"We'll deal with it as it comes": A Qualitative Analysis of Romantic Partners' Dyadic Coping in Cystic Fibrosis.

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 (Mage=42.3, 43.8% identified as cisgender male, 56.2% identified as cisgender female) and their romantic partners (Mage=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.

Qualitative Analysis of Perspectives on Lung Transplant among People with Cystic Fibrosis.

RATIONALE: Lung transplant (LTx) is a potentially life-saving 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; to identify transplant information needs that CF clinicians are well-positioned to address. METHODS: We performed semi-structured 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 CF clinic, and experiences with LTx. Thematic analysis was utilized to organize the qualitative data. Exemplar quotes were chosen to illustrate domains that emerged pertaining to the research objectives. RESULTS: Fifty-five PwCF, 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.

Identification of prognostic biomarkers for antibiotic associated nephrotoxicity in cystic fibrosis.

BACKGROUND: Our objective was to discover novel urinary biomarkers of antibiotic-associated nephrotoxicity using an ex-vivo human microphysiological system (MPS) and to translate these findings to a prospectively enrolled cystic fibrosis (CF) population receiving aminoglycosides and/or polymyxin E (colistin) for a pulmonary exacerbation. METHODS: We populated the MPS with primary human kidney proximal tubule epithelial cells (PTECs) from three donors and modeled nephrotoxin injury through exposure to 50 µg/mL polymyxin E for 72 h. We analyzed gene transcriptional responses by RNAseq and tested MPS effluents. We translated candidate biomarkers to a CF cohort via analysis of urine collected prior to, during and two weeks after antibiotics and patients were followed for a median of 3 years after antibiotic use. RESULTS: Polymyxin E treatment resulted in a statistically significant increase in the pro-apoptotic Fas gene relative to control in RNAseq of MPS: fold-change = 1.63, FDR q-value = 7.29 × 10-5. Effluent analysis demonstrated an acute rise of soluble Fas (sFas) concentrations that correlated with cellular injury. In 16 patients with CF, urinary sFas concentrations were significantly elevated during antibiotic treatment, regardless of development of AKI. Over a median of three years of follow up, we identified seven cases of incident chronic kidney disease (CKD). Urinary sFas concentrations during antibiotic treatment were significantly associated with subsequent development of incident CKD (unadjusted relative risk = 2.02 per doubling of urinary sFas, 95 % CI = 1.40, 2.90, p < 0.001). CONCLUSIONS: Using an ex-vivo MPS, we identified a novel biomarker of proximal tubule epithelial cell injury, sFas, and translated these findings to a clinical cohort of patients with CF.

Web-Based Survey Piloting Process as a Model for Developing and Testing Past Contraceptive Use and Pregnancy History: Cystic Fibrosis Case Study.

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.

Metabolism and pharmacokinetics of vitamin D in patients with cystic fibrosis.

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)D2 and 25(OH)D3, 1α,25-dihydroxyvitamins D2 and D3 (1α,25(OH)2D2 and 1α,25(OH)2D3), 24,25-dihydroxyvitamin D3 (24,25(OH)2D3), 4ß,25-dihydroxyvitamin D3 (4ß,25(OH)2D3), 25-hydroxyvitamin D3-3-sulfate (25(OH)D3-S), and 25-hydroxyvitamin D3-3-glucuronide (25(OH)D3-G). In a 56-day prospective pharmacokinetic study, ∼25 µg deuterium-labeled 25(OH)D3 (d6-25(OH)D3) was administered intravenously to participants (N = 5 with CF, N = 5 control subjects). Serum was analyzed for d6-25(OH)D3 and d6-24,25(OH)2D3, 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)2D (43.6 [12.7] vs. 50.7 [13.0] pg/mL), 4ß,25(OH)2D3 (52.1 [38.9] vs. 79.9 [60.2] pg/mL), and 25(OH)D3-S (17.7 [11.6] vs. 30.1 [12.3] ng/mL) (p < 0.001 for all). The pharmacokinetics of d6-25(OH)D3 and d6-24,25(OH)D3 did not differ between groups. In summary, although 25(OH)D concentrations were comparable, participants with CF had lower 1α,25(OH)2D, 4ß,25(OH)2D3, and 25(OH)D3-S concentrations than healthy controls. Neither 25(OH)D3 clearance, nor formation of 24,25(OH)2D3, 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.

Evolution of Mycobacterium abscessus in the human lung: Cumulative mutations and genomic rearrangement of porin genes in patient isolates.

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, mmpL4, porin locus and tetR 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 14C-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 14C-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.

Association between unplanned pregnancies and maternal exacerbations in cystic fibrosis.

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 (ppFEV1), 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 ppFEV1 of 75.4 and BMI of 22.5 kg/m2. PpFEV1 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.

Sexual and reproductive health experiences and care of adult women with cystic fibrosis.

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.

Clinician attitudes and practices on pregnancy planning and care in cystic fibrosis.

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 peri­pregnancy expertise within the CF community, and future studies investigating the maternal-fetal effects of CF therapies are needed.

T-cell deficiency and hyperinflammatory monocyte responses associate with Mycobacterium avium complex lung disease.

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.

Hemoptysis and the Risk for Lung Transplant or Death without Transplant in Individuals with Cystic Fibrosis in the United States.

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 (FEV1), 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 FEV1 <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.

Body Mass Index Recovery after Lung Transplant for Cystic Fibrosis.

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/m2) 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/m2) 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/m2, respectively. For subgroups with a BMI of <17 and 17-18.49 kg/m2, 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/m2; however, BMI recovery mitigated this. Preoperative BMI < 17 kg/m2 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/m2 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.

Family-building and parenting considerations for people with cystic fibrosis.

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.

Optimizing sexual and reproductive health across the lifespan in people with cystic fibrosis.

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.

Pregnancy in cystic fibrosis: Review of the literature and expert recommendations.

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.

Low body mass index as a barrier to lung transplant in cystic fibrosis.

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/m2 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 (FEV1 ≤ 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/m2 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/m2 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/m2 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.

A population-level strain genotyping method to study pathogen strain dynamics in human infections.

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.

Challenges Faced by Women with Cystic Fibrosis.

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.

Glycated Albumin Triggers an Inflammatory Response in the Human Airway Epithelium and Causes an Increase in Ciliary Beat Frequency.

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 TNFα 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.

Efficacy and safety of inhaled dry-powder mannitol in adults with cystic fibrosis: An international, randomized controlled study.

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 (FEV1) 40-90% predicted. Subjects received either mannitol 400 mg or mannitol 50 mg (control), BID via dry-powder inhaler for 26 weeks. Primary endpoint: FEV1 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 FEV1 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 FEV1 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 (FEV1) 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.