Human Airway Basal Cells Undergo Reversible Squamous Differentiation and Reshape Innate Immunity.

Histological and lineage immunofluorescence examination revealed that healthy conducting airways of humans and animals harbor sporadic poorly differentiated epithelial patches mostly in the dorsal noncartilage regions that remarkably manifest squamous differentiation. analysis demonstrated that this squamous phenotype is not due to intrinsic functional change in underlying airway basal cells. Rather, it is a reversible physiological response to persistent Wnt signaling stimulation during differentiation.

Working towards consensus in the management of pediatric chronic rhinosinusitis in cystic fibrosis.

Objective: The prevalence of chronic rhinosinusitis (CRS), defined by mucosal thickening on imaging, approaches 100% in the cystic fibrosis (CF) population. CRS is associated with significant morbidity in CF, including its ability to trigger pulmonary exacerbations. CRS in CF is typically managed by pediatricians, otolaryngologists and pulmonologists.

An open-label extension study of ivacaftor in children with CF and a CFTR gating mutation initiating treatment at age 2-5 years (KLIMB).

Background: KIWI (NCT01705145) was a 24-week, single-arm, pharmacokinetics, safety, and efficacy study of ivacaftor in children aged 2 to 5 years with cystic fibrosis (CF) and a CFTR gating mutation. Here, we report the results of KLIMB (NCT01946412), an 84-week, open-label extension of KIWI.

Methods: Children received age- and weight-based ivacaftor dosages for 84 weeks.

Effects of a primary palliative care intervention on quality of life and mental health in cystic fibrosis.

Background: Despite the significant impact of chronic symptoms on quality of life with cystic fibrosis (CF), the role of palliative care in management of this disease is not well defined. The coping, goal assessment, and relief from evolving CF symptoms (CF-CARES) model is a primary palliative care intervention designed to provide chronic symptom management at all stages of the disease. The goal of this pilot study was to estimate the effectiveness of the CF-CARES intervention on improving chronic symptoms and quality of life for people living with CF.

SMAD Signaling Restricts Mucous Cell Differentiation in Human Airway Epithelium.

Mucin-secreting goblet cell metaplasia and hyperplasia (GCMH) is a common pathological phenotype in many human respiratory diseases, including asthma, chronic obstructive pulmonary disease, cystic fibrosis, primary ciliary dyskinesia, and infections. A better understanding of how goblet cell quantities or proportions in the airway epithelium are regulated may provide novel therapeutic targets to mitigate GCMH in these devastating diseases. We identify canonical SMAD signaling as the principal pathway restricting goblet cell differentiation in human airway epithelium.

Dual SMAD Signaling Inhibition Enables Long-Term Expansion of Diverse Epithelial Basal Cells.

Functional modeling of many adult epithelia is limited by the difficulty in maintaining relevant stem cell populations in culture. Here, we show that dual inhibition of SMAD signaling pathways enables robust expansion of primary epithelial basal cell populations. We find that TGFβ/BMP/SMAD pathway signaling is strongly activated in luminal and suprabasal cells of several epithelia, but suppressed in p63+ basal cells.

Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2-5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-label, single-arm study.

Background: Ivacaftor has been shown to be a safe, effective treatment for cystic fibrosis in patients aged 6 years or older with a CFTR gating mutation. We aimed to assess the safety, pharmacokinetics, and pharmacodynamics of ivacaftor in children aged 2-5 years.

Methods: In the two-part KIWI study, we enrolled children aged 2-5 years weighing 8 kg or more with a confirmed diagnosis of cystic fibrosis and a CFTR gating mutation on at least one allele from 15 hospitals in the USA, UK, and Canada.

Fathers and Asthma Care: Paternal Involvement, Beliefs, and Management Skills.

Objective: To compare asthma care roles of maternal and paternal caregivers, and examine associations between caregiver involvement and the outcomes of adherence, morbidity, and parental quality of life (QoL).

Methods: Mothers and fathers in 63 families of children, ages 5-9 years, with persistent asthma completed semistructured interviews and questionnaires. Adherence was measured via electronic monitoring.

Development and evaluation of a palliative care curriculum for cystic fibrosis healthcare providers.

Background: Primary palliative care refers to basic skills that all healthcare providers can employ to improve quality of life for patients at any stage of disease. Training in these core skills is not commonly provided to clinicians caring for cystic fibrosis (CF) patients. The objective of this study was to assess change in comfort with core skills among care team members after participation in CF-specific palliative care training focused on management of burdensome symptoms and difficult conversations.

Trends in bone mineral density in young adults with cystic fibrosis over a 15 year period.

Background: Improvements in clinical care have led to increased life expectancy in patients with cystic fibrosis (CF) over the past several decades. Whether these improvements have had significant effects on bone health in patients with CF is unclear.

Methods: This is a cross-sectional study comparing clinical characteristics and bone mineral density (BMD) measured by dual energy X-ray absorptiometry (DXA) in adults with CF evaluated in 1995-1999 to age-, race-, and gender-matched patients with CF evaluated in 2011-2013 at the same center on calibrated DXA machines.

Compromised bone microarchitecture and estimated bone strength in young adults with cystic fibrosis.

Context: Young adults with cystic fibrosis (CF) are at risk for low bone density and fractures, but the underlying alterations in bone microarchitecture that may contribute to their increased fracture risk are currently unknown.

Objective: The main goal of this study was to use high-resolution peripheral quantitative computed tomography (HR-pQCT) to characterize the bone microarchitecture, volumetric bone mineral density (vBMD), and estimated strength of the radius and tibia in young adults with CF compared with healthy volunteers.

Design And Setting: This was a cross-sectional study at an outpatient clinical research center within a tertiary academic medical center.

Pooled analysis of two large randomised phase III inhaled mannitol studies in cystic fibrosis.

Background: To evaluate safety and efficacy of inhaled mannitol treatment in subgroups of a large global CF population.

Methods: Data were pooled from two multicentre, double-blind, randomised, controlled, parallel group phase III studies in which 600 patients inhaled either mannitol (400 mg) or control (mannitol 50 mg) twice a day for 26 weeks.

Results: Both the mean absolute change in FEV(1) (mL) and relative change in FEV(1) by % predicted from baseline for mannitol (400 mg) versus control were statistically significant (73.

Generation of multipotent lung and airway progenitors from mouse ESCs and patient-specific cystic fibrosis iPSCs.

Deriving lung progenitors from patient-specific pluripotent cells is a key step in producing differentiated lung epithelium for disease modeling and transplantation. By mimicking the signaling events that occur during mouse lung development, we generated murine lung progenitors in a series of discrete steps. Definitive endoderm derived from mouse embryonic stem cells (ESCs) was converted into foregut endoderm, then into replicating Nkx2.

Long-term inhaled dry powder mannitol in cystic fibrosis: an international randomized study.

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.

Cystic fibrosis newborn screening: using experience to optimize the screening algorithm.

Newborn screening (NBS) for cystic fibrosis (CF) offers the opportunity for early diagnosis and improved outcomes in patients with CF and has been universally available in the state of Massachusetts since 1999 using an immunoreactive trypsinogen (IRT)-DNA algorithm. Ideally, CF NBS is incorporated as part of an integrated NBS system that allows for comprehensive and coordinated education, laboratory screening, clinical follow-up, and evaluation so that evidence-based data can be used to maximize quality improvements and optimize the screening algorithm. The New England Newborn Screening Program (NENSP) retrospectively analyzed Massachusetts's CF newborn screening data that yielded decisions to eliminate a screen-positive category, maintain the IRT cutoff value that prompts the second tier DNA testing, and communicate CF relative risk to primary care providers (PCPs) based on categorization of positive CF NBS results.

Nutrient status of adults with cystic fibrosis.

Nutrition is thought to influence disease status in patients with cystic fibrosis (CF). This cross-sectional study sought to evaluate nutrient intake and anthropometric data from 64 adult outpatients with cystic fibrosis. Nutrient intake from food and supplements was compared with the Dietary Reference Intakes for 16 nutrients and outcomes influenced by nutritional status.

Population-based newborn screening for genetic disorders when multiple mutation DNA testing is incorporated: a cystic fibrosis newborn screening model demonstrating increased sensitivity but more carrier detections.

Objectives: Newborn screening for cystic fibrosis (CF) provides a model to investigate the implications of applying multiple-mutation DNA testing in screening for any disorder in a pediatric population-based setting, where detection of affected infants is desired and identification of unaffected carriers is not. Widely applied 2-tiered CF newborn screening strategies first test for elevated immunoreactive trypsinogen (IRT) with subsequent analysis for a single CFTR mutation (DeltaF508), systematically missing CF-affected infants with any of the >1000 less common or population-specific mutations. Comparison of CF newborn screening algorithms that incorporate single- and multiple-mutation testing may offer insights into strategies that maximize the public health value of screening for CF and other genetic disorders.