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OBJECTIVE: Research is needed to determine best practice for genomic testing in the context of child interstitial or diffuse lung disease (chILD). We explored parent's and child's health-related quality of life (HRQoL), parents' perceived understanding of a genomic testing study, satisfaction with information and the study and decisional regret to undertake genomic testing. METHODS: Parents of children with diagnosed or suspected chILD who were enrolled in a genomic sequencing study were invited to complete questionnaires pretesting (T1) and after receiving the result (T2). RESULTS: Parents' (T1, n=19; T2, n=17) HRQoL was lower than population norms. Study satisfaction (T1) and perceived understanding (T2) were positively correlated (rs=0.68, p=0.014). Satisfaction with information (T1 and T2) and decisional regret (T2) were negatively correlated (T1 rs=-0.71, p=0.01; T2 rs=-0.56, p=0.03). Parents reported wanting more frequent communication with staff throughout the genomic sequencing study, and greater information about the confidentiality of test results. CONCLUSIONS: Understanding of genomic testing, satisfaction with information and participation and decisional regret are inter-related. Pretest consultations are important and can allow researchers to explain confidentiality of data and the variable turnaround times for receiving a test result. Staff can also update parents when there will be delays to receiving a result.

BACKGROUND: Children's interstitial and diffuse lung disease (chILD) is a complex heterogeneous group of lung disorders. Gene panel approaches have a reported diagnostic yield of ~ 12%. No data currently exist using trio exome sequencing as the standard diagnostic modality. We assessed the diagnostic utility of using trio exome sequencing in chILD. We prospectively enrolled children meeting specified clinical criteria between 2016 and 2020 from 16 Australian hospitals. Exome sequencing was performed with analysis of an initial gene panel followed by trio exome analysis. A subset of critically ill infants underwent ultra-rapid trio exome sequencing as first-line test. RESULTS: 36 patients [median (range) age 0.34 years (0.02-11.46); 11F] were recruited from multiple States and Territories. Five patients had clinically significant likely pathogenic/pathogenic variants (RARB, RPL15, CTCF, RFXANK, TBX4) and one patient had a variant of uncertain significance (VIP) suspected to contribute to their clinical phenotype, with VIP being a novel gene candidate. CONCLUSIONS: Trio exomes (6/36; 16.7%) had a better diagnostic rate than gene panel (1/36; 2.8%), due to the ability to consider a broader range of underlying conditions. However, the aetiology of chILD in most cases remained undetermined, likely reflecting the interplay between low penetrant genetic and environmental factors.

Background: Respiratory viruses are a common cause of infection in immunosuppressed children undergoing cancer therapy. Pulmonary sequelae have been documented following respiratory viral infections (RVIs) in hematopoietic stem cell transplant (HSCT) recipients; however potential late effects in children undergoing nonmyeloablative chemotherapy have not been investigated. Aim: To evaluate the long-term pulmonary morbidity of respiratory viral infections during chemotherapy in children with acute lymphoblastic leukemia (ALL). Methods: Childhood ALL survivors, aged 7 to 18 years, greater than 6 months posttreatment were recruited. Exclusion criteria included HSCT or proven bacterial/fungal respiratory infection during treatment. Subjects were classified into “viral” or “control” groups according to retrospective medical records that documented the presence of laboratory-proven RVIs during chemotherapy. Symptom questionnaires (Liverpool, ISAAC) and lung function testing (spirometry, plethysmography, diffusing capacity, forced oscillation technique to ATS/ERS standards) were then performed cross-sectionally at the time of recruitment. Results: Fifty-four patients (31 viral, 23 control) were recruited: median (range) age 11.2 (7.2-18.1) years, and at 4.9 (0.5-13) years posttherapy. Abnormalities were detected in 17 (31%) individuals (8 viral, 9 control), with the most common being DLCO impairment (3 viral, 4 control) and reduced respiratory reactance at 5 Hz (5 viral, 6 control). Children with RVIs during chemotherapy reported more current respiratory symptoms, particularly wheeze (odds ratio [OR], 3.0; 95% confidence interval [CI]: 0.9-10.0; P =.09) and cough (OR, 2.7; 95% CI: 0.8-9.5; P =.11). No differences in lung function tests were observed between the two groups. Conclusions: Our study found children with RVIs during chemotherapy developed more long-term respiratory symptoms than controls; however, differences did not reach statistical significance. No differences

Background: The inter-jurisdictional National Mutual Acceptance (NMA) scheme for Human Research Ethics Committee (HREC) approvals of human research is designed to reduce the reported delays and costs of ethical review. Introduction of the NMA set forth an uncoupling of the ethics and governance review processes, permitting a single ethical review for multiple sites, while continuing separate governance review for each centre covering financial and operational aspects of the research project. Aim(s): To compare the time required to gain ethics and governance approvals in Australia for a non-interventional investigator-led study from December 2015 to approval times for an earlier pre-NMA study utilising a similar study design and study sites and evaluate the effect that the NMA has had on total approval time for non-interventional multi-centre projects. Method(s): We recorded the time taken to obtain ethics and governance approval at 16 sites for our nationwide low-risk non-interventional study looking at the prevalence and aetiology of non-tuberculous mycobacterial infection in people with cystic fibrosis in Australia. Result(s): Applications were submitted to three hospitals and one university HREC to conduct our study at 16 hospital sites, HREC approval took from 16 to 79 days (median 28). Subsequent site-specific governance approval at 15 hospital sites took 23-225 days (median 83). The entire process of gaining ethical and governance approval to conduct the study at 16 sites took 24 months at an estimated cost of AU$56000 (US$ 42 000). Conclusion(s): Lengthy governance approval processes negate benefits gained from centralised ethics review under the NMA.Copyright © 2018 Royal Australasian College of Physicians

BACKGROUND: Inflammation is implicated in the pathogenesis of diabetes and its complications in adults. Little is known about the relative contribution of inflammation in common types of diabetes in youth: type 1 diabetes (T1D), type 2 diabetes (T2D), and cystic fibrosis-related diabetes (CFRD). This study investigates inflammatory markers by diabetes type and complication status, and assesses indicators of inflammation and complications. METHODS: A cross-sectional study of 134 T1D, 32 T2D, 32 CFRD and 48 subjects without diabetes (including 11 with CF and normal glucose tolerance) was undertaken. Inflammation was assessed by sE-selectin by ELISA, hsCRP by turbidimetry, WCC and ESR. Nephropathy was defined by albuminuria, autonomic neuropathy by heart rate variability, and peripheral neuropathy by vibration and thermal threshold testing and retinopathy by seven-field stereoscopic fundus photography. Descriptive statistics, parametric and non-parametric ANOVA and regression analyses were performed, with significance at P < .05. RESULTS: Of 198 diabetic participants; 49% female, mean (SD) age, median diabetes duration and median HbA1c were 16 (2.5) and 6 (3-9) years, and 8.1 (6.9-9.3)%, respectively. All inflammatory markers were lower in T1D than in other diabetes groups (P < .05) but higher than in non-diabetic controls. T2D (n = 32) and CFRD (n = 32) subjects had comparable elevated levels of inflammation. Body mass index (BMI) was a strong independent explanatory variable of inflammation. In multivariate analysis, hsCRP and ESR were associated with complications in addition to HbA1c, BMI, and diastolic BP. CONCLUSIONS: Circulating inflammatory markers are elevated in adolescents with diabetes, being higher and comparable in T2D and CFRD than in T1D. Inflammation is independently associated with diabetes complications, consistent with inflammation driving vascular pathology in diabetes.

BACKGROUND: The inter-jurisdictional National Mutual Acceptance (NMA) scheme for Human Research Ethics Committee (HREC) approvals of human research is designed to reduce the reported delays and costs of ethical review. Introduction of the NMA set forth an uncoupling of the ethics and governance review processes, permitting a single ethical review for multiple sites, while continuing separate governance review for each centre covering financial and operational aspects of the research project. AIM: To compare the time required to gain ethics and governance approvals in Australia for a non-interventional investigator-led study from December 2015 to approval times for an earlier pre-NMA study utilising a similar study design and study sites and evaluate the effect that the NMA has had on total approval time for non-interventional multi-centre projects. METHODS: We recorded the time taken to obtain ethics and governance approval at 16 sites for our nationwide low-risk non-interventional study looking at the prevalence and aetiology of non-tuberculous mycobacterial infection in people with cystic fibrosis in Australia. RESULTS: Applications were submitted to three hospitals and one university HREC to conduct our study at 16 hospital sites, HREC approval took from 16 to 79 days (median 28). Subsequent site-specific governance approval at 15 hospital sites took 23-225 days (median 83). The entire process of gaining ethical and governance approval to conduct the study at 16 sites took 24 months at an estimated cost of AU$56000 (US$ 42 000). CONCLUSION: Lengthy governance approval processes negate benefits gained from centralised ethics review under the NMA.

Anxiety disorders are highly prevalent in children with asthma yet very little is known about the parenting factors that may underlie this relationship. The aim of the current study was to examine observed parenting behaviours – involvement and negativity - associated with asthma and anxiety in children using the tangram task and the Five Minute Speech Sample (FMSS). Eighty-nine parent-child dyads were included across four groups of children (8–13 years old): asthma and anxiety, anxiety only, asthma only and healthy controls. Overall, results from both tasks showed that parenting behaviours of children with and without asthma did not differ significantly. Results from a subcomponent of the FMSS indicated that parents of children with asthma were more overprotective, or self-sacrificing, or non-objective than parents of children without asthma, and this difference was greater in the non-anxious groups. The results suggest that some parenting strategies developed for parents of children with anxiety may be useful for parents of children with asthma and anxiety (e.g. strategies targeting involvement), however, others may not be necessary (e.g. those targeting negativity).

BACKGROUND: Childhood interstitial lung disease (chILD) represents a rare heterogeneous group of respiratory disorders. In the absence of randomized controlled clinical trials, global collaborations have utilized case series with an aim to standardising approaches to diagnosis and management. Australasian data are lacking. The aim of this study was to calculate prevalence and report the experience of chILD in Australasia over a decade. METHODS: Paediatric pulmonologists in Australia and New Zealand involved in the care of patients aged 0-18 years with chILD completed a questionnaire on demographics, clinical features and outcomes, over a 10 year period. These data, together with data from the 2 reference genetics laboratories, were used to calculate prevalence. RESULTS: One hundred fifteen cases were identified equating to a period prevalence (range) of 1.5 (0.8-2.1) cases/million for children aged 0-18years. Clinical data were provided on 106 patients: the <2 year group comprised 66 children, median age (range) 0.50 years (0.01-1.92); the ≥2 year group comprised 40 children, median age 8.2 years (2.0-18.0). Management approach was heterogeneous. Overall, 79% of patients had a good clinical outcome. Mortality rate was 7% in the study population. CONCLUSION: chILD is rare in Australasia. This study demonstrates variation in the investigations and management of chILD cases across Australasia, however the general outcome is favorable. Further international collaboration will help finesse the understanding of these disorders.

BACKGROUND: Patients with a Fontan circulation have reduced exercise capacity and respiratory muscle strength. Inspiratory muscle training (IMT) improves exercise capacity and quality of life in adults with heart failure. We assessed whether 6 weeks of a home-based program of IMT improves inspiratory muscle strength and the ventilatory efficiency of exercise in adolescent patients with a Fontan circulation. METHODS AND RESULTS: Twenty-three adolescent participants (aged 16±2 years) with a Fontan circulation underwent 6 weeks of IMT for 30 minutes daily. Respiratory muscle strength (maximal inspiratory pressure and expiratory pressure), lung function, and exercise capacity (cardiopulmonary exercise testing) were assessed. Fourteen of 23 participants also underwent exercise cardiac magnetic resonance imaging to examine the effects of IMT on cardiac output and systemic and pulmonary blood flow. Six weeks of IMT improved maximal inspiratory pressure by 36±24 cm H2O (61±46%) with no change in maximal expiratory pressure. Ventilatory efficiency of exercise improved after 6 weeks of IMT (from 34.2±7.8 to 32.2±5.6, P=0.04). In those who underwent exercise cardiac magnetic resonance imaging, IMT increased resting cardiac output (from 4.2±1.2 to 4.5±1.0 L/min, P=0.03) and ejection fraction (from 50.1±4.3 to 52.8±6.1%, P=0.03). CONCLUSIONS: Six weeks of IMT is associated with improved inspiratory muscle strength, ventilatory efficiency of exercise, and resting cardiac output in young Fontan patients. IMT may be a simple beneficial addition to the current management of Fontan patients, potentially reducing exercise intolerance and long-term morbidity and mortality.

Background: Rare chronic diseases of childhood are often complex and associated with multiple health issues. Such conditions present significant demands on health services, but the degree of these demands is seldom reported. This study details the utilisation of hospital services and associated costs in a single case of surfactant protein C deficiency, an example of childhood interstitial lung disease. Methods. Hospital records and case notes for a single patient were reviewed. Costs associated with inpatient services were extracted from a paediatric hospital database. Actual costs were compared to cost estimates based on both disease/procedure-related cost averages for inpatient hospital episodes and a recently implemented Australian hospital funding algorithm (activity-based funding). Results: To age 8 years and 10 months the child was a hospital inpatient for 443 days over 32 admissions. A total of 298 days were spent in paediatric intensive care. Investigations included 58 chest x-rays, 9 bronchoscopies, 10 lung function tests and 11 sleep studies. Comprehensive disease management failed to prevent respiratory decline and a lung transplant was required. Costs of inpatient care at three tertiary hospitals totalled $966,531 (Australian dollars). Disease- and procedure-related cost averages underestimated costs of paediatric inpatient services for this patient by 68%. An activity-based funding algorithm that is currently being adopted in Australia estimated the cost of hospital health service provision with more accuracy. Conclusions: Health service usage and inpatient costs for this case of rare chronic childhood respiratory disease were substantial. This case study demonstrates that disease- and procedure-related cost averages are insufficient to estimate costs associated with rare chronic diseases that require complex management. This indicates that the health service use for similar episodes of hospital care is greater for children with rare diseases than other

Introduction: There is a wide range of bacterial causes for childhood empyema worldwide; however the bacterial causes in Australia are unknown. The 7-valent conjugate pneumococcal vaccine (7vPCV) was added to the national immunisation program in Australia in 2005. Aim(s): To determine the causative bacterial pathogens and pneumococcal serotypes of childhood empyema in Australia, and the efficacy of the 7vPCV. Method(s): A research network comprising all 13 major paediatric hospitals in Australia recruited empyema patients over a 2 year period. Blood and pleural fluid underwent standard culture. Additionally all pleural fluid underwent polymerase chain reaction (PCR) to identify Streptococcus pneumoniae (SP) - targeting autolysin (lytA), Haemophilus influenzae (HI), Mycoplasma pneumoniae, Chlamydia pneumoniae, Staphylococcus aureus (SA) and methicillin-resistant SA (MRSA). All SP PCR-positive specimens were tested using multiplex PCR reverse line blot assays to identify individual, or groups of related serotypes. Result(s): 143 children, 81 male, median age 4.9 (range 0.4-15.5) years were recruited. of 124 blood cultures; 27 (21.8%) were positive as follows: SP, n=16 (59.3%); Streptococcus pyogenes, n=2 (7.4%); coagulase-negative staphylococcus n=3 (11.1%); Neisseria meningitidis, n=1 (3.7%); HI, n=1 (3.7%); MRSA, n=1 (3.7%); Streptococcus sanguinis, n=1 (3.7%); Actinomyces naeslundii, n=1 (3.7%). Two bacteria were isolated from one patient: Staphylococcus hominis (3.7%) and SA (3.7%). Forty seven (33.6%) of 140 pleural fluid samples were culture positive: S. pyogenes, n=14 (29.8%); SP, n=10 (21.3%); SA, n=9 (19.1%); MRSA, n=5 (10.6%); Streptococcus milleri, n=3 (6.4%); coagulase-negative staphylococcus, n=2 (4.3%); Pseudomonas aeruginosa, n=1 (2.1%); Mycobacterium tuberculosis, n=1 (2.1%); Staphylococcus cohnii, n=1 (2.1%); Bacillus cereus, n=1 (2.1%).Two or more organisms were isolated from two subjects; one with MRSA and SA and one with Eikenella corrodens (2.1%)