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Background: Most clinical trials with time-to-event primary outcomes are designed assuming constant event rates and proportional hazards over time. Non-constant event rates and non-proportional hazards are seen increasingly frequently in trials. The objectives of this review were firstly to identify whether non-constant event rates and time-dependent treatment effects were allowed for in sample size calculations of trials, and secondly to assess the methods used for the analysis and reporting of time-to-event outcomes including how researchers accounted for non-proportional treatment effects.Methods: We reviewed all original reports published between January and June 2017 in four high impact medical journals for trials for which the primary outcome involved time-to-event analysis. We recorded the methods used to analyse and present the main outcomes of the trial and assessed the reporting of assumptions underlying these methods. The sample size calculation was reviewed to see if the effect of either non-constant hazard rates or anticipated non-proportionality of the treatment effect was allowed for during the trial design.Results: From 446 original reports we identified 66 trials with a time-to-event primary outcome encompassing trial start dates from July 1995 to November 2014. The majority of these trials (73%) had sample size calculations that used standard formulae with a minority of trials (11%) using simulation for anticipated changing event rates and/or non-proportional hazards. Well-established analytical methods, Kaplan-Meier curves (98%), the log rank test (88%) and the Cox proportional hazards model (97%), were used almost exclusively for the main outcome. Parametric regression models were considered in 11% of the reports. Of the trials reporting inference from the Cox model, only 11% reported any results of testing the assumption of proportional hazards.Conclusions: Our review confirmed that when designing trials with time-to-event primary outcomes, methodologies assuming constant event rates and proportional hazards were predominantly used despite potential efficiencies in sample size needed or power achieved using alternative methods. The Cox proportional hazards model was used almost exclusively to present inferential results, yet testing and reporting of the pivotal assumption underpinning this estimation method was lacking. [ABSTRACT FROM AUTHOR]

Background: There are no medications known that improve the outcome of infants with bronchiolitis. Studies have shown the management of bronchiolitis to be varied. Objectives: To describe medication use at the seven study hospitals from a recent multi-centre randomised controlled trial on hydration in bronchiolitis (comparative rehydration in bronchiolitis [CRIB]). Methods: A retrospective analysis of extant data of infants between 2 months (corrected for prematurity) and 12 months of age admitted with bronchiolitis identified through the CRIB trial. CRIB study records, medical records, pathology and radiology databases were used to collect data using a standardised form and entered in a single site database. Medications investigated included salbutamol, adrenaline, steroids, ipratropium bromide, normal saline, hypertonic saline, steroids and antibiotics. Results: There were 3456 infants available for analysis, of which 42.0% received at least one medication during hospitalisation. Medication use varied by site between 27.0 and 48.7%. The most frequently used medication was salbutamol (25.5%). Medication use in general, and salbutamol use in particular, increased by 8.2 and 9.3%, respectively, per month after 4 months of age; from 22.9 and 3.6% at 4 months to 81.4 and 68.8% at 11 months. In infants admitted to the intensive care unit (ICU) compared with those not admitted to ICU 81.6 and 39.5%, respectively, received medication at one point during the hospital stay. Conclusions: Medication was used for infants with bronchiolitis frequently and variably in Australia and New Zealand. Medication use increased with age. Better strategies for translating evidence into practice are needed. [ABSTRACT FROM AUTHOR]

Objectives To describe the rate of intensive care unit (ICU) admission, type of ventilation support provided and risk factors for ICU admission in infants with bronchiolitis. Design Retrospective review of hospital records and Australia and New Zealand Paediatric Intensive Care (ANZPIC) registry data for infants 2-12 months old admitted with bronchiolitis. Setting Seven Australian and New Zealand hospitals. These infants were prospectively identified through the comparative rehydration in bronchiolitis (CRIB) study between 2009 and 2011. Results Of 3884 infants identified, 3589 charts were available for analysis. Of 204 (5.7%) infants with bronchiolitis admitted to ICU, 162 (79.4%) received ventilation support. Of those 133 (82.1%) received non-invasive ventilation (high flow nasal cannula [HFNC] or continuous positive airway pressure [CPAP]) 7 (4.3%) received invasive ventilation alone and 21 (13.6%) received a combination of ventilation modes. Infants with comorbidities such as chronic lung disease (OR 1.6 [95% CI 1.0-2.6]), congenital heart disease (OR 2.3 [1.5-3.5]), neurological disease (OR 2.2 [1.2-4.1]) or prematurity (OR 1.5 [1.0-2.1]), and infants 2-6 months of age (OR 1.5 [1.1-2.0]) were more likely to be admitted to ICU. Respiratory syncitial virus positivity did not increase the likelihood of being admitted to ICU (OR 1.1 [95% CI 0.8-1.4]). HFNC use changed from 13/53 (24.5% [95% CI 13.7-38.3]) patient episodes in 2009 to 39/91 (42.9% [95% CI 32.5-53.7]) patient episodes in 2011. Conclusion Admission to ICU is an uncommon occurrence in infants admitted with bronchiolitis, but more common in infants with comorbidities and prematurity. The majority are managed with non-invasive ventilation, with increasing use of HFNC. [ABSTRACT FROM AUTHOR]

Objective Bronchiolitis is the most common lower respiratory tract infection in infants and the leading cause of hospitalisation. We aimed to assess whether intravenous hydration ( IVH) was more cost-effective than nasogastric hydration ( NGH) as a planned secondary economic analysis of a randomised trial involving 759 infants (aged 2-12 months) admitted to hospital with a clinical diagnosis of bronchiolitis and requiring non-oral hydration. No Australian cost data exist to aid clinicians in decision-making around interventions in bronchiolitis. Methods Cost data collections included hospital and intervention-specific costs. The economic analysis was reduced to a cost-minimisation study, focusing on intervention-specific costs of IVH versus NGH, as length of stay was equal between groups. All analyses are reported as intention to treat. Results Intervention costs were greater for IVH than NGH ($113 vs $74; cost difference of $39 per child). The intervention-specific cost advantage to NGH was robust to inter-site variation in unit prices and treatment activity. Conclusion Intervention-specific costs account for <10% of total costs of bronchiolitis admissions, with NGH having a small cost saving across all sites. [ABSTRACT FROM AUTHOR]

The modern environment is associated with an increasing burden of non-communicable diseases (NCDs). Mounting evidence implicates environmental exposures, experienced early in life (including in utero), in the aetiology of many NCDs, though the cellular/molecular mechanism(s) underlying this elevated risk across the life course remain unclear. Epigenetic variation has emerged as a candidate mediator of such effects. The Barwon Infant Study (BIS) is a population-derived birth cohort study (n = 1074 infants) with antenatal recruitment, conducted in the south-east of Australia (Victoria). BIS has been designed to facilitate a detailed mechanistic investigation of development within an epidemiological framework. The broad objectives are to investigate the role of specific environmental factors, gut microbiota and epigenetic variation in early-life development, and subsequent immune, allergic, cardiovascular, respiratory and neurodevelopmental outcomes. Participants have been reviewed at birth and at 1, 6, 9 and 12 months, with 2- and 4-year reviews under way. Biological samples and measures include: maternal blood, faeces and urine during pregnancy; infant urine, faeces and blood at regular intervals during the first 4 years; lung function at 1 month and 4 years; cardiovascular assessment at 1 month and 4 years; skin-prick allergy testing and food challenge at 1 year; and neurodevelopmental assessment at 9 months, 2 and 4 years. Data access enquiries can be made at [www.barwoninfantstudy.org.au] or via [peter.vuillermin@deakin.edu.au]. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to describe antibiotic exposure in Australian infants during the first year of life, focusing on antibiotic class, indication, risk factors associated with exposure and comparison with international counterparts.Methods: The Barwon Infant Study is a birth cohort study (n = 1074) with an unselected antenatal sampling frame from a large regional centre in Victoria, Australia. Longitudinal data on infection and medication were collected at 1, 3, 6, 9 and 12 months by parental questionnaire and from general practitioner and hospital records. Predictors of questionnaire non-completion were identified. A total of 660 infants with complete serial data were comprehensively examined. Antibiotic exposure was calculated as (i) antibiotic prescriptions and (ii) antibiotic days-exposed per person-year.Results: Mean antibiotic prescription rate was 0.92 prescriptions (95% confidence interval (CI), 0.83-1.02) per person-year, with the highest rates in those aged <1 month (1.50 (95% CI, 1.09-1.91) per person-year). A total of 50.0% of infants were exposed to at least one antibiotic in their first year of life. Increasing number of siblings was associated with increased antibiotic exposure. Penicillin with extended spectrum (365 of 661 antibiotic prescriptions, 52.6%) and cephalosporins (12.0%) were the most frequently prescribed antibiotics. One fifth of antibiotics were prescribed for respiratory tract infections and bronchiolitis.Conclusion: Australian infants in this large population-based study are exposed to considerably more antibiotics than the majority of their international counterparts. Interventions aimed at addressing avoidable prescribing by medical practitioners and modifiable risk factors associated with antibiotic exposure may reduce antibiotic use. [ABSTRACT FROM AUTHOR]