared with a doubling of the dose of the inhaled glucocorticoid (primary superiority comparison) or the addition of the LABA salmeterol (secondary noninferiority comparison)., Results: The use of tiotropium resulted in a superior primary outcome, as compared with a doubling of the dose of an inhaled glucocorticoid, as assessed by measuring the morning peak expiratory flow (PEF), with a mean difference of 25.8 liters per minute (P<0.001) and superiority in most secondary outcomes, including evening PEF, with a difference of 35.3 liters per minute (P<0.001); the proportion of asthma-control days, with a difference of 0.079 (P=0.01); the forced expiratory volume in 1 second (FEV1) before bronchodilation, with a difference of 0.10 liters (P=0.004); and daily symptom scores, with a difference of -0.11 points (P<0.001). The addition of tiotropium was also noninferior to the addition of salmeterol for all assessed outcomes and increased the prebronchodilator FEV1 more than did salmeterol, with a difference of 0.11 liters (P=0.003)., Conclusions: When added to an inhaled glucocorticoid, tiotropium improved symptoms and lung function in patients with inadequately controlled asthma. Its effects appeared to be equivalent to those with the addition of salmeterol. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00565266.).

Background: PCR studies have demonstrated evidence of Mycoplasma pneumoniae and Chlamydophila pneumoniae in the lower airways of patients with asthma., Objective: To test the hypothesis that clarithromycin would improve asthma control in individuals with mild-to-moderate persistent asthma that was not well controlled despite treatment with low-dose inhaled corticosteroids., Methods: Adults with an Asthma Control Questionnaire score ≥1.5 after a 4-week period of treatment with fluticasone propionate were entered into a PCR-stratified randomized, controlled trial to evaluate the effect of 16 weeks of either clarithromycin or placebo, added to fluticasone, on asthma control in individuals with or without lower airway PCR evidence of M pneumoniae or C pneumoniae., Results: A total of 92 participants were randomized. Twelve (13%) subjects demonstrated PCR evidence of M pneumoniae or C pneumoniae in endobronchial biopsies; 80 were PCR-negative for both organisms. In PCR-positive participants, clarithromycin yielded a 0.4 ± 0.4 unit improvement in the Asthma Control Questionnaire score, with a 0.1 ± 0.3 unit improvement in those allocated to placebo. This between-group difference of 0.3 ± 0.5 (P = .6) was neither clinically nor statistically significant. In PCR-negative participants, a nonsignificant between-group difference of 0.2 ± 0.2 units (P = .3) was observed. Clarithromycin did not improve lung function or airway inflammation but did improve airway hyperresponsiveness, increasing the methacholine PC(20) by 1.2 ± 0.5 doubling doses (P = .02) in the study population., Conclusion: Adding clarithromycin to fluticasone in adults with mild-to-moderate persistent asthma that was suboptimally controlled by low-dose inhaled corticosteroids alone did not further improve asthma control. Although there was an improvement in airway hyperresponsiveness with clarithromycin, this benefit was not accompanied by improvements in other secondary outcomes., (Copyright © 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: The majority of new cases of cystic fibrosis (CF) are diagnosed before age 2 years. Diagnoses in older individuals have increased because of improved genetic testing and increased awareness of the disease. A comprehensive description of clinical, genetic, and microbiologic characteristics of adult-age presentation of CF does not exist. We compare newly diagnosed CF in adults with newly diagnosed CF in children and adolescents in the United States., Methods: This is a cross-sectional study of new CF diagnoses from the Cystic Fibrosis Foundation Patient Registry between 1995 and 2005. Diagnostic, microbiologic, and clinical features during year of diagnosis were analyzed for subjects by age group. Descriptive statistics were calculated for variables on characteristics by age group., Results: A total of 9,766 new diagnoses of CF were reported to the Registry between 1995 and 2005. The proportion of adult diagnoses increased significantly in the years 2001 to 2005 as compared with 1995 to 2000 (9.0% vs 7.7%, P = .012). FEV(1)% predicted decreased with increasing age at diagnosis (P < .001). Infection with Pseudomonas aeruginosa was most common in adults (P < .001). Both the number of positive sweat chloride tests and prevalence of DeltaF508 mutation, the most common mutation in the United States, decreased significantly with older age at diagnosis (P < .001)., Conclusions: Between 1995 and 2005, the proportion of new diagnoses of CF in adults in the United States increased significantly. Adults present with commonly described CF respiratory disease (Pseudomonas aeruginosa infection and reduced lung function), but have lower sweat chloride values and lower frequency of DeltaF508 mutation. Knowledge of clinical characteristics and diagnostic limitations of adult patients presenting with CF will hopefully lead to earlier recognition and intervention.

Background: Although guidelines recommend anti-inflammatory therapy for persistent asthma, recent studies suggest that 25% to 35% of patients with asthma may not improve lung function with inhaled corticosteroids., Objective: To evaluate potential biomarkers of predicting short-term (6-week) response to inhaled corticosteroid with subsequent evaluation of responders and nonresponders to asthma control over a longer interval (16 additional weeks)., Methods: Eighty-three subjects with asthma off steroid were enrolled in this multicenter study. Biomarkers and asthma characteristics were evaluated as predictors of inhaled corticosteroid response over a 6-week trial for changes in FEV(1) and methacholine PC(20). After this, an additional 4-month trial evaluated asthma control., Results: Although multiple baseline predictors had significant correlations with improvements for short-term inhaled steroid success, the only strong correlations (r >or= +/- 0.6) were albuterol reversibility (r = 0.83; P < .001), FEV(1)/forced vital capacity (r = -0.75; P < .001), and FEV(1) % predicted (r = -0.71; P < .001). Dividing the subjects in the short-term inhaled steroid trial into responders (>5% FEV(1) improvement) and nonresponders (

Background: The American Lung Association Asthma Clinical Research Centers (ALA-ACRC) reported that the inactivated influenza vaccine is safe for patients with asthma and recommended its use to reduce the morbidity associated with infection., Objective: Because the ALA-ACRC's recommendation would include vaccination of all patients with asthma, including those with severe asthma and first-time vaccinees, we conducted a parallel study to address whether patients with asthma who report bronchospasm after vaccination might be demonstrating a hypersensitivity response to the vaccine., Methods: Thirty-two adult patients with asthma from the ALA-ACRC cohort were recruited. Subjects were randomly assigned to receive influenza vaccine or placebo and then recorded asthma symptoms and peak expiratory flow rates for 14 days. On day 14, influenza vaccine and egg antigen-induced mononuclear cell proliferation and IFN-gamma, IL-5, and IL-4 production were measured and compared with symptoms., Results: Increased influenza but not egg antigen-induced mononuclear cell proliferation was present among vaccinated subjects. These responses were unrelated to asthma exacerbations after vaccine. There were no differences in cytokine production in response to either influenza or egg antigen in association with asthma exacerbations., Conclusions: Episodes of bronchospasm after influenza vaccination do not seem related to hypersensitivity to the vaccine.

A central bronchus that is readily visible end-on in approximately 50% of normal frontal chest radiographs is the bronchus to the anterior segment of either upper lobe. Bronchial wall thickening, or "cuffing," is considered to be a radiographic sign of an asthmatic exacerbation and is cited as a useful sign in a number of leading textbooks; however, to the authors' knowledge, no prior chest radiographic study has quantitatively assessed this specific sign in a population of asthmatics suffering an acute exacerbation. Posterior chest radiographs were reviewed retrospectively for 51 nonasthmatic, nonsmoking control subjects and for 45 adult asthmatic subjects during an acute exacerbation of moderate to severe asthma. Readers were blinded as to whether the radiograph was from an asthmatic or control subject. If visible end-on, the bronchus to the anterior segment of either upper lobe was assessed by measuring the diameter of the lumen and the thickness of the bronchial wall. At least one clearly defined bronchus to the anterior segment of an upper lobe was visible end-on in 22 patients (43%) in the control group and in 21 patients (47%) in the asthma group (p = NS). Mean wall thickness was 0.7 +/- 0.1 mm in the control group and 0.8 +/- 0.1 mm in the asthma group (p = 0.04). Lumen/wall thickness was 3.1 +/- 0.2 (SEM) in the control group and 2.5 +/- 0.2 in the asthma group (p = 0.055). The presence of bronchial wall thickness does not reliably distinguish radiographs of acutely asthmatic from normal individuals.