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Rationale: Pulmonary exacerbations (PEx) remain the most common cause of morbidity, recurrent hospitalization, and diminished survival in people with cystic fibrosis (PWCF) and are characterized by excess inflammation. Corticosteroids are potent, widely available antiinflammatory drugs. However, corticosteroid efficacy data from randomized controlled trials in PWCF are limited. Objectives: To determine whether adjunctive systemic corticosteroid therapy is associated with improved outcomes in acute CF PEx. Methods: We performed a secondary analysis of Standardized Treatment of Pulmonary Exacerbations 2 (STOP2), a large multicenter randomized controlled trial of antimicrobial treatment durations for adult PWCF presenting with PEx, that included the use of corticosteroids as a stratification criterion in its randomization protocol. Corticosteroid treatment effects were determined after propensity score matching for covariates including age, sex, baseline forced expiratory volume in 1 second (FEV 1 ), genotype, and randomization arm. The primary outcome measure was the change in percentage predicted FEV 1 (ppFEV 1 ). Symptoms, time to next PEx, and the incidence of adverse events (AEs) and serious adverse events (SAEs) were assessed as secondary endpoints. Phenotypic factors associated with the clinical decision to prescribe steroids were also investigated. Results: Corticosteroids were prescribed for 168 of 982 PEx events in STOP2 (17%). Steroid prescription was associated with decreased baseline ppFEV 1 , increased age, and female sex. Cotreatment with corticosteroids was independent of treatment arm allocation and did not result in greater mean ppFEV 1 response, longer median time to next PEx, or more substantial symptomatic improvement compared with propensity-matched PWCF receiving antibiotics alone. AEs were not increased in corticosteroid-treated PWCF. The total number of SAEs-but not the number of corticosteroid-related or PEx-related SAEs-was higher among patients receiving corticosteroids. Conclusions: Empiric, physician-directed treatment with systemic corticosteroids, although common, is not associated with improved clinical outcomes in PWCF receiving antibiotics for PEx. Clinical trial registered with www.clinicaltrials.gov (NCT02781610).

Rationale: Rates of viral respiratory infection (VRI) are similar in people with cystic fibrosis (CF) and the general population; however, the associations between VRI and CF pulmonary exacerbations (PEx) require further elucidation. Objectives: To determine VRI prevalence during CF PEx and evaluate associations between VRI, clinical presentation, and treatment response. Methods: The STOP2 (Standardized Treatment of Pulmonary Exacerbations II) study was a multicenter randomized trial to evaluate different durations of intravenous antibiotic therapy for PEx. In this ancillary study, participant sputum samples from up to three study visits were tested for respiratory viruses using multiplex polymerase chain reactions. Baselines and treatment-associated changes in mean lung function (percent predicted forced expiratory volume in 1 s) , respiratory symptoms (Chronic Respiratory Infection Symptom Score), weight, and C-reactive protein were compared as a function of virus detection. Odds of PEx retreatment within 30 days and future PEx hazard were modeled by logistic and Cox proportional hazards regression, respectively. Results: A total of 1,254 sputum samples from 621 study participants were analyzed. One or more respiratory viruses were detected in sputum samples from 245 participants (39.5%). Virus-positive participants were more likely to be receiving CF transmembrane conductance regulator modulator therapy (45% vs. 34%) and/or chronic azithromycin therapy (54% vs. 44%) and more likely to have received treatment for nontuberculous Mycobacterium infection in the preceding 2 years (7% vs. 3%). At study visit 1, virus-positive participants were more symptomatic (mean Chronic Respiratory Infection Symptom Score, 53.8 vs. 51.1), had evidence of greater systemic inflammation (log 10 C-reactive protein concentration, 1.32 log 10 mg/L vs. 1.23 log 10 mg/L), and had a greater drop in percent predicted forced expiratory volume in 1 second from the prior 6-month baseline (5.8 vs. 3.6). Virus positivity was associated with reduced risk of future PEx (hazard ratio, 0.82; 95% confidence interval, 0.69-0.99; P  = 0.034) and longer median time to next PEx (255 d vs. 172 d; P  = 0.021) compared with virus negativity. Conclusions: More than one-third of STOP2 participants treated for a PEx had a positive test result for a respiratory virus with more symptomatic initial presentation compared with virus-negative participants, but favorable long-term outcomes. More refined phenotyping of PEx, taking VRIs into account, may aid in optimizing personalized management of PEx.Clinical trial registered with www.clinicaltrials.gov (NCT02781610).

Previous studies indicate that hospital rather than home treatment of pulmonary exacerbations (PEx) in people with cystic fibrosis (CF) can improve outcomes. We evaluated characteristics of adult participants from the Standardized Treatment of Pulmonary Exacerbations (STOP2) trial with two separate comparisons: (1) those who were treated initially in hospital (N = 768) to those treated initially at home (N = 214) and (2) those treated only in hospital (N = 328) to those who were treated only at home or both at home and in hospital (N = 654). Participants who had Medicaid insurance, were treated for shorter duration, and traveled longer to reach treatment centers were more likely to have been treated initially in the hospital. Having Medicaid insurance, being treated for a shorter duration, and being male were associated with being treated only in the hospital. This analysis suggests decisions about the location of treatment are based on pragmatic factors rather than on clinical characteristics., Competing Interests: Declaration of Competing Interest Grants from the Cystic Fibrosis Foundation in part supported the salaries of LSG, RNH, SLH, PAF, CHG, NEW, DBS, and LK. Grants from the NIH in part supported the salaries of SLH, PAF, and CHG. DBS received payments for committee work from the Cystic Fibrosis foundation. DBS's institution also grant support payments from Gilead Sciences and the CHEST Foundation. DBS received personal payment for participation on an advisory board for Vertex Pharmaceuticals., (Copyright © 2023. Published by Elsevier B.V.)

The South Carolina cystic fibrosis (CF) newborn screening (NBS) program changed in 2019 to include CFTR genotyping for babies with top 4% immunoreactive trypsinogen, which improves sensitivity and timeliness but increases carrier detection. Carrier identification has genetic implications for the family and parents of NBS+ babies have increased emotional distress. Genetic counseling (GC) may increase parent understanding and reduce anxiety yet is not uniformly offered at CF centers. We report our early results after implementing GC for NBS+ families at the time of sweat chloride testing based on GC availability, which resulted in an unselected GC- control arm. Sixteen mothers (GC+ = 9, GC- = 7) participated in an online survey about their experience. Responses were analyzed in aggregate and for differences between GC+ and GC- groups. All-respondent sadness and anxiety increased with notification of the NBS+ result and decreased after sweat test results. Anxiety and sadness were greater in GC- compared to GC+ until after the diagnosis was resolved, though emotional differences between the groups were not statistically significant. On a scale of 0 = not at all to 10 = extremely, GC was rated very helpful (mean 9.0, range 5-10), informative (mean 8.9, range 4-10), comforting (mean 9.1, range 6-10), and minimally distracting (mean 1.8, range 0-9). All participants correctly identified that a risk for a child to have CF exists when both parents are (at least) carriers. Delivery of NBS results to respondents varied by timing, informant, and information given. The child's pediatrician notified 10 (62.5%) of the NBS+ result. Parents felt they were notified in a timely manner (68.8%), by someone knowledgeable about NBS (62.5%), the sweat test (62.5%), CF (43.8%), and genetics (43.8%) and who cared about them (81.3%). Parents felt worried (81.3%), confused (81.3%), empowered (25%), and other (sad, shocked, scared, overwhelmed, devastated, defeated). Data from this single-center study suggest benefit of GC, that families would value earlier contact with an expert, and that prompt diagnostic resolution may reduce duration of parental distress., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Following availability of the highly effective cystic fibrosis (CF) transmembrane conductance regulator modulator, elexacaftor/tezacaftor/ivacaftor, there was a near doubling of pregnancies reported in the United States (US) in people with CF. We sought to determine health impacts of planned (PP) versus unplanned pregnancies (UP)., Methods: We collected retrospective pregnancy data from January 2010-December 2020 from 11 US CF centers. After adjusting for potential confounding effects, we conducted multivariable, multilevel longitudinal regression analysis using mixed effect modeling to assess whether changes in percent predicted forced expiratory volume in one second (ppFEV 1 ), body mass index (BMI), and pulmonary exacerbations (PEx) 1-year-pre- to 1-year-post-pregnancy were associated with pregnancy planning., Results: Our analysis included 163 people with 226 pregnancies; the cohort had a mean age at conception of 29.6 years, mean pre-pregnancy ppFEV 1 of 75.4 and BMI of 22.5 kg/m 2 . PpFEV 1 declined in both PP (adjusted decline of -2.5 (95% CI: -3.8, -1.2)) and UP (adjusted decline of -3.0 (95% CI: -4.6, -1.4)) groups, they did not differ from each other (p = 0.625). We observed a difference in change in the annual number of PEx pre- to post-pregnancy (PP: 0.8 (0.7, 1.1); UP: 1.3 (1.0, 1.7); interaction effect p = 0.029). In a subset of people with available infant data, infants resulting from UP had more preterm births, lower APGAR scores, and more intensive care unit stays., Conclusions: Following UP, there is an increased trajectory for PEx and potentially for infant complications compared to PP. Clinicians should consider increased surveillance in the setting of UP., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that would cause bias to the content of this manuscript. GP – no conflicts; JTC, ML, AW, NW, TK, AU, MA, AR, LB, JG, DH, SM, PF, RJ – CF Foundation institutional research funding for work related to this manuscript; Additional conflicts of interest unrelated to the content of this manuscript may be included in the attached ICMJE disclosures., (Copyright © 2023 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

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: Pulmonary exacerbations (PEx) remain a major cause of morbidity and mortality in people with cystic fibrosis (PWCF). Although the combination cystic fibrosis transmembrane conductance regulator (CFTR) modulators lumacaftor/ivacaftor and tezacaftor/ivacaftor have been shown to reduce PEx frequency, their influence on clinical and biochemical responses to acute PEx treatment is unknown., Methods: We performed a secondary analysis of STOP2, a large multicenter randomized controlled trial of antimicrobial treatment durations for adult PWCF presenting with PEx. Propensity score matching was used to compare outcomes in antibiotic-treated F508del/F508del PWCF receiving lumacaftor/ivacaftor or tezacaftor/ivacaftor with those observed in antibiotic-treated F508del/F508del controls not receiving CFTR modulator therapy. The primary outcome measure was the change in percent predicted FEV 1 (ppFEV 1 ) following completion of intravenous (IV) antibiotics, with post-antibiotic changes in symptoms, serum C-reactive protein (CRP) concentrations and weight included as secondary endpoints., Results: Among 982 PEx events in randomized PWCF, 480 were homozygous for F508del, of whom 289 were receiving lumacaftor/ivacaftor or tezacaftor/ivacaftor at initiation of antibiotic therapy. Modulator-treated F508del/F508del PWCF did not demonstrate greater improvements in ppFEV 1 , symptoms, serum CRP or weight following antibiotic treatment compared to modulator-naïve controls matched for age, sex, baseline ppFEV 1 , genotype, body mass index, initial CRP, initial symptoms, exacerbation history, diabetic status, randomization arm and concomitant medical therapy., Conclusion: In the acute setting, CFTR modulator therapy with lumacaftor/ivacaftor or tezacaftor/ivacaftor does not convey additional clinical or biochemical advantage above standardized PEx treatment in F508del/F508del PWCF., Competing Interests: Declaration of Competing Interest O.J.McE. has been an investigator for Chiesi and Grifols. P.A.F. has been an investigator for Novartis, Novoteris, Proteostasis, Savara, Sound, Chiesi and Vertex. C.H.G. has been an investigator for Boehringer Ingelheim and a DSMB chair for Novartis. The remaining authors have no relevant or competing interests to disclose., (Copyright © 2023. Published by Elsevier B.V.)

Background: Hyperglycemia could affect treatment response during cystic fibrosis (CF) exacerbations. We aimed to evaluate the prevalence and associations of hyperglycemia with exacerbation outcomes. We also evaluated feasibility of continuous glucose monitoring (CGM) during exacerbations., Methods: The STOP2 study assessed efficacy and safety of different durations of intravenous antibiotics for CF exacerbations. We conducted a secondary data analysis of random glucose levels measured as part of clinical care during exacerbations. A small subset of participants also underwent CGM per research protocol. The associations between hyperglycemia, defined as random glucose ≥140 mg/dL, and changes in weight and lung function with exacerbation treatment were evaluated with linear regression after adjustment for confounding variables., Results: Glucose levels were available for 182 STOP2 participants of mean (SD) age 31.6 (10.8) years, baseline percent predicted (pp) FEV1 53.6 (22.5); 37% had CF related diabetes and 27% were on insulin. Hyperglycemia was detected in 44% of participants. Adjusted mean difference (95% CI) was 1.34% (-1.39, 4.08) (p = 0.336) for change in ppFEV1 and 0.33 kg (-0.11, 0.78) (p = 0.145) for change in weight between hyperglycemic and non-hyperglycemic groups. Ten participants not on antidiabetic agents in the 4 weeks prior to enrollment underwent CGM; mean (SD) time spent >140 mg/dL was 24.6% (12.5) with 9/10 participants spending >4.5% time >140 mg/dL., Conclusions: Hyperglycemia identified with random glucose is prevalent during CF exacerbations but not associated with changes in lung function or weight with exacerbation treatment. CGM is feasible and may provide a useful tool for hyperglycemia monitoring during exacerbations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Clinical trials are essential in the translation of biomedical discoveries to new clinical interventions and therapeutics. Successful multisite clinical trials require qualified site investigators with an understanding of the full spectrum of processes and requirements from trial identification through closeout. New site investigators may be deterred by competing demands on their time, the complexity of administrative and regulatory processes for trial initiation and conduct, and limited access to experienced mentor networks. We established a Clinical Trialist Training Program (CTTP) and complimentary Clinical Trials Bootcamp at our institution to address these barriers and increase the number of local site investigators enabled to lead successful clinical trials. An initial cohort of four CTTP scholars received salary support with protected time, didactic training, assistance with study identification and start-up navigation, and quarterly progress meetings. By the end of the 12-month program, this initial cohort identified 33 new trials, utilized feasibility assessments, and reported being on target to sustain their protected time from new clinical trials. Bootcamp attendees demonstrated increased knowledge of resources, offices, and processes associated with clinical trial conduct. Our results support providing compensated protected time, training, and access to experienced clinical research professionals to enable clinicians to become successful site investigators., Competing Interests: The authors have no conflicts of interest to report., (© The Author(s) 2023.)

Background: Patients with bronchiectasis experience persistent symptoms and frequent pulmonary exacerbations; this study investigated the frequency of exacerbations and all-cause hospitalisation., Methods: This longitudinal, retrospective, claims database study (IBM® MarketScan®) identified patients aged ≥18 years from 1 July 2015 through 30 September 2018. Exacerbations were identified by bronchiectasis inpatient claim or a healthcare interaction, followed by antibiotic prescription within 7 days. Patients with ≥36 months of continuous health plan enrolment (12 months preceding the first bronchiectasis claim, i.e. , baseline period and ≥24 months of follow-up) were included. Patients with cystic fibrosis at baseline were excluded. A multivariable logistic regression model identified baseline factors associated with having ≥2 exacerbations over the 2-year follow-up period., Results: In total, 14 798 patients with bronchiectasis were identified; 64.5% were female, 82.7% were aged ≥55 years and 42.7% had ≥2 exacerbations at baseline. Having ≥2 exacerbations after 2 years was positively associated with chronic macrolide use, long-acting β2 agonist use, gastro-oesophageal reflux disease, heart failure and Pseudomonas aeruginosa . Frequent exacerbations (≥2) at baseline were significantly associated with greater likelihood of experiencing ≥2 exacerbations during the first and second year's follow-up (unadjusted odds ratios 3.35 (95% CI 3.1-3.6) and 2.96 (95% CI 2.8-3.2), respectively). The proportion of patients experiencing ≥1 all-cause hospitalisation cumulatively increased from 41.0% in the first year of follow-up to 51.1% over 2 years' follow-up., Conclusion: Frequent exacerbations in patients with bronchiectasis may increase the likelihood of future exacerbations over 2 years of follow-up, with increased hospitalisation rates over time., Competing Interests: Conflicts of interest: J. Wu reports support for the present manuscript from Insmed; the author is a current employee of Insmed and has stock and stock option, outside the submitted work. Conflicts of interest: M. Hassan reports support for the present manuscript from Insmed; the author is a current employee of Insmed and has stock, outside the submitted work; receipt of medical writing support from Insmed, outside the submitted work. Conflicts of interest: P.A. Flume reports support for the present manuscript from Insmed; grants or contracts from Insmed, outside the submitted work; and consulting fees from Insmed, outside the submitted work. Conflicts of interest: S. Fucile reports support for the present manuscript from Insmed; the author is a current employee of Insmed and has stock and stock option, outside the submitted work. Conflicts of interest: J. Feliciano reports support for the present manuscript from Insmed; the author is a current employee of Insmed and has stock, outside the submitted work; receipt of medical writing support from Insmed, outside the submitted work. Conflicts of interest: A. Chatterjee reports support for the present manuscript from Insmed; the author is a current employee of Insmed and has stock and stock option, outside the submitted work. Conflicts of interest: M. Lucci has nothing to disclose., (Copyright ©The authors 2023.)

Background: Mycobacterium abscessus is a virulent human pathogen. Treatment is complex and often poorly tolerated with suboptimal rates of eradication, highlighting the need for improved therapeutics. This study reports clinical experience with omadacycline for treatment of M abscessus infections at five large nontuberculous mycobacterial (NTM) disease clinics across the United States to better understand long-term safety and tolerability., Methods: We conducted a multicenter retrospective chart review of adults with M abscessus infections. All patients treated with omadacycline as part of a multidrug therapeutic regimen through December 2021 were included. Clinical data from time of omadacycline initiation and up to 12 months of follow-up were collected. Descriptive statistics were performed., Results: Analysis included 117 patients. Among patients with M abscessus isolate subspeciation, 58 of 71 (81.7%) were M abscessus spp abscessus . In isolates with reported drug susceptibility testing, 15 of 70 (21.4%) had confirmed susceptibility to macrolides. The most common site of infection was lungs. Median duration omadacycline treatment was 8 months (range, 0.25-33 months; interquartile range, 4-15 months). Omadacycline was discontinued in 60 patients (51.3%); 20 completed planned treatment course, 23 experienced intolerance or adverse event leading to drug cessation, and 17 stopped due to cost, death (unrelated to NTM infection or therapy), or another reason. In those with pulmonary disease, 44 of 95 (46%) had 1 or more negative cultures at time of final microbiological assessment, with 17 of 95 (18%) achieving culture conversion., Conclusions: This study reports data supporting long-term safety and tolerability of omadacycline along with signal of effectiveness in treatment of M abscessus infections., Competing Interests: Potential conflicts of interest. C. M. M. receives grant support from the Cystic Fibrosis Foundation. C. D. V. receives research grant support from NTMir and the Medical Research Foundation of Oregon. D. A.-H. receives grant support from AN2 Therapeutics, Insmed, Boehringer Ingelheim, Hill-Rom, and Zambone. C. L. D. conducts contracted research with AN2 Therapeutics, Bugworks, Insmed, and Paratek Pharma; serves as a consultant for Genentech, Pfizer, and Cepheid; serves as an advisory board member for AN2 Therapeutics, AstraZeneca, Hyfe, Insmed, Juvabis, Mannkind Corporation, Matinas BioPharma Holdings, Paratek Pharma, Spero Therapeutics, and Zambone; and is part of data monitoring committees for Ostuka Pharmaceutical, Eli Lilly and Company, and the Bill & Melinda Gates Foundation. K. N. O. receives grant support for Beyond Air and serves as an advisory board member for Pfizer, Mannkind Corporation, Spero Therapeutics, Paratek Pharma, and AN2 Therapeutics. K. L. W. receives research support from Insmed, Paratek Pharma, Red Hill Biopharma, AN2 Therapeutics, Renovion, and Spero Therapeutics and serves as a consultant for Insmed, Paratek Pharma, Red Hill Biopharma, AN2 Therapeutics, Renovion, and Spero Therapeutics. P. A. F. receives grant support from AbbVie, Aceragen, AN2 Therapeutics, Armata, AstraZeneca, Cystic Fibrosis Foundation Therapeutics, Insmed, Janssen, NIH, Novavax, RedHill, Sound Pharmaceuticals, Spero, and Vertex Pharmaceuticals and serves as a consultant for Aceragen, AN2, Arrevus, Chiesi, Eloxx Pharmaceuticals, Insmed, Ionis Pharmaceuticals, Janssen Research and Development, McKesson, Siona, Spero Therapeutics, and Vertex Pharmaceuticals. All other authors report no potential conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Diagnostic testing is fundamental to medicine. However, studies of diagnostic testing in respiratory medicine vary significantly in terms of their methodology, definitions, and reporting of results. This has led to often conflicting or ambiguous results. To address this issue, a group of 20 respiratory journal editors worked to develop reporting standards for studies of diagnostic testing based on a rigorous methodology to guide authors, peer reviewers, and researchers when conducting studies of diagnostic testing in respiratory medicine. Four key areas are covered, including defining the reference standard of truth, measures of dichotomous test performance when used for dichotomous outcomes, measures of multichotomous test performance for dichotomous outcomes, and what constitutes a useful definition of diagnostic yield. The importance of using contingency tables for reporting results is addressed with examples from the literature. A practical checklist is provided as well for reporting studies of diagnostic testing., Competing Interests: Disclosure: D.E.O.: Research grant Intuitive Surgical, UpToDate author; prior ABIM test writing committee pulmonary medicine. D.F.K.: consulting fees from NOAH Medical, Boston Scientific and I am an Associate Editor for UpToDate. The remaining authors declare no conflict of interest or other disclosures., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Study 661-110 (EXTEND) is a phase 3, open-label, three-part rollover study designed to assess the long-term safety and efficacy of tezacaftor/ivacaftor (TEZ/IVA) in participants aged ≥12 years homozygous for F508del (F/F) or heterozygous for F508del and a residual function mutation (F/RF). TEZ/IVA was shown to be safe and efficacious for up to 120 weeks in Part A. Here we report results from Part B, which evaluated safety and efficacy for an additional 96 weeks., Methods: Part B enrolled participants aged ≥12 years with CF and F/F or F/RF genotypes who completed TEZ/IVA treatment in either Study 661-110 Part A, Study 661-112 (F/F), or Study 661-114 (F/F). Participants received TEZ 100 mg/IVA 150 mg fixed-dose combination once daily (morning) and IVA 150 mg once daily (evening) for 96 weeks. Safety endpoints included adverse events (AEs) and serum liver function tests. Efficacy endpoints included absolute change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV 1 ) and pulmonary exacerbation (PEx) rate., Results: 464 participants were enrolled from Part A (n=377) and other eligible studies (n=87); 463 received ≥1 dose of TEZ/IVA. Overall, 92.2% had ≥1 AE, 0.9% had AEs leading to treatment discontinuation, and 29.4% reported serious AEs. The most common AEs, which were generally consistent with common manifestations of CF, included infective PEx of CF, cough, nasopharyngitis, hemoptysis, and headache. Lung function was maintained over 96 weeks in both genotype groups. PEx rates per year were comparable with Part A., Conclusions: TEZ/IVA was generally safe and well tolerated over a further 96 weeks; safety data were consistent with Part A. Improvements in ppFEV 1 and PEx rates were maintained for an additional 96 weeks in Part B., Competing Interests: Declaration of Competing Interests PAF reports grants and personal fees from Vertex Pharmaceuticals outside the submitted work. RSH, HP-D, NA, MH, IB, and JLS are employees of Vertex Pharmaceuticals and may own stock or stock options in Vertex Pharmaceuticals. DC is a former employee of Vertex Pharmaceuticals and owns stock or stock options in Vertex Pharmaceuticals. GS reports personal fees from and advisory boards for Vertex Pharmaceuticals during the conduct of the study, and grants from Vertex Pharmaceuticals and personal fees from Gilead Sciences outside the submitted work., (Copyright © 2022 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Bronchiectasis (BE) is a chronic condition characterized by airway dilation as a consequence of a variety of pathogenic processes. It is often associated with persistent airway infection and an inflammatory response resulting in cough productive of purulent sputum, which has an adverse impact on quality of life. The prevalence of BE is increasing worldwide. Treatment guidelines exist for managing BE, but they are generally informed by a paucity of high-quality evidence. This review presents the findings of a scientific advisory board of experts held in the United States in November 2020. The main focus of the meeting was to identify unmet needs in BE and propose ways to identify research priorities for the management of BE, with a view to developing evidence-based treatment recommendations. Key issues identified include diagnosis, patient evaluation, promoting airway clearance and appropriate use of antimicrobials. Unmet needs include effective pharmacological agents to promote airway clearance and reduce inflammation, control of chronic infection, clinical endpoints to be used in the design of BE clinical trials, and more accurate classification of patients using phenotypes and endotypes to better guide treatment decisions and improve outcomes., Competing Interests: Declaration of competing interest Patrick A. Flume has received grant support from Abbvie, Armata, AstraZeneca, Corbus Pharmaceuticals, Cystic Fibrosis Foundation Therapeutics, Insmed, Janssen, Merck, National Institutes of Health, Novartis, Novoteris, Novovax, Proteostasis Therapeutics, Savara, Sound Pharmaceuticals, Inc. and Vertex Pharmaceuticals, Inc., and consultancy fees from Arrevus, Chiesi, Corbus Pharmaceuticals, Eloxx Pharmaceuticals, Hill-Rom, Insmed, Ionis Pharmaceuticals, Janssen Research and Development, McKesson, Merck, Novartis, Polyphor, Proteostasis Therapeutics, Santhera, Savara and Vertex Pharmaceuticals, Inc. Ashwin Basavaraj has acted as a consultant and advisory board participant for Insmed, Hill-Rom, Dymedso, Physioassist and Zambon, is a principal investigator in a clinical trial with Hill-Rom, and has received grant support from Insmed. Bryan Garcia has received grant support from the Cystic Fibrosis Foundation, CHEST Foundation, and consulting honoraria from Zambon, Insmed, Synspira and Resbiotic. Kevin Winthrop has received grant support from Pfizer, BMS, Insmed and the Cystic Fibrosis Foundation, and consulting honoraria from Novartis, Zambon, Insmed, Janssen, Redhills Biopharma, Paratek and Bayer. Emily Di Mango reports receiving advisory board fees from Zambon in 2019 and from Contrafect Pharmaceuticals in 2021. Charles L. Daley has received grant support from the Cystic Fibrosis Foundation, Insmed, Spero, Paratek and BugWorks, and consulted with AstraZeneca, Genentech, Pfizer, Insmed, Spero, Paratek, Beyond Air, AN2, Matinas and Zambon. Julie V. Philley has received grant support from Insmed, AN2, Paratek, Redhill, Electromed, Zambon and Hill Rom, and has been a consultant for Insmed, Paratek, AN2 and Electromed. Emily Henkle has been an advisory board participant for Zambon. Anne E. O'Donnell has received grant support from Insmed, Paratek, Redhill, Zambon, Janssen, and Astra Zeneca and has received consulting honoraria from Insmed, Paratek, Zambon, Boehringer Ingelheim, Astra Zeneca and Electromed. Mark Metersky has been a consultant for Savara, Insmed, International Biophysics, Zambon and Boehringer Ingelheim, and received clinical trial funding from Insmed., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Electronic (e)-phenotype specification by noninformaticist investigators remains a challenge. Although validation of each patient returned by e-phenotype could ensure accuracy of cohort representation, this approach is not practical. Understanding the factors leading to successful e-phenotype specification may reveal generalizable strategies leading to better results., Materials and Methods: Noninformaticist experts (n = 21) were recruited to produce expert-mediated e-phenotypes using i2b2 assisted by a honest data-broker and a project coordinator. Patient- and visit-sets were reidentified and a random sample of 20 charts matching each e-phenotype was returned to experts for chart-validation. Attributes of the queries and expert characteristics were captured and related to chart-validation rates using generalized linear regression models., Results: E-phenotype validation rates varied according to experts' domains and query characteristics (mean = 61%, range 20-100%). Clinical domains that performed better included infectious, rheumatic, neonatal, and cancers, whereas other domains performed worse (psychiatric, GI, skin, and pulmonary). Match-rate was negatively impacted when specification of temporal constraints was required. In general, the increase in e-phenotype specificity contributed positively to match-rate., Discussions and Conclusions: Clinical experts and informaticists experience a variety of challenges when building e-phenotypes, including the inability to differentiate clinical events from patient characteristics or appropriately configure temporal constraints; a lack of access to available and quality data; and difficulty in specifying routes of medication administration. Biomedical query mediation by informaticists and honest data-brokers in designing e-phenotypes cannot be overstated. Although tools such as i2b2 may be widely available to noninformaticists, successful utilization depends not on users' confidence, but rather on creating highly specific e-phenotypes., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Question: There is an increasing prevalence of nontuberculous mycobacteria pulmonary disease (NTM-PD) in the US. Treatment of NTM-PD typically requires multiple medications, which can be associated with unpleasant morbidity and eradication of infection is difficult. Therefore, there is a critical need for novel effective and well-tolerated therapies. Recent in vitro data and case reports have suggested that nitric oxide, inhaled as a gas (gNO), has antimicrobial activity against NTM. We sought to investigate the effect of gNO in patients with NTM-PD in an open-label proof of concept trial., Methods: Eligible participants had NTM-PD with persistently positive respiratory cultures for NTM even if on antibiotic treatment. Participants were treated with gNO for 50 min three times daily, five days per week, for three weeks (total of 15 treatment days)., Results: Ten participants, of whom nine were on long-term NTM antibiotic therapy, were enrolled. All participants completed the regimen without interruption or discontinuation. Small increases in methemoglobin were noted during treatment, and all resolved to baseline within 2 h. Four participants (40%) met the primary outcome measure of negative sputum cultures after three weeks of therapy. Following treatment discontinuation, three of these participants were again culture positive during the 3-month post-treatment monitoring period, although with measures suggesting low bacterial burden., Answer: Patients tolerated a 3-week regimen of gNO without safety concerns, and despite highly refractory disease four individuals completed the study with negative cultures, although three were again positive in subsequent months. These data support further investigation of gNO as a potential therapy for NTM-PD., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Better health and longer survival for many people with cystic fibrosis (PwCF) compels the continued evolution of the CF care model. Designed to deliver specialized care for a complex chronic condition, the model is organized around interdisciplinary healthcare teams at dedicated care centers. Introduction of CFTR modulators and the COVID-19 pandemic have catalyzed the model's evolution. Many PwCF on modulator therapies are experiencing better health and considering changes in their daily care routines. Some of the growing number of adults with CF are experiencing age-associated co-morbidities, requiring coordination with new specialists. The pandemic accelerated the use of telehealth, revealing tradeoffs from new configurations of care delivery. Herein we review the implications of these recent shifts and offer recommendations to improve the quality of care coordinated across the interdisciplinary teams and an expanding field of subspecialists, while supporting the ability of the patient to take on greater responsibility in disease management., Competing Interests: Declarations of Competing Interest None., (Copyright © 2022. Published by Elsevier B.V.)

Objectives: To (1) examine the feasibility of combining lower extremity aerobic exercise (AEx) with a virtual reality (VR) upper extremity (UE) rehabilitation intervention and (2) provide an estimate of effect size for the combined intervention on UE function, aerobic capacity, and health-related quality of life., Design: Single-group feasibility trial., Setting: Research laboratory., Participants: Community-dwelling individuals with mild to moderate impairment of the UE at least 6 months post stroke (N=10; male, n=6; female n=4; mean age, 54 years)., Intervention: All participants received 18 sessions over a nominal 2-3 sessions per week schedule of a combined AEx and VR-UE rehabilitation intervention. During each session, participants completed 15 minutes of lower extremity AEx followed by playing a VR-UE rehabilitation game for approximately 20 minutes., Main Outcome Measures: Feasibility was evaluated by metrics of adherence, retention, treatment acceptability, data completeness, and adverse events. UE function, aerobic capacity (peak oxygen consumption [Vo 2 peak]), and quality of life were assessed with the Fugl-Meyer Assessment of Upper Extremity (FMA-UE), expired gas exchange analysis, and Stroke Impact Scale (SIS), respectively., Results: Adherence was 100%, and there were no withdrawals or losses to follow-up to report. Participants completed the intervention in 49±14 days. Cohen's d z effect size calculations indicated the intervention elicited medium effects on FMA-UE ( d z =0.50) and SIS memory domain ( d z =0.46) and large effects on absolute Vo 2 peak ( d z =1.46), relative Vo 2 peak ( d z =1.21), SIS strength ( d z =1.18), and SIS overall recovery domains ( d z =0.81)., Conclusions: Combining lower extremity AEx and VR-UE rehabilitation appears feasible in the clinical research setting. Fifteen minutes of lower extremity AEx performed at vigorous intensity appears to elicit clinically meaningful benefits in chronic stroke. Further examination of the combination of lower extremity AEx and VR-UE rehabilitation and its effects on physical function and quality of life is warranted.

Strong emphasis has been placed historically on increasing weight and improving nutritional status in cystic fibrosis patients. Due to correlation between nutritional indices (e.g. BMI) and lung function, CF Nutrition Guidelines have recommended BMI percentile goals at the 50th percentile or higher. Trends in increasing BMI across CF programs suggest significantly increasing proportions of overweight and obese status in recent years. We identify that between 2000 and 2019 there has been a relative decrease in underweight status by ∼40%, simultaneously with a > 300% increase in overweight status, and >400% increase in obesity. Patient specific factors associated with higher prevalence of obesity included age ≥46, living in a zip code where the median income was < $20,000, having at least one allele with a class IV or V mutation, a ppFEV 1 >90 prescribed ivacaftor, and not prescribed pancreatic enzymes. Program specific factors were not identified., Competing Interests: Declaration of Competing Interest The authors whose names are listed immediately below certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript., (Copyright © 2022. Published by Elsevier B.V.)

Background: With advances in medical care, patients with cystic fibrosis are more commonly living into adulthood, yet there are limited data describing the need for GI surgery and its outcomes in adult cystic fibrosis patients., Objective: We aim to use a national administrative database to evaluate trends in abdominal GI surgery and associated postoperative outcomes among adult cystic fibrosis patients., Design: This was a national retrospective cohort study., Setting: A national all-payor administrative database from 2000 to 2014 was used., Patients: Patients included adults (age ≥18 years) with cystic fibrosis undergoing abdominal GI surgery., Main Outcome Measures: The primary outcome was trend over time in number of surgical admissions. Secondary outcomes included morbidity and mortality by procedure type., Results: We identified 3075 admissions for abdominal surgery, of which 28% were elective. Major GI surgical procedures increased over the study period ( p < 0.01), whereas appendectomy and cholecystectomy did not demonstrate a clear trend ( p = 0.90). The most common procedure performed was cholecystectomy ( n = 1280; 42%). The most common major surgery was segmental colectomy ( n = 535; 18%). Obstruction was the most common surgical indication ( n = 780; 26%). For major surgery, in-hospital mortality was 6%, morbidity was 37%, and mean length of stay was 15.9 days (SE 1.2)., Limitations: The study is limited by a lack of granular physiological and clinical data within the administrative data source., Conclusions: Major surgical admissions for adult patients with cystic fibrosis are increasing, with the majority being nonelective. Major surgery is associated with significant morbidity, mortality, and prolonged length of hospital stay. These findings may inform perioperative risk for adult patients with cystic fibrosis in need of GI surgery. See Video Abstract at http://links.lww.com/DCR/B850 ., Procedimientos Quirrgicos Abdominales En Pacientes Adultos Con Fibrosis Qustica Cules Son Los Riesgos: ANTECEDENTES:Con los avances en la medicina, los pacientes con fibrosis quística viven más comúnmente hasta la edad adulta, pero hay datos escasos que describan la necesidad de cirugía gastrointestinal y sus resultados en pacientes adultos con fibrosis quística.OBJETIVO:Nuestro objetivo es utilizar una base de datos administrativa nacional para evaluar las tendencias en la cirugía gastrointestinal abdominal y los resultados posoperatorios asociados entre los pacientes adultos con fibrosis quística.DISEÑO:Estudio de cohorte retrospectivo nacional.AJUSTE:Base de datos administrativa nacional de todas las instituciones pagadoras desde 2000 a 2014.PACIENTES:Todos los pacientes adultos (edad> 18) con fibrosis quística sometidos a cirugía gastrointestinal abdominal.PRINCIPALES MEDIDAS DE RESULTADO:El resultado primario fue la tendencia a lo largo del tiempo en el número de ingresos quirúrgicos. Los resultados secundarios incluyeron morbilidad y mortalidad por tipo de procedimiento.RESULTADOS:Identificamos 3.075 ingresos por cirugía abdominal de los cuales el 28% fueron electivos. Los procedimientos quirúrgicos gastrointestinales mayores aumentaron durante el período de estudio (p <0,01) mientras que la apendicectomía y la colecistectomía no demostraron una tendencia clara (p = 0,90). El procedimiento realizado con mayor frecuencia fue la colecistectomía (n = 1.280; 42%). La cirugía mayor más común fue la colectomía segmentaria (n = 535; 18%). La obstrucción fue la indicación quirúrgica más común (n = 780; 26%). Para la cirugía mayor, la mortalidad hospitalaria fue del 6%, la morbilidad del 37% y la estadía media de 15,9 días (EE 1,2).LIMITACIONES:El estudio está limitado por la falta de datos clínicos y fisiológicos granulares dentro de la fuente de datos administrativos.CONCLUSIONES:Los ingresos quirúrgicos mayores de pacientes adultos con fibrosis quística están aumentando y la mayoría no son electivos. La cirugía mayor se asocia con una morbilidad y mortalidad significativas y una estancia hospitalaria prolongada. Estos hallazgos pueden informar el riesgo perioperatorio para pacientes adultos con fibrosis quística que necesitan cirugía gastrointestinal. Consulte Video Resumen en http://links.lww.com/DCR/B850 . (Traducción-Dr. Felipe Bellolio )., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Colon and Rectal Surgeons.)

Background: The purpose of these analyses was to determine whether overall costs were reduced in cystic fibrosis (CF) patients experiencing pulmonary exacerbation (PEx) who received shorter versus longer durations of treatment., Methods: Among people with CF experiencing PEx, we calculated 30-day inpatient, outpatient, emergency room, and medication costs and summed these to derive total costs in 2020 USD. Using the Kaplan-Meier sample average (KMSA) method, we calculated adjusted costs and differences in costs within two pairs of randomized groups: early robust responders (ERR) randomized to receive treatment for 10 days (ERR-10 days) or 14 days (ERR-14 days), and non-early robust responders (NERR) randomized to receive treatment for 14 days (NERR-14 days) or 21 days (NERR-21 days)., Results: Patients in the shorter treatment duration groups had shorter lengths of stay per hospitalization (mean ± standard deviation (SD) for ERR-10 days: 7.9 ± 3.0 days per hospitalization compared to 10.1 ± 4.2 days in ERR-14 days; for NERR-14 days: 8.7 ± 4.9 days per hospitalization compared to 9.6 ± 6.5 days in NERR-21 days). We found statistically significantly lower adjusted mean costs (95% confidence interval) among those who were randomized to receive shorter treatment durations (ERR-10 days: $60,800 ($59,150 - $62,430) vs $74,420 ($72,610 - $76,450) in ERR-14 days; NERR-14 days: $66,690 ($65,960-$67,400) versus $74,830 ($73,980-$75,650) in NERR-21 days)., Conclusions: Tied with earlier evidence that shorter treatment duration was not associated with worse clinical outcomes, our analyses indicate that treating with shorter antimicrobial durations can reduce costs without diminishing clinical outcomes., Competing Interests: Declaration of Competing Interest Grants from the Cystic Fibrosis Foundation in part supported the salaries of LSG, RNH, DLP, AT, SLH, PAF, CHG, NEW, DBS, DRV, and LK. Grants from the NIH in part supported the salaries of SLH, PAF, and CHG. DBS received payments for committee work from the Cystic Fibrosis foundation. DBS's institution also grant support payments from Gilead Sciences and the CHEST Foundation. DBS received personal payment for participation on an advisory board for Vertex Pharmaceuticals., (Copyright © 2022. Published by Elsevier B.V.)

We report elexacaftor-tezacaftor-ivacaftor (ETI) treatment of a F508del carrier who was pregnant with a F508del homozygous fetus. At 23-weeks gestation meconium ileus (MI) was evident on ultrasound including dilated, hyperechoic bowel, which persisted on subsequent imaging. Through shared decision-making, the mother began ETI at 32 weeks with intent to treat fetal MI. The ultrasound findings persisted at treatment day 13, but bowel dilation had resolved by imaging on treatment day 27. A female infant was delivered vaginally at 36 weeks with no complications. The mother continued ETI while breastfeeding. Stool elastase at age 2 weeks was 240 mcg/g. Sweat chloride measurement was 64 and 62 mEq/L. Maternal and infant liver function testing have been normal. Maternal ETI treatment likely led to resolution of the MI and there is evidence supporting continued infant benefit through breastmilk. Logistical and ethical considerations regarding treatment of a carrier mother for infant benefit are discussed., Competing Interests: Declaration of Competing Interest Patrick Flume receives research support and consultation fees from Vertex Pharmaceuticals. All other authors declare no conflict of interest., (Copyright © 2022 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Patients with cystic fibrosis (CF) and pancreatic insufficiency are at risk for suboptimal fat absorption, inability to maintain weight, poor growth, and increased gastrointestinal (GI) symptoms due to malabsorption. Enteral nutrition (EN) is used to supplement caloric intake and requires pancreatic enzyme replacement for effective digestion. We evaluated the relationship between long-term use of an in-line digestive enzyme cartridge with EN and changes in anthropometric measures and GI symptoms in patients with CF., Methods: This is a single-center, retrospective case review of patients with CF using a digestive enzyme cartridge with EN. Data were collected from the patient medical records and included weight, height, body mass index, EN regimen, and reported GI symptoms., Results: Thirteen pediatric and five adult patients with a mean age of 12.6 years used a digestive enzyme cartridge with EN for a period of 3-27 months. Most patients (n = 14) had been using oral digestive enzymes with EN before using the digestive enzyme cartridge, whereas four started from the onset of EN. The indications to convert from oral enzymes to the digestive enzyme cartridge included poor growth (72.2%) and poor tolerance of EN (69.2%). There was a reduction in reported GI symptoms after initiating use of the digestive enzyme cartridge. After 12 months of digestive cartridge use, there were improvements in anthropometrics., Conclusions: This real-world experience with prolonged use of a digestive enzyme cartridge with EN demonstrated improved clinical outcomes and a reduction in GI symptoms in patients with CF., (© 2022 American Society for Parenteral and Enteral Nutrition.)

Background: Mycobacterial time to positivity (TTP) in liquid culture media has predictive value for longer term outcomes in pulmonary tuberculosis, but has not been thoroughly studied in nontuberculous mycobacterial pulmonary disease. This study sought to evaluate for association between TTP and sputum culture conversion to negative in pulmonary disease caused by Mycobacterium avium complex (MAC)., Methods: Data from the CONVERT trial (NCT02344004) that evaluated efficacy of guideline-based-therapy with or without amikacin liposome inhalation suspension in adults with refractory MAC-PD (Mycobacterium avium complex pulmonary disease) were analyzed. We evaluated TTP measures for sputum obtained prior to study treatment initiation and at monthly visits, assessing reproducibility of measures as well as association of TTP with culture conversion on treatment., Results: Data from 71 participants with at least one screening visit TTP value were analyzed. For participants who provided more than one sputum sample at a given visit, there was moderate between-sample reliability, with median intraclass correlation coefficient 0.62 (IQR 0.50, 0.70). Median TTP at screening was longer in those participants who subsequently achieved vs. did not achieve culture conversion (10.5 [IQR 9.4] days vs. 4.2 [IQR 2.8] days, p = 0.0002). Individuals with culture conversion by study treatment month 6 were more likely to have a screening TTP > 5 days compared to those who did not achieve culture conversion (OR 15.4, 95% CI 1.9, 716.7, p = 0.0037) and had increasing TTPs over time., Conclusions: TTP prior to and on treatment is associated with microbiological treatment response in patients with MAC-PD., (© 2022. The Author(s).)

Background: People with cystic fibrosis (CF) heterozygous for F508del-CFTR and a minimal function CFTR mutation (F/MF) that results in no CFTR protein or results in CFTR protein that is not responsive to tezacaftor, ivacaftor, and tezacaftor/ivacaftor in vitro comprise a sizeable percentage of the US CF population. This retrospective, cross-sectional, observational study aimed to characterize CF burden in this subpopulation., Methods: People ≥2 years of age in the US CF Foundation Patient Registry with a CF diagnosis, F/MF genotype, and ≥1 encounters in 2017 were included. Descriptive analyses assessed lung function, nutritional parameters, microbiology, hospitalization and pulmonary exacerbation rates, and CF-related complications. Results were stratified by age group; select characteristics were summarized by percent predicted FEV 1 (ppFEV 1 ) and ethnicity., Results: 5348 people met inclusion criteria. Rates of positive bacterial cultures, pulmonary exacerbations, and hospitalizations were generally higher in older age groups. Prevalence of prescribed symptomatic CF therapies was substantial and also generally higher in older age groups. ppFEV 1 was lower in older age groups. A greater percentage of adolescents and adults reported complications, including cirrhosis, osteoporosis, osteopenia, and sinus disease, than younger age groups. Increased prevalence of cultured Pseudomonas aeruginosa and prescribed chronic therapy was seen with decreasing ppFEV 1 . In each age group, ppFEV 1 was slightly higher in the non-Hispanic cohort than in the Hispanic cohort., Conclusions: People with F/MF genotypes have substantial disease burden that worsened in older age groups consistent with the progressive nature of CF, indicating need for additional treatment options in this subpopulation., Competing Interests: Declaration of Competing Interest All authors received nonfinancial assistance (assistance with manuscript preparation) from ArticulateScience LLC, which received funding from Vertex Pharmaceuticals Incorporated. Additional disclosures are as follows: GSS reports personal fees from Vertex; KVB and JB are employees of Vertex and may own stock or stock options in Vertex; EB is a former employee of Vertex and may own stock or stock options in the company; SJM is an employee of ICON Clinical Research, which received funding from various pharmaceutical, biotechnology, and device companies for providing clinical research services and received funding from Vertex for analytical services during the conduct of this study; MWK reports grants and personal fees from Vertex; PAF reports grants and personal fees from Vertex., (Copyright © 2021. Published by Elsevier B.V.)

Rationale: People with cystic fibrosis (CF) experience acute worsening of respiratory symptoms and lung function known as pulmonary exacerbations. Treatment with intravenous antimicrobials is common; however, there is scant evidence to support a standard treatment duration. Objectives: To test differing durations of intravenous antimicrobials for CF exacerbations. Methods: STOP2 (Standardized Treatment of Pulmonary Exacerbations 2) was a multicenter, randomized, controlled clinical trial in exacerbations among adults with CF. After 7-10 days of treatment, participants exhibiting predefined lung function and symptom improvements were randomized to 10 or 14 days' total antimicrobial duration; all others were randomized to 14 or 21 days' duration. Measurements and Main Results: The primary outcome was percent predicted FEV 1 (ppFEV 1 ) change from treatment initiation to 2 weeks after cessation. Among early responders, noninferiority of 10 days to 14 days was tested; superiority of 21 days compared with 14 days was compared for the others. Symptoms, weight, and adverse events were secondary. Among 982 randomized people, 277 met improvement criteria and were randomized to 10 or 14 days of treatment; the remaining 705 received 21 or 14 days of treatment. Mean ppFEV 1 change was 12.8 and 13.4 for 10 and 14 days, respectively, a ‒0.65 difference (95% CI [‒3.3 to 2.0]), excluding the predefined noninferiority margin. The 21- and 14-day arms experienced 3.3 and 3.4 mean ppFEV 1 changes, a difference of ‒0.10 (‒1.3 to 1.1). Secondary endpoints and sensitivity analyses were supportive. Conclusions: Among adults with CF with early treatment improvement during exacerbation, ppFEV 1 after 10 days of intravenous antimicrobials is not inferior to 14 days. For those with less improvement after one week, 21 days is not superior to 14 days. Clinical trial registered with www.clinicaltrials.gov (NCT02781610).

Background: Nontuberculous mycobacterial pulmonary disease (NTM-PD) is an uncommon mycobacterial infection characterized by worsening lung function and increased health care resource utilization; however, the overall risk for hospitalization among patients with NTM-PD remains unclear., Research Question: What is the hospitalization risk among older adults with NTM-PD?, Study Design and Methods: A retrospective, nested, case-control study was conducted by using the Medicare claims database. Cases were defined as patients with ≥ 2 NTM-PD claims ≥ 30 days apart between January 1, 2007, and December 31, 2015. The study included individuals aged ≥ 65 years with ≥ 12 months of continuous enrollment in both Parts A and B before the first NTM-PD diagnosis. Cases were matched 1:2 to Medicare beneficiaries without NTM-PD (control subjects) according to age and sex. Hospitalizations following the first NTM-PD claim were compared between case and control subjects by using univariate and multivariate analyses., Results: A total of 35,444 case subjects and 65,467 matched control subjects (mean age, 76.6 years; 70% female; ≥ 87% White) were identified. Baseline comorbidities, particularly pulmonary comorbidities, were more common in case subjects than in control subjects (81.1% vs 17.7% for COPD; 44.6% vs 0.6% for bronchiectasis). All-cause hospitalization was observed in 65.7% of case subjects and 44.9% of control subjects. Unadjusted annual hospitalization rates were significantly (P < .05) greater among case subjects than control subjects. Case subjects also had a significantly shorter time to hospitalization than control subjects. The increased burden due to hospitalization was reflected in multivariate analysis adjusting for baseline comorbidities. All-cause hospitalization in patients with NTM-PD relative to control subjects was 1.2 times more likely (relative risk, 1.23; 95% CI, 1.21-1.25; P < .0001) with a 46% greater hazard (hazard ratio, 1.46; 95% CI, 1.43-1.50; P < .0001)., Interpretation: Patients with NTM-PD were significantly more likely to be hospitalized, had greater annualized hospitalization rates, and had shorter time to hospitalization than age- and sex-matched control subjects without NTM-PD. These findings highlight the significantly increased burden of hospitalizations among patients with NTM-PD., (Published by Elsevier Inc.)

Background: Mannitol is a mucoactive hyperosmotic agent used as add-on therapy in patients with cystic fibrosis (CF), administered twice-daily (BID) via a small, portable, breath-actuated dry-powder inhaler. This study was conducted to provide confirmatory evidence of mannitol's efficacy and safety in adults., Methods: This multicenter, double-blind, randomized, parallel-group, controlled clinical trial recruited adults (aged ≥18 years) with CF, and forced expiratory volume in 1 second (FEV 1 ) 40-90% predicted. Subjects received either mannitol 400 mg or mannitol 50 mg (control), BID via dry-powder inhaler for 26 weeks. Primary endpoint: FEV 1 averaged over the 26-week treatment period., Results: Of 423 subjects randomized (209 or 214 receiving mannitol 400 mg BID or control, respectively), 373 (88.2%) completed the study, with a similar proportion completing in the two groups. For FEV 1 averaged over 26 weeks, mannitol 400 mg BID was statistically superior to control (adjusted mean difference 54 mL [95% CI 8, 100 mL]; p = 0.020). This was supported by sensitivity analyses of the primary endpoint, and by observed improvements in secondary pulmonary function endpoints (eg, absolute adjusted mean difference in percent predicted FEV 1 averaged over 26 weeks 1.21% [0.07%, 2.36%]; p = 0.037). Adverse events were mainly mild or moderate in severity, with treatment-related adverse events in 15.5 and 12.2% of subjects receiving mannitol 400 mg BID and control, respectively., Conclusions: In adults with CF, mannitol 400 mg BID inhaled as a dry-powder statistically significantly improved lung function (FEV 1 ) compared with control, with this improvement supported by sensitivity analyses and secondary pulmonary function endpoints. Mannitol had a good overall safety and tolerability profile. ClinicalTrials.gov: NCT02134353., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

1 Cystic fibrosis (CF) is an autosomal recessive genetic condition with multisystemic disease manifestations, the most prominent of which occur in the respiratory system. Despite significant developments in disease understanding and therapeutics, each contributing to improved lung function and survival in patients with CF, several pulmonary complications, including pneumothorax, massive hemoptysis, and respiratory failure, continue to occur. In this review, we briefly describe each of these complications and their management and discuss how they impact the care and disease trajectory of individuals in whom they occur. Finally, we discuss the evolving role that palliative care and CF transmembrane conductance regular modulator therapies play in the natural disease course and care of patients with CF., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

People with cystic fibrosis (CF) are highly susceptible to bacterial infections of the airways. By adulthood, chronic Pseudomonas aeruginosa ( Pa ) is the most prevalent infective organism and is difficult to eradicate owing to its adaptation to the CF lung microenvironment. Long-term suppressive treatment with inhaled antimicrobials is the standard care for reducing exacerbation frequency, improving quality of life and increasing measures of lung function. Levofloxacin (a fluoroquinolone antimicrobial) has been approved as an inhaled solution in Europe and Canada, for the treatment of adults with CF with chronic P. aeruginosa pulmonary infections. Here, we review the clinical principles relating to the use of inhaled antimicrobials and inhaled levofloxacin for the management of P. aeruginosa infections in patients with CF.

Background: In the CONVERT study, treatment with amikacin liposome inhalation suspension (ALIS) added to guideline-based therapy (GBT) met the primary end point of increased culture conversion by month 6 in patients with treatment-refractory Mycobacterium avium complex lung disease (ALIS plus GBT, 29% [65/224] vs GBT alone, 8.9% [10/112]; P < .0001)., Research Question: In patients who achieved culture conversion by month 6 in the CONVERT study, was conversion sustained (negative sputum culture results for 12 months with treatment) and durable (negative sputum culture results for 3 months after treatment) and were there any additional safety signals associated with a full treatment course of 12 months after conversion?, Study Design and Methods: Adults were randomized 2:1 to receive ALIS plus GBT or GBT alone. Patients achieving culture conversion by month 6 continued therapy for 12 months followed by off-treatment observation., Results: More patients randomized to ALIS plus GBT (intention-to-treat population) achieved conversion that was both sustained and durable 3 months after treatment vs patients randomized to GBT alone (ALIS plus GBT, 16.1% [36/224] vs GBT alone, 0% [0/112]; P < .0001). Of the patients who achieved culture conversion by month 6, 55.4% of converters (36/65) in the ALIS plus GBT treated arm vs no converters (0/10) in the GBT alone arm achieved sustained and durable conversion (P = .0017). Relapse rates through 3 months after treatment were 9.2% (6/65) in the ALIS plus GBT arm and 30.0% (3/10) in the GBT alone arm. Common adverse events among ALIS plus GBT-treated patients (dysphonia, cough, dyspnea, hemoptysis) occurred mainly within the first 8 months of treatment., Interpretation: In a refractory population, conversion was sustained and durable in more patients treated with ALIS plus GBT for 12 months after conversion than in those treated with GBT alone. No new safety signals were associated with 12 months of treatment after conversion., Trial Registry: ClinicalTrials.gov; No.: NCT02344004; URL: www.clinicaltrials.gov., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

COVID-19 pandemic exerts a health care emergency around the world. The illness severity is heterogeneous. It is mostly unknown why some individuals who are positive for SARS-CoV-2 antibodies stay asymptomatic while others show moderate to severe disease symptoms. Reliable biomarkers for early detection of the disease are urgently needed to attenuate the virus's spread and help make early treatment decisions. Bioactive sphingolipids play a crucial role in the regulation of viral infections and pro-inflammatory responses involved in the severity of COVID-19. However, any roles of sphingolipids in COVID-19 development or detection remain unknown. In this study, lipidomics measurement of serum sphingolipids demonstrated that reduced sphingosine levels are highly associated with the development of symptomatic COVID-19 in the majority (99.24%) SARS-CoV-2-infected patients compared to asymptomatic counterparts. The majority of asymptomatic individuals (73%) exhibited increased acid ceramidase (AC) in their serum, measured by Western blotting, consistent with elevated sphingosine levels compared to SARS-CoV-2 antibody negative controls. AC protein was also reduced in almost all of the symptomatic patients' serum, linked to reduced sphingosine levels, measured in longitudinal acute or convalescent COVID-19 samples. Thus, reduced sphingosine levels provide a sensitive and selective serologic biomarker for the early identification of asymptomatic versus symptomatic COVID-19 patients., (© 2021. The Author(s).)

Rationale: Patients with refractory Mycobacterium avium complex (MAC) lung disease have limited treatment options. In the CONVERT study, amikacin liposome inhalation suspension (ALIS) added to guideline-based therapy (GBT) increased culture conversion rates versus GBT alone by Month 6. Limited data are available regarding >6-month treatment in a refractory population. Objectives: Evaluate 12-month safety, tolerability, and efficacy of ALIS+GBT. Methods: Adults with refractory MAC lung disease not achieving culture conversion by CONVERT Month 6 could enroll in this open-label extension (INS-312) to receive 590 mg once-daily ALIS+GBT for 12 months. Two cohorts enrolled: the "ALIS-naive" cohort included patients randomized to GBT alone in CONVERT, and the "prior-ALIS" cohort included those randomized to ALIS+GBT in CONVERT. Safety and tolerability of ALIS over 12 months (primary endpoint) and culture conversion by Months 6 and 12 were assessed. Results: In the ALIS-naive cohort, 83.3% of patients ( n  = 75/90) experienced respiratory treatment-emergent adverse events (TEAEs), and 35.6% ( n  = 32) had serious TEAEs; 26.7% ( n  = 24) achieved culture conversion by Month 6 and 33.3% ( n  = 30) by Month 12. In the prior-ALIS cohort, 46.6% of patients ( n  = 34/73) experienced respiratory TEAEs, and 27.4% ( n  = 20) had serious TEAEs; 9.6% ( n  = 7) achieved culture conversion by Month 6 (≤14 mo ALIS exposure) and 13.7% ( n  = 10) by Month 12 (≤20 mo ALIS exposure). Nephrotoxicity-related TEAEs and measured hearing decline were infrequent in both cohorts. Conclusions: In up to 20 months of ALIS use, respiratory TEAEs were common, nephrotoxicity and hearing decline were infrequent, and culture conversion continued beyond 6 months of therapy.Clinical trial registered with www.clinicaltrials.gov (NCT02628600).

Background: Tezacaftor-ivacaftor is an approved cystic fibrosis transmembrane conductance regulator (CFTR) modulator shown to be efficacious and generally safe and well tolerated over 8-24 weeks in phase 3 clinical studies in participants aged 12 years or older with cystic fibrosis homozygous for the Phe508del CFTR mutation (F/F; study 661-106 [EVOLVE]) or heterozygous for the Phe508del CFTR mutation and a residual function mutation (F/RF; study 661-108 [EXPAND]). Longer-term (>24 weeks) safety and efficacy of tezacaftor-ivacaftor has not been assessed in clinical studies. Here, we present results of study 661-110 (EXTEND), a 96-week open-label extension study that assessed long-term safety, tolerability, and efficacy of tezacaftor-ivacaftor in participants aged 12 years or older with cystic fibrosis who were homozygous or heterozygous for the Phe508del CFTR mutation., Methods: Study 661-110 was a 96-week, phase 3, multicentre, open-label study at 170 clinical research sites in Australia, Europe, Israel, and North America. Participants were aged 12 years or older, had cystic fibrosis, were homozygous or heterozygous for Phe508del CFTR, and completed one of six parent studies of tezacaftor-ivacaftor: studies 661-103, 661-106, 661-107, 661-108, 661-109, and 661-111. Participants received oral tezacaftor 100 mg once daily and oral ivacaftor 150 mg once every 12 h for up to 96 weeks. The primary endpoint was safety and tolerability. Secondary endpoints were changes in lung function, nutritional parameters, and respiratory symptom scores; pulmonary exacerbations; and pharmacokinetic parameters. A post-hoc analysis assessed the rate of lung function decline in F/F participants who received up to 120 weeks of tezacaftor-ivacaftor in studies 661-106 (F/F) and/or 661-110 compared with a matched cohort of CFTR modulator-untreated historical F/F controls from the Cystic Fibrosis Foundation Patient Registry. Primary safety analyses were done in all participants from all six parent studies who received at least one dose of study drug during this study. This study was registered at ClinicalTrials.gov (NCT02565914)., Findings: Between Aug 31, 2015, to May 31, 2019, 1044 participants were enrolled in study 661-110 from the six parent studies of whom 1042 participants received at least one dose of study drug and were included in the safety set. 995 (95%) participants had at least one TEAE; 22 (2%) had TEAEs leading to discontinuation; and 351 (34%) had serious TEAEs. No deaths occurred during the treatment-emergent period; after the treatment-emergent period, two deaths occurred, which were both deemed unrelated to study drug. F/F (106/110; n=459) and F/RF (108/110; n=226) participants beginning tezacaftor-ivacaftor in study 661-110 had improvements in efficacy endpoints consistent with parent studies; improvements in lung function and nutritional parameters and reductions in pulmonary exacerbations observed in the tezacaftor-ivacaftor groups in the parent studies were generally maintained in study 661-110 for an additional 96 weeks. Pharmacokinetic parameters were also similar to those in the parent studies. The annualised rate of lung function decline was 61·5% (95% CI 35·8 to 86·1) lower in tezacaftor-ivacaftor-treated F/F participants versus untreated matched historical controls., Interpretation: Tezacaftor-ivacaftor was generally safe, well tolerated, and efficacious for up to 120 weeks, and the safety profile of tezacaftor-ivacaftor in study 661-110 was consistent with cystic fibrosis manifestations and with the safety profiles of the parent studies. The rate of lung function decline was significantly reduced in F/F participants, consistent with cystic fibrosis disease modification. Our results support the clinical benefit of long-term tezacaftor-ivacaftor treatment for people aged 12 years or older with cystic fibrosis with F/F or F/RF genotypes., Funding: Vertex Pharmaceuticals Incorporated., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The SARS-CoV-2 viral pandemic has induced a global health crisis, which requires more in-depth investigation into immunological responses to develop effective treatments and vaccines. To understand protective immunity against COVID-19, we screened over 60,000 asymptomatic individuals in the Southeastern United States for IgG antibody positivity against the viral Spike protein, and approximately 3% were positive. Of these 3%, individuals with the highest anti-S or anti-RBD IgG level showed a strong correlation with inhibition of ACE2 binding and cross-reactivity against non-SARS-CoV-2 coronavirus S-proteins. We also analyzed samples from 94 SARS-CoV-2 patients and compared them with those of asymptomatic individuals. SARS-CoV-2 symptomatic patients had decreased antibody responses, ACE2 binding inhibition, and antibody cross-reactivity. Our study shows that healthy individuals can mount robust immune responses against SARS-CoV-2 without symptoms. Furthermore, IgG antibody responses against S and RBD may correlate with high inhibition of ACE2 binding in individuals tested for SARS-CoV-2 infection or post vaccination., Competing Interests: All authors declare no competing interests., (© 2021 The Authors.)

Background: Chronic lung infections and their treatment pose risks for the development of antimicrobial resistance (AMR) in people with cystic fibrosis (PWCF). In this study, we evaluated the attitudes of healthcare providers' (HCP) and PWCF or their parents' toward AMR within the international CF community., Methods: HCP and PWCF identified through listservs and CF-related organizations were asked to complete an AMR centered survey, with additional questions on antimicrobial stewardship (AMS) for HCP. Descriptive analyses are reported., Results: The responding 443 HCP and 464 PWCF/Parents were from 30 and 25 countries, respectively. Sixty-two percent of HCP and 56% of PWCF stated they were "very concerned" about AMR, with Pseudomonas spp. and Burkholderia spp. considered the most concerning organisms for both HCP and PWCF/Parents. Non-tuberculous mycobacteria were of greater concern to HCP compared to PWCF/Parents. There was a discrepancy regarding AMR education to PWCF, with 80% of HCP stating having discussed this with PWCF/Parents, but only 50% of PWCF recalling such discussions., Conclusion: These results highlight that AMR is relevant to CF HCP and PWCF internationally, indicating that educational tools and research are warranted., (Copyright © 2020. Published by Elsevier B.V.)

Introduction: COVID-19 altered research in Clinical and Translational Science Award (CTSA) hubs in an unprecedented manner, leading to adjustments for COVID-19 research., Methods: CTSA members volunteered to conduct a review on the impact of CTSA network on COVID-19 pandemic with the assistance from NIH survey team in October 2020. The survey questions included the involvement of CTSAs in decision-making concerning the prioritization of COVID-19 studies. Descriptive and statistical analyses were conducted to analyze the survey data., Results: 60 of the 64 CTSAs completed the survey. Most CTSAs lacked preparedness but promptly responded to the pandemic. Early disruption of research triggered, enhanced CTSA engagement, creation of dedicated research areas and triage for prioritization of COVID-19 studies. CTSAs involvement in decision-making were 16.75 times more likely to create dedicated diagnostic laboratories (95% confidence interval [CI] = 2.17-129.39; P < 0.01). Likewise, institutions with internal funding were 3.88 times more likely to establish COVID-19 dedicated research (95% CI = 1.12-13.40; P < 0.05). CTSAs were instrumental in securing funds and facilitating establishment of laboratory/clinical spaces for COVID-19 research. Workflow was modified to support contracting and IRB review at most institutions with CTSAs. To mitigate chaos generated by competing clinical trials, central feasibility committees were often formed for orderly review/prioritization., Conclusions: The lessons learned from the COVID-19 pandemic emphasize the pivotal role of CTSAs in prioritizing studies and establishing the necessary research infrastructure, and the importance of prompt and flexible research leadership with decision-making capacity to manage future pandemics., Competing Interests: The authors have no conflicts of interest to declare., (© The Association for Clinical and Translational Science 2021.)

Introduction: The coronavirus disease 2019 (COVID-19) created major disruptions at academic centers and healthcare systems globally. Clinical and Translational Science Awards (CTSA) fund hubs supported by the National Center for Advancing Translational Sciences provideinfrastructure and leadership for clinical and translational research at manysuch institutions., Methods: We surveyed CTSA hubs and received responses from 94% of them regarding the impact of the pandemic and the processes employed for the protection of research personnel and participants with respect to the conduct of research, specifically for studies unrelated to COVID-19., Results: In this report, we describe the results of the survey findings in the context of the current understanding of disease transmission and mitigation techniques., Conclusions: We reflect on common practices and provide recommendations regarding lessons learned that will be relevant to future pandemics, particularly with regards to staging the cessation and resumption of research activities with an aim to keep the workforce, research participants, and our communities safe in future pandemics., Competing Interests: The authors have no conflicts of interest to declare., (© The Association for Clinical and Translational Science 2021.)

Aminoglycosides are commonly used to treat infections in CF patients and are highly ototoxic. The incidence of tobramycin-induced hearing loss, tinnitus, vertigo or dizziness (ototoxicity) varies widely from 0 to 56% secondary to variation in patient enrollment, dosing, audiometry, and ototoxic criteria. The aim of this study is to determine the incidence of ototoxicity after one course of once-daily IV tobramycin in CF patients. Adult CF patients with acute pulmonary exacerbations were enrolled on IV tobramycin (10 mg/kg/d, ≥10 days). Pure-tone audiometry was performed for standard and extended high frequencies in the sensitive range for ototoxicity (SRO). American-Speech-Language-Hearing-Association cochleotoxicity criteria were applied. Distortion product otoacoustic emissions (DPOAE) and the words-in-noise-test (WINT) were assessed. Tinnitus Functional Index (TFI) and Vertigo Symptoms Scale (VSS) were used. Eighteen CF patients, mean age 31.1 (18-59), were enrolled. The incidence of cochleotoxic change from baseline at 2 and 4 weeks post-treatment was 89% and 93%. For DPOAE, a measure of outer hair-cell function, the incidence of ≥5 dB decrease was 82% and 80%. For WINT, a measure of word recognition, the incidence of ≥10% decrease was 17% and 40%. For TFI, the incidence of ≥10pt increase was 12% and 8%, and for VSS, the incidence of ≥6pt increase was 0% and 8%. One course of IV tobramycin was sufficient to cause hearing loss and other ototoxic symptoms four weeks after treatment ended. Audiometric measures were more sensitive to ototoxic change than TFI & VSS. Age and duration of tobramycin treatment were not obvious factors for predicting ototoxicity., (Copyright © 2020. Published by Elsevier B.V.)

The US Food and Drug Administration convened a workshop to discuss clinical trial design challenges and considerations related to the treatment of nontuberculous mycobacterial pulmonary disease, to include topics such as clinical trial end points, duration, and populations. The clinicians participating in the meeting provide here their interpretation of the discussion, which included US Food and Drug Administration and industry representatives. The treatment of nontuberculous mycobacterial pulmonary disease typically includes multiple antibiotics for a prolonged period and can be difficult to tolerate; there is a great need for new treatment options. Most individuals have a microbiologic response to therapy, but data correlating decreasing bacillary load with patient-reported outcomes or measured functional improvement are lacking. Accordingly, trial designs for new therapeutic agents should incorporate both microbiologic and clinical outcome measures and select appropriate study candidates with capacity for measurable change of such outcome measures. The need for shorter study designs, early primary end points, and placebo control arms was highlighted during the workshop., (Copyright © 2020 American College of Chest Physicians. All rights reserved.)

Background: Current guidelines recommend at least once yearly screening for nontuberculous mycobacteria (NTM) in Cystic Fibrosis (CF), however screening practices remain widely variable. This study evaluates current practices among United States CF centers with specific focus on clinical predictive factors for NTM screening., Methods: The CF Patient Registry (CFFPR) was queried for CF patients ages 10 and older with NTM cultures completed between 2010-2014. Predictors for screening were assessed using univariate and multivariate logistic regression. Centers were evaluated by groups based on screening rates for analysis of clinical drivers of screening., Results: From 2010-2014 a total of 22,739 patients were identified with 17,177 (75.5%) tested for NTM during this time. In the overall cohort, those who were tested for NTM had lower pulmonary function (70.7% vs 83.9%), higher annual average of visits with pulmonary exacerbations (1.0 vs 0.3), and higher rate of coinfection with Pseudomonas aeruginosa (PA) as well as Methicillin resistant Staphylococcus aureus (MRSA). Among CF centers, pulmonary function, exacerbations, and coinfections with PA and MRSA were predictive of NTM screening in the lower screening cohort while pulmonary function was not predictive of screening in the highest screening cohort. Those programs who screened at a higher rate were successful in identifying NTM in more CF patients., Conclusion: NTM screening practices vary widely among United States CF centers with many centers testing only on clinical changes. With higher rates of testing shown as successful in identifying more patients with NTM, routine screening should be emphasized in CF care going forward., Competing Interests: Declaration of Competing Interests Patrick Flume reports grants and personal fees from Bayer Healthcare AG, grants and personal fees from Insmed, grants from Novoteris, personal fees from Eloxx Pharmaceuticals, personal fees from Horizon Pharma, outside the submitted work. Derek Low and Dulaney Wilson declare there are no conflicts of interest related to this work., (Copyright © 2020. Published by Elsevier B.V.)

Antimicrobials have undoubtedly improved the lives of people with CF, but important antimicrobial-related toxicities and the emergence of antimicrobial-resistant bacteria associated with their use must be considered. Antimicrobial stewardship (AMS) is advocated across the spectrum of healthcare to promote the appropriate use of antimicrobials to preserve their current effectiveness and to optimise treatment, and it is clear that AMS strategies are applicable to and can benefit both non-CF and CF populations. This perspective explores the definition and components of an AMS program, the current evidence for AMS, and the reasons why AMS is a challenging concept in the provision of CF care. We also discuss the elements of CF care which align with AMS programs and principles and propose research priorities for AMS in CF., Competing Interests: Declaration of Competing Interest Drs. Kahl, Maples, Holmes and Muhlebach have nothing to disclose. Dr. Cogen reports grants from the Cystic Fibrosis Foundation outside of this work. Dr. McColley reports disclosures from Vertex Pharmaceuticals, Gilead Sciences, and grants from Northwestern University Clinical and Translational Sciences Institute outside of this work. Dr. Roberts reports grants and personal fees from MSD, grants from QPEX, personal fees from Discuva, personal fees from Accelerate Diagnostics, grants and personal fees from Biomerieux, grants and personal fees from Pfizer and grants from The Medicines Company outside of this work. Dr. Winthrop reports grants and personal fees from Pfizer, personal fees from AbbVie, personal fees from UCB, personal fees from Lilly, personal fees from Galapagos, personal fees from GSK, personal fees from Roche, personal fees from Gilead, grants from BMS, and grants from Insmed outside of this work. Dr. Morris reports and receives salary support from the Sinai Health and University Health Network in his role as Director of their Antimicrobial Stewardship Program. Dr. Flume reports grants outside of this submitted work from the European Cystic Fibrosis Society, the Cystic Fibrosis Foundation, Cystic Fibrosis Trust, Cystic Fibrosis Canada, Cystic Fibrosis Australia, and Novoteris. Dr. Flume also receives personal fees from Insmed outside this submitted work. Dr. VanDevanter reports personal fees from AbbVie, Albumedix, AN2, Aradigm, Armata, Arrevus, Calithera, Chiesi USA, Cipla, Corbus, Cystic Fibrosis Foundation, Eloxx, Enbiotix, Eveo, Galephar, Horizon, IBF, ICON clinical sciences, Ionis, Kala, Merck, Microbion, NDA, Protalix, PTC, Pulmocide, Recida, Savara, Vast, and Vertex outside of this work. Dr. Waters reports grants from Gilead and Astrazenca outside of this work. Dr. Elborn reports grants from Innovative Medicines Institute, Framework Seven, European Commission, Medical Research Council, and Bronch UK during the conduct of the study. Dr. Saiman reports grants from the CF Foundation, Merck, and AztraZeneca outside of this work. Dr. Bell reports grants and other support from Vertex, Galapagos and AbbVie outside of this work., (Copyright © 2020. Published by Elsevier B.V.)

Background: Antimicrobial susceptibility testing (AST) is a cornerstone of infection management in cystic fibrosis. However, there is little evidence that AST predicts the clinical outcome of CF antimicrobial treatment. It has been suggested there is a need for careful consideration of current AST use by the CF community., Methods: We engaged a group of experts consisting of pulmonary (adult and pediatric) and infectious disease clinicians, microbiologists, and pharmacists representing a broad international experience. We conducted an iterative systematic survey (Delphi) to determine and quantify consensus regarding key questions facing CF clinicians in the use of respiratory culture results including what tests to order, when to obtain them, and how to act upon the results of the testing., Results: Consensus was reached for many questions but there was not universal agreement to the questions that were addressed. There were some differences with respect to cultures obtained for surveillance compared to when there is clinical worsening. Areas of general consensus include when and how respiratory cultures should be performed, what information should be reported, and when AST should be performed. A key finding is that clinical response to treatment is used to guide treatment decisions rather than AST results., Conclusions: Recommendations are presented regarding questions related to microbiology testing for patients with CF. We have also offered recommendations for priority research questions., Competing Interests: Declaration of Competing Interest None., (Copyright © 2019 European Cystic Fibrosis Society. All rights reserved.)

Background: Most studies of pulmonary exacerbations (PEx) in cystic fibrosis (CF) focus on intravenous (IV)-treated PEx, though most PEx are treated with oral antibiotics. Our objectives were to describe predictors of antibiotic choice and outcomes for PEx initially identified in clinic., Methods: For each patient in the U.S. CF Foundation Patient Registry, we selected the first PEx recorded at a clinic visit in 2013-14 following a clinic visit without a PEx. We used multivariable logistic regression to determine associations between clinical characteristics and antibiotic treatment choice. We determined outcomes in the 90 days after the first PEx., Results: Among 14,265 patients with a PEx initially identified in clinic, 21.4% received no antibiotics, 61.5% received new oral and/or inhaled antibiotics, and 17.0% had IV antibiotics within 14 days. Compared to IV antibiotics, patients more likely to receive new oral and/or inhaled antibiotics: were male, <13 years old, had BMI >10th percentile or 18.5 kg/m 2 , >90 days between clinic visits, FEV 1  > 70% predicted at the PEx, no prior-year IV-treated PEx, FEV 1 decline <10% predicted, and private insurance. Following the PEx, 30.3% of patients had no clinical encounters within 90 days. Treatment with IV antibiotics within 90 days occurred for 23.7% treated without antibiotics, 22.8% of new oral and/or inhaled antibiotics, and 27.1% of IV antibiotics., Conclusion: Most PEx identified in clinic are treated with new oral and/or inhaled antibiotics. Markers of disease severity are associated with antibiotic treatment choice. Many patients had no follow-up evaluation within 90 days of treatment., (Copyright © 2019 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

ClinicalTrials.gov is a web-based resource which provides the general public, healthcare professionals, patients, and caregivers access to privately and publicly supported clinical trials and trial results. The web site is maintained by the National Library of Medicine (NLM) at the National Institutes of Health (NIH) (ClinicalTrials.gov Background, 2018). The penalties for non-compliance with the legal obligations under FDAAA 801 (Food and Drug Administration Amendments Act of 2007) and the NIH requirements for registering and reporting results on studies within certain timeframes can result in large monetary fines and the withholding of federal funds (ClinicalTrials.gov FDAAA 801 and the Final Rule, 2019). Years following, in 2016, the Final Rule expanded upon the requirement with additional data elements for both registration and result submission records in accordance of FDAAA 801 (ClinicalTrials.gov FDAAA 801 and the Final Rule, 2019). The Medical University of South Carolina (MUSC), along with the institution's Office of Clinical Research and Regulatory Knowledge & Support group, identified issues affecting their own compliance rate with FDAAA 801 and the NIH and implemented several processes to overcome these challenges. In short, these processes included hiring a designated full-time ClinicalTrials.gov coordinator, implementing a workflow that identifies trials early in the IRB approval process requiring registration (without effecting study start up timelines), assisting researchers when navigating the registration and results reporting process through one-on-one consultations, Lunch and Learns, and disseminating new training tools as they become available. Over the next 12 months the results of this approach demonstrated a marked increase to 98% overall compliance with these federal regulations which may provide valuable guidance for other institutions working toward improved compliance rates., (© 2020 Published by Elsevier Inc.)