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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]

BACKGROUND: We hypothesized that adding 5 days of prednisone to standard therapy for acute pulmonary exacerbations in patients with cystic fibrosis (CF) would result in a more rapid and greater increase in lung function. METHODS: CF patients with an acute pulmonary exacerbation were randomized to receive oral placebo or prednisone, 2 mg/kg/d up to 60 mg, on days 1 to 5 in addition to standard therapy. Study evaluations on days 1 to 6, 14, and 42 included spirometry, glucose measurements, sputum analysis, and symptom scores. RESULTS: Twelve subjects were randomized to each arm. The slope of FEV(1) between day 1 and day 6 did not differ between evaluable subjects in the prednisone vs placebo groups (52 mL/d vs 51 mL/d, respectively). Mean increase in FEV(1) percentage of predicted did not differ significantly between prednisone vs placebo groups (day 6 [mean +/- SD], 12.2 +/- 5.2% vs 8.1 +/- 10.5%; day 14, 14.7 +/- 8.8% vs 10.2 +/- 11.2%, respectively). Sputum inflammatory markers and symptom scores decreased between day 1 and day 14, but mean values did not differ between groups. Glucosuria occurred in six prednisone subjects, two of whom had hyperglycemia develop. CONCLUSIONS: In this pilot study, addition of oral corticosteroids to standard CF pulmonary exacerbation therapy did not result in a statistically significant effect on lung function or sputum markers of inflammation. Based on a trend toward improvement in pulmonary function with prednisone therapy, we obtained information for power calculations for a definitive study: 250 randomized subjects are required to detect a four-percentage-point treatment effect in FEV(1) percentage of predicted at day 14 to discriminate between null and alternative hypotheses. [ABSTRACT FROM AUTHOR]

Background: Chronic progressive lung disease is the most serious complication of cystic fibrosis (CF). Glutathione plays an important role in the protection of the CF lung against oxidant-induced lung injury.Objectives: We hypothesized that a polymorphism in a novel candidate gene that regulates glutathione synthesis might influence CF lung disease.Methods: In a cross-sectional study, subjects were recruited from CF clinics in Seattle and multiple centers in Canada. We tested for an association between CF lung disease and a functional polymorphism in the glutamate-cysteine ligase catalytic subunit (GCLC) gene. Multiple linear regression was used to test for association between polymorphisms of GCLC and severity of CF lung disease while adjusting for age, Pseudomonas aeruginosa infection, and cystic fibrosis transmembrane conductance regulator (CFTR) genotype. Analysis was repeated for patients with CF stratified by CFTR genotype.Measurements and Main Results: A total of 440 subjects with CF participated in the study (51% male; mean [+/- SD] age, 26 +/- 11 yr; mean FEV(1), 62 +/- 28% predicted). In the total population, there was a trend toward an association between GCLC genotypes and CF lung disease (linear regression coefficient [SEM], 1.68 [1.0]; p = 0.097). In the stratified analysis, there was a highly significant association between GCLC genotype and CF lung function in subjects with a milder CFTR genotype (linear regression coefficient [SEM], 5.5 (1.7); p = 0.001).Conclusions: In patients with CF with a milder CFTR genotype, there is a strong association between functional polymorphisms of the GCLC gene and CF lung disease severity. [ABSTRACT FROM AUTHOR]

Rationale: The randomized clinical trial has been an important tool for expanding our knowledge of disease. This study is the first to compare trial participants to the entire eligible population.Methods: We performed a cohort analysis using data from the Cystic Fibrosis Foundation Registry database between 1992 and 1998.Measurements and Main Results: There were 8,735 patients older than 6 yr followed for the entire period. Of the patients, 2,635 patients (30.2%) were enrolled in at least 1 of 32 Institutional Review Board-approved clinical trials, with an average annual participation rate of 7%. Patients enrolled in clinical trials had more advanced disease as judged by FEV(1)% predicted (68 vs. 77%, p < 0.001), higher rates of Pseudomonas aeruginosa infection (71 vs. 65%, p < 0.01), and were more likely to have private insurance (odds ratio [OR], 1.25; 95% confidence interval [CI], 1.14-1.37) and be white (OR, 1.98; 95% CI, 1.44-2.70). No sex differences were noted. Despite the worse clinical status at baseline, clinical trial participants had a lower average annual rate of decline in lung function (1.33%/yr; 95% CI, 1.20, 1.46; compared with 1.52%; 95% CI, 1.43-1.60).Conclusions: These results show that the overall participation rate is very high. Despite more advanced disease at baseline, lung function decline was lower in trial participants; the cause of this difference is unclear. The differences seen in insurance status are concerning. Efforts should be made to ensure adequate representation from different social demographic groups. [ABSTRACT FROM AUTHOR]

Rationale: Exercise-induced bronchoconstriction (EIB) is a highly prevalent condition with unclear pathogenesis. Two competing theories of the pathogenesis of EIB differ regarding the inflammatory basis of this condition.Objectives: Our goals were to establish whether epithelial cell and mast cell activation with release of inflammatory mediators occurs during EIB and how histamine and cysteinyl leukotriene antagonists alter the airway events occurring during EIB.Methods: Induced sputum was used to measure mast cell mediators and eicosanoids at baseline and 30 minutes after exercise challenge in 25 individuals with asthma with EIB. In a randomized, double-blind crossover study, the cysteinyl leukotriene antagonist montelukast and antihistamine loratadine or two matched placebos were administered for two doses before exercise challenge.Main Results: The percentage of columnar epithelial cells in induced sputum at baseline was associated with the severity of EIB. After exercise challenge, histamine, tryptase, and cysteinyl leukotrienes significantly increased and prostaglandin E(2) and thromboxane B(2) significantly decreased in the airways, and there was an increase in columnar epithelial cells in the airways. The concentration of columnar epithelial cells was associated with the levels of histamine and cysteinyl leukotrienes in the airways. Treatment with montelukast and loratadine inhibited the release of cysteinyl leukotrienes and histamine into the airways, but did not inhibit the release of columnar epithelial cells into the airways.Conclusions: These data indicate that epithelial cells, mast cell mediators, and eicosanoids are released into the airways during EIB, supporting an inflammatory basis for EIB. [ABSTRACT FROM AUTHOR]

Induced sputum has been used to study airway inflammation. We sought to determine whether markers of infection and inflammation in induced sputum were a useful and safe outcome measure in cystic fibrosis. We hypothesized that bacterial density and inflammatory content of induced sputum would decrease after antibiotic therapy. Induced sputum was assayed for bacterial density, cell count, and differential and inflammatory markers before and after treatment with intravenous antibiotics. Fifty-five of the 72 subjects enrolled (mean age +/- SD 18.2 +/- 7.9 years) completed the study. FEV1 increased by an average 0.3 +/- 0.3 L (10.4 +/- 8.7% predicted FEV1), p<0.0001; density of Pseudomonas aeruginosa and Staphylococcus aureus decreased by 2.4 +/- 3.1 log10 cfu/g (p<0.0005) and 4.0 +/- 2.3 log10 cfu/ml (p<0.0001), respectively; neutrophil count decreased by 0.4 +/- 0.6 log10 cells/ml (p<0.0001), interleukin-8 concentration by 0.5 +/- 1.3 log10 pg/ml (p<0.05), and neutrophil elastase by 0.4 +/- 0.7 log10 microg/ml (p<0.005). Seven of 127 (6%) sputum induction procedures showed a decrease in FEV1 of 20% or more. We conclude that markers in induced sputum may be useful, noninvasive outcome measures to assess response to therapies in cystic fibrosis studies. [ABSTRACT FROM AUTHOR]

In the decade since the gene for cystic fibrosis (CF) was discovered, research into potential therapeutic interventions has progressed on a number of different fronts. The vast majority of morbidity and mortality in CF results from inflammation and infection of the airways. Direct delivery of antibacterials to the airway secretions via a nebuliser is an attractive therapeutic option, and a novel formulation of tobramycin designed for such a purpose has been demonstrated to improve spirometry and decrease the need for intravenous antibacterials. In addition, early clinical trials are studying the effects of small peptides with antibiotic properties (defensins) delivered directly to the airways. Inflammation, whether secondary to infection or an independent feature of CF, leads to progressive bronchiectasis. Anti-inflammatories such as prednisone and possibly ibuprofen have been shown to decrease the rate of respiratory decline in patients with CF but have tolerability profiles that limit clinical usefulness. Macrolides also have anti-inflammatory properties and clinical trials are now ongoing to assess the efficacy of these agents in CF. Multiple agents, including uridine triphosphate (UTP), genistein, phenylbutyrate and CPX (cyclopentyl dipropylxanthine), have been demonstrated in cell culture to at least partially correct the primary defect of ion transport related to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). No agent of this class has yet demonstrated clinical effectiveness, but several are in preclinical and early clinical trials. Finally, gene therapy that allows for the incorporation and expression of wild-type CFTR in respiratory epithelial cells would be definitive therapy for CF. However, multiple barriers to delivery and expression need to be overcome. With research proceeding on these multiple fronts, new therapies for pulmonary complications promise to continue to increase the life expectancy of individuals with CF. [ABSTRACT FROM AUTHOR]

Background: Over 1000 mutations of the cystic fibrosis transmembrane conductance regulator gene (CFTR) that cause cystic fibrosis have been identified. We examined the effect of CFTR genotype on mortality and disease phenotype.Methods: Using the US Cystic Fibrosis Foundation National Registry, we did a retrospective cohort study to compare standardised mortality rates for the 11 most common genotypes heterozygous for DeltaF508 with those homozygous for DeltaF508. Of the 28455 patients enrolled in the registry at the time of our analysis, 17853 (63%) were genotyped. We also compared the clinical phenotype, including lung function, age at diagnosis, and nutritional measures, of 22 DeltaF508 heterozygous genotypes. Mortality rates and clinical phenotype were also compared between genotypes classified into six classes on the basis of their functional effect on CFTR production.Findings: Between 1991 and 1999, genetic and clinical data were available for 17853 patients with cystic fibrosis, which was 63% of the total cohort. There were 1547 deaths during the 9 years of follow-up. In the analysis of the 11 most common genotypes, DeltaF508/R117H, DeltaF508/DeltaI507, DeltaF508/3849+10kbC-->T, and DeltaF508/2789+5G-->A had a significantly lower mortality rate (4.7, 8.0, 11.9, and 4.4, respectively) than the genotype homozygous for DeltaF508 (21.8, p=0.0060). DeltaF508/R117H, DeltaF508/DeltaI507, DeltaF508/ 3849+10 kbC-->T, DeltaF508/2789+5G-->A, and DeltaF508/A455E have a milder clinical phenotype. Outcomes for all functional classes were compared with that of class II (containing DeltaF508 homozygotes) and classes IV and V had a significantly lower mortality rate and milder clinical phenotype.Interpretation: Patients with cystic fibrosis have distinct genetic subgroups that are associated with mild clinical manifestations and low mortality. These differences in phenotype are also related to the functional classification of CFTR genotype. [ABSTRACT FROM AUTHOR]

Rationale: Lung transplant (LTx) is a potentially lifesaving treatment option for individuals with advanced cystic fibrosis (CF), but more people with CF (PwCF) and advanced lung disease die each year than undergo transplant in the United States. Little is known about these individuals' LTx information needs and factors influencing their decision-making process related to transplant. Objectives: To examine PwCF's experiences with and preferences for provision of LTx information and to identify transplant information needs that CF clinicians are well positioned to address. Methods: We performed semistructured qualitative interviews in two separate cohorts: PwCF without LTx and PwCF with LTx between July 2019 and June 2020. Questions focused on awareness and knowledge about LTx, perspectives related to communication about transplant in the CF clinic, and experiences with LTx. Thematic analysis was used to organize the qualitative data. Exemplar quotes were chosen to llustrate domains that emerged pertaining to the research objectives. Results: Fifty-five PwCF, including 35 without LTx and 20 with LTx, participated. One-third of PwCF without LTx had normal or near-normal lung function. Key common domains among PwCF with and without LTx were identified, including information needs, connections with LTx recipients, and conversations with CF clinicians. For PwCF with and without transplant, concrete information needs were identified: success or survival, social support, surgery, recovery/pain, and quality of life post-transplant. The importance of connecting with LTx recipients to hear their stories and experiences was emphasized by both PwCF with and without transplant. Important considerations for timing and content of discussions with CF clinicians were identified, including having information presented early (before LTx referral is needed) and in limited detail at first. PwCF without LTx wanted to understand how LTx was relevant to them, with a focus on the unique experience of CF. PwCF with LTx emphasized the need for a centralized resource for LTx information. Conclusions: The findings provide content areas for CF clinicians to focus on as they proactively initiate conversations about LTx and support the development of tools to aid in discussions about LTx for PwCF.

Background: Although cystic fibrosis (CF) is a progressive, life-limiting, genetic disease, recent advances have extended survival, allowing persons with CF the time and physical and mental health to form romantic relationships. Previous studies have shown the importance of dyadic coping to positive psychosocial functioning and relationship satisfaction for people with serious chronic illness and their romantic partners, but little work has been done with persons with CF and their partners. The present study examines dyadic coping processes in persons with CF and their romantic partners., Methods: Sixteen adults with moderate to severe CF (M age =42.3, 43.8% identified as cisgender male, 56.2% identified as cisgender female) and their romantic partners (M age =43.8, 56.3% identified as cisgender male, 43.7% identified as cisgender female) participated in individual semi-structured interviews focused on topics related to quality of life, communication, and palliative care. We conducted a directed content analysis utilizing Berg and Upchurch's (2007) developmental-contextual theoretical model to examine dyadic coping processes in persons with CF and their romantic partners., Results: Consistent with the developmental-contextual model of dyadic coping, couples described adapting to health and functional declines that occurred over time. Dyads were aligned in their appraisals of illness representation, illness ownership, and perspectives of illness as a shared stressor; they used shared coping mechanisms that included supportive and collaborative actions rather than uninvolved or controlling strategies., Conclusions: We recommend family-based approaches to medical decision-making and goals of care conversations with persons with CF and their partners, aligning those approaches with supportive and collaborative coping configurations. This may improve psychosocial outcomes for patients and their partners., Competing Interests: Conflict of Interest Statement: None of the authors has a financial or other conflict of interest to disclose.

Background: Mycobacterium abscessus subspecies massiliense ( M. massiliense ) is increasingly recognized as an emerging bacterial pathogen, particularly in cystic fibrosis (CF) patients and CF centres' respiratory outbreaks. We characterized genomic and phenotypic changes in 15 serial isolates from two CF patients (1S and 2B) with chronic pulmonary M. massiliense infection leading to death, as well as four isolates from a CF centre outbreak in which patient 2B was the index case., Results: Comparative genomic analysis revealed the mutations affecting growth rate, metabolism, transport, lipids (loss of glycopeptidolipids), antibiotic susceptibility (macrolides and aminoglycosides resistance), and virulence factors. Mutations in 23S rRNA, mmpL 4, porin locus and tet R genes occurred in isolates from both CF patients. Interestingly, we identified two different spontaneous mutation events at the mycobacterial porin locus: a fusion of two tandem porin paralogs in patient 1S and a partial deletion of the first porin paralog in patient 2B. These genomic changes correlated with reduced porin protein expression, diminished 14 C-glucose uptake, slower bacterial growth rates, and enhanced TNF-α induction in mycobacteria-infected THP-1 human cells. Porin gene complementation of porin mutants partly restored 14 C-glucose uptake, growth rate and TNF-α levels to those of intact porin strains., Conclusions: We hypothesize that specific mutations accumulated and maintained over time in M. massiliense , including mutations shared among transmissible strains, collectively lead to more virulent, host adapted lineages in CF patients and other susceptible hosts.

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.)

Patients with cystic fibrosis (CF) commonly have lower circulating concentrations of 25-hydroxyvitamin D (25(OH)D) than healthy populations. We comprehensively compared measures of vitamin D metabolism among individuals with CF and healthy control subjects. In a cross-sectional study, serum from participants with CF (N = 83) and frequency-matched healthy control subjects by age and race (N = 82) were analyzed for: 25(OH)D 2 and 25(OH)D 3 , 1α,25-dihydroxyvitamins D 2 and D 3 (1α,25(OH) 2 D 2 and 1α,25(OH) 2 D 3 ), 24,25-dihydroxyvitamin D 3 (24,25(OH) 2 D 3 ), 4β,25-dihydroxyvitamin D 3 (4β,25(OH) 2 D 3 ), 25-hydroxyvitamin D 3 -3-sulfate (25(OH)D 3 -S), and 25-hydroxyvitamin D 3 -3-glucuronide (25(OH)D 3 -G). In a 56-day prospective pharmacokinetic study, ∼25 μg deuterium-labeled 25(OH)D 3 (d 6 -25(OH)D 3 ) was administered intravenously to participants (N = 5 with CF, N = 5 control subjects). Serum was analyzed for d 6 -25(OH)D 3 and d 6 -24,25(OH) 2 D 3 , and pharmacokinetic parameters were estimated. In the cross-sectional study, participants with CF had similar mean (SD) total 25(OH)D concentrations as control subjects (26.7 [12.3] vs. 27.7 [9.9] ng/mL) and had higher vitamin D supplement use (53% vs. 22%). However, participants with CF had lower total 1α,25(OH) 2 D (43.6 [12.7] vs. 50.7 [13.0] pg/mL), 4β,25(OH) 2 D 3 (52.1 [38.9] vs. 79.9 [60.2] pg/mL), and 25(OH)D 3 -S (17.7 [11.6] vs. 30.1 [12.3] ng/mL) (p < 0.001 for all). The pharmacokinetics of d 6 -25(OH)D 3 and d 6 -24,25(OH)D 3 did not differ between groups. In summary, although 25(OH)D concentrations were comparable, participants with CF had lower 1α,25(OH) 2 D, 4β,25(OH) 2 D 3 , and 25(OH)D 3 -S concentrations than healthy controls. Neither 25(OH)D 3 clearance, nor formation of 24,25(OH) 2 D 3 , appears to account for these differences and alternative mechanisms for low 25(OH)D in CF (i.e., decreased formation, altered enterohepatic recirculation) should be explored., Competing Interests: Declarations of Competing Interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Individuals with complex, chronic diseases are now living longer, making reproductive health an important topic to address in the health care setting. Self-respondent surveys are a feasible way to collect past contraceptive use and pregnancy history to assess contraceptive safety and effectiveness. Because sensitive topics, such as contraception and pregnancy outcomes, can vary across social groups or cultures, piloting questions and evaluating survey administration procedures in the target population are necessary for precise and reliable responses before wide distribution., Objective: This study aimed to develop a precise and reliable survey instrument and related procedures among individuals with cystic fibrosis regarding contraceptive use and obstetrical history., Methods: We piloted and tested web-based questions related to contraceptive use and pregnancy history among 50 participants with and those without cystic fibrosis aged 18 to 45 years using a 3-tier process. Findings from each tier informed changes to the questionnaire before testing in the subsequent tier. Tier 1 used cognitive pretesting to assess question understanding and the need for memory prompts. In tier 2, we used test-retest self- and interviewer-administered approaches to assess question reliability, evaluate response missingness, and determine confidence between 2 types of survey administration approaches. In tier 3, we tested the questionnaire for clarity, time to complete, and whether additional prompts were necessary., Results: In tier 1, respondents suggested improvements to the web-based survey questions and to the written and visual prompts for better recall regarding past contraceptive use. In tier 2, the test-retest reliability between self- and interviewer-administrative procedures of "ever use" contraceptive method questions was similar, with percent absolute agreement ranging between 84% and 100%. When the survey was self-administered, the percentage of missing responses was higher and respondent confidence about month and year when contraceptive methods were used was lower. Most respondents reported that they preferred the self-administered survey because it was more convenient and faster to complete., Conclusions: Our 3-tier process to pilot web-based survey questions related to contraceptive and obstetrical history in our complex disease population helped us tailor content and format questions before wide dissemination to our target population. Results from this pilot study informed the subsequent larger study design to include a 10% respondent test-retest self- and interviewer-administered quality control component to better inform imputation procedures of missing data., (©Emily M Godfrey, Malaika R Schwartz, Karen D Hinckley Stukovsky, Danielle Woodward, Amalia S Magaret, Moira L Aitken. Originally published in JMIR Formative Research (https://formative.jmir.org), 18.07.2023.)

Background: People with cystic fibrosis (CF) are living longer and healthier lives as a result of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies, and are pursuing pregnancy. As the number of pregnancies in CF continue to increase, clinician attitudes and practices regarding care of pregnant people with CF remain largely unknown., Objective: To evaluate the current attitudes and practices of CF clinicians regarding pregnancy planning and care in CF., Methods: We conducted a national survey investigating practice patterns related to pregnancy care in CF. We used descriptive statistics to summarize responses and paired t-tests to compare population means., Results: A total of 93 clinicians completed the survey. Eighty-six percent of respondents believed family planning and pregnancy discussions should start before the age of 21 years, of which 67% believed these discussions should occur prior to age 18 years. Our results demonstrate variability in CF clinician comfort and management of various aspects of pregnancy care in CF including 1) potential complications of pregnancy 2) continuation of chronic CF therapies 3) continuation of CFTR modulators during pregnancy and lactation, and 4) approach to treatment of pulmonary exacerbation during pregnancy., Conclusions: As more people with CF pursue pregnancy in the era of CFTR modulators, CF providers should be initiating discussions surrounding pregnancy early and often. Establishing best practices in the management of pregnancy in CF, expanding peri‑pregnancy expertise within the CF community, and future studies investigating the maternal-fetal effects of CF therapies are needed., Competing Interests: Declaration of Competing Interest All authors have no financial conflict of interest to disclose related to this study., (Copyright © 2022 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: As survival and health improve in people with cystic fibrosis (CF), more women with CF (wwCF) are considering their sexual and reproductive health (SRH). This study compared SRH experiences, behaviors, and care utilization of wwCF to the general population and defined CF-impacted considerations and care preferences., Methods: We surveyed wwCF aged ≥25 years regarding SRH and compared results to the US National Survey of Family Growth (NSFG;n = 4357) and friend controls(n = 123). We used descriptive statistics and chi-squared/Fisher's exact testing and linear regression for comparisons., Results: A total of 460 wwCF (mean age 36.1 years) completed the survey. WwCF were less likely to report current contraceptive use (43%vs76% NSFG, p<0.001;60% friends, p = 0.005). Nearly 25% of wwCF reported worsened CF symptoms during their menstrual cycles, 50% experienced urinary incontinence, and 80% vulvovaginal candidiasis. WwCF were significantly less likely to be parents (46%vs62% friends, p = 0.015) and to have experienced pregnancy (37%vs78% NSFG, p<0.001;58% friends, p = 0.002). More wwCF required medical assistance to conceive (29%vs12% NSFG, p<0.001 and 5% friends, p<0.001). Eighty-four percent of wwCF view their CF doctor as their main physician and 41% report no primary care provider (vs19% friends; p<0.001). WwCF report suboptimal rates of contraceptive and preconception counseling/care and are less likely to have received HPV vaccination (42%vs55%friends, p = 0.02). Despite desiring SRH conversations with their CF team, <50% report discussing SRH topics., Conclusion: WwCF have significantly different SRH experiences than non-CF peers. They report suboptimal SRH care compared to their preferences highlighting an urgent need to encourage SRH counseling/care in the CF model., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose related to this work. This study was funded by the Cystic Fibrosis Foundation (KAZMER18A0).|, (Copyright © 2022. Published by Elsevier B.V.)

Rationale: Hemoptysis is a common and important complication in persons with cystic fibrosis (PwCF). Despite this, there is limited literature on the impact of hemoptysis on contemporary cystic fibrosis (CF) outcomes. Objectives: Evaluate whether hemoptysis increases the risk of lung transplant or death without a transplant in PwCF. Methods: We reviewed a dataset of PwCF ages 12 years or older from the CFFPR (CF Foundation Patient Registry) that included 29,587 individuals. We identified hemoptysis as our predictor of interest and categorized PwCF as either no hemoptysis, any hemoptysis (submassive and/or massive), or massive hemoptysis. We subsequently evaluated whether hemoptysis, as defined above, was associated with death without transplant or receipt of lung transplant via logistic regression. We adjusted for age, sex, body mass index, forced expiratory volume in one second (FEV 1 ), number of exacerbations, supplemental oxygen use, CF-related diabetes, and Pseudomonas aeruginosa colonization status. Subgroup analyses were performed in advanced lung disease, defined as PwCF with an FEV 1  <40% predicted. Results: PwCF with any form of hemoptysis were more likely to progress to lung transplant or die without transplant than PwCF who did not have hemoptysis (odds ratio [OR], 1.3 [95% confidence interval (CI), 1.1-1.7]). The effect size of these associations was larger when hemoptysis events were classified as "massive" (massive hemoptysis OR, 2.2 [95% CI, 1.2-3.8]) or in PwCF with advanced lung disease (massive hemoptysis in advanced lung disease OR, 3.2 [95% CI 1.3-8.2]). Conclusions: Hemoptysis is associated with an increased risk of lung transplant and death without a transplant in PwCF, especially among those with massive hemoptysis or advanced lung disease. Our results suggest that hemoptysis functions as a useful predictor of serious outcomes in PwCF and may be important to incorporate into risk prediction models and/or transplant decisions in CF.

Immunological mechanisms of susceptibility to nontuberculous mycobacterial (NTM) disease are poorly understood. To understand NTM pathogenesis, we evaluated innate and antigen-specific adaptive immune responses to Mycobacterium avium complex (MAC) in asymptomatic individuals with a previous history of MAC lung disease (MACDZ). We hypothesized that Mav-specific immune responses are associated with susceptibility to MAC lung disease. We measured MAC-, NTM-, or MAC/Mtb-specific T-cell responses by cytokine production, expression of surface markers, and analysis of global gene expression in 27 MACDZ individuals and 32 healthy controls. We also analyzed global gene expression in Mycobacterium avium -infected and uninfected peripheral blood monocytes from 17 MACDZ and 17 healthy controls. We were unable to detect increased T-cell responses against MAC-specific reagents in MACDZ compared to controls, while the responses to non-mycobacteria derived antigens were preserved. MACDZ individuals had a lower frequency of Th1 and Th1* T-cell populations. In addition, MACDZ subjects had lower transcriptional responses in PBMCs stimulated with a mycobacterial peptide pool (MTB300). By contrast, global gene expression analysis demonstrated upregulation of proinflammatory pathways in uninfected and M. avium -infected monocytes, i.e. a hyperinflammatory in vitro response, derived from MACDZ subjects compared to controls. Together, these data suggest a novel immunologic defect which underlies MAC pathogenesis and includes concurrent innate and adaptive dysregulation which persists years after completion of treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lindestam Arlehamn, Benson, Kuan, Dill-McFarland, Peterson, Paul, Nguyen, Gilman, Saito, Taplitz, Arentz, Goss, Aitken, Horne, Shah, Sette and Hawn.)

Rationale: Many lung transplant recipients with cystic fibrosis (CF) have low preoperative body mass index (BMI); however, post-transplant BMI recovery is not well understood. Objectives: To evaluate BMI recovery (⩾18.5 kg/m 2 ) among CF lung transplant recipients with low preoperative BMI and to investigate the association of survival with BMI recovery. Methods: The United Network for Organ Sharing and CF Foundation patient registries (June 2005-December 2016) were used to identify CF lung transplant recipients. Among recipients surviving ⩾1 year, Cox modeling compared post-transplant 1-year conditional survival between recipients with low (<17 and 17-18.49 kg/m 2 ) versus normal preoperative BMI, stratified by BMI recovery. Results: Of 1,977 CF lung transplant recipients, 272 (14%) and 449 (23%) had a preoperative BMI of <17 and 17-18.49 kg/m 2 , respectively. For subgroups with a BMI of <17 and 17-18.49 kg/m 2 , 29% versus 49%, respectively, of those alive at 1 year recovered their BMI. Among recipients with low preoperative BMI, adjusted post-transplant 1-year conditional survival was worse than that in those with preoperative BMI ⩾ 18.5 kg/m 2 ; however, BMI recovery mitigated this. Preoperative BMI < 17 kg/m 2 had an adjusted hazard ratio of 1.29 (95% confidence interval [CI], 0.92-1.81) with BMI recovery versus 1.57 (95% CI, 1.09-2.25) without recovery, and preoperative BMI 17-18.49 kg/m 2 had an adjusted hazard ratio of 1.28 (95% CI, 1.02-1.61) with BMI recovery versus 1.72 (95% CI, 1.14-2.59) without recovery. Conclusions: Patients with lower preoperative BMI were less likely to achieve BMI recovery within 1 year. However, for those who did, BMI recovery within 1 year after transplant was associated with longer survival.

Cystic fibrosis (CF) was historically a disease largely afflicting children. Due to therapeutic advancements, there are now more adults with CF than children. In the past decade, medications including Cystic Fibrosis Transmembrane conductance Regulator (CFTR) modulators became available that treat the underlying cause of CF and are dramatically improving lung function as well as quality and quantity of life for people with CF. As a result, more women with CF are becoming pregnant. We gathered a panel of experts in CF care, family planning, high risk obstetrics, nutrition, genetics and women with CF to review current literature on pregnancies and to provide care recommendations for this unique population., Competing Interests: Declaration of Competing Interest JT, RJ, NW, MA and TK received grant funding from the CF Foundation for the Women's Health Research Working Group related to this work. Conflicts of interest unrelated to this work are included in a supplemental document., (Copyright © 2021. Published by Elsevier B.V.)

Rationale: Low body mass index (BMI) may influence lung transplant decisions for patients with advanced cystic fibrosis (CF) lung disease., Objective: Determine whether patients with advanced CF lung disease and BMI ≤17 kg/m 2 are less likely to be listed for lung transplant or have a higher risk of death without listing compared to those with higher BMI., Methods: Using merged United Network for Organ Sharing and CF Foundation Patient Registries, we identified adults with onset of advanced lung disease (FEV 1 ≤ 40% predicted) between May-2005 and December-2016. We analyzed survival using competing risks regression with cause-specific risks of listing for lung transplant and death without listing. BMI ≤ 17 kg/m 2 was our predictor., Measurements and Main Results: Among 5,121 CF patients with advanced lung disease, 23% were listed for lung transplant (n = 1,201), 23% died without listing (n = 1,190), and 44% were alive without listing (n = 2,730) as of December-2016. Patients with BMI ≤ 17 kg/m 2 were less likely to be listed for transplant (HR 0.69; 95% CI 0.57, 0.83) and more likely to die without listing (HR 1.63; 95% CI 1.41, 1.88). We identified important regional variations in the likelihood of referral and listing, based on BMI., Conclusions: Patients with advanced CF lung disease and BMI ≤ 17 kg/m 2 are less likely to be listed for lung transplant and have a higher risk of dying without listing, compared to those with higher BMI. Regional differences suggest access to transplant for malnourished CF patients may be limited by location., (Copyright © 2021 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

With improved therapies, people with cystic fibrosis are living longer and healthier lives and increasingly have questions surrounding their sexual and reproductive health. This article will summarize the important issues of which providers should be aware during the lifespan of people with cystic fibrosis, including puberty, adulthood, and menopause. A wide range of sexual and reproductive health topics are addressed such as puberty, transgender and gender nonbinary identities, contraception, sexually transmitted infections, hypogonadism, sexual functioning, cyclical hemoptysis, and urinary incontinence. We discuss gaps in knowledge and current evidence as well as management strategies to optimize care. Our goal is to support providers to enable them to give comprehensive care throughout the lifespan of people with cystic fibrosis., (© 2021 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

As people with cystic fibrosis (CF) live longer and healthier lives, increasing numbers are considering the full range of reproductive options for their futures, including parenthood, pregnancy, or pregnancy prevention. As the face of CF changes, the CF care model must adapt to meet the reproductive health needs of both parents and nonparents with CF. This article summarizes the reproductive goals and family-building concerns faced by people with CF, including fertility, pregnancy, and alternative paths to parenthood, the impact of parenthood on mental and physical health, and important future research., (© 2021 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

A hallmark of chronic bacterial infections is the long-term persistence of 1 or more pathogen species at the compromised site. Repeated detection of the same bacterial species can suggest that a single strain or lineage is continually present. However, infection with multiple strains of a given species, strain acquisition and loss, and changes in strain relative abundance can occur. Detecting strain-level changes and their effects on disease is challenging because most methods require labor-intensive isolate-by-isolate analyses, and thus, only a few cells from large infecting populations can be examined. Here, we present a population-level method for enumerating and measuring the relative abundance of strains called population multi-locus sequence typing (PopMLST). The method exploits PCR amplification of strain-identifying polymorphic loci, next-generation sequencing to measure allelic variants, and informatic methods to determine whether variants arise from sequencing errors or low-abundance strains. These features enable PopMLST to simultaneously interrogate hundreds of bacterial cells that are cultured en masse from patient samples or are present in DNA directly extracted from clinical specimens without ex vivo culture. This method could be used to detect epidemic or super-infecting strains, facilitate understanding of strain dynamics during chronic infections, and enable studies that link strain changes to clinical outcomes.

Competing Interests: Declaration of Competing Interest No conflicts to disclose.

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

Women with cystic fibrosis (CF) face several unaddressed concerns related to their health. These areas of concern include explanations and guidance on a sex disparity in outcomes, timing of puberty, effects of contraception, prevalence of infertility and impact of pregnancy, and prevention of urinary incontinence and osteoporosis. These understudied topics leave women with numerous unanswered questions about how to manage sexual and reproductive health in the setting of CF. Because people with CF are living longer and healthier lives, there is an increasing awareness of these important aspects of care and multiple ongoing studies to address these understudied topics., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The role of inflammation in airway epithelial cells and its regulation are important in several respiratory diseases. When disease is present, the barrier between the pulmonary circulation and the airway epithelium is damaged, allowing serum proteins to enter the airways. We identified that human glycated albumin (GA) is a molecule in human serum that triggers an inflammatory response in human airway epithelial cultures. We observed that single-donor human serum induced IL-8 secretion from primary human airway epithelial cells and from a cystic fibrosis airway cell line (CF1-16) in a dose-dependent manner. IL-8 secretion from airway epithelial cells was time dependent and rapidly increased in the first 4 h of incubation. Stimulation with GA promoted epithelial cells to secrete IL-8, and this increase was blocked by the anti-GA antibody. The IL-8 secretion induced by serum GA was 10-50-fold more potent than TNF α or LPS stimulation. GA also has a functional effect on airway epithelial cells in vitro , increasing ciliary beat frequency. Our results demonstrate that the serum molecule GA is pro-inflammatory and triggers host defense responses including increases in IL-8 secretion and ciliary beat frequency in the human airway epithelium. Although the binding site of GA has not yet been described, it is possible that GA could bind to the receptor for advanced glycated end products (RAGE), known to be expressed in the airway epithelium; however, further experiments are needed to identify the mechanism involved. We highlight a possible role for GA in airway inflammation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Aitken, Somayaji, Hinds, Pier, Droguett, Rios, Skerrett and Villalon.)

Background: Cystic fibrosis (CF) airways disease varies widely among patients with identical cystic fibrosis transmembrane conductance regulator (CFTR) genotypes. Robust airway inflammation is thought to be deleterious in CF; inter-individual variation in Toll-like receptor (TLR)-mediated innate immune inflammatory responses (TMIIR) might account for a portion of the phenotypic variation. We tested if TMIIR in people with CF are different than those of healthy controls, and whether higher TMIIR in people with CF are associated with reduced lung function., Methods: We cultured whole blood from clinically stable subjects with CF (n = 76) and healthy controls (n = 45) with TLR agonists, and measured cytokine production and expression of TLR-associated genes. We tested for differences in TLR-stimulated cytokine levels between subjects with CF and healthy subjects, and for associations between cytokine and gene expression levels with baseline lung function (forced expiratory volume in one second percent predicted (FEV 1 %)) and decline in FEV 1 % over time., Results: TMIIR in blood from subjects with CF were lower than in healthy controls. Expression of TLR regulators SARM1, TOLLIP, and AKT1 were downregulated in CF. In subjects with CF we found that lower TLR4-agonist-induced IL-8 was associated with lower FEV 1 % at enrollment (p<0.001) and with greater five year FEV 1 % decline (p<0.001)., Conclusions: TMIIR were lower in people with CF relative to healthy controls; however, unexpectedly, greater whole blood TMIIR were positively associated with lung function in people with CF. These findings suggest a complex interaction between inflammation and disease in people with CF., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest., (Copyright © 2019. Published by Elsevier B.V.)

Objectives: To examine contraceptive use, pregnancy intention and the association of hormonal contraceptive type with adverse health outcomes among women with cystic fibrosis (CF)., Study Design: We recruited 150 women with CF, ages 18-49 from three adult CF programs to complete an online survey regarding their pregnancy and contraceptive use history. Survey findings were merged with retrospective clinical information from the CF Foundation Patient Registry (CFFPR). We used descriptive analyses to report contraceptive method and pregnancy frequencies, and logistic regression to examine the association between contraceptive method type and adverse health outcomes., Results: Combined hormonal contraceptives were the most commonly used methods (42%), followed by condoms (34%), and long-acting reversible contraceptives methods (27%). Thirty-three percent (n = 50) reported ever being pregnant, half of whom reported having at least one unplanned pregnancy. We found no significant association for mucoid Pseudomonas aeruginosa infection among progestin-only (aOR 1.53, 95% CI 0.07-32.2) and estrogen-containing hormonal contraceptive users (aOR 3.9, 95 % CI 0.20-76.5). Risk of osteoporosis was elevated among women with CF who used depot-medroxyprogesterone acetate compared to non-users (OR 5.36, 95% CI 1.00-29.12)., Conclusions: Both contraceptive use and unplanned pregnancy among women with CF are common. Associations between hormonal contraceptive use and adverse pulmonary or bone outcomes among women with CF are inconclusive due to the study s small sample size. Larger studies are warranted., Implications: Women with CF should be informed about the risks and benefits of contraceptives in the context of their disease. CFFPR data capturing contraceptive method use may be the most efficient way to elucidate the association of hormonal contraceptives on disease in women with CF., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aims/hypothesis: The aim of this study was to determine the mechanism(s) for hypoglycaemia occurring late following oral glucose loading in patients with cystic fibrosis (CF)., Methods: A 3 h 75 g OGTT was performed in 27 non-diabetic adults with CF who were classified based on this test as experiencing hypoglycaemia (glucose <3.3 mmol/l with or without symptoms or glucose <3.9 mmol/l with symptoms, n = 14) or not (n = 13). Beta cell function, incretin (glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic peptide [GIP]) and counterregulatory hormone responses (glucagon, catecholamines, growth hormone and cortisol) were assessed., Results: The two groups did not differ in age, weight or BMI. There were more male participants and individuals with pancreatic exocrine insufficiency in the hypoglycaemia group. Fasting plasma glucose did not differ between the two groups (5.3 ± 0.16 vs 5.3 ± 0.10 mmol/l). Both fasting insulin (20.7 ± 2.9 vs 36.5 ± 4.8 pmol/l; p = 0.009) and C-peptide (0.38 ± 0.03 vs 0.56 ± 0.05 nmol/l; p = 0.002) were lower in those who experienced hypoglycaemia. Following glucose ingestion, glucose concentrations were significantly lower in the hypoglycaemia group from 135 min onwards, with a nadir of 3.2 ± 0.2 vs 4.8 ± 0.3 mmol/l at 180 min (p < 0.001). The test was terminated early in three participants because of a glucose level <2.5 mmol/l. Insulin and C-peptide concentrations were also lower in the hypoglycaemia group, while incretin hormone responses were not different. Modelling demonstrated that those experiencing hypoglycaemia were more insulin sensitive (439 ± 17.3 vs 398 ± 13.1 ml min -1  m -2 , p = 0.074 based on values until 120 min [n = 14]; 512 ± 18.9 vs 438 ± 15.5 ml min -1  m -2 , p = 0.006 based on values until 180 min [n = 11]). In line with their better insulin sensitivity, those experiencing hypoglycaemia had lower insulin secretion rates (ISR fasting : 50.8 ± 3.2 vs 74.0 ± 5.9 pmol min -1  m -2 , p = 0.002; ISR OGTT : 44.9 ± 5.0 vs 63.4 ± 5.2 nmol/m 2 , p = 0.018) and beta cell glucose sensitivity (47.4 ± 4.5 vs 79.2 ± 7.5 pmol min -1  m -2 [mmol/l] -1 , p = 0.001). Despite the difference in glucose concentrations, there were no significant increases in glucagon, noradrenaline, cortisol or growth hormone levels. Adrenaline increased by only 66% and 61% above baseline at 165 and 180 min when glucose concentrations were 3.8 ± 0.2 and 3.2 ± 0.2 mmol/l, respectively., Conclusions/interpretation: Hypoglycaemia occurring late during an OGTT in people with CF was not associated with the expected counterregulatory hormone response, which may be a consequence of more advanced pancreatic dysfunction/destruction.

Background: Reduced BMI is an absolute contraindication for lung transplantation (LTx) at most centers in the United States. The objective of this study was to quantify post-LTx survival of moderate to severely underweight patients with cystic fibrosis (CF) (BMI < 17 kg/m 2 ) in the United States relative to normal-weight recipients with CF and other frequently transplanted patient cohorts., Methods: Using United Network for Organ Sharing Registry data (undergoing transplant from June 2005-November 2015), Kaplan-Meier estimates of median posttransplant survival were calculated for all patients with CF, COPD, and idiopathic pulmonary fibrosis (IPF), as well as low and normal weight CF subgroups. Cox regression modeling stratified according to transplant center assessed risk of posttransplant mortality in recipients with CF and a BMI < 17 kg/m 2 compared with recipients with COPD (reference)., Results: Median posttransplant survival (95% CI) for CF, COPD, and IPF was 7.9 (7.2-8.6), 5.9 (5.6-6.2), and 5.5 (5.2-5.8) years, respectively. Although an absolute decrease was noted in posttransplant survival for recipients with CF and a BMI < 17 kg/m 2 , compared with those with CF and a BMI ≥ 17 kg/m 2 (7.0 years [4.5-7.9] vs 8.2 years [7.3-9.0]), Cox modeling found no increased mortality risk (adjusted hazard ratio, 1.09; 95% CI, 0.90-1.32; P = .38). There was no difference in posttransplant mortality between patients with CF and a BMI < 17 kg/m 2 and recipients with COPD and all BMIs (adjusted hazard ratio, 1.04; 95% CI, 0.86-1.25; P = .71)., Conclusions: Transplant recipients with CF and a BMI < 17 kg/m 2 had posttransplant survival rates comparable to those of other groups frequently undergoing transplantation. BMI < 17 kg/m 2 as a single risk factor in the CF population should not be treated as an absolute contraindication to LTx., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: OFD1 has long been recognized as the gene implicated in the classic dysmorphology syndrome, oral-facial-digital syndrome type I (OFDSI). Over time, pathogenic variants in OFD1 were found to be associated with X-linked intellectual disability, Joubert syndrome type 10 (JBTS10), Simpson-Golabi-Behmel syndrome type 2 (SGBS2), and retinitis pigmentosa. Recently, OFD1 pathogenic variants have been implicated in primary ciliary dyskinesia (PCD), a disorder of the motile cilia with a phenotype that includes recurrent oto-sino-pulmonary infections, situs abnormalities, and decreased fertility., Methods: We describe three male patients with PCD who were found to have hemizygous pathogenic variants in OFD1, further supporting that PCD is part of a clinical spectrum of OFD1-related disorders. In addition, we provide a review of the available clinical literature describing patients with OFD1 variants and highlight the phenotypic variability of OFD1-related disease., Results: Some individuals with hemizygous OFD1 variants have PCD, either apparently isolated or in combination with other features of OFD1-related disorders., Conclusion: As clinicians consider the presence or absence of conditions allelic at OFD1, PCD should be considered part of the spectrum of OFD1-related disorders. Understanding the OFD1-related disease spectrum may allow for more focused genetic testing and more timely management of treatable sequelae., (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Referral for lung transplantation is a complex process that typically begins with a discussion in cystic fibrosis (CF) clinic. We performed a secondary analysis of interviews conducted at the University of Washington CF Clinic as part of a study of unmet palliative care needs, June 2015 - January 2016, among adults with moderate-to-severe CF-related lung disease. Content analysis methods were used to identify themes related to discussion of lung transplant in CF clinic. Thirty-two of 48 interviews (67%) addressed transplant. An individual's willingness to discuss transplant was not necessarily related to the degree of lung function impairment. Patients reported reliance on CF physicians as a source of accurate information about transplant. Individuals with CF sometimes reported feeling too old or not worthy of transplant. Many had apprehensive or ambivalent feelings towards transplant. Patient-identified barriers and facilitators to lung transplant discussions can inform physicians as they discuss transplant in CF clinic., (Copyright © 2019. Published by Elsevier B.V.)

Background: Macrophage plasticity allows cells to adopt different phenotypes, a property with important implications in disorders such as cystic fibrosis (CF) and asthma., Objective: We sought to examine the transcriptional and functional significance of macrophage repolarization from an M1 to an M2 phenotype and assess the role of a common human genetic disorder (CF) and a prototypical allergic disease (asthma) in this transformation., Methods: Monocyte-derived macrophages were collected from healthy subjects and patients with CF and polarized to an M2 state by using IL-4, IL-10, glucocorticoids, apoptotic PMNs, or azithromycin. We performed transcriptional profiling and pathway analysis for each stimulus. We assessed the ability of M2-repolarized macrophages to respond to LPS rechallenge and clear apoptotic neutrophils and used murine models to determine conserved functional responses to IL-4 and IL-10. We investigated whether M2 signatures were associated with alveolar macrophage phenotypes in asthmatic patients., Results: We found that macrophages exhibit highly diverse responses to distinct M2-polarizing stimuli. Specifically, IL-10 activated proinflammatory pathways and abrogated LPS tolerance, allowing rapid restoration of LPS responsiveness. In contrast, IL-4 enhanced LPS tolerance, dampening proinflammatory responses after repeat LPS challenge. A common theme observed across all M2 stimuli was suppression of interferon-associated pathways. We found that CF macrophages had intact reparative and transcriptional responses, suggesting that macrophage contributions to CF-related lung disease are primarily shaped by their environment. Finally, we leveraged in vitro-derived signatures to show that allergen provocation induces distinct M2 state transcriptional patterns in alveolar macrophages., Conclusion: Our findings highlight the diversity of macrophage polarization, attribute functional consequences to different M2 stimuli, and provide a framework to phenotype macrophages in disease states., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Cystic fibrosis (CF) is a disease in which nutritional barriers are diverse and common, with malnutrition greatly influencing pulmonary trajectory and overall outcomes. Despite this, the most effective methods to optimize CF nutrition are unknown, and literature describing patients' perspectives on their specific nutritional needs is lacking, particularly in the modern era of CF care. This study aimed to identify the most important nutritional needs and desired health-improvement resources in a contemporary adult CF cohort., Methods: A 14-question investigator-designed survey addressing nutrition concerns, preferred health-improvement resources, and dietary/exercise routines was administered to CF adults. Clinical characteristics and survey responses are presented with descriptive statistics, and responses compared by body mass index (BMI) category (<18.5 kg/m 2 ; 18.5-24.99 kg/m 2 ; 25-29.99 kg/m 2 ; ≥30 kg/m 2 ), gender, and socioeconomic status using Chi square or Fisher's Exact testing., Results: Of 66 total patients, nine (13.6%) were underweight (BMI <18.5 kg/m 2 ), while 19 (28.8%) were overweight or obese (BMI ≥ 25kg/m 2 ). In the overall cohort, the most common primary concern was preventing weight loss [in 20/66 patients (30.3%)], but there were significant differences by BMI (p< 0.001), with the most common concern in the overweight subgroup being preventing weight gain. Fifteen (46.9%) men (BMI mean 20.7, range 16.4-29.2 kg/m 2 ) listed preventing weight loss as the primary concern, compared to only 5 (14.7%) women (BMI mean 18.4, range 16.2-19.9 kg/m 2 ), representing a trend toward a difference in primary concerns by gender (p=0.066).The most commonly desired health-improvement resource was online CF nutrition and fitness information, found in 26 patients (39.4%) in the overall cohort, without significant differences by BMI (p=0.814) or gender (p=0.199). Financial assistance was the preferred resource in 17 (26.2%), without differences by socioeconomic status (p=0.367)., Conclusions: We identified a wide variety of nutritional needs in CF adults, including a high prevalence of overweight status, many patients desiring weight loss, and many seeking financial resources. Our findings support the individualization of modern-day CF nutrition programs and development of online resources, in an effort to address the heterogeneous barriers that exist in the contemporary CF population and improve outcomes in patients with the disease., Competing Interests: Competing interests: The authors declare that they have no competing interests.

The lack of new antibiotics is among the most critical challenges facing medicine. The problem is particularly acute for Gram-negative bacteria. An unconventional antibiotic strategy is to target bacterial nutrition and metabolism. The metal gallium can disrupt bacterial iron metabolism because it substitutes for iron when taken up by bacteria. We investigated the antibiotic activity of gallium ex vivo, in a mouse model of airway infection, and in a phase 1 clinical trial in individuals with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa airway infections. Our results show that micromolar concentrations of gallium inhibited P. aeruginosa growth in sputum samples from patients with CF. Ex vivo experiments indicated that gallium inhibited key iron-dependent bacterial enzymes and increased bacterial sensitivity to oxidants. Furthermore, gallium resistance developed slowly, its activity was synergistic with certain antibiotics, and gallium did not diminish the antibacterial activity of host macrophages. Systemic gallium treatment showed antibiotic activity in murine lung infections. In addition, systemic gallium treatment improved lung function in people with CF and chronic P. aeruginosa lung infection in a preliminary phase 1 clinical trial. These findings raise the possibility that human infections could be treated by targeting iron metabolism or other nutritional vulnerabilities of bacterial pathogens., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: Chronic Pseudomonas aeruginosa lung infection is associated with significant morbidity and mortality in cystic fibrosis (CF). It is not known whether recent advances in care have affected the rates of chronic infection. We aimed to determine if the rates of developing new chronic P. aeruginosa infection among adolescents and adults with CF significantly changed over time., Methods: The cohort consisted of individuals with CF followed in the Cystic Fibrosis Foundation Patient Registry aged ≥13 years without chronic P. aeruginosa at baseline. Multivariable regression models accounting for within-patient correlation were used to assess the change in rate of developing chronic P. aeruginosa infection between 2003 and 2012., Results: A total of 15504 individuals were followed for a median of 5 (interquartile range, 2-9) years. The annual rates of developing new chronic P. aeruginosa decreased from 14.3% in 2003 to 6.4% in 2012. After adjusting for potential confounders, relative risk (RR) of developing chronic P. aeruginosa infection decreased significantly over time compared to 2003 (P value test of trend < .001). Compared with 2003, the RR of developing chronic P. aeruginosa infection in 2012 was 0.33 (95% confidence interval, 0.30-0.37). No significant increases in risk of chronic infections with other major CF bacterial pathogens relative to 2003 were identified., Conclusions: Among individuals with CF, a significant decrease in the risk and rates of developing chronic P. aeruginosa infection between 2003 and 2012 was observed. Whether this decline results in changes in clinical outcomes warrants further exploration.

Background: Persons with cystic fibrosis (CF) experience high morbidity and mortality, yet little is known about their palliative care needs and how clinicians may address these needs., Objectives: (1) To identify palliative care and advance care planning needs of patients with CF and their families; and (2) to identify clinicians' potential roles in meeting these needs., Methods: A mixed-methods study of adult patients (age ≥18 years) with moderate-to-severe CF [forced expiratory volume in the first second (FEV 1 ) <65% predicted] were recruited from a CF Center. Semi-structured interviews (30-60 minutes) and questionnaires were administered in person or by phone. Grounded theory was used to analyze the interviews. Questionnaires were analyzed descriptively., Results: Forty-nine patients (FEV 1 % range = 19%-63%) participated; the participation rate was 80% for eligible patients. Three main domains of palliative care needs were identified: (1) to be listened to, feel heard, and be "seen"; (2) understanding the context around CF and its trajectory, with the goal of preparing for the future; and (3) information about, and potential solutions to, practical and current circumstances that cause stress. In questionnaires, few patients (4.3%) reported talking with their clinician about their wishes for care if they were to become sicker, but mixed-methods data demonstrated that more than half of participants were willing to receive palliative care services provided those services were adapted to CF., Conclusion: Patients expressed a need for and openness to palliative care services, as well as some reluctance. They appreciated clinician communication that was open, forthcoming, and attuned to individualized concerns.

Introduction: Mycobacterium abscessus infection in cystic fibrosis (CF) patients can lead to poor outcomes. Early diagnosis is important, but there are no studies outlining specific imaging features of M. abscessus in CF., Objectives: To describe the computed tomography (CT) findings of early M. abscessus infection in our CF population., Methods: Thirteen CF patients with sputum cultures positive for M. abscessus from 2006 to 2013 were identified at our institution. Clinical characteristics including culture dates and lung function were reviewed. Positive cultures were classified as "disease" versus "colonization" based on published criteria. Chest CT scans were reviewed at times closest to initial infection, and features including bronchiectasis, mucous plugging, consolidation, ground glass opacities, nodules, and cavitation were evaluated. Brody scores were calculated to evaluate extent of CF lung disease., Results: All patients had bronchiectasis and mucous plugging, with 10 of 13 (76.9%) in an upper lobe distribution. Consolidation was seen in 12 of 13 (92.3%) patients, 8 (61.5%) patients had nodules, and 5 (38.5%) with cavitation. The average Brody score was 59.5, which was no different than previously described CF cohorts without M. abscessus. There were no significant differences between subjects with disease versus colonization., Conclusion: The most common CT features of early M. abscessus in our CF population include bronchiectasis, mucus plugging, and consolidation, but the findings did not reveal a unique radiologic signature. CT at this initial time point may not distinguish early M. abscessus infection from background lung disease or mycobacterial colonization in CF patients., (© 2016 John Wiley & Sons Ltd.)