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Translational research should examine racism and bias and improve health equity. We designed and implemented a course for the Master of Science in Clinical Investigation program of the Northwestern University Clinical and Translational Sciences Institute. We describe curriculum development, content, outcomes, and revisions involving 36 students in 2 years of “Anti-Racist Strategies for Clinical and Translational Science.” Ninety-six percent of students reported they would recommend the course. Many reported changes in research approaches based on course content. A course designed to teach anti-racist research design is feasible and has a positive short-term impact on learners.

Summary Background A previous phase 3 study showed that lumacaftor–ivacaftor was generally safe and well tolerated over 24 weeks of treatment in children aged 2–5 years with cystic fibrosis homozygous for the F508del-CFTR mutation. In this study, we aimed to assess the long-term safety of lumacaftor–ivacaftor in a rollover study of children who participated in this previous phase 3 study. Methods In this multicentre, phase 3, open-label, extension study (study 116; VX16-809-116), we assessed safety of lumacaftor–ivacaftor in children included in a previous multicentre, phase 3, open-label study (study 115; VX15-809-115). The study was done at 20 cystic fibrosis care centres in the USA and Canada. Children aged 2–5 years with cystic fibrosis homozygous for the F508del-CFTR mutation who completed 24 weeks of lumacaftor–ivacaftor treatment in study 115 received weight-based and age-based doses of oral lumacaftor–ivacaftor: children weighing less than 14 kg and aged younger than 6 years at study 116 screening received lumacaftor 100 mg–ivacaftor 125 mg every 12 h; children weighing 14 kg or more and aged younger than 6 years at screening received lumacaftor 150 mg–ivacaftor 188 mg every 12 h; and children aged 6 years or older received lumacaftor 200 mg–ivacaftor 250 mg every 12 h. Children received treatment for up to 96 weeks, equivalent to up to 120 weeks of treatment in total from the start of study 115 to completion of study 116. The primary endpoint was the safety and tolerability of the study drug in all participants who had received lumacaftor–ivacaftor for 24 weeks in study 115 and had received at least one dose in study 116. Secondary endpoints included change from baseline in study 115 at week 96 of study 116 in sweat chloride concentration, growth parameters, markers of pancreatic function, and lung clearance index (LCI) parameters in all children who received at least one dose of lumacaftor–ivacaftor in study 116. This study is registered with ClinicalTrials.gov, NCT03125395. Findings This extension study ran from May 12, 2017, to July 17, 2019. Of 60 participants enrolled and who received lumacaftor–ivacaftor in study 115, 57 (95%) were included in study 116 and continued to receive the study drug. A total of 47 (82%) of 57 participants completed 96 weeks of treatment. Most participants (56 [98%] of 57) had at least one adverse event during study 116, most of which were mild (19 [33%] participants) or moderate (29 [51%] participants) in severity. The most common adverse events were cough (47 [82%] participants), nasal congestion (25 [44%] participants), pyrexia (23 [40%] participants), rhinorrhoea (18 [32%] participants), and vomiting (17 [30%] participants). A total of 15 (26%) participants had at least one serious adverse event; most were consistent with underlying cystic fibrosis or common childhood illnesses. Respiratory adverse events occurred in five (9%) participants, none of which were serious or led to treatment discontinuation. Elevated aminotransferase concentrations, most of which were mild or moderate in severity, occurred in ten (18%) participants. Three (5%) participants discontinued treatment due to adverse events (two due to increased aminotransferase concentrations [one of whom had concurrent pancreatitis], considered as possibly related to study drug; and one due to gastritis and metabolic acidosis, considered unlikely to be related to study drug). No clinically significant abnormalities or changes were seen in electrocardiograms, vital signs, pulse oximetry, ophthalmological examinations, or spirometry assessments. Improvements in secondary endpoints observed in study 115 were generally maintained up to week 96 of study 116, including improvements in sweat chloride concentration (mean absolute change from study 115 baseline at week 96 of study 116 −29·6 mmol/L [95% CI −33·7 to −25·5]), an increase in growth parameters and pancreatic function, and stable lung function relative to baseline, as measured by the LCI. Interpretation Lumacaftor–ivacaftor was generally safe and well tolerated, and treatment effects were generally maintained for the duration of the extension study. These findings support the use of lumacaftor–ivacaftor for up to 120 weeks in young children with cystic fibrosis aged 2 years and older homozygous for the F508del-CFTR mutation. Funding Vertex Pharmaceuticals Incorporated.

Newborn screening (NBS) algorithms for cystic fibrosis (CF) vary in the United State of America and include different cystic fibrosis transmembrane conductance regulator (CFTR) variants. CFTR variant distribution varies among racial and ethnic groups.Our objectives were to identify differences in detection rate by race and ethnicity for CFTR variant panels, identify each US state detection rate for CFTR variant panels, and describe the rate of false-negative NBS and delayed diagnoses by race and ethnicity.This is a cross-sectional analysis of the detection rate of at least 1 CFTR variant for seven panels by race and ethnicity in genotyped people with CF (PwCF) or CFTR-related metabolic syndrome (CRMS)/CFTR-related disorders in CF Foundation Patient Registry (CFFPR) in 2020. We estimated the case detection rate of CFTR variant panels by applying the detection rate to Census data. Using data from CFFPR, we compared the rate of delayed diagnosis or false-negative NBS by race and ethnicity.For all panels, detection of at least 1 CFTR variant was highest in non-Hispanic White PwCF (87.5%-97.0%), and lowest in Black, Asian, and Hispanic PwCF (41.9%-93.1%). Detection of at least 1 CFTR variant was lowest in Black and Asian people with CRMS/CFTR-related disorders (48.4%-64.8%). States with increased racial and ethnic diversity have lower detection rates for all panels. Overall, 3.8% PwCF had a false-negative NBS and 11.8% had a delayed diagnosis; Black, Hispanic, and mixed-race PwCF were overrepresented.CFTR variant panels have lower detection rates in minoritized racial and ethnic groups leading to false-negative NBS, delayed diagnosis, and likely health disparities.

Rationale: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be efficacious and safe in patients ≥12 years of age with cystic fibrosis and at least one F508del-CFTR (cystic fibrosis trans...

We evaluated whether implementation of cystic fibrosis (CF) newborn screening (NBS) leads to equitable timeliness of initial evaluation. We compared age at first event (AFE, age at sweat test, encounter and/or care episode) between infants categorized as Black/African American, American Indian/ Native Alaskan, Asian, and/or Hispanic and/or other (Group 1) to White and not Hispanic infants (Group 2).This retrospective cohort study from the Cystic Fibrosis Foundation Patient Registry (CFFPR) included infants born 2010-2018. Race and ethnicity categories followed US Census definitions. The primary outcome was AFE; the secondary outcome was weight for age (WFA) z-score averaged 12 to24 months. We compared distributions by Wilcoxon rank-sum test and proportions by Chi-square or Fisher's exact tests. A nested cohort study used a linear mixed effects model of variables that affect WFA, chosen a priori, to evaluate associations with 1-year WFA z-score.Among 6354 infants, 21% were in Group 1. Group 1 median AFE was 31 days (IQR 19, 49) and Group 2 was 22 days (IQR 14,36) (p.001). Median WFA z-score at 1-2 years was lower in Group 1. In 3017 infants with complete data on variables of interest, AFE, Black race, CFTR variant class I-III, prematurity and public insurance were associated with lower 1-year WFA z-score.Differences in AFE for infants with CF from historically marginalized groups may exacerbate long standing health disparities. We speculate that inequitable identification of CFTR gene variants and/or bias may influence timeliness of evaluation after an out-of-range NBS.

PurposeThe electronic health record, data science advances, and dynamic environmental and infectious threats to child health highlight the need for harmonized and interoperable approaches to pediatric cardiopulmonary exercise testing (CPET). Accordingly, we developed a terminology harmonization in exercise medicine and exercise science domain analysis model (THEMES DAM) to structure CPET data elements.MethodsTHEMES DAM identified 114 data elements, including participant information, calibration, equipment, protocols, laboratory personnel, encouragement strategies, and analysis procedures. We used the THEMES DAM, vetted by the international data standards organization HL7, to construct a current-state survey of pediatric CPET centers in the United States. Forty-eight of 101 centers responded to a questionnaire covering seven major topic areas (38 items).ResultsCenters predominantly performed between 100 and 500 tests annually. Cardiac disease represented 55% of referrals. Almost all centers calibrated gas concentrations and flow daily, but 42% never calibrated their treadmill or cycle ergometers. All centers measured V̇O2peakbut calculated differently. Centers used a variety of protocols (e.g., for treadmill: 61%, Bruce; 43%, modified Bruce; 59%, other); 44% calculated CPET slopes from submaximal portions of CPET (e.g., V̇O2-HR). All centers verbally encouraged participants, but only 40% used a standardized approach. The interpretation of CPET was done by physicians (60%), exercise physiologists (25%), exercise technicians (10%), nurses (1%), or others (4%). Ninety-one percent would agree to collaborate in multicenter research, 89% to establish dynamic reference values, and 83% to better interpret CPET.ConclusionsThe survey data and the implementation of THEMES DAM could accelerate interoperability across multiple centers. This would facilitate a nimble approach to create pediatric reference values responsive to the constantly changing health environment and stimulate novel approaches to CPET research and clinical application.

During the year 2019, research and case reports or series in the field of cystic fibrosis (CF) were in abundance. To adequately address the large body of CF research published during 2019, the CF year in review will be divided into three sections. This report is the second section, focusing specifically on new research related to pulmonary disease and infections. Additional sections will concentrate on CF transmembrane conductance regulator modulators and the multisystem effects of CF. It is an exciting time to be providing care for patients and their families with CF with all the exciting new discoveries that will be shared in these reviews.

During the year 2019, research and case reports/series in the field of cystic fibrosis (CF) were in abundance. To adequately address the large body of CF research published during 2019, the CF year in review will be divided into three sections. This report is the first section, focusing specifically on new research related to cystic fibrosis transmembrane conductance regulator modulator therapy. Additional sections will concentrate on pulmonary and infections research and the multisystem effects of CF. It is an exciting time to be providing care for patients and their families with CF with all the exciting new discoveries that will be shared in these reviews.

BACKGROUND Diagnostic sweat testing is required for infants with positive newborn-screening (NBS) tests for cystic fibrosis (CF). Infants have "quantity not sufficient" (QNS) sweat volumes more often than older children. A comprehensive study of QNS sweat volumes in infants has not previously been reported. METHODS We surveyed US CF Centers to obtain QNS rates in all infants who had sweat testing at under 14 days and under 3 months of age. We then calculated QNS rates reported to the Cystic Fibrosis Foundation Patient Registry (CFFPR) 2010-2018 in 10-day increments from 1 to 60 days of life. We compared QNS sweat test rates in preterm (

Background: Clinical trials of 7% hypertonic saline (HTS) in cystic fibrosis (CF) show short- and long-term benefits, including improved pulmonary function and reduced exacerbation risk. Adverse effects of HTS include bronchospasm, and guidelines recommend tolerance be tested in a clinical environment before prescribing. We evaluated the rate of, and risk factors for, intolerance of HTS at a single pediatric CF program. Methods: Single-center retrospective study in patients with CF, aged 6–20 years, who received an HTS test dose between 2006 and 2017. HTS intolerance was defined as either a ≥10% decline in forced expiratory volume in 1 s (FEV(1)) percent predicted or wheezing/severe cough. Results: Fifty-one patients met inclusion criteria, and 13 (25%) showed intolerance of 7% HTS. There were trends toward higher rates of comorbidities in the patients intolerant versus tolerant of HTS, including allergies and/or rhinitis 85% versus 66% (P = 0.30) and sinus disease 85% versus 58% (P = 0.10). A trend toward more methicillin-sensitive Staphylococcus aureus (58% vs. 31%, P = 0.09) and asthma (42% vs. 24%, P = 0.09) was seen in patients tolerant of HTS. Demographics, pulmonary function, nutritional parameters, laboratory tests, respiratory cultures, chronic therapies, and antibiotics for exacerbations did not differ. Conclusions: In our program, 1:4 children with CF exhibited objective findings of HTS intolerance. There were trends suggesting higher frequency of allergies and rhinosinusitis in intolerant children. Assessing tolerance of HTS before prescribing chronic daily therapy is important. Larger studies are needed to more accurately define the incidence of intolerance and risk factors.

INTRODUCTION Newborn screening (NBS) for cystic fibrosis (CF) was implemented in all US states and DC by 2010. This hypothesis-generating study was designed to form the basis of additional analyses and to plan quality improvement initiatives. The aims were to describe the outcomes of infants with CF born during the first 9 years of universal NBS. METHODS We included participants in the CF Foundation Patient Registry born 2010-2018 with age of recorded CF diagnosis 0-365 days old. We compared the age of center-reported diagnosis, age at first CF event (defined as earliest sweat test, clinic visit, or hospitalization), demographics, and outcomes between three cohorts born between 2010-2012, 2013-2015, and 2016-2018. RESULTS In 6354 infants, the median age at first CF event decreased from the first to the third cohort. Weight-for-age (WFA) was

Median cystic fibrosis (CF) survival has increased dramatically over time due to several factors, including greater availability and use of antimicrobial therapies. During the progression of CF lung disease, however, the emergence of multidrug antimicrobial resistance can limit treatment effectiveness, threatening patient longevity. Current planktonic-based antimicrobial susceptibility testing lacks the ability to predict clinical response to antimicrobial treatment of chronic CF lung infections. There are numerous reasons for these limitations including bacterial phenotypic and genotypic diversity, polymicrobial interactions, and impaired antibiotic efficacy within the CF lung environment. The parallels to other chronic diseases such as non-CF bronchiectasis are discussed as well as research priorities for moving forward.

The management of portal hypertension (PHT) in children with well compensated cirrhosis and cystic fibrosis (CF) is controversial. We present our experience with distal splenorenal shunting (DSRS) for the treatment of PHT as an alternative to liver transplantation (LT).Between 2008 and 2017, 5 CF children underwent a DSRS at a pediatric hepatobiliary and transplantation referral center. LT (n = 9) was reserved for patients with decompensated cirrhosis. Statistical analysis was done using the paired t-test (p 0.05 considered significant).Mean PELD/MELD score was significantly lower for DSRS patients than LT (3 ± 6 vs 28 ± 4, p 0.001). All 5 DSRS patients had grade III-IV varices. One bled prior to surgery. After DSRS, spleen size decreased significantly from 8.4 ± 1.5 cm to 4.4 ± 1.8 cm (p = 0.019). Mean platelet count remained stable (87.8 ± 48 to 91.8 ± 35, p = 0.9). There were no postoperative complications. No DSRS patient experienced variceal bleeding following shunt creation. Liver function tests remained stable in the DSRS group, and no patient required a liver transplant (median follow up 4.65 years, range 1.24-7.79).Patients with cystic fibrosis who have well-compensated cirrhosis and symptomatic portal hypertension can be palliated with distal splenorenal shunting and do not need liver transplants. These patients can undergo shunting with minimal morbidity.Case series with no comparison group.IV.

The efficacy, safety, and tolerability of lumacaftor and ivacaftor are established in patients aged 6 years and older with cystic fibrosis, homozygous for the F508del-CFTR mutation. We assessed the safety, pharmacokinetics, pharmacodynamics, and efficacy of lumacaftor and ivacaftor in children aged 2-5 years.In this multicentre, phase 3, open-label, two-part study, we enrolled children aged 2-5 years, weighing at least 8 kg at enrolment, with a confirmed diagnosis of cystic fibrosis who were homozygous for the F508del-CFTR mutation. Children received lumacaftor 100 mg and ivacaftor 125 mg (bodyweight14 kg) or lumacaftor 150 mg and ivacaftor 188 mg (bodyweight ≥14 kg) orally every 12 h for 15 days in part A (to assess pharmacokinetics and safety) and for 24 weeks in part B (to assess safety, pharmacokinetics, pharmacodynamics, and efficacy). Children could participate in part A, part B, or both. Children were enrolled into part A at five sites in the USA and into part B at 20 sites in North America (USA, 17 sites; Canada, three sites). The primary endpoints of the study were the pharmacokinetics (part A) and safety (part B) of lumacaftor and ivacaftor; all analyses were done in children who received at least one dose of lumacaftor and ivacaftor. Secondary endpoints in part A were safety and pharmacokinetics of the metabolites of lumacaftor and ivacaftor, and in part B included pharmacokinetics in children who received at least one dose of lumacaftor and ivacaftor and absolute changes from baseline in sweat chloride concentration, growth parameters, and markers of pancreatic function. This study is registered with ClinicalTrials.gov, number NCT02797132.The study was done from May 13, 2016, to Sept 8, 2017. 12 children enrolled in part A, 11 of whom completed the 15-day treatment period and enrolled in part B. 60 children enrolled in part B, 56 of whom completed the 24-week treatment period. Safety and pharmacokinetics were consistent with the well characterised safety profile of lumacaftor and ivacaftor. In part B, most children (59 [98%] of 60 children) had one or more treatment-emergent adverse events; most events were mild to moderate in severity. The most common adverse events were cough (38 [63%] of 60), vomiting (17 [28%]), pyrexia (17 [28%]), and rhinorrhoea (15 [25%]). Serious adverse events occurred in four children: infective pulmonary exacerbation of cystic fibrosis (n=2), gastroenteritis viral (n=1), and constipation (n=1). Three (5%) of 60 children discontinued treatment because of elevated serum aminotransferase concentrations. Mean sweat chloride concentrations decreased by 31·7 mmol/L, biomarkers of pancreatic function improved (fecal elastase-1 concentrations increased and serum immunoreactive trypsinogen concentrations decreased), and growth parameters increased at week 24.Lumacaftor and ivacaftor were generally safe and well tolerated in children aged 2-5 years with cystic fibrosis for 24 weeks. Efficacy findings also suggest that early intervention with lumacaftor and ivacaftor has the potential to modify the course of disease.Vertex Pharmaceuticals Incorporated.

Background Improved lung function and fewer pulmonary exacerbations (PEx) were observed with lumacaftor/ivacaftor (LUM/IVA) in patients with cystic fibrosis homozygous for F508del. It is unknown whether PEx reduction extends to patients without early lung function improvement. Methods Post hoc analyses of pooled phase 3 data (NCT01807923, NCT01807949) categorized LUM/IVA-treated patients by percent predicted forced expiratory volume in 1 s (ppFEV1) change from baseline to day 15 into threshold categories (absolute change ≤0 vs >0; relative change Results LUM (400 mg q12h)/IVA (250 mg q12h)–treated patients (n = 369) experienced significantly fewer PEx vs placebo, regardless of threshold category. With LUM/IVA, PEx rate per patient per year was 0.60 for those with absolute change in ppFEV1 > 0 and 0.85 for those with absolute change ≤0 (respective rate ratios vs placebo [95% CI]: 0.53 [0.40–0.69; P Conclusions LUM/IVA significantly reduced PEx, even in patients without early lung function improvement.

Introduction: Newborn screening (NBS) for cystic fibrosis (CF) was implemented in all US states and DC by 2010. This hypothesis generating study was designed to form the basis of additional research and to plan quality improvement initiatives. The aims were to describe the outcomes of infants with CF born during the first 9 years of universal NBS. Methods: We included participants in the CF Foundation Patient Registry born 2010-2018 with age at first CF event (first sweat test, clinic visit or hospitalization) by age 365 days. We assessed age of center-reported diagnosis, age at first CF event, demographics and outcomes for three consecutive 3-year cohorts born in 2010-2012, 2013-2015, and 2016-2018. Results: In 6354 infants, median age at diagnosis was earlier than median age at first CF event, which decreased from 1st cohort to 3rd cohort. Weight-for-age (WFA) was < 10th percentile in about 40% of infants at the first CF Center visit. Median WFA z-score at 1-2 years was > 0 but height-for-age (HFA) z-score was < 0 through age 5-6 years. The second cohort had a higher HFA z-score than the first cohort at age 5-6 years. Pseudomonas aeruginosa infection rates decreased over time. About 1/3 of infants were hospitalized in the first year of life across cohorts. Conclusion: Over 9 years of CF NBS, median age at first CF event decreased. CF NBS had positive health impacts but improving nutritional deficits and reducing infant hospitalizations remain targets for improvement.

Background Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are disease-modifying medications for cystic fibrosis (CF) and are shown to be efficacious for only specific CFTR mutations. CFTR mutation frequency varies by ancestry, which is different from but related to demographic racial and ethnic group. Eligibility for CFTR modulator therapy has not been previously reported by race and ethnicity. Methods We conducted a cross-sectional study of patients in the 2018 CF Foundation Patient Registry. We analyzed the percentage of patients in each US Census defined racial and ethnic group eligible for CFTR modulators based on CFTR mutations approved by the US FDA and then based on both mutations and FDA approval by age. We compared lung function based on CFTR modulator eligibility and prescription. Findings Based on CFTR mutations alone, 92.4% of non-Hispanic White patients, 69.7% of Black/African American patients, 75.6% of Hispanic patients, and 80.5% of other race patients eligible for CFTR modulators. For each CFTR modulator, Black/African American patients were least likely to have eligible mutations, and non-Hispanic White patients were most likely. There was no difference in the disparity between racial and/or ethnic groups with the addition of current FDA approval by age. The lowest pulmonary function in the cohort was seen in non-Hispanic White, Black/African American, and Hispanic patients not eligible for CFTR modulators. Interpretation Patients with CF from minority groups are less likely to be eligible for CFTR modulators. Because people with CF who are racial and ethnic minorities have increased disease severity and earlier mortality, this will further contribute to health disparities.

Introduction The 2017-2018 National Survey of Children's Health estimates that 30 million (42%) US children have experienced at least one adverse childhood experience (ACE), including abuse, neglect, and household dysfunction. ACEs negatively impact long-term health, and there has been no study of ACEs in cystic fibrosis (CF). We assessed willingness to disclose ACEs experienced by children with CF by surveying their parents and adults with CF. Methods We anonymously surveyed parents of children with CF and adults with CF at the Northwestern University/Lurie Children's CF Center to determine their willingness to disclose ACEs. Results The survey was completed by 46/157 (29%) parents and 36/105 (34%) adults with CF. Few parents (22%) and adults (17%) were willing to discuss most or all specific ACEs, more were willing to disclose the number of ACEs experienced in a category (57% parents, 47% adults), and the majority were willing to participate in anonymous research about ACEs (76% parents, 67% adults). Most parents (63%) and adults (50%) would prefer to have ACEs screened separately from their CF appointment, and most parents (63%) and adults (56%) wanted to learn more about ACEs from a member of their care team. Conclusions Participants preferred to disclose the number of categorical ACEs rather than specific ACEs and most were open to participating in anonymous ACEs research. More research is needed before implementing screening. Educating patients, parents, and providers about ACEs and appropriate interventions when ACES are identified is needed for both research and clinical applications of ACEs screening.

During the year 2019, numerous research studies and other reports were published that are interesting and instructive to professionals who care for people with cystic fibrosis (CF) and their families. This report is the third of 3 CF year in review articles and focuses on the multisystem manifestations of CF care. Previous articles have addressed cystic fibrosis transmembrane regulator modulators and reports on CF pulmonary disease and airway infections. It is an exciting time to be involved in care and research that aims to improve care for people with CF and their families.

INTRODUCTION: Prior literature shows that neonates with cystic fibrosis (CF) are more likely to be born low birth weight (LBW

International audience; The concentration of chloride in sweat remains the most robust biomarker for confirmatory diagnosis of cystic fibrosis (CF), a common life-shortening genetic disorder. Early diagnosis via quantitative assessment of sweat chloride allows prompt initiation of care and is critically important to extend life expectancy and improve quality of life. The collection and analysis of sweat using conventional wrist-strapped devices and iontophoresis can be cumbersome, particularly for infants with fragile skin, who often have insufficient sweat production. Here, we introduce a soft, epidermal microfluidic device ("sweat sticker") designed for the simple and rapid collection and analysis of sweat. Intimate, conformal coupling with the skin supports nearly perfect efficiency in sweat collection without leakage. Real-time image analysis of chloride reagents allows for quantitative assessment of chloride concentrations using a smartphone camera, without requiring extraction of sweat or external analysis. Clinical validation studies involving patients with CF and healthy subjects, across a spectrum of age groups, support clinical equivalence compared to existing device platforms in terms of accuracy and demonstrate meaningful reductions in rates of leakage. The wearable microfluidic technologies and smartphone-based analytics reported here establish the foundation for diagnosis of CF outside of clinical settings.

Antimicrobials have undoubtedly improved the lives of people with CF, but important antimicrobial-related toxicities and the emergence of antimicrobial-resistant bacteria associated with their use must be considered. Antimicrobial stewardship (AMS) is advocated across the spectrum of healthcare to promote the appropriate use of antimicrobials to preserve their current effectiveness and to optimise treatment, and it is clear that AMS strategies are applicable to and can benefit both non-CF and CF populations. This perspective explores the definition and components of an AMS program, the current evidence for AMS, and the reasons why AMS is a challenging concept in the provision of CF care. We also discuss the elements of CF care which align with AMS programs and principles and propose research priorities for AMS in CF.

IntroductionA growing population of adults living with severe, chronic childhood-onset health conditions has created a need for specialized health care delivered by providers who have expertise both in adult medicine and in those conditions. Optimal care of these patients requires systematic approaches to healthcare transition (HCT). Guidelines for HCT exist, but gaps in care occur, and there are limited data on outcomes of HCT processes.MethodsThe Single Disease Workgroup of the Lifespan Domain Task Force of the National Center for Advancing Translational Sciences Clinical and Translational Science Award programs convened a group to review the current state of HCT and to identify gaps in research and practice. Using cystic fibrosis and sickle cell disease as models, key themes were developed. A literature search identified general and disease-specific articles. We summarized key findings.ResultsWe identified literature characterizing patient, parent and healthcare provider perspectives, recommendations for transition care, and barriers to effective transition.ConclusionsWith increased survival of patients with severe childhood onset diseases, ongoing study of effective transition practices is essential as survival increases for severe childhood onset diseases. We propose pragmatic methods to enhance transition research to improve health and key outcomes.

Understanding variability in cystic fibrosis (CF) health outcomes requires an understanding of factors that go far beyond Cystic Fibrosis Transmembrane Receptor (CFTR) function caused by different gene mutations. Social and environmental factors that influence health have a significant influence on the trajectory of health in CF and in other chronic diseases. In this article, we review demographic factors associated with poorer health outcomes in CF, known and postulated biological mechanisms of these outcomes, and interventions that healthcare teams can implement that may reduce outcome disparities.

In this article, we highlight cystic fibrosis (CF) reports published in Pediatric Pulmonology during 2017. We also include articles from a variety of journals that are related or are of special interest to clinicians.

Rationale The association between CFTR genotype, sweat chloride and mortality has been inconsistent, but no previous analyses have examined the association stratified by individual genotypes. Objectives To evaluate the genotype-specific association between sweat chloride and mortality. Methods The CFF Patient Registry was assessed and included all patients in the registry between 1996 and 2012 with at least one F508del allele. We excluded patients without a documented genotype or plausible sweat chloride level. The primary outcome was time to mortality during the observation period. We examined 15 genotypes using the three most prevalent alleles in each of 5 classes. We compared subgroups of sweat chloride using Kaplan-Meier curves, log-rank tests, and multivariable Cox PH models. The overall predictive value of sweat chloride on mortality was assessed using area under the receiver operating characteristic curves. Measurements and main results 18,893 subjects met inclusion criteria. Sweat chloride distribution was similar across genotypes in patients with class 1 mutations, but was significantly different across genotypes in mutation classes 2–5. The R117H/F508del genotype patients demonstrated an association between sweat chloride and mortality (HR: 1.32 for every 10mmol/L increase in sweat chloride [95% CI 1.12–1.54]. There were also significant associations in patients with F508del/F508del, I507del/F508del, G551D/F508del and 2789+5G→A/F508del genotypes, though the clinical relevance for these genotypes is unclear. Conclusions There is significant variability in sweat chloride distribution across CFTR class 2–5 genotypes. The relationship between sweat chloride and mortality varies by genotype with a relatively strong relationship in R117H/F508del patients.

In this article, we highlight cystic fibrosis (CF) research and case reports published in Pediatric Pulmonology during 2016. We also include articles from a variety of journals that are thematically related to these articles, or are of special interest to clinicians.

Cystic fibrosis (CF) research and case reports were robust in the year 2018. This report summarizes publications related the multisystem effects of CF, pulmonary exacerbations, new and expanded therapies other than cystic fibrosis transmembrane conductance regulator modulator studies, and patient-reported priorities and outcomes.

Extracellular circulating miRNAs (ECmiRNAs) play a crucial role in cell-to-cell communication and serve as non-invasive biomarkers in a wide range of diseases, but their abundance and functional relevance in cystic fibrosis (CF) remain poorly understood. In this study, we employed microarray technology to identify aberrantly expressed plasma ECmiRNAs in CF and elucidate the functional relevance of their targets. Overall, we captured several ECmiRNAs abundantly expressed in CF. Expression levels of 11 ECmiRNAs differed significantly between CF and healthy control (HC) samples (FDR AGO1, DICER1, HMGA1, and MYC. The top pathways influenced by all targets were primarily signal transduction pathways associated with CF, including PI3K/Akt-, Wnt/β catenin-, glucocorticoid receptor-, and mTor signaling pathways. Our results suggest ECmiRNAs may be clinically relevant in CF and warrant further study.

Cystic fibrosis research and case reports were robust in the year 2018. This report summarizes research and cases related to Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulator therapies, inflammation and infection, epidemiology and the physiologic, and imaging assessment of disease.

Although cystic fibrosis (CF) is attributed to dysfunction of a single gene, the relationships between the abnormal gene product and the development of inflammation and progression of lung disease are not fully understood, which limits our ability to predict an individual patient’s clinical course and treatment response. To better understand CF progression, we characterized the molecular signatures of CF disease status with plasma-based functional genomics. Peripheral blood mononuclear cells (PBMCs) from healthy donors were cultured with plasma samples from CF patients ( n = 103) and unrelated, healthy controls ( n = 31). Gene expression levels were measured with an Affymetrix microarray (GeneChip Human Genome U133 Plus 2.0). Peripheral blood samples from a subset of the CF patients ( n = 40) were immunophenotyped by flow cytometry, and the data were compared with historical data for age-matched healthy controls ( n = 351). Plasma samples from another subset of CF patients ( n = 56) and healthy controls ( n = 16) were analyzed by multiplex enzyme-linked immunosorbent assay (ELISA) for numerous cytokines and chemokines. Principal component analysis and hierarchical clustering of induced transcriptional data revealed disease-specific plasma-induced PBMC profiles. Among 1,094 differentially expressed probe sets, 51 genes were associated with pancreatic sufficient status, and 224 genes were associated with infection with Pseudomonas aeruginosa. The flow cytometry and ELISA data confirmed that various immune modulators are relevant contributors to the CF molecular signature. This study provides strong evidence for distinct molecular signatures among CF patients. An understanding of these molecular signatures may lead to unique molecular markers that will enable more personalized prognoses, individualized treatment plans, and rapid monitoring of treatment response.

Objectives: New or increased cough is an important sign of pulmonary exacerbation. There is unmet need to objectively quantify and analyse cough trends in early life. Advances in flexible electronics and materials allow development of soft, skin-like, accelerometer-based wearable devices that seamlessly interface with the human body in unique locations, enabling the simultaneous capture of low-frequency body, chest, and throat motion along with high-frequency vocal, throat, and lung sound signals associated with various body processes including coughs and vital signs. Methods: A small, flexible, fully wireless, accelerometer-based mechano-acoustic sensor (MAS) was applied using gentle adhesives to the suprasternal notch of 10 paediatric CF subjects during regular clinic visits. A 15-minute protocol consisting of eliciting cough, throat clearing, speech, and laughs in various head/body orientations, ambient environments, and physical activity intensities. The MAS recorded at a high bandwidth 1.6kHz rate and automatically uploaded to a cloud server upon replacement on a wireless charging platform. Results: The captured sensor data was analysed using an existing machine learning algorithm developed for COVID-19 symptom tracking. Preliminary results show the device differentiates cough from other vocal, respiratory noises and motion artifacts, both at rest and during activity. A majority of children found the device to be acceptable, though device size and adhesive removal caused minor discomfort for some. Conclusion: The extraction of well-classified cough events is feasible, facilitating further analysis of cough episode duration, force, and clinically relevant features associated with early decompensation, response to treatment, and daily symptom tracking. Objective measurement of cough may be useful as a clinical study outcome measure and for clinical monitoring. Future work will include evaluation for longer time periods during stability and pulmonary exacerbations.

Rationale Aminoglycoside (AG) resistance of Pseudomonas aeruginosa in cystic fibrosis (CF) is associated with poorer clinical outcomes and is usually due to overexpression of the efflux pump MexXY. MexXY is regulated by mexZ , one of the most commonly mutated genes in CF P. aeruginosa isolates. Little is known about the evolutionary relationship between AG resistance, MexXY expression and mexZ mutations. Objectives To test the hypothesis that AG resistance in P. aeruginosa develops in parallel with higher MexXY expression and mexZ mutations. Methods CF P. aeruginosa isolates were compared for chronically infected (CI) adults, CI children and children with new infection. Measurements One P. aeruginosa isolate from each patient was analysed for mexZ mutations, mexY mRNA expression and amikacin resistance. Main results 56 patients with CF were enrolled: 21 children with new P. aeruginosa infection, 18 CI children and 17 CI adults. Amikacin resistance and mexY mRNA expression were higher in cohorts with longer P. aeruginosa infection. The prevalence of non-conservative mexZ mutations was 0%, 33% and 65% in children with new infection, CI children and CI adults, respectively. The same trend was seen in the ratio of non-conservative to non-synonymous mexZ mutations. Of isolates with non-conservative mexZ mutations, 59% were amikacin-resistant compared with 18% of isolates with non-synonymous mutations. The doubling rate of amikacin resistance and non-conservative mexZ mutations was approximately 5 years. Conclusions P. aeruginosa mexZ mutations undergo positive selection resulting in increased mexY mRNA expression and amikacin resistance and likely play a role in bacterial adaption in the CF lung.

In this article, we highlight cystic fibrosis (CF) research published in Pediatric Pulmonology during 2015. Articles from other journals that reflect similar themes, and those of special importance, are also included. Pediatr Pulmonol. 2016;51:754-765. © 2016 Wiley Periodicals, Inc.

Ivacaftor is indicated for treatment of cystic fibrosis (CF) mediated by 10 mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene that causes gating or partial function abnormalities. In placebo-controlled and open-label studies, ivacaftor-treated subjects showed improved pulmonary function, nutrition and quality of life measures. This article reviews ivacaftor safety.Safety findings in ivacaftor clinical trials, and reported subsequently, were accessed by a PubMed search using key words "VX-770" or "ivacaftor". Additional information was accessed via Google Search. Transaminitis was noted in ivacaftor and combination lumacaftor-ivacaftor trials. Ivacaftor was associated with cataracts in juvenile rat pups in pre-clinical studies; non-congenital cataracts have been found in children taking ivacaftor. Ivacaftor is a CYP3A substrate; CYP3A inhibitors and inducers should be avoided during its administration. Ivacaftor and its M1 metabolite may inhibit CYP3A and P-gp; therefore, ivacaftor may increase systemic exposure to drugs which are substrates of CYP3A and/or P-gp, increasing the potential for adverse events.Ivacaftor therapy may be associated with ocular and hepatic side effects; specific recommendations for monitoring are available. Potential drug interactions should be evaluated in patients taking ivacaftor. High clinical efficacy suggests that the risk benefit ratio of ivacaftor favors therapy.