Sarath C. Ranganathan

Background: We aimed to quantify associations of cardiovascular (CV) large and small artery measures with body composition and body mass (1) separately and (2) in combination in 11- to 12-year-old children and their parents. Methods: In the population-based cross-sectional Child Health CheckPoint study (1495 children, mean 12 ± 0.4 years, 49.3% girls; 1496 parents, mean 44.3 ± 5.0 years, 86.7% mothers), we measured weight, height, body composition [truncal fat, non-truncal fat, fat-free mass (FFM)], and CV functional (blood pressure, pulse wave velocity, arterial elasticity) and structural (carotid intima-media thickness, retinal arteriolar/venular caliber) outcomes. Using compositional data analyses, we examined associations of body composition (expressed as log ratios) and body mass (multiplicative total) with CV measures in separate and combined models. Results: Mean BMI z-score was 0.3 in children [standard deviation (SD) 1.0, 4.5% obese], and mean BMI was 27.9 in parents (SD 6.1, 28.8% obese). In both children and adults, more adverse CV measurements were associated with higher %truncal fat, %non-truncal fat, and body mass and lower %FFM. Compared with normal-weight children, children with obesity had poorer CV measures (e.g., 1 SD faster pulse wave velocity, 0.5 SD lower arterial elasticity), with higher body mass and lower %FFM mainly accounting for these relationships. All relationships were similar, albeit larger, for parents. Conclusion: Poorer CV health in both generations was associated with higher body mass, lower %FFM, and, to a lesser extent, higher %truncal and non-truncal fat. Trials could test whether weight reduction interventions with vs. without FFM preservation differentially improve CV functional and structural precursors.

Tobramycin is commonly used for the treatment of pulmonary exacerbations in children with cystic fibrosis (CF). Currently, a standard dose of 10 mg/kg daily is used in all children. We aim to develop a population pharmacokinetic (popPK) model of tobramycin in children with CF and determine the: (i) effect of cystic fibrosis transmembrane conductance regulator (CFTR) modulators on tobramycin pharmacokinetics (PK); (ii) attainment of the commonly used serum steady state area under the concentration-time curve target (AUC24,ss) of 80-110 mg/L⋅h with standard dosing; and (iii) generate an optimized fully individualized dosing strategy to improve target attainment. Multicenter prospective observational study of children with CF aged 0-19 years receiving IV tobramycin who had ≥1 serum concentration measured. A popPK model was developed using nonlinear mixed-effect modeling, and simulations were performed to assess study aims. Overall, 63 children had 450 serum tobramycin concentrations. A one-compartment popPK model, including age, weight, a renal maturation model, and estimated glomerular filtration rate as covariates, was developed. With standard dosing, 1/3 of children achieved the target AUC24,ss with younger children (<2 years) having the lowest probability of target attainment (PTA) (15%). The optimized dosing regimen improved target attainment in all children, increasing the PTA in children <2 years to 62%. CFTR modulator drugs did not affect tobramycin PK. Standard tobramycin dosing in children with CF achieves poor attainment of target serum AUC24,ss, particularly in children <2 years. A fully individualized approach (available at https://www.kidscalc.org/) improved target attainment in all children. CFTR modulators had a negligible effect on tobramycin PK.

Rationale: The effect of moderate to late preterm (MLP) birth (32-36 completed weeks' gestation) on childhood respiratory health is unclear. Objectives: To assess the effect of being born MLP, compared with being born at term (≥37 completed weeks' gestation), on lung function and respiratory morbidity at 9-10 years of age. Methods: A prospective cohort study was conducted among children born MLP or at term at the Royal Women's Hospital (Victoria, Australia). Participants completed pre and postbronchodilator spirometry, measurement of diffusing capacity of the lung for carbon monoxide, plethysmography, and multiple-breath washout at 9-10 years of age. Parents completed the ISAAC (International Study of Asthma and Allergies in Childhood) questionnaire. Mean differences in z-scores of lung function outcomes and risk ratio for ISAAC outcomes between those born MLP and those born at term were estimated using regression models with adjustment for potential confounding. Multiple imputation was used to handle missing data. Results: A total of 148 of 201 children born MLP and 120 of 201 term-born control subjects were assessed at 9-10 years. Compared with control subjects, children born MLP had lower mean z-scores for forced expiratory volume in 1 second (mean difference, -0.35 [95% confidence interval (CI), -0.61 to -0.08]), ratio of forced expiratory volume in 1 second to forced vital capacity (mean difference, -0.29 [95% CI, -0.58 to -0.01]), forced expiratory flow at 25-75% of forced vital capacity (-0.33 [95% CI, -0.62 to -0.04]), and diffusing capacity of the lung for carbon monoxide (-0.24 [95% CI, -0.45 to -0.03]). Participants born MLP had higher risk of experiencing asthma symptoms (risk ratio, 1.52 [95% CI, 1.08-2.14]). Conclusions: Children born MLP have lower lung function and increased risk of exhibiting asthma symptoms compared with term-born peers at 9-10 years. Such findings at the end of the first decade of life may portend adverse consequences for respiratory health in adulthood.

Background: Chronic pulmonary infection with pathogens such as Pseudomonas aeruginosa is associated with lung function decline and increased mortality in people with cystic fibrosis (CF). The relationship between sputum bacterial load and the severity of pulmonary exacerbations remains unclear. This study aimed to explore the relationship between sputum bacterial load and clinical response to antibiotic treatment of pulmonary exacerbations in children with CF. Methods: Multicentre prospective longitudinal study of children with CF receiving IV tobramycin for a pulmonary exacerbation who had prior isolation of Gram-negative bacteria and able to expectorate sputum. Lung function (FEV1) and sputum bacterial load were assessed. Bacterial load was performed using quantitative PCR on either intact (live) bacterial cells or all bacterial DNA (live + dead) and targeted either P. aeruginosa only or all bacteria. Results: Twelve children (14 admissions) were enrolled and each provided ≥2 sputum samples; 11 children (13 admissions) also had ≥2 FEV1 measurements. In 10 admissions where FEV1 improved, five showed a reduction in all live bacteria, with a median reduction by 8.65 × 106 copies/g (73 % reduction). Live P. aeruginosa was detected in 8/10 children and in seven, a median reduction of 2.99 × 107 copies/g (90 % reduction) was observed. Improved FEV1 correlated with greater reductions in live + dead P. aeruginosa (ρ = -0.63, p = 0.04). Conclusions: A greater reduction in total sputum P. aeruginosa bacterial load (live + dead) was associated with improved lung function (FEV1) in children with CF receiving tobramycin.

Objective: To examine the prospective associations between infant sleep patterns and subsequent autism characteristics and diagnosis in a population-derived sample. Methods: Population-derived birth cohort study in Victoria, Australia's Barwon region, with 1074 mother-infant pairs recruited from June 2010 to 2013. Methods: Infant sleep characteristics via the Brief Infant Sleep Questionnaire at 6 months (n=925) and 12 months (n=885). Parent-reported autism characteristics measured using the Child Behaviour Checklist for Ages 1½-5 (CBCL/1½-5; n=676) at 2 years and Strengths and Difficulties Questionnaire for report for ages 4-10 (SDQ/P4-10; n=791) at 4 years. Autism Diagnostic and Statistical Manual for Mental Disorders fifth edition (DSM-5) diagnoses (n=64) were confirmed by 11.5 years. Results: At 6 months, each 10% increase (~1 hour) in night sleep duration was associated with fewer autism characteristics at 2 years (4.5% decrease, CBCL/1½-5) and 4 years (4.5% decrease, SDQ/P4-10) and 22% lower autism DSM-5 diagnosis odds by 11.5 years (adjusted mean difference (AMD): -0.02, 95% CI: -0.04 to -0.01; AMD: -0.02, 95% CI: -0.03 to -0.007; adjusted OR (AOR): 0.78, 95% CI: 0.65 to 0.94). At 12 months, each 25% increase in sleep latency (~5 min) was associated with more autism characteristics (1.5% increase, CBCL/1½-5, AMD: 0.006, 95% CI: 0.002 to 0.01) and 7.7% higher autism diagnosis odds (AOR: 1.08, 95% CI: 1.03 to 1.13). Among diagnosed school-aged children, 42% used melatonin in the past month. Conclusions: Poor infant sleep quality was linked to increased autism characteristics and diagnosis odds in a population-derived Australian sample. The extent to which this reflects common determinants of poor sleep and autism is not known. These findings suggest early monitoring of sleep issues as a potential autism indicator.