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RATIONALE: New treatment strategies are needed to improve airway clearance and reduce the morbidity and the time burden associated with cystic fibrosis (CF). OBJECTIVES: To determine whether long-term treatment with inhaled mannitol, an osmotic agent, improves lung function and morbidity. METHODS: Double-blind, randomized, controlled trial of inhaled mannitol, 400 mg twice a day (n = 192, 'treated' group) or 50 mg twice a day (n = 126, 'control' group) for 26 weeks, followed by 26 weeks of open-label treatment. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was absolute change in FEV(1) from baseline in treated versus control groups, averaged over the study period. Secondary endpoints included other spirometric measurements, pulmonary exacerbations, and hospitalization. Clinical, microbiologic, and laboratory safety were assessed. The treated group had a mean improvement in FEV(1) of 105 ml (8.2% above baseline). The treated group had a relative improvement in FEV(1) of 3.75% (P = 0.029) versus the control group. Adverse events and sputum microbiology were similar in both treatment groups. Exacerbation rates were low, but there were fewer in the treated group (hazard ratio, 0.74; 95% confidence interval, 0.42-1.32; P = 0.31), although this was not statistically significant. In the 26-week open-label extension study, FEV(1) was maintained in the original treated group, and improved in the original control group to the same degree. CONCLUSIONS: Inhaled mannitol, 400 mg twice a day, resulted in improved lung function over 26 weeks, which was sustained after an additional 26 weeks of treatment. The safety profile was also acceptable, demonstrating the potential role for this chronic therapy for CF. Clinical trial registered with www.clinicaltrials.gov (NCT 00630812). [ABSTRACT FROM AUTHOR]

RATIONALE: Cystic fibrosis (CF) is a recessive genetic disease characterized by dehydration of the airway surface liquid and impaired mucociliary clearance. As a result, individuals with the disease have difficulty clearing pathogens from the lung and experience chronic pulmonary infections and inflammation. There may be intermittent pulmonary exacerbations or acute worsening of infection and obstruction, which require more intensive therapies. Hemoptysis and pneumothorax are complications commonly reported in patients with cystic fibrosis. OBJECTIVES: This document presents the CF Foundation's Pulmonary Therapies Committee recommendations for the treatment of hemoptysis and pneumothorax. METHODS: The committee recognized that insufficient data exist to develop evidence-based recommendations and so used the Delphi technique to formalize an expert panel's consensus process and develop explicit care recommendations. MEASUREMENTS AND MAIN RESULTS: The expert panel completed the survey twice, allowing refinement of recommendations. Numeric responses to the questions were summarized and applied to a priori definitions to determine levels of consensus. Recommendations were then developed to practical treatment questions based upon the median scores and the degree of consensus. CONCLUSIONS: These recommendations for the management of the patient with CF with hemoptysis and pneumothorax are designed for general use in most individuals but should be adapted to meet specific needs as determined by the individuals, their families, and their health care providers. It is hoped that the guidelines provided in this manuscript will facilitate the appropriate application of these treatments to improve and extend the lives of all individuals with cystic fibrosis. [ABSTRACT FROM AUTHOR]

The natural history of cystic fibrosis lung disease is one of chronic progression with intermittent episodes of acute worsening of symptoms frequently called acute pulmonary exacerbations These exacerbations typically warrant medical intervention. It is important that appropriate therapies are recommended on the basis of available evidence of efficacy and safety. The Cystic Fibrosis Foundation therefore established a committee to define the key questions related to pulmonary exacerbations, review the clinical evidence using an evidence-based methodology, and provide recommendations to clinicians. It is hoped that these guidelines will be helpful to clinicians in the treatment of individuals with cystic fibrosis. [ABSTRACT FROM AUTHOR]

Cystic fibrosis (CF) is a genetic disease characterized by dehydration of airway surface liquid and impaired mucociliary clearance. As a result, there is difficulty clearing pathogens from the lung, and patients experience chronic pulmonary infections and inflammation. Clearance of airway secretions has been a primary therapy for those with CF, and a variety of airway clearance therapies (ACTs) have been developed. Because ACTs are intrusive and require considerable time and effort, it is important that appropriate techniques are recommended on the basis of available evidence of efficacy and safety. Therefore, the Cystic Fibrosis Foundation established a committee to examine the clinical evidence for each therapy and provide guidance for their use. A systematic review was commissioned, which identified 7 unique reviews and 13 additional controlled trials that addressed one or more of the comparisons of interest and were deemed eligible for inclusion. Recommendations for use of the ACTs were made, balancing the quality of evidence and the potential harms and benefits. The committee determined that, although there is a paucity of controlled trials that assess the long-term effects of ACTs, the evidence quality overall for their use in CF is fair and the benefit is moderate. The committee recommends airway clearance be performed on a regular basis in all patients. There are no ACTs demonstrated to be superior to others, so the prescription of ACTs should be individualized. Aerobic exercise is recommended as an adjunctive therapy for airway clearance and for its additional benefits to overall health. [ABSTRACT FROM AUTHOR]

RATIONALE: Cystic fibrosis is a recessive genetic disease characterized by dehydration of the airway surface liquid and impaired mucociliary clearance. As a result, individuals with the disease have difficulty clearing pathogens from the lung and experience chronic pulmonary infections and inflammation. Death is usually a result of respiratory failure. Newly introduced therapies and aggressive management of the lung disease have resulted in great improvements in length and quality of life, with the result that the median expected survival age has reached 36 years. However, as the number of treatments expands, the medical regimen becomes increasingly burdensome in time, money, and health resources. Hence, it is important that treatments should be recommended on the basis of available evidence of efficacy and safety. OBJECTIVES: The Cystic Fibrosis Foundation therefore established a committee to examine the clinical evidence for each therapy and to provide guidance for the prescription of these therapies. METHODS: The committee members developed and refined a series of questions related to drug therapies used in the maintenance of pulmonary function. We addressed the questions in one of three ways, based on available evidence: (1) commissioned systematic review, (2) modified systematic review, or (3) summary of existing Cochrane reviews. CONCLUSIONS: It is hoped that the guidelines provided in this article will facilitate the appropriate application of these treatments to improve and extend the lives of all individuals with cystic fibrosis. [ABSTRACT FROM AUTHOR]

Abstract Since the discovery of the gene associated with cystic fibrosis (CF), there has been tremendous progress in the care of patients with this disease. New therapies have entered the market and are part of the standard treatment of patients with CF, and have been associated with marked improvement in survival. Now there are even more promising therapies directed at different components of the pathophysiology of this disease. In this review, our current knowledge of the pathophysiology of lung disease in patients with CF is described, along with the current treatment of CF lung disease, and the therapies in development that offer great promise to our patients.

Persistent neutrophilic inflammation is a central feature in both the pathogenesis and progression of bronchiectasis (BE). Neutrophils release neutrophil serine proteases (NSPs), such as neutrophil elastase, cathepsin G and proteinase 3. When chronically high levels of free NSP activity exceed those of protective antiproteases, structural lung destruction, mucosal-related defects, further susceptibility to infection and worsening of clinical outcomes can occur. Despite the defined role of prolonged, high levels of NSPs in BE, no drug that controls neutrophilic inflammation is licensed for the treatment of BE. Previous methods of suppressing neutrophilic inflammation (such as direct inhibition of neutrophil elastase) have not been successful; however, an emerging therapy designed to address neutrophil-mediated pathology, inhibition of the cysteine protease cathepsin C (CatC, also known as dipeptidyl peptidase 1), is a promising approach to ameliorate neutrophilic inflammation, since this may reduce the activity of all NSPs implicated in BE pathogenesis, and not just neutrophil elastase. Current data suggest that CatC inhibition may effectively restore the protease-antiprotease balance in BE and improve disease outcomes as a result. Clinical trials for CatC inhibitors in BE have reported positive Phase III results. In this narrative review, we discuss the role of high NSP activity in BE, and how this feature drives the associated morbidity and mortality seen in BE. This review discusses therapeutic approaches aimed at treating neutrophilic inflammation in the BE lung, summarising clinical trial outcomes, and highlighting the need for more treatment strategies that effectively address chronic neutrophilic inflammation in BE., (Copyright ©The authors 2024.)

Background: Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators are available to the majority of people with CF in the United States; little is known about pregnancy outcomes with modulator use. The aim of this retrospective study was to determine the impact of CFTR modulators on maternal outcomes., Research Question: Does pregnancy differentially affect outcomes in female subjects with CF with and without CFTR modulator exposure?, Study Design and Methods: Data on pregnancies from 2010 to 2021 were collected from 11 US adult CF centers. Multivariable longitudinal regression analysis was performed to assess whether changes in percent predicted FEV 1 (ppFEV 1 ), BMI, pulmonary exacerbations (PEx), and Pseudomonas aeruginosa prevalence differed from prior to, during, and following pregnancy according to CFTR modulator use while adjusting for confounders. Infant outcomes are also described based on maternal modulator use., Results: Among 307 pregnancies, mean age at conception was 28.5 years (range, 17-42 years), prepregnancy ppFEV 1 was 74.2, and BMI was 22.3 kg/m 2 . A total of 114 pregnancies (37.1%) had CFTR modulator exposure during pregnancy (77 with highly effective modulator therapy [HEMT] and 37 with other modulators). The adjusted mean change in ppFEV 1 from prepregnancy to during pregnancy was -2.36 (95% CI, -3.56 to -1.16) in the unexposed group and 2.60 (95% CI, 0.23 to 4.97) in the HEMT group, with no significant change from during pregnancy to 1 year postpregnancy. There was an overall decline in ppFEV 1 from prepregnancy to postpregnancy in the no modulator group (-2.56; 95% CI, -3.62 to -1.49) that was not observed in the HEMT group (1.10; 95% CI, -1.13 to 3.34). PEx decreased from prepregnancy to postpregnancy in the HEMT group, and BMI increased from prepregnancy to during pregnancy in all groups but with no significant change postpregnancy. Missing infant outcomes data precluded firm conclusions., Interpretation: We observed superior pregnancy and postpregnancy pulmonary outcomes in individuals who used HEMT, including a preservation of ppFEV 1 , compared with those unexposed to HEMT., Competing Interests: Financial/Nonfinancial Disclosures 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. J. L. T.-C,. M. L., A. W., N. E. W., T. M. K., A.U., A.H.R., S.L., J. L. G., D.H., S.M., P. A. F., and R. J. report Cystic Fibrosis Foundation institutional research funding for work related to the manuscript. Additional conflicts of interest unrelated to the content of the manuscript are included in the attached ICMJE disclosures. None declared: (G. P., S. C., S. R.)., (Copyright © 2024 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Interdisciplinary teams care for people with cystic fibrosis (pwCF) at specialized treatment centers. These teams have laid the foundation for the cystic fibrosis (CF) care model responsible for gains in health outcomes and quality of life within the CF community. However, the landscape of CF care is transforming, invigorated by new technologies, accessibility of cystic fibrosis transmembrane conductance regulator (CFTR) therapies, and increased utilization of telemedicine. In light of these advances, it is appropriate to re-evaluate the CF care team structure. This position paper offers guidance for the structure of a CF care center designed to meet the evolving needs of the CF community. Fundamental to the proposed center structure is recognition of pwCF and their families as integral members of their care teams, underpinning the necessity for shared decision making, awareness of social determinants of health, and active partnership between all healthcare professionals involved in the care of pwCF., Competing Interests: Declaration of competing interest The authors declare no conflict of interest. However, many authors are members of interdisciplinary teams and those CF Centers receive funding from the CF Foundation., (Copyright © 2024 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Specialized care is provided to people with cystic fibrosis (pwCF) by interdisciplinary teams nested within the CF Foundation's accredited care center network. This network allows for standardization of the care model, implementation of clinical care guidelines, efficient communication, and outcomes reporting. Recent developments have impacted this care model. Increased access to CFTR modulator therapies has improved overall health for many, although not all pwCF. The COVID-19 pandemic resulted in a rapid adoption of telemedicine and remote monitoring to ensure continuity of CF care. A collaboration of care providers, pwCF, and parent caregivers reevaluated key aspects of the current care model and considered potential modifications based on a widening range of needs. Available evidence was used to evaluate components of routine clinical practice and identify potential adaptations to care. The review included identification of patient characteristics warranting intensive monitoring, while embracing patient-centric care, and emphasizing the integration of telemedicine and at-home health technologies. Despite the changing landscape, the importance of the relationship between pwCF, their support system, and the care team was confirmed as a timeless and foundational aspect of the care model. Shared decision making, partnership, and coproduced care plans between pwCF and their CF care teams guide the best adaptations of the care model to support individual priorities and wellbeing. As health care advances and pwCF age, further research is needed to understand the impact of the care model on long-term health outcomes and to identify best practices that support pwCF to live longer healthier lives., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Rapidly emerging clinical trends offer the opportunity to amend guidance on issues pertaining to CF care delivery. A national survey was conducted to gather perspectives on CF care including potential adaptations to the care model to best meet the needs of this population., Methods: A survey instrument was developed to capture perspectives on CF care. People with CF (pwCF), including those post lung transplant, caregivers and care teams were surveyed. Descriptive statistics were calculated to characterize respondents and responses., Results: In-person, routine visits with the CF care teams were valued by survey respondents. However, reduced in-person visit frequency from the standard three-month interval was supported for individuals in a stable state of health. This was particularly true for pwCF ages two or older and on a modulator. Lung function, pulmonary exacerbation frequency, and transition periods were noted to influence preference for visit frequency. Integrating telehealth with remote monitoring in between visits was broadly supported. For shared care between CF teams and other medical providers (transplant teams and primary care providers (PCP)), good communication, easily accessible health records, and convenient locations were important., Conclusions: Survey findings support adapting CF care based on individual needs and life transitions. Themes identified can inform future areas of study and resource development to support successful modification of the CF care model and shared decision-making between patients and their care providers., 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 © 2024. Published by Elsevier B.V.)

Rationale: The American Thoracic Society recommended switching to race-neutral spirometry reference equations, as race is a social construct and to avoid normalizing disparities in lung function due to structural racism. Understanding the impact of the race-neutral equations on percent predicted forced expiratory volume in one second (ppFEV 1 ) in people with cystic fibrosis (PwCF) will help prepare patients and providers to interpret pulmonary function test results., Objective(s): To quantify the impact of switching from Global Lung Initiative (GLI) 2012 race-specific to GLI 2022 Global race-neutral reference equations on the distribution of ppFEV 1 among PwCF of different races., Methods: Cross-sectional analysis of FEV 1 among PwCF ages ≥6 years in the 2021 U.S. Cystic Fibrosis Foundation Patient Registry. We describe the absolute difference in ppFEV 1 between the two reference equations by reported race and the effect of age and height on this difference., Results: With the switch to GLI Global, ppFEV 1 will increase for White (median increase 4.7, (IQR: 3.1; 6.4)) and Asian (2.6 (IQR: 1.6; 3.7)) individuals and decrease for Black individuals (-7.7, (IQR: -10.9; -5.2)). Other race categories will see minimal changes in median ppFEV 1 . Individuals with higher baseline ppFEV 1 and younger age will see a greater change in ppFEV 1 (i.e., a greater improvement among White and Asian individuals and a greater decline among Black individuals)., Conclusions: Switching from GLI 2012 race-specific reference equations to GLI 2022 Global race-neutral equations will result in larger reductions in ppFEV 1 among Black individuals with CF than increases among White and Asian people with CF., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Elizabeth Cromwell reports financial support was provided by Cystic Fibrosis Foundation. If there are other authors, they 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 © 2024. Published by Elsevier B.V.)

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.

Background: Cystic fibrosis (CF) pulmonary exacerbation (PEx) treatment guidelines suggest that Pseudomonas aeruginosa (Pa) airway infection be treated with two antipseudomonal agents., Methods: We retrospectively studied treatment responses for STOP2 PEx treatment trial (NCT02781610) participants with a history of Pa infection. Mean lung function and symptom changes from intravenous (IV) antimicrobial treatment start to Visit 2 (7 to 10 days later) were compared between those receiving one, two, and three+ antipseudomonal classes before Visit 2 by ANCOVA. Odds of PEx retreatment with IV antimicrobials within 30 days and future IV-treated PEx hazard were modeled by logistic and Cox proportional hazards regression, respectively. Sensitivity analyses limited to the most common one-, two-, and three-class regimens, to only IV/oral antipseudomonal treatments, and with more stringent Pa infection definitions were conducted., Results: Among 751 participants, 50 (6.7%) were treated with one antipseudomonal class before Visit 2, while 552 (73.5%) and 149 (19.8%) were treated with two and with three+ classes, respectively. Females and participants with a negative Pa culture in the prior month were more likely to be treated with a single class. The most common single, double, and triple class regimens were beta-lactam (BL; n = 42), BL/aminoglycoside (AG; n = 459), and BL/AG/fluoroquinolone (FQ; n = 73). No lung function or symptom response, odds of retreatment, or future PEx hazard differences were observed by number of antipseudomonal classes administered in primary or sensitivity analyses., Conclusions: We were unable to identify additional benefit when multiple antipseudomonal classes are used to treat PEx in people with CF and Pa., (Copyright © 2022. Published by Elsevier B.V.)

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: In the STOP2 (Standardized Treatment of Pulmonary Exacerbations-2) study, intravenous (IV) antimicrobial treatment duration for adults with cystic fibrosis (CF) experiencing pulmonary exacerbations (PEx) was determined based on initial treatment response. The impact of home vs hospital care remains an important clinical question in CF. Our hypothesis was that STOP2 participants treated at home would have less improvement in lung function compared to those treated in the hospital., Methods: Treating clinicians determined PEx treatment location, which was a stratification factor for STOP2 randomization. Lung function, weight, and symptom recovery were evaluated by treatment location. Propensity scores and inverse probability treatment weighting were used to test for differences in clinical response by treatment location., Results: In all, 33% of STOP2 participants received IV antimicrobials in the hospital only, 46% both in the hospital and at home, and 21% at home only. Mean (95% CI) ppFEV 1 improvement was significantly (p < 0.05) lower for those treated at home only, 5.0 (3.5, 6.5), compared with at home and in the hospital, 7.0 (5.9, 8.1), and in the hospital only, 8.0 (6.7, 9.4). Mean weight (p < 0.001) and symptom (p < 0.05) changes were significantly smaller for those treated at home only compared to those treated in the hospital only., Conclusions: Compared to PEx treatment at home only, treatment in the hospital was associated with greater mean lung function, respiratory symptom, and weight improvements. The limitations of home IV therapy should be addressed in order to optimize outcomes for adults with CF treated at home., (Copyright © 2021. Published by Elsevier B.V.)

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).)