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Childhood lung infection is often associated with prominent neutrophilic airway inflammation and excess production of proteases such as neutrophil elastase (NE). The mechanisms responsible for this inflammation are not well understood. One potentially relevant pathway is the production of extracellular traps by neutrophils (NETs) and macrophages (METs). The aim of this study was to measure NET and MET expression in children and the effect of deoxyribonculease (DNase) 1 and alpha1-antitrypsin (AAT) on this process. We studied 76 children (median age of 4.0 years) with cystic fibrosis or chronic cough who underwent investigational bronchoscopy. NETs, METs and neutrophil elastase activity in bronchoalveolar lavage (BAL) samples were measured using confocal microscopy and functional assays. The effects of DNase 1 and AAT on NET/MET expression and neutrophil elastase activity were examined in vitro. Both subject groups had airway neutrophilia with prominent BAL production of NETs with neutrophil elastase co-expression; the mean %+/-standard error of the mean of neutrophils expressing NETs in the cystic fibrosis group was 23.3+/-2.8% and in the non-cystic fibrosis group was 28.4+/-3.9%. NET expression was higher in subjects who had detectable neutrophil elastase activity (p0.0074). The percentage of macrophages expressing METs in the cystic fibrosis group was 10.7+/-1.2% and in the non-cystic fibrosis group was 13.2+/-1.9%. DNase 1 decreased NET/MET expression (p<0.0001), but increased neutrophil elastase activity (p0.0137). The combination of AAT and DNase 1 reduced neutrophil elastase activity (p0.0049). We observed prominent extracellular trap formation in symptomatic children with and without cystic fibrosis. This innate inflammatory response was down-regulated by a combination of currently available therapeutics.Copyright © The authors 2021.

Little is known about early predictors of later cystic fibrosis (CF) structural lung disease. This study examined early predictors of progressive structural lung abnormalities in children who completed the Australasian CF Bronchoalveolar Lavage (ACFBAL) clinical trial at age 5-years and participated in an observational follow-up study (CF-FAB). Eight Australian and New Zealand CF centres participated in CF-FAB and provided follow-up chest computed-tomography (CT) scans for children who had completed the ACFBAL study with baseline scans at age 5-years. CT scans were annotated using PRAGMA-CF scoring. Ordinal regression analysis and linear regression were used to investigate associations between PRAGMA-CF (Perth-Rotterdam Annotated Grid Morphometric Analysis for CF) outcomes at follow-up and variables measured during the ACFBAL study. 99 out of 157 ACFBAL children (mean+/-SD age 13+/-1.5 years) participated in the CF-FAB study. The probability of bronchiectasis at follow-up increased with airway disease severity on the baseline CT scan. In multiple regression (retaining factors at p<0.05) the extent of bronchiectasis at follow-up was associated with baseline atelectasis (OR 7.2, 95% CI 2.4-22; p 0.001), bronchoalveolar lavage (BAL) log2 interleukin (IL)-8 (OR 1.2, 95% CI 1.05-1.5; p=0.010) and body mass index z-score (OR 0.49, 95% CI 0.24-1.00; p=0.05) at age 5 years. Percentage trapped air at follow-up was associated with BAL log2 IL-8 (coefficient 1.3, 95% CI 0.57-2.1; p<0.001) at age 5 years. The extent of airway disease, atelectasis, airway inflammation and poor nutritional status in early childhood are risk factors for progressive structural lung disease in adolescence.Copyright © ERS 2020

Background: Cystic fibrosis (CF) lung disease commences in infancy, and understanding the role of the microbiota in disease pathogenesis is critical. This study examined and compared the lower airway microbiota of infants with and without CF and its relationship to airway inflammation in the first months of life. Method(s): Infants newly-diagnosed with CF were recruited into a single-centre study in Melbourne, Australia from 1992 to 2001. Bronchoalveolar lavage was performed at study entry. Healthy infants undergoing bronchoscopy to investigate chronic stridor acted as controls. Quantitative microbiological culture was performed and inflammatory markers were measured contemporaneously. 16S ribosomal RNA gene analysis was performed on stored samples. Result(s): Thirteen bronchoalveolar samples from infants with CF and nine from control infants, collected at median ages of 1.8-months (25th-75th percentile 1.5 to 3.1-months) and 5-months (25th-75th percentile 2.9 to 8.2-months) respectively, provided 16S rRNA gene data. Bacterial biomass was positively associated with inflammation. Alpha diversity was reduced in infants with CF and between-group compositional differences were apparent. These differences were driven by increased Staphylococcus and decreased Fusobacterium and were most apparent in symptomatic infants with CF. Conclusion(s): In CF lung disease, differences in lower airway microbial community composition and structure are established by age 6-months.Copyright © 2018 European Cystic Fibrosis Society.

Introduction: Children and adolescents with cystic fibrosis (CF) experience sleep disturbance, elevated symptoms of depression and reduced health-related quality of life (HRQOL). We aimed to investigate the relationship between sleep quality, mood and HRQOL in children with CF and healthy controls. Material(s) and Method(s): Children (7-12 years) and adolescents (13-18 years) with CF, free from pulmonary exacerbation, and healthy controls completed sleep evaluation including 14 days of actigraphy recordings and one night of oximetry. Age appropriate questionnaires assessed mood (Children's Depression Inventory; CDI or Beck's Depression Inventory; BDI), HRQOL (Cystic Fibrosis Questionnaire; CFQ-R or Pediatric Quality of Life Inventory; PedsQL), and daytime sleepiness (Pediatric Daytime Sleepiness Scale; PDSS). Result(s): 87 children and adolescents with CF and 55 controls were recruited. Children with CF (7-12 years) had poorer objective sleep quality, more daytime sleepiness and higher CDI total scores, indicating lower mood, than controls, with a negative correlation between CDI score and sleep efficiency. Children with CF and controls with lower mood were sleepier. Adolescents with CF (13-18 years) demonstrated poorer objective sleep quality and more sleepiness than controls, but no difference in mood scores. Reduced objective sleep quality was significantly correlated with lower CFQ-R scores for physical and emotional functioning, vitality, treatment burden, health perceptions, social, role and respiratory health. There was also a significant association between increased daytime sleepiness and lower CFQ-R scores for vitality and role in adolescents with CF. In both control groups (7-18 years) there was no correlation between sleep quality and mood or HRQOL. Conclusion(s): In clinically stable children and adolescents with CF, impaired sleep quality and daytime sleepiness is related to lower mood and quality of life in an age-specific manner. Future research shou

Background: We aimed to investigate the relationship between sleep quality, mood and health-related quality of life (HRQOL) in children with CF and controls. Method(s): Children (7-12 years) and adolescents (13-18 years) with CF and controls completed sleep evaluation: overnight oximetry and 14 days of actigraphy. Age-appropriate questionnaires assessed mood (Children's Depression Inventory; CDI or Beck's Depression Inventory), HRQOL (CF Questionnaire-Revised; CFQ-R or PedsQL), and sleepiness (Pediatric Daytime Sleepiness Scale). Result(s): 87 CF and 55 controls recruited. Children with CF had poorer sleep quality, more sleepiness and lower mood than controls, with a negative correlation between mood score and sleep efficiency. Sleepiness score was predictive of mood score and multiple CFQ-R domains. Adolescents with CF also demonstrated poorer sleep and more sleepiness than controls, but no difference in mood. Reduced sleep quality predicted lower CFQ-R scores. No correlation between sleep, mood or HRQOL in controls. Conclusion(s): In children and adolescents with CF, impaired sleep quality is associated with lower mood and HRQOL in an age-specific manner. Future research will aid understanding of effective strategies for prevention and treatment of mood disorders and sleep disturbance in children with CF.Copyright © 2017

Rationale In infants and young children with cystic fibrosis, lower airway infection and inflammation are associated with adverse respiratory outcomes. However, the role of lower airway microbiota in the pathogenesis of early cystic fibrosis lung disease remains uncertain. Objectives To assess the development of the lower airway microbiota over time in infants and young children with cystic fibrosis, and to explore its association with airway inflammation and pulmonary function at age 6years. Methods Serial, semi-annual bronchoscopies and bronchoalveolar lavage (BAL) procedures were performed in infants newly diagnosed with cystic fibrosis following newborn screening. Quantitative microbiological cultures and inflammatory marker (interleukin 8 and neutrophil elastase) measurements were undertaken contemporaneously. 16S ribosomal RNA gene sequencing was conducted on stored BAL samples. Spirometry results recorded at 6years of age were extracted from medical records. Measurements and main results Ninety-five BAL samples provided 16S ribosomal RNA gene data. These were collected from 48 subjects aged 1.2-78.3months, including longitudinal samples from 27 subjects and 13 before age 6months. The lower airway microbiota varied, but diversity decreased with advancing age. Detection of recognised cystic fibrosis bacterial pathogens was associated with reduced microbial diversity and greater lower airway inflammation. There was no association between the lower airway microbiota and pulmonary function at age 6years. Conclusions In infants with cystic fibrosis, the lower airway microbiota is dynamic. Dominance of the microbiota by recognised cystic fibrosis bacterial pathogens is associated with increased lower airway inflammation, however early microbial diversity is not associated with pulmonary function at 6years of age.Copyright © 2017 Published by the BMJ Publishing Group Limited.

Background Sleep disturbance is common in children with cystic fibrosis (CF) however there are limited studies investigating the causes for poor sleep quality. In a cross sectional observational study we aimed to evaluate the clinical correlates of sleep disturbance in this population. Methods Children with CF (7-18 years) free from pulmonary exacerbation completed medical review, overnight oximetry, the OSA-18 and 14 days of actigraphy recordings with a sleep diary. Results In addition to FEV1 < 80% and low baseline SpO2, CF-related diabetes, PEG feeding and co-morbid behaviour disorder were associated with lower objective sleep quantity. Paternal smoking and a family member with a mood disorder were also associated with sleep disturbance. The use of electronic devices before bedtime was associated with lower sleep quantity and quality. FEV1, nocturnal cough, age and a behaviour disorder predicted sleep duration. FEV1, nocturnal cough, SpO2 nadir and asthma predicted sleep efficiency. Conversely, sleep efficiency independently predicted FEV1. Conclusions Reduced sleep quality in children with CF is related to lung health and co-morbidities. However, family characteristics and poor sleep hygiene in the child were also associated with sleep disturbance. Optimal management of CF would seem to be the primary intervention to alleviate children's sleep disturbance, however our data raises additional targets for attempts to improve sleep.Copyright © 2017 European Cystic Fibrosis Society

Infection plays a critical role in the pathogenesis of cystic fibrosis (CF) lung disease. Over the past two decades, the application of molecular and extended culture-based techniques to microbial analysis has changed our understanding of the lungs in both health and disease. CF lung disease is a polymicrobial disorder, with obligate and facultative anaerobes recovered alongside traditional pathogens in varying proportions, with some differences observed to correlate with disease stage. While healthy lungs are not sterile, differences between the lower airway microbiota of individuals with CF and disease-controls are already apparent in childhood. Understanding the evolution of the CF airway microbiota, and its relationship with clinical treatments and outcome at each disease stage, will improve our understanding of the pathogenesis of CF lung disease and potentially inform clinical management. This review summarizes current knowledge of the early development of the respiratory microbiota in healthy children and then discusses what is known about the airway microbiota in individuals with CF, including how it evolves over time and where future research priorities lie.Copyright © 2017 Wiley Periodicals, Inc.

Introduction/Aim: Infection plays a critical role in the pathogenesis of early cystic fibrosis (CF) lung disease. Differences in the nasopharyngeal microbiota of subjects with CF and healthy controls are apparent from early infancy. This study aimed to compare the composition and structure of the lower airway microbiota of infants below 12 months of age with and without CF. Method(s): Bronchoscopies and bronchoalveolar lavage (BAL) procedures were performed in infants newly diagnosed with CF following newborn screening. Infants undergoing clinically-indicated bronchoscopy were recruited as controls. Quantitative microbiological culture and inflammatory marker (interleukin-8 and neutrophil elastase) measurements were undertaken contemporaneously. 16S ribosomal RNA gene sequencing was conducted on stored samples. Result(s): Seventeen infants with CF (median age 2.6 months (interquartile range (IQR) 1.6-4.9 months); male 59%; P.Phe508del homozygous 71%) and nine control infants (median age 5.0 months (IQR 2.9-8.2 months); male 78%) contributed BAL samples. Diversity was reduced in CF compared with control BAL samples (median shannon diversity index 1.3 (IQR 0.9-2.0) and 2.0 (IQR 1.4-2.3) respectively). Firmicutes was the most prevalent phylum in both groups, accouting for 76.9% and 49% of total reads respectively, however Staphylococcus was predominant in CF samples only (39.8% total reads). The next most prevalent genera in the CF samples were Streptococcus (15.0%), Haemophilus (9.9%), Granulicatella (9.2%) and Gemella (6.7%). In contrast, the five most abundant genera in the control samples were Streptococcus (30.0%), Fusobacterium (12.8%), Neisseria (12.4%), Gemella (6.3%) and Veillonella (6.1%). Staphylococcus and Haemophilus each accounted for 0.4% of total reads. Conclusion(s): There are substantial perturbations in the structure and composition of the lower airway microbiota of infants with CF in the first months of life, most notably increased prevalence of Sta

Objective To measure sleep patterns and quality, objectively and subjectively, in clinically stable children with cystic fibrosis (CF) and healthy control children, and to examine the relationship between sleep quality and disease severity. Study design Clinically stable children with CF and healthy control children (7-18 years of age) were recruited. Sleep patterns and quality were measured at home with actigraphy (14 days). Overnight peripheral capillary oxygen saturation was measured via the use of pulse oximetry. Daytime sleepiness was evaluated by the Pediatric Daytime Sleepiness Scale (PDSS) and subjective sleep quality by the Sleep Disturbance Scale for Children and Obstructive Sleep Apnea-18. Results A total of 87 children with CF and 55 control children were recruited with no differences in age or sex. Children with CF had significantly lower total sleep time and sleep efficiency than control children due to frequent awakenings and more wake after sleep onset. In children with CF, forced expiratory volume in 1 second and overnight peripheral capillary oxygen saturation nadir correlated positively with total sleep time and sleep efficiency and negatively with frequency of awakenings and wake after sleep onset. Patients with CF had significantly greater Sleep Disturbance Scale for Children (45 vs 35; P<.001), Obstructive Sleep Apnea-18 (35 vs 24; P<.001), and PDSS scores (14 vs 11; P<.001). There was a negative correlation between PDSS and forced expiratory volume in 1 second (r=-0.23; P<.05). Conclusions Even in periods of clinical stability, children with CF get less sleep than their peers due to more time in wakefulness during the night rather than less time spent in bed. Objective measures of sleep disturbance and subjective daytime sleepiness were related to disease severity. In contrast, parents of children with CF report high levels of sleep disturbance unrelated to disease severity.Copyright © 2016 Elsevier Inc.

We have measured parity-violating asymmetries in elastic electron-proton scattering over the range of momentum transfers 0.12 ≤ Q2 ≤ 1.0 GeV2. These asymmetries, arising from interference of the electromagnetic and neutral weak interactions, are sensitive to strange quark contributions to the currents of the proton. The measurements were made at JLab using a toroidal spectrom- eter to detect the recoiling protons from a liquid hydrogen target. The results indicate non-zero, Q2 dependent, strange quark contributions and provide new information beyond that obtained in previous experiments.

Background: In 2012 clinical management of children having adenotonsillectomy (AT) for suspected obstructive sleep apnea (OSA) at our tertiary centre changed based on previous research: children with severe obstructive sleep apnea (OSA) at increased risk of post-operative respiratory adverse events (AE) identified using home overnight oximetry or polysomnography (PSG) were managed post-operatively in a high nurse/patient ratio unit in the ward (high acuity unit, HAU) rather than in the intensive care unit (ICU) as previously. Objective(s): To examine the post-operative respiratory AE post AT in HAU. Method(s): A retrospective audit was performed of children having AT on the HAU list from Oct 2012-Sept 2014, identifying clinical information, pre-operative testing for OSA and post-operative course. Result(s): 343 children underwent elective adenotonsillectomy at our tertiary centre in the study period, of whom 79 had surgery on the HAU list (16F; median age 4.2 year (range 1.2-14.7); median weight-for-age centile 77.9% (IQR 44-98.7%)). 75 had moderate/severe OSA by oximetry (n = 44) or PSG (n = 31) criteria. 77 of 79 children had oxygen therapy in the recovery room (median 20 min, IQR 15-40 min). 18 (23%) had at least one AE outside the recovery room, which were observed (n = 2) or treated with oxygen therapy (n = 14) or repositioning (n = 2). Obesity increased the risk of an AE (10/25 obese vs 8/54 non obese, p = 0.01), as did the presence of a major comorbidity (5/9 with comorbidity vs 13/70 without, p = 0.03). There were no admissions from the HAU to ICU. 63 patients (83%) stayed only one night in hospital (median 1 d, range 1-5 d). Conclusion(s): In a cohort of children with known moderate-severe OSA, post-operative AE after AT were all managed in the HAU. Post-operative care in HAU provides safe and effective care for high-risk children post-AT, minimizing admissions to ICU.Copyright © 2016.

We have measured the beam-normal single-spin asymmetry in elastic scattering of transversely polarized 3 GeV electrons from unpolarized protons at Q2=0.15, 0.25 (GeV/c)2. The results are inconsistent with calculations solely using the elastic nucleon intermediate state and generally agree with calculations with significant inelastic hadronic intermediate state contributions. An provides a direct probe of the imaginary component of the 2γ exchange amplitude, the complete description of which is important in the interpretation of data from precision electron-scattering experiments.

We have measured parity-violating asymmetries in elastic electron-proton scattering over the range of momentum transfers 0.12≤Q2≤1.0 GeV2. These asymmetries, arising from interference of the electromagnetic and neutral weak interactions, are sensitive to strange-quark contributions to the currents of the proton. The measurements were made at Jefferson Laboratory using a toroidal spectrometer to detect the recoiling protons from a liquid hydrogen target. The results indicate nonzero, Q2 dependent, strange-quark contributions and provide new information beyond that obtained in previous experiments.

Background: We describe Pseudomonas aeruginosa acquisitions in children with cystic fibrosis (CF) aged <=. 5-years, eradication treatment efficacy, and genotypic relationships between upper and lower airway isolates and strains from non-CF sources. Method(s): Of 168 CF children aged <=. 5-years in a bronchoalveolar lavage (BAL)-directed therapy trial, 155 had detailed microbiological results. Overall, 201/271 (74%) P. aeruginosa isolates from BAL and oropharyngeal cultures were available for genotyping, including those collected before and after eradication therapy. Result(s): Eighty-two (53%) subjects acquired P. aeruginosa, of which most were unique strains. Initial eradication success rate was 90%, but 36 (44%) reacquired P. aeruginosa, with genotypic substitutions more common in BAL (12/14) than oropharyngeal (3/11) cultures. Moreover, oropharyngeal cultures did not predict BAL genotypes reliably. Conclusion(s): CF children acquire environmental P. aeruginosa strains frequently. However, discordance between BAL and oropharyngeal strains raises questions over upper airway reservoirs and how to best determine eradication in non-expectorating children.Copyright © 2014 European Cystic Fibrosis Society.

Background: Person-to-person transmission is a potential pathway of Pseudomonas aeruginosa acquisition in cystic fibrosis. Reports of cross-infection of shared cystic-fibrosis-specific P aeruginosa strains across large geographical distances are concerning. Therefore, we aimed to assess the extent to which patient movement between cystic fibrosis centres contributes to dissemination. Method(s): We did a cross-sectional study to assess movement of patients with cystic fibrosis who were infected with P aeruginosa between Sept 3, 2007, and June 16, 2010, at 18 Australian cystic fibrosis centres. We applied social network analysis to patient movement data from P aeruginosa-infected patients to assess the role of patient mobility in P aeruginosa genotype prevalence. We generated networks linking treatment centres based on the movement of patients attending adult and paediatric cystic fibrosis centres, and compared these with the movement of patients infected with all P aeruginosa strains, unique strains, and predominant Australian shared strains (AUST-01 and AUST-02). We summarised connectivity using degree centrality, in-degree centrality, out-degree centrality, and k-core estimates. Infection control and surveillance practices were also assessed by use of a questionnaire. Finding(s): 983 patients (mean age 25 years [SD 10]; 551 [56%] male) provided 2887 P aeruginosa isolates for ERIC-PCR genotyping, which yielded 531 distinct genotypes: 493 unique strains in 373 patients and 38 shared strains in 610 patients. AUST-01 infections were associated with higher in-degree centrality (p=0.004) and k-core (p=0.005) estimates and AUST-02 infections with higher degree centrality (p=0.002), out-degree centrality (p=0.002), and k-core (p=0.007) estimates for the previous health-care facilities; associations for the present cystic fibrosis centre were not significant. These findings were significant for adult patients (AUST-01 in-degree centrality p=0.004 and k-core p=0.005; AUST-02

Objectives To determine whether bronchoalveolar lavage (BAL)-directed therapy for infants and young children with cystic fibrosis (CF), rather than standard therapy, was justified on the grounds of a decrease in average costs and whether the use of BAL reduced treatment costs associated with hospital admissions. Study design Costs were assessed in a randomized controlled trial conducted in Australia and New Zealand on infants diagnosed with CF after newborn screening and assigned to receive either BAL-directed or standard therapy until they reached 5 years of age. A health care funder perspective was adopted. Resource use measurement was based on standardized data collection forms administered for patients across all sites. Unit costs were obtained primarily from government schedules. Results Mean costs per child during the study period were Australian dollars (AUD)92 860 in BAL-directed therapy group and AUD90 958 in standard therapy group (mean difference AUD1902, 95% CI AUD-27 782 to 31 586, P =.90). Mean hospital costs per child during the study period were AUD57 302 in the BAL-directed therapy group and AUD66 590 in the standard therapy group (mean difference AUD-9288; 95% CI AUD-35 252 to 16 676, P =.48). Conclusions BAL-directed therapy did not result in either lower mean hospital admission costs or mean costs overall compared with managing patients with CF by a standard protocol based upon clinical features and oropharyngeal culture results alone. Following on our previous findings that BAL-directed treatment offers no clinical advantage over standard therapy at age 5 years, flexible bronchoscopy with BAL cannot be recommended for the routine management of preschool children with CF on the basis of overall cost savings. Copyright © 2014 Elsevier Inc. All rights reserved.

Objectives: Post-operative respiratory adverse events (AE) are frequent in children having adenotonsillectomy (AT) for obstructive sleep apnea (OSA). Many hospitals have a policy of routine admission to the intensive care unit (ICU) after surgery for children at highest risk. We aimed to determine the frequency and severity of post-operative AE in children admitted to ICU, to assess the appropriateness of this care plan. Method(s): A retrospective chart review was carried out all children admitted to the pediatric intensive care unit after AT for OSA from January 2007 to December 2009. AE were classified as mild, including requirement for supplemental O2 or repositioning to improve airway or severe, including bag and mask ventilation, CPAP, re-intubation, placement of oropharyngeal airway or unplanned ICU admission for airway compromise. Result(s): 72 children were identified (21 female, median age 2.8 years). There were 29 AE in 26 patients (36%), including 23 (31.9%) who suffered a mild AE and 6 (8.3%) who had a severe AE. Age, sex, the presence of co-morbidity or the presence of severe OSA did not predict severe AE in this group. Median time to first AE was 165. min. Four of the six severe AE occurred in the post-anesthetic care unit (PACU). There were 60 children who did not have an AE in PACU, of whom 59 did not have a severe AE in the post-operative period, giving a negative predictive value for no worse than a mild AE following an uncomplicated course in PACU of 98.3%. Conclusion(s): Our data confirm high rates of AE after AT for high risk patients, however, only 8% suffered a severe AE truly necessitating care in ICU. This outcome was very unlikely if an AE did not occur in PACU. We therefore conclude that routine post-operative ICU care for high risk children may be avoided if prolonged monitoring in the PACU is possible, with admission to ICU reserved for high-risk children with an early AE. © 2014 Elsevier Ireland Ltd.

Recent molecular-typing studies suggest cross-infection as one of the potential acquisition pathways for Pseudomonas aeruginosa in patients with cystic fibrosis (CF). In Australia, there is only limited evidence of unrelated patients sharing indistinguishable P. aeruginosa strains. We therefore examined the point-prevalence, distribution, diversity and clinical impact of P. aeruginosa strains in Australian CF patients nationally. 983 patients attending 18 Australian CF centres provided 2887 sputum P. aeruginosa isolates for genotyping by enterobacterial repetitive intergenic consensus-PCR assays with confirmation by multilocus sequence typing. Demographic and clinical details were recorded for each participant. Overall, 610 (62%) patients harboured at least one of 38 shared genotypes. Most shared strains were in small patient clusters from a limited number of centres. However, the two predominant genotypes, AUST-01 and AUST-02, were widely dispersed, being detected in 220 (22%) and 173 (18%) patients attending 17 and 16 centres, respectively. AUST-01 was associated with significantly greater treatment requirements than unique P. aeruginosa strains. Multiple clusters of shared P. aeruginosa strains are common in Australian CF centres. At least one of the predominant and widespread genotypes is associated with increased healthcare utilisation. Longitudinal studies are now needed to determine the infection control implications of these findings. Copyright ©ERS 2013.

Introduction: In adults with cystic fibrosis (CF) sleep complaints are common and are associated with depressed mood. There is a paucity of international data regarding both sleep quality in children with CF and its impact on mood. We aimed to examine the relationship of sleep quality to mood in a group of children with clinically stable CF. Method(s): Children with stable CF who were free from pulmonary exacerbation and age matched healthy control children (age range 7-18 y) were recruited. Each had 2 weeks of sleep recorded by sleep diary together with questionnaires [OSA-18, Paediatric Daytime Sleepiness Scale (PDSS), Sleep Disturbance Scale for Children (SDSC)]. Questionnaires were also used to assess mood (Children's Depression Inventory, Beck Depression Inventory-Youth). Data were compared between groups with one way ANOVA with Student Newman Kuels posthoc analysis if normally distributed or Kruskal-Wallis one way ANOVA on Ranks with Dunns posthoc analysis if not. Regression analysis was performed in the CF group to examine associations between mood and sleep questionnaires. Result(s): 46 CF (24M/22F) and 39 control (19M/20F) children completed the study, and were well-matched for age (median 11 y for both). The mean (+/- SD) FEV1 in the CF group was 80 +/- 19% predicted. CF and control subjects had similar sleep duration (median 9.2 +/- 1 h during the week and 9.4 +/- 1 h at weekends) and no differences in frequency of night waking. Children with CF had higher total scores than controls for the OSA-18 (median 35 vs 24, p < 0.05), PDSS (mean 14.3 +/- 4.5 vs 10.2 +/- 4.4, p < 0.001) and SDSC (median 45.5 vs 35.0, p < 0.05). Children with CF also exhibited higher mood scores (reflecting lower mood) than controls (median 5 vs 3, p < 0.05). In the CF group, there was no correlation between mood scores and any of the sleep questionnaire total scores or FEV1. Conclusion(s): Children with clinically stable CF have lower mood and significantly more sleep problems than

Background Newborn screening allows novel treatments for cystic fibrosis (CF) to be trialled in early childhood before irreversible lung injury occurs. As respiratory exacerbations are a potential trial outcome variable, we determined their rate, duration and clinical features in preschool children with CF; and whether they were associated with growth, lung structure and function at age 5 years. Methods Respiratory exacerbations were recorded prospectively in Australasian CF Bronchoalveolar Lavage trial subjects from enrolment after newborn screening to age 5 years, when all participants underwent clinical assessment, chest CT scans and spirometry. Results 168 children (88 boys) experienced 2080 exacerbations, at an average rate of 3.66 exacerbations per person-year; 80.1% were community managed and 19.9% required hospital admission. There was an average increase in exacerbation rate of 9% (95% CI 4% to 14%; p<0.001) per year of age. Exacerbation rate differed by site (p<0.001) and was 26% lower (95% CI 12% to 38%) in children receiving 12 months of prophylactic antibiotics. The rate of exacerbations in the first 2 years was associated with reduced forced expiratory volume in 1 s z scores. Ever having a hospitalmanaged exacerbation was associated with bronchiectasis (OR 2.67, 95% CI 1.13 to 6.31) in chest CT scans, and lower weight z scores at 5 years of age (coefficient -0.39, 95% CI -0.74 to -0.05). Conclusions Respiratory exacerbations in young children are markers for progressive CF lung disease and are potential trial outcome measures for novel treatments in this age group.

Introduction: Children with cystic fibrosis (CF) may experience poor sleep quality and nocturnal hypoxemia. We aimed to compare sleep duration, questionnaire measures of sleep disturbance and overnight oxygen saturation (SpO2) in clinically stable children with CF and age matched control children. Method(s): Children with CF and age matched healthy control children (age range 7-18 y) were recruited. All were studied over 2 weeks with sleep recorded by sleep diary together with questionnaires [OSA-18, Paediatric Daytime Sleepiness Scale (PDSS), Sleep Disturbance Scale for Children (SDSC)]. Overnight SpO2 was measured for one night using pulse oximetry (Masimo Rad-7 set at 2 sec averaging). Data were compared between groups with one way ANOVA with Student Newman Kuels posthoc analysis if normally distributed or Kruskal-Wallis one way ANOVA on Ranks with Dunns posthoc analysis if not. Regression analysis was performed in the CF group to examine associations between oximetry and sleep questionnaires. Result(s): 46 CF (24M/22F) and 39 control (19M/20F) children completed the study, and were well-matched for age (median 11 y for both). The mean ( +/- SD) FEV1 in the CF group was 80 +/- 19% predicted. CF and control subjects had similar sleep duration (median 9.2 +/- 1 h during the week and 9.4 +/- 1 h at weekends) and no differences in duration of night wakings. Children with CF had significantly lower mean SpO2 than controls (96.9 +/- 1.7% vs 98.4 +/- 0.8%, p < 0.001), and the SpO2 nadir was also lower (89.2 +/- 4.8% vs 91.9 +/- 2.5%, p < 0.05). In addition, children with CF had higher total scores than controls on the OSA-18 (median 35 vs 24, p < 0.05), the PDSS (mean 14.3 +/- 4.5 vs 10.2 +/- 4.4, p < 0.001) and the SDSC (median 45.5 vs 35.0, p < 0.05), with higher values for all SDSC subscales with the exception of arousal. In the CF group, there was no correlation between mean or nadir SpO2 or FEV1 and total scores of the OSA-18, PDSS or SDSC. Conclusion(s): Children

Background: Newborn screening allows novel treatments for cystic fibrosis (CF) to be trialled in early childhood before irreversible lung injury occurs. As respiratory exacerbations are a potential trial outcome variable, we determined their rate, duration and clinical features in preschool children with CF; and whether they were associated with growth, lung structure and function at age 5 years. Method(s): Respiratory exacerbations were recorded prospectively in Australasian CF Bronchoalveolar Lavage trial subjects from enrolment after newborn screening to age 5 years, when all participants underwent clinical assessment, chest CT scans and spirometry. Result(s): 168 children (88 boys) experienced 2080 exacerbations, at an average rate of 3.66 exacerbations per person-year; 80.1% were community managed and 19.9% required hospital admission. There was an average increase in exacerbation rate of 9% (95% CI 4% to 14%; p<0.001) per year of age. Exacerbation rate differed by site (p<0.001) and was 26% lower (95% CI 12% to 38%) in children receiving 12 months of prophylactic antibiotics. The rate of exacerbations in the first 2 years was associated with reduced forced expiratory volume in 1 s z scores. Ever having a hospital-managed exacerbation was associated with bronchiectasis (OR 2.67, 95% CI 1.13 to 6.31) in chest CT scans, and lower weight z scores at 5 years of age (coefficient -0.39, 95% CI -0.74 to -0.05). Conclusion(s): Respiratory exacerbations in young children are markers for progressive CF lung disease and are potential trial outcome measures for novel treatments in this age group. Copyright Article author (or their employer) 2013.

Objective: To compare three cystic fibrosis (CF) newborn screening strategies used in Victoria since 1989. Design, setting and participants: Retrospective review of newborn screening and clinical records for people with CF born in Victoria between 1989 and 2008 to compare screening strategies: repeat immunoreactive trypsinogen (IRT) testing (IRT/IRT, 1989-1990), IRT and p.F508del mutation analysis (IRT/ p.F508del, 1991-2006) and IRT with analysis of 12 CFTR mutations (IRT/12 mutations, 2007-2008). Main Outcome Measure(s): Total number of infants screened, people identified with CF (by screening or clinical diagnosis), number of CF-affected terminations of pregnancy, and number of carriers detected. Result(s): There were 420 people born with CF (live-birth prevalence, 1/3139; 95% CI, 1/2853-1/3462) and 78 CF-affected pregnancy terminations (overall prevalence, 1/2647; 95% CI, 1/2425-1/2896). Of the babies born with CF, 283 (67.4%) were detected by newborn screening alone, 61 (14.5%) had meconium ileus, 33 (7.9%) had a family history of CF, nine (2.1%) were diagnosed antenatally, and 34 (8.1%) were missed by screening (17 missed because IRT level was < 99th percentile, two with repeat IRT level not elevated, 14 without a screened CFTR mutation, and one with missing data). The sensitivities of the protocols were 86.6% for IRT/IRT, 89.9% for IRT/p.F508del, and 95.8% for IRT/ 12 mutations. Including 12 mutations in the analysis detected one patient who would otherwise have been missed and, had this protocol been implemented from 1989, it would have detected four others. Conclusion(s): Most babies with CF without meconium ileus, a family history or antenatal diagnosis are detected by newborn screening. Despite improved sensitivity with the 12-mutation analysis, most infants detected would have been diagnosed using the IRT/p.F508del protocol.

Objectives: Vitamin A and E deficiency is common in cystic fibrosis (CF). These vitamins have immunomodulating properties and we determined whether decreased serum vitamin A and E levels in young infants are associated with early CF lung disease and lower airway inflammation. Method(s): A post-hoc analysis was undertaken on previous data collected prospectively in 39 newly diagnosed infants identified by a newborn CF screening programme. Assessment of CF genotype, nutrition, pancreatic status, serum retinol and alpha-tocopherol levels was performed at diagnosis. Pulmonary status was determined clinically, by Brasfield chest radiographic scores and analysis of bacterial counts and inflammatory indices in bronchial lavage (BL) fluid. These assessments were repeated 12 months later. Result(s): At diagnosis, 20 out of 39 (51%) CF infants had low serum retinol (mean (SD) 0.7 (0.3) mumol/L) and 9/38 (24%) had low alpha-tocopherol (mean (SD) 13.4 (8.4) mumol/L) levels. Dietary energy intake was related to serum retinol concentrations at diagnosis (r2 = 0.27; P = 0.001). At 1 year, serum retinol and alpha-tocopherol levels had normalized following vitamin A and E supplementation. Respiratory symptoms, radiographic scores and BL inflammatory indices systematically deteriorated during infancy, reaching significance for free neutrophil elastase activity (9 out of 29 vs 21 out of 33; P = 0.01) and IL-8 levels (79 vs 416; P = 0.046) in BL fluid. No association was seen between serum vitamin levels at diagnosis and airway inflammatory indices at either diagnosis or 12 months later. Conclusion(s): We found in this CF birth cohort no evidence to implicate vitamin A or E deficiency in the development of lung disease or airway inflammation during infancy.

The detection of a clonal Pseudomonas aeruginosa strain in 21% of children attending a cystic fibrosis clinic during 1999, which may have led to a worse prognosis, prompted strict infection control measures, including cohort segregation. We determined whether these strategies interrupted cross-infection within the clinic. Patients from 1999 were observed and a cross-sectional study of the 2002 clinic was performed. By 2002, the epidemic strain prevalence had decreased from 21 to 14% (p = 0.03), whereas the proportion of patients with nonepidemic P. aeruginosa strains was unchanged. The age- and sex-adjusted relative risk for epidemic strains among sputum producers in 2002 compared with 1999 was 0.64 (95% confidence interval, 0.47, 0.87; p = 0.004). Increased mortality or transfer to another clinic did not explain this reduction. Although children with epidemic strains may have had increased mortality (adjusted odds ratio, 2.0; 95% confidence interval, 0.6-6.8), they did not demonstrate greater morbidity than those with other P. aeruginosa isolates. Successful Infection control measures provided additional indirect evidence for person-to-person transmission of an epidemic strain within the clinic. Further studies are needed to resolve whether cohort segregation completely eliminates cross-infection and if acquisition of epidemic isolates is associated with worse outcomes.

Controversy exists over whether the lower airway inflammation that characterizes cystic fibrosis (CF) is initiated primarily by the genetic defect. To determine if inflammation precedes infection, we examined bronchoalveolar lavage (BAL) fluid cytology, cytokines (interleukin (IL)-1beta, IL-4, IL-5, IL-6, IL-8, IL-10, and tumor necrosis factor-alpha), and free neutrophil elastase activity from 70 CF (aged 1.5-71 months) children detected by newborn screening and 19 (aged 2.0-48 months) controls with chronic stridor. CF subjects were selected and categorized as pristine (13 aged <=6 months, lacking prior respiratory symptoms and exposure to antibiotics, and without respiratory pathogens on BAL), infected (42 with viruses or >=105 colony-forming units/ml of pathogenic bacteria in BAL), and uninfected (15 aged >=6 months, asymptomatic, not taking antibiotics at bronchoscopy, and free of pathogens in their BAL). To further resolve if inflammation develops without infection, inflammatory mediators in paired annual BAL samples from 38 CF subjects were measured, and results were grouped according to whether BAL showed persistence (n = 6), acquisition (n = 8), clearance (n = 13), or absence (n = 11) of infection. While pristine, uninfected, and control subjects had similar BAL profiles, infected patients showed elevated inflammatory indices, including increased IL-10 (P < 0.001). Pristine subjects had the fewest signs of inflammation. Analysis of BAL pairs found differences between the four infection groups for changes in neutrophil percentages, IL-8 (P < 0.001), and free neutrophil elastase (P = 0.009). Infection was associated with elevated inflammatory mediators in BAL fluid. In contrast, minimal or reduced signs of inflammation accompanied absence of eradication of infection from BAL fluid. We conclude that in CF, infection initiates and sustains airway inflammation. © 2005 Wiley-Liss, Inc.