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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]

Context: Azithromycin is recommended as therapy for cystic fibrosis (CF) patients with chronic Pseudomonas aeruginosa infection, but there has not been sufficient evidence to support the benefit of azithromycin in other patients with CF.Objective: To determine if azithromycin treatment improves lung function and reduces pulmonary exacerbations in pediatric CF patients uninfected with P. aeruginosa.Design, Setting, and Participants: A multicenter, randomized, double-blind placebo-controlled trial was conducted from February 2007 to July 2009 at 40 CF care centers in the United States and Canada. Of the 324 participants screened, 260 were randomized and received study drug. Eligibility criteria included age of 6 to 18 years, a forced expiratory volume in the first second of expiration (FEV(1)) of at least 50% predicted, and negative respiratory tract cultures for P. aeruginosa for at least 1 year. Randomization was stratified by age of 6 to 12 years vs 13 to 18 years and by CF center.Intervention: The active group (n = 131) received 250 mg (weight 18-35.9 kg) or 500 mg (weight > or = 36 kg) of azithromycin 3 days per week (Monday, Wednesday, and Friday) for 168 days. The placebo group (n = 129) received identically packaged placebo tablets on the same schedule.Main Outcome Measures: The primary outcome was change in FEV(1). Exploratory outcomes included additional pulmonary function end points, pulmonary exacerbations, changes in weight and height, new use of antibiotics, and hospitalizations. Changes in microbiology and adverse events were monitored.Results: The mean (SD) age of participants was 10.7 (3.17) years. The mean (SD) FEV(1) at baseline and 168 days were 2.13 (0.85) L and 2.22 (0.86) L for the azithromycin group and 2.12 (0.85) L and 2.20 (0.88) L for the placebo group. The difference in the change in FEV(1) between the azithromycin and placebo groups was 0.02 L (95% confidence interval [CI], -0.05 to 0.08; P = .61). None of the exploratory pulmonary function end points were statistically significant. Pulmonary exacerbations occurred in 21% of the azithromycin group and 39% of the placebo group. Participants in the azithromycin group had a 50% reduction in exacerbations (95% CI, 31%-79%) and an increase in body weight of 0.58 kg (95% CI, 0.14-1.02) compared with placebo participants. There were no significant differences between groups in height, use of intravenous or inhaled antibiotics, or hospitalizations. Participants in the azithromycin group had no increased risk of adverse events, but had less cough (-23% treatment difference; 95% CI, -33% to -11%) and less productive cough (-11% treatment difference; 95% CI, -19% to -3%) compared with placebo participants.Conclusion: In children and adolescents with CF uninfected with P. aeruginosa, treatment with azithromycin for 24 weeks did not result in improved pulmonary function.Trial Registration: clinicaltrials.gov Identifier: NCT00431964. [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: We recently reported a randomized, placebo-controlled trial of azithromycin in patients with cystic fibrosis (CF) that demonstrated a 6.2% improvement in the 168-d relative change in FEV[1] among azithromycin participants compared with placebo participants.Objectives: In the current analyses, heterogeneity of treatment response and the association between FEV[1] and the risk of pulmonary exacerbations were investigated.Methods: The time to first pulmonary exacerbation, hospitalization rates, and antibiotic use were compared between participants categorized by their relative change in FEV[1]% predicted (>/= 5 vs. < 5% improvement) at Day 168. Pulmonary function and exacerbation responses were compared in subgroups of participants characterized by long-term concomitant medications and baseline lung function.Measurements: All available data from the 185 randomized participants in the azithromycin trial were included in these analyses.Main Results: Compared with placebo participants, a reduced risk of pulmonary exacerbations was observed both among azithromycin participants with >/= 5% and those with < 5% relative improvement in FEV[1]. Similarly, decreased hospitalization rates and decreased use of oral quinolone and nonquinolone antibiotics were observed in azithromycin participants regardless of improvement in FEV[1]. Subgroup analyses demonstrated that overall, participants on long-term aerosolized tobramycin and/or rhDNase had worse baseline lung function, but still benefited from azithromycin, as evidenced by a lower risk of exacerbations.Conclusions: Azithromycin participants experienced benefits in exacerbation parameters regardless of FEV[1] response or subgroup. These data have implications for clinical practice and the design of clinical trials. [ABSTRACT FROM AUTHOR]

Background: Factors associated with severe COVID-19 infection have been identified; however, the impact of infection on longer-term outcomes is unclear. The objective of this study was to examine the impact of COVID-19 infection on the trajectory of lung function and nutritional status in people with cystic fibrosis (pwCF)., Methods: This is a retrospective global cohort study of pwCF who had confirmed COVID-19 infection diagnosed between January 1, 2020 and December 31, 2021. Forced expiratory volume in one second percent predicted (ppFEV 1 ) and body mass index (BMI) twelve months prior to and following a diagnosis of COVID-19 were recorded. Change in mean ppFEV 1 and BMI were compared using a t-test. A linear mixed-effects model was used to estimate change over time and to compare the rate of change before and after infection., Results: A total of 6,500 cases of COVID-19 in pwCF from 33 countries were included for analysis. The mean difference in ppFEV 1 pre- and post-infection was 1.4 %, (95 % CI 1.1, 1.7). In those not on modulators, the difference in rate of change pre- and post-infection was 1.34 %, (95 % CI -0.88, 3.56) per year (p = 0.24) and -0.74 % (-1.89, 0.41) per year (p = 0.21) for those on elexacaftor/tezacaftor/ivacaftor. No clinically significant change was noted in BMI or BMI percentile before and after COVID-19 infection., Conclusions: No clinically meaningful impact on lung function and BMI trajectory in the year following infection with COVID-19 was identified. This work highlights the ability of the global CF community to unify and address critical issues facing pwCF., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors of this manuscript receive funding in the form of consulting fees or honoraria from Vertex Pharmaceuticals, Chiesi Pharmaceuticals, Enterprise Therapeutics, Gilead Sciences, GSK, Astra-Zeneca, Insmed, MSD, Sanofi, Viartis, Zambon, Limbic, Effrx Pharmaceuticals and Omron. Additionally, there is an author who serves on the Novartis Data and Safety Monitoring Board. There are several authors who are employed by the Cystic Fibrosis Foundation (CFF). The CFF, to advance drug development and search for a cure, have contracts with several companies to help fund the development of potential treatments and/or cures for cystic fibrosis. Pursuant to these contracts, CFF may receive milestone-based payments, equity interests, royalties on the net sales of therapies, and/or other forms of consideration. Resulting revenue received by CFF is used in support of our mission. See “How Drugs Get on the Pipeline” on the CFF website for more information. Additionally, CFF may license CFF Patient Registry data to some companies to monitor drug safety as part of the U.S. Food and Drug Administration's required Phase 4 clinical trials process and to encourage research aimed at improving the care of people with CF, while maintaining our obligation and commitment to protect the privacy of Registry participants. In connection with these licenses, and upon request, CFF may also assist company researchers in interpreting CFF Patient Registry data to aid in designing, analyzing, and interpreting real world studies in CF., (Copyright © 2024. Published by Elsevier B.V.)

There is paucity of literature on the health outcomes following liver transplantation (LT) in people with cystic fibrosis (pwCF). We aim to evaluate changes in lung function following LT in pwCF. We performed a retrospective cohort study of pwCF who underwent LT between 1987 and 2019 in the United States and Canada. Simultaneous lung-liver transplants and individuals who had lung transplant prior to LT were excluded. We analyzed pre-LT and post-LT percent predicted forced expiratory volume in 1 second, body mass index, rates of pulmonary exacerbation, and post-LT overall survival. A total of 402 LT recipients were included. The median age of transplant was 14.9 years and 69.7% of the transplants were performed in children less than 18 years old. The rate of decline in percent predicted forced expiratory volume in 1 second was attenuated after LT from -2.2% to -0.7% predicted per year with a difference of 1.5% predicted per year (95% CI, 0.8, 2.2; p < 0.001). Following LT, the rate of decline in body mass index was reduced, and there were fewer pulmonary exacerbations (0.6 pre vs. 0.4 post; rate ratio 0.7, p < 0.01). The median survival time post-transplant was 13.9 years and the overall probability of survival at 5 years was 77.6%. Those with higher lung function pre-LT had a lower risk of death post-LT, and those with genotypes other than F508 deletion had worse survival. LT in pwCF occurs most often in children and adolescents and is associated with a slower rate of decline in lung function and nutritional status, and a reduction in pulmonary exacerbations., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Background: High daily doses of pancreatic enzyme replacement therapy (PERT) were historically associated with risk of fibrosing colonopathy (FC) in people with cystic fibrosis (pwCF), leading to development of PERT dosing guidelines and reformulated products. This study quantified incidence of FC in pwCF treated with PERT following those measures., Methods: This large prospective cohort study included eligible pwCF enrolled in the Cystic Fibrosis Foundation Patient Registry with ≥1 clinic visit in 2012-2014 and follow-up through 2020. Data on PERT exposure, demographics, and medical history were collected. Clinical data, imaging, and histopathology of suspected cases were examined by an independent adjudication panel of physicians familiar with this complication., Results: Base Study Population included 26,025 pwCF who contributed 155,814 person-years [mean (SD) 6.0 (2.0) years] of follow-up. Over 7.8 years, 29 pwCF had suspected FC; three cases were confirmed by adjudication, 22 cases were confirmed as not FC, and four cases were indeterminate. There were 22,161 pwCF exposed to any PERT, with mean PERT use time of 5.583 person-years and mean daily dose of 8328 U lipase per kg per day. All three confirmed cases and four indeterminate cases of FC occurred during current use of PERT. Incidence rates per 1000 person-years exposed were 0.0242 (95 % CI [0.0050, 0.0709]) for confirmed FC and 0.0566 (95 % CI [0.0227, 0.1166]) for indeterminate or confirmed FC., Conclusions: The incidence of FC in pwCF is very low in the era of current treatment guidelines and more stringent quality standards for PERT products., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests: Stephanie E. Chiuve and Lino Rodrigues Jr are full-time employees of AbbVie Inc., which marketed one of the pancreatic enzymes included in the study. They hold stock and stock options. Their work on this study was done as part of their employment. At the time of this study, Daniel Fife was a full-time employee of Janssen Research & Development, LLC, which marketed one of the pancreatic enzymes included in the study and held stock and stock options. As an employee, he received travel support and pension rights from Johnson & Johnson, the parent company of Janssen Research & Development. His work on this study was done as part of his employment. He has since retired from Janssen Research & Development, LLC. During the time of the study, he was on the board of directors of the International Society for Pharmacoepidemiology (ISPE) and was the Industry Council Chair of ISPE. Gerhard Leitz is a full-time employee of Janssen Research & Development, LLC, which marketed one of the pancreatic enzymes included in the study and holds stock and stock options. His work on this study was done as part of his employment. Craig Peterson is a full-time employee of VIVUS LLC., which marketed one of the pancreatic enzymes included in this study. At the time of this study, he held stock and stock options in VIVUS LLC., and his work on this study was done as part of his employment. Amanda Rennig and Neil M. Campbell are employed by Digestive Care, Inc., which marketed one of the pancreatic enzymes included in this study. At the time of this study, they did not hold stock or stock options in Digestive Care, Inc., and their work on this study was done as part of their employment. Dennis Decktor is a full-time employee (initially a contract employee) of Nestle, which marketed one of the pancreatic enzymes included in this study. His work on this study was done as part of his employment. Christopher Dowd was employed by the Cystic Fibrosis Foundation during the time of the study, which was paid by all the sponsors to conduct the study. Bruce C. Marshall was employed by the Cystic Fibrosis Foundation during the time of the study, which was paid by all the sponsors to conduct the study. Drucy Borowitz was a consultant for the Cystic Fibrosis Foundation during the development of the study and served as the chair of the Adjudication Committee for which her employer, Jacobs School of Medicine and Biomedical Sciences, received compensation. In 2016, she became an employee for the Cystic Fibrosis Foundation and her work on this study was done as part of her employment. As of 2020, she is no longer an employee or consultant to the Cystic Fibrosis Foundation. She received consulting fees as a member of a scientific advisory board for Synspira Therapeutics. The active members of the Adjudication Committee and the third-party reviewers of radiology and pathology were: Drucy Borowitz, MD, Sarah Jane Schwarzenberg, MD, John Stevens, MD, Maria Mascarenhas, MBBS, Bruce Pawel, MD, J. Michael Zerin, MD, Boaz Karmazyn, MD, F. Glen Seidel, MD. The medical monitor for this study was Christopher H. Goss, MD, MSc. This study was managed by Cystic Fibrosis Foundation Therapeutics (CFFT) and the Therapeutics Development Network Coordinating Center (TDNCC). It was conducted within the CFF-accredited care center network with guidance, input, review, and approval by the sponsors, including development of materials; recruitment, training, and management of sites; and data management and analysis. An independent adjudication committee was formed to validate the diagnosis of FC based on a prospective case definition and decision rules. The CFFT identified the panel of experts and mediated the adjudication process., (Copyright © 2023. Published by Elsevier B.V.)

Introduction: Re-transplant is an option for those who develop end-stage lung disease due to rejection; however, little data exist following re-transplantation in cystic fibrosis (CF)., Methods: Data from the Canadian CF Registry and US CF Foundation Patient Registry supplemented with data from United Network for Organ Sharing were used. Individuals who underwent a 2nd lung transplant between 2005 and 2019 were included. The Kaplan-Meier method was used to estimate the probability of survival post-second transplant at 1, 3, and 5-years., Results: Of those people who were waitlisted for a second transplant (N = 818), a total of 254 (31%) died waiting, 395 (48%) were transplanted and 169 (21%) people were alive on the waitlist. Median survival time after 2nd lung transplant was 3.3 years (95% CI: 2.8-4.1). The 1-, 3- and 5-year survival rates were 77.4% (95% CI: 73.1-82%), 52% (95% CI: 46.7-58%) and 39.4% (95% CI: 34.1-45.6%)., Conclusions: Survival following second lung transplant in CF patients is lower than estimates following the first transplant. Over half of subjects who are potentially eligible for a second transplant die without receiving a second organ. This warrants further investigation., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: Deaths among those lost to follow-up (LTFU) in the Cystic Fibrosis Foundation Patient Registry (CFFPR) are critically important to the epidemiology of cystic fibrosis (CF). Unreported deaths could impact estimates of survival if LTFU is associated with disease trajectory., Methods: We characterized the LTFU population (1986-2017) from the CFFPR and identified deaths via linkage with the National Death Index (NDI). Median predicted survival age and conditional survival were estimated with and without additional deaths and person-time from the NDI., Results: Of the 10,582 individuals LTFU in the CFFPR, 2,460 (23.2%) matched to an NDI death record. Individuals who died after LTFU with a CF diagnosis were 43% female, 91% White/non-Hispanic, 59% had advanced CF lung disease based on last CFFPR recorded forced expiratory volume in one second (FEV 1 ) %predicted <40 and 18% were post-lung transplant. Median predicted survival age during the most recent period available, 2013-2017, increased from 44.3 years (95% CI: 43.2, 45.7) to 45.8 years (95% CI 44.5, 47.1) with the inclusion of NDI data., Conclusions: Inclusion of deaths and additional person-time among those LTFU changed the point estimate of median predicted survival for most time periods and increased the point estimate from 2009 onwards., 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 Elsevier Inc. All rights reserved.)

Background: The Cystic Fibrosis Foundation Patient Registry (CFFPR) collects data on individuals with cystic fibrosis (CF) in the United States (US). In 2012, the US CF population was estimated at 33,292 to 34,327 individuals, with 81-84% CFFPR participation., Methods: In this study, we update these estimates via simulation to account for uncertainty in CF incidence by race or Hispanic ethnicity, initiation of CF newborn screening (NBS) programs by state, and updated cumulative survival for CF births 1968-2020. We defined registry participation as the proportion of individuals alive as of 2020 with any prior CFFPR participation as well as the proportion with contributing data in 2019 or 2020; we summarize CFFPR participation for those born prior to 1968., Results: We estimated the 2020 prevalent CF population between 1968-2020 to be 38,804 (95% Uncertainty Interval (UI): 38,532 to 39,065) individuals, with 77% of the prevalent CF population contributing recent data. CFFPR participation differs by age (54% of those born in 1968) and exceeds >90% of the population born in 2009 or later., Conclusions: We demonstrate that the CFFPR remains a valid data source generalizable to the CF population. High participation among younger individuals may reflect the success of newborn screening programs and early referral to CF care. If engagement can be sustained, the percentage of individuals participating in the CFFPR will grow over time and there is an opportunity to identify factors associated with loss to follow up among older individuals to optimize the quality of the CFFPR data., Competing Interests: Conflict of interest statement The authors have no conflict of interest to disclose., (Copyright © 2023 The Author(s). Published by Elsevier B.V. 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.)

Introduction: The Cystic Fibrosis (CF) Foundation sponsored the design, pilot testing, and implementation of the CF Learning Network (CFLN) to explore how the Foundation's Care Center Network (CCN) could become a learning health system. Six years after the design, the Foundation commissioned a formative mixed methods evaluation of the CFLN to assess: CFLN participants' understanding of program goals, attributes, and perceptions of current and future impact., Methods: We performed semi-structured interviews with CFLN participants to identify perceived goals, attributes, and impact of the network. Following thematic analyses, we developed and distributed a survey to CFLN members and a matched sample of CCN programs to understand whether the themes were unique to the CFLN., Results: Interviews with 24 CFLN participants were conducted. Interviewees identified the primary CFLN goal as improving outcomes for people living with CF, with secondary goals of providing training in quality improvement (QI), creating a learning community, engaging all stakeholders in improvement, and spreading best practices to the CCN. Project management, use of data, common QI methods, and the learning community were seen as critical to success. Survey responses were collected from 103 CFLN members and 25 CCN members. The data revealed that CFLN respondents were more likely than CCN respondents to connect with other CF programs, routinely use data for QI, and engage patient and family partners in QI., Conclusions: Our study suggests that the CFLN provides value beyond that achieved by the CCN. Key questions remain about whether spread of the CFLN could improve outcomes for more people living with CF., Competing Interests: Authors Bruce C. Marshall and Kathryn A. Sabadosa are employees of the Cystic Fibrosis Foundation. The authors state they have no conflicts of interest., (© 2022 The Authors. Learning Health Systems published by Wiley Periodicals LLC on behalf of University of Michigan.)

Background: This international study aimed to characterise the impact of acute SARS-CoV-2 infection in people with cystic fibrosis and investigate factors associated with severe outcomes. Methods Data from 22 countries prior to 13 th December 2020 and the introduction of vaccines were included. It was de-identified and included patient demographics, clinical characteristics, treatments, outcomes and sequalae following SARS-CoV-2 infection. Multivariable logistic regression was used to investigate factors associated with clinical progression to severe COVID-19, using the primary outcome of hospitalisation with supplemental oxygen., Results: SARS-CoV-2 was reported in 1555 people with CF, 1452 were included in the analysis. One third were aged <18 years, and 9.4% were solid-organ transplant recipients. 74.5% were symptomatic and 22% were admitted to hospital. In the non-transplanted cohort, 39.5% of patients with ppFEV1<40% were hospitalised with oxygen verses 3.2% with ppFEV >70%: a 17-fold increase in odds. Worse outcomes were independently associated with older age, non-white race, underweight body mass index, and CF-related diabetes. Prescription of highly effective CFTR modulator therapies was associated with a significantly reduced odds of being hospitalised with oxygen (AOR 0.43 95%CI 0.31-0.60 p<0.001). Transplanted patients were hospitalised with supplemental oxygen therapy (21.9%) more often than non-transplanted (8.8%) and was independently associated with the primary outcome (Adjusted OR 2.45 95%CI 1.27-4.71 p=0.007)., Conclusions: This is the first study to show that there is a protective effect from the use of CFTR modulator therapy and that people with CF from an ethnic minority are at more risk of severe infection with SARS-CoV-2., Competing Interests: COI Statement All authors declare no conflicts of interest in relationship to this work. Outside of this work the following authors declare payments or honoraria to them or their institution for a combination of lectures, presentations, educational events, advisory boards, steering groups, grants or consultancy fees: SC-Vertex, Chiesi, Profile, Zambon. RC- Vertex, P-RB – Astra-Zeneca, Boehringer Ingelheim, GSK, Insmed, Chiesi, Pfizer, Vertex, Zambon. I deM – Vertex,LN – Vertex, Boehringer,LVS-F – Vertex, AS -Vertex., (Copyright © 2022. Published by Elsevier B.V.)

Multisystem inflammatory syndrome in children (MIS-C) is a hyperinflammatory state that occurs after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We present 2 cases of MIS-C after SARS-CoV-2 vaccination; 1 patient had evidence of recent SARS-CoV-2 infection. Our findings suggest that vaccination modulates the pathogenesis of MIS-C.

Rationale: A previous analysis found significantly higher lung function in the US paediatric cystic fibrosis (CF) population compared with the UK with this difference apparently decreasing in adolescence and adulthood. However, the cross-sectional nature of the study makes it hard to interpret these results., Objectives: To compare longitudinal trajectories of lung function in children with CF between the USA and UK and to explore reasons for any differences., Methods: We used mixed effects regression analysis to model lung function trajectories in the study populations. Using descriptive statistics, we compared early growth and nutrition (height, weight, body mass index), infections ( Pseudomonas aeruginosa , Staphylococcus aureus ) and treatments (rhDnase, hypertonic saline, inhaled antibiotics)., Results: We included 9463 children from the USA and 3055 children from the UK with homozygous F508del genotype. Lung function was higher in the USA than in the UK when first measured at age six and remained higher throughout childhood. We did not find important differences in early growth and nutrition, or P.aeruginosa infection. Prescription of rhDNase and hypertonic saline was more common in the USA. Inhaled antibiotics were prescribed at similar levels in both countries, but Tobramycin was prescribed more in the USA and colistin in the UK. S. aureus infection was more common in the USA than the UK., Conclusions: Children with CF and homozygous F508del genotype in the USA had better lung function than UK children. These differences do not appear to be explained by early growth or nutrition, but differences in the use of early treatments need further investigation., Competing Interests: Competing interests: DKS, SC and DT-R were supported by the Strategic Research Centre 'CF-EpiNet: Harnessing data to improve lives' funded by the Cystic Fibrosis Trust. DT-R is funded by the MRC on a Clinician Scientist Fellowship (MR/P008577/1). RS was supported by grants from the Cystic Fibrosis Foundation (SZCZES18AB0) and NIH/NHLBI (R01 HL141286). CHG was supported by grants from the Cystic Fibrosis Foundation, the NIH (UM1 HL119073, P30 DK089507, U01 HL114589, UL1 TR000423) and the FDA (R01 FD003704). RHK is supported by a UKRI Future Leaders Fellowship (MR/S017968/1)., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

The findings of this body of work are presented in the eight articles included in this supplement. The impact and perspectives of adult and pediatric care teams and patient/families are covered with special attention to mental health care, the financial and personnel impacts within care programs, the experiences of vulnerable and underrepresented patient populations, and implementation of remoting monitoring. Commentaries from colleagues provide a broader perspective, offering reflections on the findings and their implications regarding the future CF care model., Competing Interests: Declaration of Competing Interest KAS, AF, BCM are employees of the Cystic Fibrosis Foundation. ECN received grant funding from the Cystic Fibrosis Foundation (NELSON20QI0)., (Copyright © 2021. Published by Elsevier B.V.)

Background: Although guidelines for inhaled therapies for individuals with cystic fibrosis (CF) are available, recommendations for compressors/nebulizers to optimize care are lacking. The CF Foundation (CFF) convened a multidisciplinary task force to assess the use, durability, accessibility, and cost burden of compressors/nebulizers., Methods: Online surveys were developed and distributed to 287 CFF programs and adults with CF and parents of children with CF (adults with CF/parents)., Results: Health care providers from 38 states completed the survey (59% response rate). Respiratory therapists were mostly responsible to coordinate ordering nebulizers and compressors. Durable medical equipment companies were the most common source of acquisition of compressors (71.8%) and nebulizers (45.9%). A majority of health care providers did not feel the compressors were durable (51.1%) or that they could get enough nebulizers to their patients (69.2%). Barriers to procure compressors were reported. The survey was completed by 734 adults with CF/parents from 48 states. Most adults with CF/parents rated their compressor as durable (65.8%); however, 85.5% of respondents reported some user-experience problem(s). "Hoses popping off" and "increased nebulization time" were most commonly reported. Almost 20% of respondents did not have access to a compressor at some point in the previous year. Most adults with CF/parents did not change compressor filters per manufacturer's recommendation (40% never). Adults with CF/parents reported performing a median of 4 inhaled treatments per day. Median use of nebulizers was 6 months. Most adults with CF/parents thought they had enough nebulizers (53.7%). Individuals with CF doing more inhaled treatments reported more compressor malfunctions. The median out-of-pocket expense was $75-99 and $50-74 for compressors and nebulizers, respectively., Conclusions: Although the perceptions of health care providers and adults with CF/parents differed to a certain extent, the surveys uncovered several significant issues that may compromise quality of care. Improvement in access to devices and education are needed., (Copyright © 2021 by Daedalus Enterprises.)

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: Understanding how health outcomes differ for patients with advanced cystic fibrosis (CF) lung disease living in the United States compared with Canada has health policy implications., Research Question: What are rates of lung transplant (LTx) and rates of death without LTx in the United States and Canada among individuals with FEV 1  < 40% predicted?, Study Design and Methods: This was a retrospective population-based cohort study, 2005 to 2016, using the US CF Foundation, United Network for Organ Sharing, and Canadian CF registries. Individuals with CF and at least two FEV 1 measurements < 40% predicted within a 5-year period, age ≥ 6 years, without prior LTx were included. Multivariable competing risk regression for time to death without LTx (LTx as a competing risk) and time to LTx (death as a competing risk) was performed., Results: There were 5,899 patients (53% male) and 905 patients (54% male) with CF with FEV 1  < 40% predicted living in the United States and Canada, respectively. Multivariable competing risk regression models identified an increased risk of death without LTx (hazard ratio [HR], 1.79; 95% CI, 1.52-2.1) and decreased LTx (HR, 0.66; 95% CI, 0.58-0.74) among individuals in the United States compared with Canada. More pronounced differences were seen in the patients in the United States with Medicaid/Medicare insurance compared with Canadians (multivariable HR for death without LTx, 2.24 [95% CI, 1.89-2.64]; multivariable HR for LTx, 0.54 [95% CI, 0.47-0.61]). Patients of nonwhite race were also disadvantaged (multivariable HR for death without LTx, 1.56 [95% CI, 1.32-1.84]; multivariable HR for LTx, 0.47 [95% CI, 0.36-0.62])., Interpretation: There are lower rates of LTx and an increased risk of death without LTx for US patients with CF with FEV 1  < 40% predicted compared with Canadian patients. Findings are more striking among US patients with CF with Medicaid/Medicare health insurance, and nonwhite patients in both countries, raising concerns about underuse of LTx among vulnerable populations., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Individuals with cystic fibrosis (CF) now have an increased life expectancy, due to advances in care provided by a multidisciplinary team. The care model has expanded over time to include multiple subspecialties. The Cystic Fibrosis Foundation conducted a survey of Care Center Directors and identified a need for pediatric and adult gastroenterologists with expertise in the diagnosis and treatment of intestinal, pancreatic and hepatic complications of CF. To address this need, the Developing Innovative GastroEnterology Specialty Training (DIGEST) program was created. The development, implementation, and early results of this training program are reported herein., Competing Interests: Declaration of Competing Interest None of the authors has any real or perceived conflict of interest pertaining to the content of the manuscript., (Copyright © 2020. Published by Elsevier B.V.)

Background: Previous literature in cystic fibrosis (CF) has shown a 10-year survival gap between Canada and the United States (US). We hypothesized that differential access to and survival after lung transplantation may contribute to the observed gap. The objectives of this study were to compare CF transplant outcomes between Canada and the US and estimate the potential contribution of transplantation to the survival gap., Methods: Data from the Canadian CF Registry and the US Cystic Fibrosis Foundation Patient Registry supplemented with data from United Network for Organ Sharing were used. The probability of surviving after transplantation between 2005 and 2016 was calculated using the Kaplan‒Meier method. Survival by insurance status at the time of transplantation and transplant center volume in the US were compared with those in Canada using Cox proportional hazard models. Simulations were used to estimate the contribution of transplantation to the survival gap., Results: Between 2005 and 2016, there were 2,653 patients in the US and 470 in Canada who underwent lung transplantation for CF. The 1-, 3-, and 5-year survival rates were 88.3%, 71.8%, and 60.3%, respectively, in the US compared with 90.5%, 79.9%, and 69.7%, respectively, in Canada. Patients in the US were also more likely to die on the waitlist (p < 0.01) than patients in Canada. If the proportion of who underwent transplantation and post-transplant survival in the US were to increase to those observed in Canada, we estimate that the survival gap would decrease from 10.8 years to 7.5 years., Conclusions: Differences in waitlist mortality and post-transplant survival can explain up to a third of the survival gap observed between the US and Canada., (Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

The approval of aztreonam lysine for inhalation solution (AZLI) raised concerns that additional antibiotic exposure would potentially affect the susceptibility profiles of Pseudomonas aeruginosa isolates from cystic fibrosis (CF) patients. This 5-year, prospective, observational study tracked susceptibility changes and clinical outcomes in CF patients in the United States with chronic P. aeruginosa infection. Sputum cultures were collected annually (2011 to 2016). The primary study endpoint was the proportion of subjects whose least susceptible P. aeruginosa isolate had an aztreonam MIC that was >8 μg/ml (parenteral breakpoint) and increased ≥4-fold compared with the least susceptible isolate from the previous year. Annualized data for pulmonary exacerbations, hospitalizations, and percent of predicted forced expiratory volume in 1 s (FEV 1 % predicted) were obtained from the CF Foundation Patient Registry and compared between subjects meeting and those not meeting the primary endpoint. A total of 510 subjects were enrolled; 334 (65%) completed the study. A consistent proportion of evaluable subjects (13 to 22%) met the primary endpoint each year, and AZLI use during the previous 12 months was not associated with meeting the primary endpoint. While the annual declines in lung function were comparable for subjects meeting and those not meeting the primary endpoint, more pulmonary exacerbations and hospitalizations were experienced by those who met it. The aztreonam susceptibility of P. aeruginosa remained consistent during the 5-year study. The relationship between P. aeruginosa isolate susceptibilities and clinical outcomes is complex; reduced susceptibility was not associated with an accelerated decline in lung function but was associated with more exacerbations and hospitalizations, likely reflecting increased overall antibiotic exposure. (This study has been registered at ClinicalTrials.gov under identifier NCT01375036.)., (Copyright © 2021 Keating et al.)

Background: The presence of co-morbidities, including underlying respiratory problems, has been identified as a risk factor for severe COVID-19 disease. Information on the clinical course of SARS-CoV-2 infection in children with cystic fibrosis (CF) is limited, yet vital to provide accurate advice for children with CF, their families, caregivers and clinical teams., Methods: Cases of SARS-CoV-2 infection in children with CF aged less than 18 years were collated by the CF Registry Global Harmonization Group across 13 countries between 1 February and 7 August 2020., Results: Data on 105 children were collated and analysed. Median age of cases was ten years (interquartile range 6-15), 54% were male and median percentage predicted forced expiratory volume in one second was 94% (interquartile range 79-104). The majority (71%) of children were managed in the community during their COVID-19 illness. Out of 24 children admitted to hospital, six required supplementary oxygen and two non-invasive ventilation. Around half were prescribed antibiotics, five children received antiviral treatments, four azithromycin and one additional corticosteroids. Children that were hospitalised had lower lung function and reduced body mass index Z-scores. One child died six weeks after testing positive for SARS-CoV-2 following a deterioration that was not attributed to COVID-19 disease., Conclusions: SARS-CoV-2 infection in children with CF is usually associated with a mild illness in those who do not have pre-existing severe lung disease., Competing Interests: Declaration of Competing Interest None related to this work. P-RB: Not related to this work: reports personal fees from Astra-Zeneca, Boehringer Ingelheim, Chiesi, GSK, Insmed, Novartis, Pfizer, grants and personal fees from Vertex, personal fees from Zambon SBC: Not related to this work: personal fees from Chiesi Pharmaceuticals, Zambon and Insmed and personal fees and non-financial support from Vertex Pharmaceuticals. CG: Not related to this work: reports grants from CF Foundation, European Commission, NIH, FDA; personal fees from Gilead Sciences (Chair of a Grant Review Committee), Novartis (DSMB Chair for a Clinical Trial); other fees Boehringer Ingelheim (serving as US lead in a phase 2 trial of novel therapy) and Vertex Pharmaceuticals (honoraria for talk at UK LEAD conference). LN: Not related to this work: reports that he received institutional fees for site participation in clinical trials from Vertex Pharmaceuticals and Boehringer Ingelheim LVRFSF Not related to this work: reports grants and personal fees from Vertex Pharmaceuticals and Boehringer Ingelheim, grants from Timpel and Diagnostics of America (DASA), personal fees from Roche do Brasil, AbbVie, Sanofi and Glenmark. MB Not related to this work: investigator-led research grants from Pfizer and Roche Diagnostics; speaker fees paid to Newcastle University from Novartis, Roche Diagnostics and TEVA. Travel expenses to educational meetings Boehringer Ingelheim and Vertex Pharmaceuticals. RB, RC, MZ, CC, HC, AF, AJ, NK, BM, MDP-V, PM-L, KGB, IJH: none, (Copyright © 2020. Published by Elsevier B.V.)

With the growing SARS-CoV-2 pandemic, we need to better understand its impact in specific patient groups like those with Cystic Fibrosis (CF). We report on 181 people with CF (32 post-transplant) from 19 countries diagnosed with SARS-CoV-2 prior to 13 June 2020. Infection with SARS-CoV-2 appears to exhibit a similar spectrum of outcomes to that seen in the general population, with 11 people admitted to intensive care (7 post-transplant), and 7 deaths (3 post-transplant). A more severe clinical course may be associated with older age, CF-related diabetes, lower lung function in the year prior to infection, and having received an organ transplant. Whilst outcomes in this large cohort are better than initially feared overall, possibly due to a protective effect of the relatively younger age of the CF population compared to other chronic conditions, SARS-CoV-2 is not a benign disease for all people in this patient group., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare relating to this work., (Copyright © 2020 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Healthcare coproduction engages patients and clinicians to design and execute services, yet little is known about tools that facilitate coproduction. Our objective was to understand uptake, experiences, benefits, and limitations of a dashboard to support patient-clinician partnerships within the cystic fibrosis (CF) community., Methods: People living with CF (PwCF) and clinicians co-designed a dashboard that displayed patient-reported and clinical data. Eight CF programmes, including 21 clinicians, and 131 PwCF participated in a pilot study of the dashboard. We conducted descriptive statistics and thematic analyses of surveys (82 PwCF; 21 clinicians); semi-structured interviews (13 PwCF; 8 care teams); and passively-collected usage data., Results: Two-thirds of the 82 PwCF used the dashboard during a visit, and 59% used it outside a visit. Among 48 PwCF using the dashboard outside the clinic, 92% viewed their health information and 46% documented concerns or requests. Most of the 21 clinicians used the dashboard to support visit planning (76%); fewer used it during a visit (48%). The dashboard supported discussions of what matters most (69% PwCF; 68% clinicians). Several themes emerged: access to patient outcomes data allows users to learn more deeply; participation in pre-visit planning matters; coproduction is made possible by inviting new ways to partner; and lack of integration with existing information technology (IT) systems is limiting., Conclusions: A dashboard was feasible to implement and use. Future iterations should provide patients access to their data, be simple to use, and integrate with IT systems in use by clinicians and PwCF., Competing Interests: Declaration of Competing Interest Jordan Dunitz, Adrienne Savant, Brooke Moore, Michelle Prickett, Terri Laguna, Cindy Brady, Morgan Soper, Sarah Jain, and Whitney Gore report grant subcontracts from Dartmouth College to conduct work associated with design and pilot-testing of CFHC. Eugene Nelson, Kathryn Sabadosa, and Aricca Van Citters report grant funding from the Robert Wood Johnson Foundation and Cystic Fibrosis Foundation. Alex Gifford reports grant funding from the Cystic Fibrosis Foundation. Terri Laguna reports grant funding from the Cystic Fibrosis Foundation and the National Institutes of Health, is a grant reviewer for the Cystic Fibrosis Foundation and a member of a National Institute of Health study section; and receives an honorarium for participating on a Physician Advisory Board for Vertex Pharmaceuticals. Eugene Nelson owns stock in Quality Data Management (QDM). Bruce Marshall, Jonathan Flath, Madeline Elmhirst, and Maureen Riordan report no conflicts of interest., (Copyright © 2020. Published by Elsevier B.V.)

Introduction: In this long-term, postapproval, observational study, data from the US Cystic Fibrosis Foundation Patient Registry and the UK Cystic Fibrosis Registry were used to evaluate the impact of ivacaftor treatment on cystic fibrosis (CF) by comparing outcomes in ivacaftor-treated patients with those in matched untreated comparator patients. Registry data from up to 5 years of ivacaftor availability in the US and up to 4 years of availability in the UK were evaluated., Methods: Starting in the first year of ivacaftor availability, ivacaftor-treated patients in each registry were matched 1:5 to comparator patients who never received ivacaftor. Clinical endpoints were evaluated in annual cross-sectional safety analyses. The key endpoints were death, organ transplants, pulmonary exacerbation, and hospitalization. Relative risks and 95% CIs were calculated to compare the ivacaftor and comparator cohorts in each registry., Results: Here, we report the complete and final results of the annual cross-sectional safety analyses across the duration of the study, with up to 5 years of follow-up. Data show a pattern of lower risk of death, transplant, pulmonary exacerbation, and hospitalization among ivacaftor-treated patients in both registries., Conclusions: Ivacaftor-treated patients had consistently favorable clinical outcomes relative to untreated comparators, and no new safety concerns were identified. While general limitations of observational research apply, these findings support disease modification by CF transmembrane conductance regulator (CFTR) modulator therapy with ivacaftor. Future research of novel CFTR modulators will need to explore alternative methods for comparator selection for evaluation of clinical data given the evolving landscape of CF treatment.

Information is lacking on the clinical impact of the novel coronavirus, SARS-CoV-2, on people with cystic fibrosis (CF). Our aim was to characterise SARS-CoV-2 infection in people with cystic fibrosis., Methods: Anonymised data submitted by each participating country to their National CF Registry was reported using a standardised template, then collated and summarised., Results: 40 cases have been reported across 8 countries. Of the 40 cases, 31 (78%) were symptomatic for SARS-CoV-2 at presentation, with 24 (60%) having a fever. 70% have recovered, 30% remain unresolved at time of reporting, and no deaths have been submitted., Conclusions: This early report shows good recovery from SARS-CoV-2 in this heterogeneous CF cohort. The disease course does not seem to differ from the general population, but the current numbers are too small to draw firm conclusions and people with CF should continue to strictly follow public health advice to protect themselves from infection., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare relating to this work., (Copyright © 2020. Published by Elsevier B.V.)

Background: Ivacaftor is the first in a class of drugs, CFTR modulators, that target the underlying defect in cystic fibrosis (CF). This long-term observational safety study evaluated CF disease progression in patients treated with ivacaftor in a real-world setting for up to 5 years., Methods: Data from existing US and UK CF patient registries were used to assess longitudinal patterns in lung function, nutritional status, pulmonary exacerbations and hospitalizations, CF-related diabetes (CFRD), and Pseudomonas aeruginosa in ivacaftor-treated vs untreated comparator cohorts matched by age, sex, and disease severity., Results: US analyses included 635 ivacaftor-treated patients and 1874 comparators followed for 5 years from year 1 of market availability (2012-2016). Evaluation of outcome patterns from pretreatment baseline (2011) through year 5 (2016), showed that relative to comparators, ivacaftor-treated patients had better preserved lung function (mean change in percent predicted FEV 1 , -0.7 percentage points with ivacaftor vs -8.3 percentage points in comparators) and improved nutritional status (mean body mass index change +2.4 kg/m 2 with ivacaftor vs +1.6 kg/m 2 in comparators). US patients treated with ivacaftor had significantly lower frequencies of exacerbations and hospitalizations in each of the 5 years of follow-up relative to pretreatment baseline and comparators. Favorable trends in CFRD and P. aeruginosa prevalence were also observed. Findings from the smaller UK registry were directionally similar to and consistent with US findings., Conclusions: This observational study represents the largest longitudinal analysis of patients treated with ivacaftor in a real-world setting. The findings support disease modification by CFTR modulation with ivacaftor., Competing Interests: Conflict of interest statement All authors received nonfinancial support (assistance with manuscript preparation) from ArticulateScience LLC, which received funding from Vertex Pharmaceuticals. Additional disclosures are as follows: NV, KM, JE, DC, ST, CS, and MH: employee of Vertex Pharmaceuticals and may own stock or stock options in Vertex Pharmaceuticals. MWK: grants, personal fees, and nonfinancial support from Vertex Pharmaceuticals, during the course of the study; grants and nonfinancial support from the Cystic Fibrosis Foundation (CFF); grants, personal fees, and nonfinancial support from Corbus, Laurent, PTC, and Savara; personal fees and nonfinancial support from Chiesi, Celtaxsys, Genentech, and Merck; personal fees from Albumedix, Anthera, Ionis, Paranta, Protalix, and Santhera outside the submitted work. GSS: grants and personal fees from Vertex Pharmaceuticals outside the submitted work. AE and BCM: other support from several pharmaceutical companies during the conduct of the study (The CFF has entered into therapeutic development award agreements and licensing agreements to assist with the development of CFTR modulators that may result in intellectual property rights, royalties and other fees provided to CFF by various pharmaceutical companies). SCC: service agreement between Vertex Pharmaceuticals and Cystic Fibrosis Services Limited for statistical analysis. DB: member of the Steering Committee of the UK CF Registry, which provided data for this study., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Ivacaftor is the first cystic fibrosis transmembrane conductance regulator (CFTR) modulator demonstrating clinical benefit in patients with cystic fibrosis (CF). As ivacaftor is intended for chronic, lifelong use, understanding long-term effects is important for patients and healthcare providers., Objective: This ongoing, observational, postapproval safety study evaluates clinical outcomes and disease progression in ivacaftor-treated patients using data from the US and the UK CF registries following commercial availability., Methods: Annual analyses compare ivacaftor-treated and untreated matched comparator patients for: risks of death, transplantation, hospitalisation, pulmonary exacerbation; prevalence of CF-related complications and microorganisms and lung function changes in a subset of patients who initiated ivacaftor in the first year of commercial availability. Results from the 2014 analyses (2 and 3 years following commercial availability in the UK and USA, respectively) are presented here., Results: Analyses included 1256 ivacaftor-treated and 6200 comparator patients from the USA and 411 ivacaftor-treated and 2069 comparator patients from the UK. No new safety concerns were identified based on the evaluation of clinical outcomes included in the analyses. As part of safety evaluations, ivacaftor-treated US patients were observed to have significantly lower risks of death (0.6% vs 1.6%, p=0.0110), transplantation (0.2% vs 1.1%, p=0.0017), hospitalisation (27.5% vs 43.1%, p<0.0001) and pulmonary exacerbation (27.8% vs 43.3%, p<0.0001) relative to comparators; trends were similar in the UK. In both registries, ivacaftor-treated patients had a lower prevalence of CF-related complications and select microorganisms and had better preserved lung function., Conclusions: While general limitations of observational research apply, analyses revealed favourable results for clinically important outcomes among ivacaftor-treated patients, adding to the growing body of literature supporting disease modification by CFTR modulation with ivacaftor., Eu Pas Registration Number: EUPAS4270., Competing Interests: Competing interests: MH, CS, ST and NV are employees of Vertex Pharmaceuticals Incorporated and may own stock or stock options in that company. LB and LB are former employees of Vertex Pharmaceuticals Incorporated and may own stock or stock options in that company. GSS has served on advisory boards for Vertex Pharmaceuticals Incorporated and on the US CFFPR committee. AE is an employee and AS is a contractor for the US CF Foundation, which provided data for this study. BCM is an employee of the CF Foundation. DB and SN are members of the Steering Committee of the UK CF Registry, which provided data for this study. MWK is a consultant to Vertex Pharmaceuticals Incorporated., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Cystic fibrosis (CF) patients from Canada have better-reported post-lung transplant survival compared to patients from the United States. We hypothesized the clinical characteristics of CF patients prior to lung transplant differ between the two countries., Methods: Population-based cohort study utilizing combined Canadian CF Registry and US CF Foundation Patient Registry data from 1986 to 2013. Demographic and clinical variables were analyzed prior to lung transplant., Results: Between 1986 and 2013, 607 (10.2%) CF patients underwent lung transplantation in Canada and 3428 (7.5%) in the United States. A lower proportion of recipients had growth of B. cepacia complex prior to transplant in the United States compared to Canada (0.8% vs 4.3%). Lung function was similar between recipients from the two countries. The proportion of patients classified as underweight was significantly higher in the United States compared to Canada (39.8% vs 28.0%; SD 26.1) despite higher rates of feeding tube use (42.5% vs 28.6%; SD 29.0)., Conclusions: CF lung transplant recipients from the United States have similar lung function, lower rates of B. cepacia complex, and worse nutritional parameters prior to transplant compared to counterparts in Canada. Future studies are necessary to evaluate the impact of these differences on post-transplant survival., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Between 2002 and 2006 France launched a national cystic fibrois (CF) newborn screening program; organized a network of specialized CF care centers; and issued CF diagnostic and treatment standards. To continue to build on this success in 2007 the Cystic Fibrosis Center of Expertise for Rare Diseases (CF CERD) of Nantes-Roscoff in partnership with the French CF Society, the French CF Association (Vaincre la Mucoviscidose), and all CF center leaders from across the country agreed to pursue center-level improvement in medical outcomes for people with CF by adapting the U.S. Cystic Fibrosis Foundation's (US CFF) national initiative, Accelerating the Rate of Improvement in CF Care. To launch the Program to Improve Results and Expertise in CF (le Programme d'Amélioration des Résultats et de l'Expertise en Mucoviscidose - PHARE-M), French leaders pursued mentorship and guidance from leaders at the US CFF, the Dartmouth Institute (TDI), and clinical care teams at CF centers across the U.S., Methods: The following activities enabled the Nantes-Roscoff CF CERD team members and a parent, involved with the French CF Association board and a quality engineer by training, to gain the leadership and quality improvement knowledge and skills necessary to implement the PHARE-M program: 1) regularly attending national meetings, tracking publications, and leveraging existing partnerships; 2) completing two sabbaticals to visit U.S. CF centers and enrolling in academic and professional training courses; and, 3) inviting US CFF and TDI leaders to France to meet key opinion leaders and frontline teams., Conclusions: The Nantes-Roscoff CF CERD team successfully adapted the US CFF's initiative to accelerate improvement in CF care by establishing a partnership with U.S. leaders to communicate and exchange strategies and lessons learned; intentionally studying and adapting the Clinical Microsystems approach to quality improvement; and learning directly from the experience of frontline teams in the U.S. They continue to partner with U.S. leaders and are seeking to collaborate with European colleagues to continue to improve care for individuals with CF and their families across Europe.

In this article, we describe existing CF registries with a focus on US registry data collected through the CF Foundation Patient Registry (CFFPR) and the Epidemiologic Study of CF (ESCF); highlight what registries have taught us regarding epidemiology of CF; showcase the impact of registries on research and clinical care; and discuss future directions. This manuscript complements the plenary address given by Dr Wayne Morgan at the 2016 North American CF Conference by summarizing the key points from the presentation and providing additional detail and information., (© 2017 Wiley Periodicals, Inc.)

Background: There are many challenges to providing end-of-life care (EOLC) to people with cystic fibrosis (CF)., Methods: Chart abstraction was used to examine EOLC in adults with CF who died between 2011 and 2013., Results: We reviewed 248 deaths from 71 CF care centers. Median age at death was 29years (range 18-73). While median FEV1 was in the severe lung disease category (FEV1<40%), 38% had mild or moderate lung disease in the year preceding death. The most common location of death was the intensive care unit (ICU, 39%), and 12% of decedents were listed for lung transplant. Fewer of those dying in the ICU personally participated in advance care planning or utilized hospice or Palliative Care Services (p<0.05)., Conclusions: Adults dying with CF in the United States most commonly die in an ICU, with limited and variable use of hospice and Palliative Care Services. Palliative care and advance care planning are recommended as a routine part of CF care., (Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: The Standardized Treatment of Pulmonary Exacerbations (STOP) program has the intent of defining best practices in the treatment of pulmonary exacerbations (PEx) in patients with cystic fibrosis (CF). The objective of this analysis was to describe the clinical presentations of patients admitted for intravenous (IV) antibiotics and enrolled in a prospective observational PEx study as well as to understand physician treatment goals at the start of the intervention., Methods: We enrolled adolescents and adults admitted to the hospital for a PEx treated with IV antibiotics. We recorded patient and PEx characteristics at the time of enrollment. We surveyed treating physicians on treatment goals as well as their willingness to enroll patients in various study designs. Additional demographic and clinical data were obtained from the CF Foundation Patient Registry., Results: Of 220 patients enrolled, 56% were female, 19% were adolescents, and 71% were infected with P. aeruginosa. The mean (SD) FEV 1 at enrollment was 51.1 (21.6)% predicted. Most patients (85%) experienced symptoms for ≥7days before admission, 43% had received IV antibiotics within the previous 6months, and 48% received oral and/or inhaled antibiotics prior to IV antibiotic initiation. Forty percent had ≥10% FEV 1 decrease from their best value recorded in the previous 6months, but for 20% of patients, their enrollment FEV 1 was their best FEV 1 recorded within the previous 6months. Physicians reported that their primary treatment objectives were lung function recovery (53%) and improvement of symptoms (47%) of PEx. Most physicians stated they would enroll patients in studies involving 10-day (72%) or 14-day (87%), but not 7-day (29%), treatment regimens., Conclusions: Based on the results of this study, prospective studies are feasible and physician willingness for interventional studies of PEx exists. Results of this observational study will help design future PEx trials., (Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Ionic-liquid (IL) mixtures hold great promise, as they allow liquids with a wide range of properties to be formed by mixing two common components rather than by synthesizing a large array of pure ILs with different chemical structures. In addition, these mixtures can exhibit a range of properties and structural organization that depend on their composition, which opens up new possibilities for the composition-dependent control of IL properties for particular applications. However, the fundamental properties, structure, and dynamics of IL mixtures are currently poorly understood, which limits their more widespread application. This article presents the first comprehensive investigation into the bulk and surface properties of IL mixtures formed from two commonly encountered ILs: 1-ethyl-3-methylimidazolium and 1-dodecyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([C 2 mim][Tf 2 N] and [C 12 mim][Tf 2 N]). Physical property measurements (viscosity, conductivity, and density) reveal that these IL mixtures are not well described by simple mixing laws, implying that their structure and dynamics are strongly composition dependent. Small-angle X-ray and neutron scattering measurements, alongside molecular dynamics (MD) simulations, show that at low mole fractions of [C 12 mim][Tf 2 N], the bulk of the IL is composed of small aggregates of [C 12 mim] + ions in a [C 2 mim][Tf 2 N] matrix, which is driven by nanosegregation of the long alkyl chains and the polar parts of the IL. As the proportion of [C 12 mim][Tf 2 N] in the mixtures increases, the size and number of aggregates increases until the C12 alkyl chains percolate through the system and a bicontinuous network of polar and nonpolar domains is formed. Reactive atom scattering-laser-induced fluorescence experiments, also supported by MD simulations, have been used to probe the surface structure of these mixtures. It is found that the vacuum-IL interface is enriched significantly in C12 alkyl chains, even in mixtures low in the long-chain component. These data show, in contrast to previous suggestions, that the [C 12 mim] + ion is surface active in this binary IL mixture. However, the surface does not become saturated in C12 chains as its proportion in the mixtures increases and remains unsaturated in pure [C 12 mim][Tf 2 N].

Background: In 2011, the median age of survival of patients with cystic fibrosis reported in the United States was 36.8 years, compared with 48.5 years in Canada. Direct comparison of survival estimates between national registries is challenging because of inherent differences in methodologies used, data processing techniques, and ascertainment bias., Objective: To use a standardized approach to calculate cystic fibrosis survival estimates and to explore differences between Canada and the United States., Design: Population-based study., Setting: 42 Canadian cystic fibrosis clinics and 110 U.S. cystic fibrosis care centers., Patients: Patients followed in the Canadian Cystic Fibrosis Registry (CCFR) and U.S. Cystic Fibrosis Foundation Patient Registry (CFFPR) between 1990 and 2013., Measurements: Cox proportional hazards models were used to compare survival between patients followed in the CCFR (n = 5941) and those in the CFFPR (n = 45 448). Multivariable models were used to adjust for factors known to be associated with survival., Results: Median age of survival in patients with cystic fibrosis increased in both countries between 1990 and 2013; however, in 1995 and 2005, survival in Canada increased at a faster rate than in the United States (P < 0.001). On the basis of contemporary data from 2009 to 2013, the median age of survival in Canada was 10 years greater than in the United States (50.9 vs. 40.6 years, respectively). The adjusted risk for death was 34% lower in Canada than the United States (hazard ratio, 0.66 [95% CI, 0.54 to 0.81]). A greater proportion of patients in Canada received transplants (10.3% vs. 6.5%, respectively [standardized difference, 13.7]). Differences in survival between U.S. and Canadian patients varied according to U.S. patients' insurance status., Limitation: Ascertainment bias due to missing data or nonrandom loss to follow-up might affect the results., Conclusion: Differences in cystic fibrosis survival between Canada and the United States persisted after adjustment for risk factors associated with survival, except for private-insurance status among U.S. patients. Differential access to transplantation, increased posttransplant survival, and differences in health care systems may, in part, explain the Canadian survival advantage., Primary Funding Source: U.S. Cystic Fibrosis Foundation.

Objective: Cystic fibrosis (CF), caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, continues to present diagnostic challenges. Newborn screening and an evolving understanding of CF genetics have prompted a reconsideration of the diagnosis criteria., Study Design: To improve diagnosis and achieve standardized definitions worldwide, the CF Foundation convened a committee of 32 experts in CF diagnosis from 9 countries to develop clear and actionable consensus guidelines on the diagnosis of CF and to clarify diagnostic criteria and terminology for other disorders associated with CFTR mutations. An a priori threshold of ≥80% affirmative votes was required for acceptance of each recommendation statement., Results: After reviewing relevant literature, the committee convened to review evidence and cases. Following the conference, consensus statements were developed by an executive subcommittee. The entire consensus committee voted and approved 27 of 28 statements, 7 of which needed revisions and a second round of voting., Conclusions: It is recommended that diagnoses associated with CFTR mutations in all individuals, from newborn to adult, be established by evaluation of CFTR function with a sweat chloride test. The latest mutation classifications annotated in the Clinical and Functional Translation of CFTR project (http://www.cftr2.org/index.php) should be used to aid in diagnosis. Newborns with a high immunoreactive trypsinogen level and inconclusive CFTR functional and genetic testing may be designated CFTR-related metabolic syndrome or CF screen positive, inconclusive diagnosis; these terms are now merged and equivalent, and CFTR-related metabolic syndrome/CF screen positive, inconclusive diagnosis may be used. International Statistical Classification of Diseases and Related Health Problems, 10th Revision codes for use in diagnoses associated with CFTR mutations are included., (Copyright © 2016. Published by Elsevier Inc.)

Background: Previous studies demonstrated increased digestive tract cancers among individuals with cystic fibrosis (CF), particularly among lung transplant recipients. We describe cancer incidence among CF and non-CF lung recipients., Methods: We used data from the US transplant registry and 16 cancer registries. Standardized incidence ratios (SIRs) compared cancer incidence to the general population, and competing risk methods were used for the cumulative incidence of colorectal cancer., Results: We evaluated 10,179 lung recipients (1681 with CF). Risk was more strongly increased in CF recipients than non-CF recipients for overall cancer (SIR 9.9 vs. 2.7) and multiple cancers including colorectal cancer (24.2 vs. 1.7), esophageal cancer (56.3 vs. 1.3), and non-Hodgkin lymphoma (61.8 vs. 9.4). At five years post-transplant, colorectal cancer was diagnosed in 0.3% of CF recipients aged <50 at transplant and 6.4% aged ≥50., Conclusions: CF recipients have increased risk for colorectal cancer, suggesting a need for enhanced screening., (Copyright © 2016 European Cystic Fibrosis Society. All rights reserved.)

Copolymers of polyhedral oligomeric silsesquioxane (POSS) and polyimide (PI) have shown remarkable resistance to atomic oxygen (AO) attack and have been proposed as replacements for Kapton on the external surfaces of spacecraft in the harsh oxidizing environment of low Earth orbit (LEO). POSS PI blends would be an economical alternative to the copolymers if they also resisted AO attack. Thus, blends of trisilanolphenyl (TSP) POSS and PI with different weight percentages of the Si 7 O 9 POSS cage were cast into films and exposed to a hyperthermal AO beam, and they were characterized in terms of their recession, mass loss, surface morphology, and surface chemistry. In order to compare the AO resistance of the blends with POSS PI copolymers, samples of previously studied copolymers were also investigated in parallel with the blends. For all POSS PI materials, the AO resistance increased with increasing AO fluence and with increasing POSS cage loading. At similar POSS cage loadings and exposure conditions, the TSP POSS PI blends showed comparable erosion yields to the POSS PI copolymers, with specific samples of blends and copolymers achieving erosion yields as low as 0.066 × 10 -24 cm 3 atom -1 with an AO fluence of 5.93 × 10 20 O atoms cm -2 . SEM and XPS analyses indicated that passivating SiO x layers were formed on the surfaces of all POSS-containing polymers during AO exposure. Thus, a TSP POSS PI blend is proposed as a low-cost variant of a POSS polyimide for use in extreme oxidizing environments, such as LEO.

Nutrition is integral to the care of individuals with cystic fibrosis (CF). Better nutritional status is associated with improved pulmonary function. In some individuals with CF, enteral tube feeding can be useful in achieving optimal nutritional status. Current nutrition guidelines do not include detailed recommendations for enteral tube feeding. The Cystic Fibrosis Foundation convened an expert panel to develop enteral tube feeding recommendations based on a systematic review of the evidence and expert opinion. These guidelines address when to consider enteral tube feeding, assessment of confounding causes of poor nutrition in CF, preparation of the patient for placement of the enteral feeding tube, management of the tube after placement and education about enteral feeding. These recommendations are intended to guide the CF care team, individuals with CF, and their families through the enteral tube feeding process., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)