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Background: Investigation of infection risk with subcutaneous versus intravenous trastuzumab and rituximab administration in an individual patient data (IPD) and published data meta-analysis of randomised controlled trials (RCTs). Methods: Databases were searched to September 2021. Primary outcomes were serious and high-grade infection. Relative-risk (RR) and 95% confidence intervals (95%CI) were calculated using random-effects models. Results: IPD meta-analysis (6 RCTs, 2971 participants, 2320 infections) demonstrated higher infection incidence with subcutaneous versus intravenous administration, without reaching statistical significance (serious: 12.2% versus 9.3%, RR 1.28, 95%CI 0.93to1.77, P = 0.13; high-grade: 12.2% versus 9.9%, RR 1.32, 95%CI 0.98to1.77, P = 0.07). With exclusion of an outlying study in post-hoc analysis, increased risks were statistically significant (serious: 13.1% versus 8.4%, RR 1.53, 95%CI 1.14to2.06, P = 0.01; high-grade: 13.2% versus 9.3%, RR 1.56, 95%CI 1.16to2.11, P < 0.01). Published data meta-analysis (8 RCTs, 3745 participants, 648 infections) demonstrated higher incidence of serious (HR 1.31, 95%CI 1.02to1.68, P = 0.04) and high-grade (HR 1.52, 95%CI 1.17to1.98, P < 0.01) infection with subcutaneous versus intravenous administration. Conclusions: Results suggest increased infection risk with subcutaneous versus intravenous administration, although IPD findings are sensitive to exclusion of one trial with inconsistent results and identified risk-of-bias. Ongoing trials may confirm findings. Clinical surveillance should be considered when switching to subcutaneous administration. PROSPERO registration CRD42020221866/CRD42020125376. [ABSTRACT FROM AUTHOR]

Background: For the design and analysis of clinical trials with time-to-event outcomes, the Cox proportional hazards model and the logrank test have been the cornerstone methods for many decades. Increasingly, the key assumption of proportionality-or time-fixed effects-that underpins these methods has been called into question. The availability of novel therapies with new mechanisms of action and clinical trials of longer duration mean that non-proportional hazards are now more frequently encountered.Methods: We compared several regression-based methods to model time-dependent treatment effects. For illustration purposes, we used selected endpoints from a large, community-based clinical trial of low dose daily aspirin in older persons. Relative and absolute estimands were defined, and analyses were conducted in all participants. Additional exploratory analyses were undertaken by selected subgroups of interest using interaction terms in the regression models.Discussion: In the trial with median 4.7 years follow-up, we found evidence for non-proportionality and a time-dependent treatment effect of aspirin on cancer mortality not previously reported in trial findings. We also found some evidence of time-dependence to an aspirin by age interaction for major adverse cardiovascular events. For other endpoints, time-fixed treatment effect estimates were confirmed as appropriate.Conclusions: The consideration of treatment effects using both absolute and relative estimands enhanced clinical insights into potential dynamic treatment effects. We recommend these analytical approaches as an adjunct to primary analyses to fully explore findings from clinical trials. [ABSTRACT FROM AUTHOR]

Background: Non-proportional hazards are common with time-to-event data but the majority of randomised clinical trials (RCTs) are designed and analysed using approaches which assume the treatment effect follows proportional hazards (PH). Recent advances in oncology treatments have identified two forms of non-PH of particular importance - a time lag until treatment becomes effective, and an early effect of treatment that ceases after a period of time. In sample size calculations for treatment effects on time-to-event outcomes where information is based on the number of events rather than the number of participants, there is crucial importance in correct specification of the baseline hazard rate amongst other considerations. Under PH, the shape of the baseline hazard has no effect on the resultant power and magnitude of treatment effects using standard analytical approaches. However, in a non-PH context the appropriateness of analytical approaches can depend on the shape of the underlying hazard.Methods: A simulation study was undertaken to assess the impact of clinically plausible non-constant baseline hazard rates on the power, magnitude and coverage of commonly utilized regression-based measures of treatment effect and tests of survival curve difference for these two forms of non-PH used in RCTs with time-to-event outcomes.Results: In the presence of even mild departures from PH, the power, average treatment effect size and coverage were adversely affected. Depending on the nature of the non-proportionality, non-constant event rates could further exacerbate or somewhat ameliorate the losses in power, treatment effect magnitude and coverage observed. No single summary measure of treatment effect was able to adequately describe the full extent of a potentially time-limited treatment benefit whilst maintaining power at nominal levels.Conclusions: Our results show the increased importance of considering plausible potentially non-constant event rates when non-proportionality of treatment effects could be anticipated. In planning clinical trials with the potential for non-PH, even modest departures from an assumed constant baseline hazard could appreciably impact the power to detect treatment effects depending on the nature of the non-PH. Comprehensive analysis plans may be required to accommodate the description of time-dependent treatment effects. [ABSTRACT FROM AUTHOR]

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]

Aim This study aimed to evaluate the effect of complementary and alternative medicine ( CAM) approaches on long-term surgical requirements, and clinical and radiographic outcomes for children with cerebral palsy and hip displacement. Method Twenty-three children with cerebral palsy and early hip displacement who were offered preventive hip surgery and whose parents declined in favour of CAM approaches were followed (13 males, 10 females; mean age 13y 9mo [ SD 3y 1mo]; mean length of follow-up 10y 2mo [ SD 2y 11mo]; 17 with spastic quadriplegia, two with spastic triplegia, and four with spastic diplegia; three with gross motor function classified at Gross Motor Function Classification System [ GMFCS] level II, four at level III, six at level IV, and 10 at level V). Principal outcome measures were progression of hip displacement (measured by migration percentage: the percentage of the femoral head sitting outside of the acetabulum), eventual need for reconstructive or salvage surgery, and long-term hip morphology (classified by the Melbourne Cerebral Palsy Hip Classification Scale). The results were compared with a previously reported cohort of 46 children who had surgery when recommended (31 males, 15 females; mean age 13y 11mo [ SD 1y 6mo]; mean length of follow-up 10y 10mo; 10 with diplegia and 36 with quadriplegia; three at GMFCS level II, 11 at level III, 20 at level IV, and 12 at level V). Results Outcomes for 23 children who had pursued CAM were analysed (mean length of follow-up 10y 2mo). Hip displacement progressed in one or both hips in all non-ambulant children ( GMFCS level IV or V). Of the 20 children with documented progressive hip displacement, eight developed pain and deformity requiring salvage surgery. An additional 11 children with progressive hip displacement had late reconstructive surgery when symptoms first started. There was strong evidence of a relationship between GMFCS and both progressive hip displacement (χ2=17.78; p=0.001) and final Melbourne Cerebral Palsy Hip Classification Scale grade (odds ratio 12.5; p=0.012; 95% confidence interval 1.7-90.4). There was also evidence of those children who pursued CAM requiring more complex surgery than the group who had surgery when recommended (odds ratio 2.5; p=0.002; 95% confidence interval 1.4-4.5). Interpretation CAM therapy did not apear to influence the progression of hip displacement in children with cerebral palsy. Most children required major reconstructive surgery or salvage surgery despite pursuing CAM. [ABSTRACT FROM AUTHOR]

Aim: The prevalence of chronic kidney disease (CKD) in the elderly is controversial because age‐related decline in kidney function may not truly reflect underlying kidney disease. We estimate the baseline prevalence and predictors of CKD using the CKD Epidemiology Collaboration (CKD‐EPIeGFR) and Berlin Initiative Study 1 (BIS1eGFR) eGFR equations in the ASPirin in Reducing Events in the Elderly (ASPREE) trial cohort of healthy older participants. Methods: GFR was estimated using CKD‐EPI and BIS1 equations. CKD was defined as eGFR <60 mL/min/1.73 m2 or ≥ 60 mL/min/1.73 m2 with urine albumin creatinine ratio (UACR) ≥ 3 mg/mmol. Logistic regression was used to identify predictors of CKD prevalence defined by each eGFR equation. Results: Data for analysis were complete for 17,762 participants. Mean age was 75.1 years (SD 5); 56.4% were female, 76.4% had hypertension, 9% had diabetes mellitus. Mean CKD‐EPIeGFR was 73.0 (SD 14.2), compared with mean BIS1eGFR of 62.7 (11.4). Median UACR was 0.8 (IQR 0.5, 1.5) mg/mmol. Prevalence of CKD by CKD‐EPIeGFR was 27% (predominantly due to normoalbuminuric stage 3a CKD), substantially lower than 47.1% by BIS1eGFR; the difference was predominantly driven by reclassification of individuals from G1 and G2 CKD to stage G3a without albuminuria. Increased prevalence of CKD by either equation was related to older age, hypertension, diabetes, or higher body mass index. Conclusions: Prevalence of CKD with CKD‐EPIeGFR was 27%, and doubled using the elderly specific BIS1eGFR, with most participants reclassified from stage 2 to stage 3a. Increased prevalence of CKD was related older age, hypertension, diabetes, or increased body mass index. SUMMARY AT A GLANCE: Chronic kidney disease (CKD) is common and increases with age even in healthy elderly people. The elderly specific Berlin Initiative Study 1 (BIS1eGFR) estimated glomerular filtration rate (eGFR) equation BIS1eGFR substantially increases CKD prevalence, largely by reclassifying elderly participants from G1 and G2 CKD to stage G3a without albuminuria to stage 3a CKD. [ABSTRACT FROM AUTHOR]

Recently, we observed a 15% decrease in the incidence of type 1 diabetes (T1D) in Australian 0-4-year-old children following the introduction of RV vaccination [[2], [3]], suggesting that RV vaccination could contribute to the primary prevention of this autoimmune disease. Australian surveillance data [[11]] show that the prevalence of RV G3 strains increased slightly along with an increase in strain diversity in the post-RV vaccine era, but G3 remains a minor component of disease-causing RV strains. RV was prevalent in nurseries, and the change to rooming-in would have altered the timing of exposure to RV, delaying it until later in the first year of life when, based on NOD mouse studies [[17]-[19]], RV might promote rather than retard development of diabetes. [Extracted from the article]

This study used a prospective community-based sample to describe patterns and predictors of language development from 4 to 7 years in verbal children (IQ ≥ 70) with autism spectrum disorder (ASD; n = 26-27). Children with typical language (TD; n = 858-861) and language impairment (LI; n = 119) were used for comparison. Children with ASD and LI had similar mean language scores that were lower on average than children with TD. Similar proportions across all groups had declining, increasing and stable patterns. Language progressed at a similar rate for all groups, with progress influenced by IQ and language ability at 4 years rather than social communication skills or diagnosis of ASD. These findings inform advice for parents about language prognosis in ASD. [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]

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]

Aim: We aimed to examine the impact of weather on hospital admissions with bronchiolitis in Australia and New Zealand.Methods: We collected data for inpatient admissions of infants aged 2-12 months to seven hospitals in four cities in Australia and New Zealand from 2009 until 2011. Correlation of hospital admissions with minimum daily temperature, wind speed, relative humidity and rainfall was examined using linear, Poisson and negative binomial regression analyses as well as general estimated equation models. To account for possible lag between exposure to weather and admission to hospital, analyses were conducted for time lags of 0-4 weeks.Results: During the study period, 3876 patients were admitted to the study hospitals. Hospital admissions showed strong seasonality with peaks in wintertime, onset in autumn and offset in spring. The onset of peak incidence was preceded by a drop in temperature. Minimum temperature was inversely correlated with hospital admissions, whereas wind speed was directly correlated. These correlations were sustained for time lags of up to 4 weeks. Standardised correlation coefficients ranged from -0.14 to -0.54 for minimum temperature and from 0.18 to 0.39 for wind speed. Relative humidity and rainfall showed no correlation with hospital admissions in our study.Conclusion: A decrease in temperature and increasing wind speed are associated with increasing incidence of bronchiolitis hospital admissions in Australia and New Zealand. [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]

Background: Clinical decision rules can help to determine the need for CT imaging in children with head injuries. We aimed to validate three clinical decision rules (PECARN, CATCH, and CHALICE) in a large sample of children.Methods: In this prospective observational study, we included children and adolescents (aged <18 years) with head injuries of any severity who presented to the emergency departments of ten Australian and New Zealand hospitals. We assessed the diagnostic accuracy of PECARN (stratified into children aged <2 years and ≥2 years), CATCH, and CHALICE in predicting each rule-specific outcome measure (clinically important traumatic brain injury [TBI], need for neurological intervention, and clinically significant intracranial injury, respectively). For each calculation we used rule-specific predictor variables in populations that satisfied inclusion and exclusion criteria for each rule (validation cohort). In a secondary analysis, we compiled a comparison cohort of patients with mild head injuries (Glasgow Coma Scale score 13-15) and calculated accuracy using rule-specific predictor variables for the standardised outcome of clinically important TBI. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12614000463673.Findings: Between April 11, 2011, and Nov 30, 2014, we analysed 20 137 children and adolescents attending with head injuries. CTs were obtained for 2106 (10%) patients, 4544 (23%) were admitted, 83 (<1%) underwent neurosurgery, and 15 (<1%) died. PECARN was applicable for 4011 (75%) of 5374 patients younger than 2 years and 11 152 (76%) of 14 763 patients aged 2 years and older. CATCH was applicable for 4957 (25%) patients and CHALICE for 20 029 (99%). The highest point validation sensitivities were shown for PECARN in children younger than 2 years (100·0%, 95% CI 90·7-100·0; 38 patients identified of 38 with outcome [38/38]) and PECARN in children 2 years and older (99·0%, 94·4-100·0; 97/98), followed by CATCH (high-risk predictors only; 95·2%; 76·2-99·9; 20/21; medium-risk and high-risk predictors 88·7%; 82·2-93·4; 125/141) and CHALICE (92·3%, 89·2-94·7; 370/401). In the comparison cohort of 18 913 patients with mild injuries, sensitivities for clinically important TBI were similar. Negative predictive values in both analyses were higher than 99% for all rules.Interpretation: The sensitivities of three clinical decision rules for head injuries in children were high when used as designed. The findings are an important starting point for clinicians considering the introduction of one of the rules.Funding: National Health and Medical Research Council, Emergency Medicine Foundation, Perpetual Philanthropic Services, WA Health Targeted Research Funds, Townsville Hospital Private Practice Fund, Auckland Medical Research Foundation, A + Trust. [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]

Objective Paediatric head injury is a common presentation to the ED. North American studies demonstrate increasing use of computed tomography (CT) brain scan (CTB) to investigate head injury. No such data exists for Australian EDs. The aim of this study was to describe CTB use in head injury over time in eight Australian EDs. Methods Retrospective ED electronic database and medical imaging database audit was undertaken for the years 2001-2010 by International Classification of Diseases (ICD) 9 or 10 code for head injury in children <16 years. EDs and medical imaging departments of eight hospitals in Australia (five tertiary referral and three mixed departments). Data for ED presentations with head injury, and all CTB performed by medical imaging were merged to obtain a data set of CTB performed within 24 h for head injury-related attendances to the ED. Descriptive and comparative analysis of CTB rates was performed. Results The rate of CTB over the decade was 10.2% (95% confidence interval (CI) 9.9-10.5). The annual rate varied from 9.5% (95% CI 8.2-10.9) to 12.5% (95% CI 11.2-13.9). CTB use did not increase over time. Median year of age at time of CT scan was 4 years, with an interquartile range of 1.5-9.4 years. Overall there was a 9.2% increase in the CTB scan rate for every additional year of age at presentation (95% CI 6.6-12.1; P < 0.001). Conclusion CTB use in head injuries did not increase during the study period, and rates of CTB were less than reported for North America. [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]

The article discusses a study that evaluated the effectiveness of obesity trial overestimation and natural reduction of body mass index (BMI) z score. Topics covered include comparison of mean changes in the BMI z score of three published obesity studies and participation bias in the Longitudinal Study of Australian Children (LSAC). Recommendations include control of intervention trials, designing studies with multiple baselines and research focus on achieving a body set-point change.

Aim Young people with type 1 diabetes mellitus living in rural and regional Australia have previously been shown to have limited access to specialised diabetes services. The Royal Children's Hospital Melbourne has been running diabetes outreach clinics to Western Victoria, Australia, for over 13 years. We aim to evaluate this service by comparing the outcomes of three outreach clinics with our urban diabetes clinic at the Royal Children's Hospital Melbourne. Methods We examine our tertiary, multidisciplinary team-based model of care, where visiting specialist medical staff work alongside local allied health teams. The local teams provide interim care between clinics utilising the same protocols and treatment practices as the tertiary centre. Longitudinal data encapsulating the years 2005-2010, as a cohort study with a control group, are reviewed. Results A total of 69 rural patients were compared with 1387 metropolitan patients. Metabolic control was comparable, with no difference in mean HbA1c (8.3%/67 mmol/mol for both groups). Treatment options varied slightly at diagnosis, while insulin pump usage was comparable between treatment settings (20.3% rural compared with 27.6% urban, P = 0.19). Of note was that the number of visits per year was higher in the rural group (3.3 per year rural compared with 2.7 urban, P < 0.001). Conclusions We conclude that the outreach service is able to provide a comparable level of care when the urban model is translated to a rural setting. This model may be further able to be extrapolated to other geographic areas and also other chronic health conditions of childhood. [ABSTRACT FROM AUTHOR]

Background Aortic intima-media thickness measured by transabdominal ultrasound (aIMT) is an intermediate phenotype of cardiovascular risk. We aimed to (1) investigate the reproducibility of aIMT in a population-derived cohort of infants; (2) establish the distribution of aIMT in early infancy; (3) compare measurement by edge-detection software to that by manual sonographic calipers; and (4) assess the effect of individual and environmental variables on image quality. Methods Participants were term infants recruited to a population-derived birth cohort study. Transabdominal ultrasound was performed at six weeks of age by one of two trained operators. Thirty participants had ultrasounds performed by both operators on the same day. Data were collected on environmental (infant sleeping, presence of a sibling, use of sucrose, timing during study visit) and individual (post-conception age, weight, gender) variables. Two readers assessed image quality and measured aIMT by edge-detection software and a subset by manual sonographic calipers. Measurements were repeated by the same reader and between readers to obtain intra-observer and inter-observer reliability. Results Aortic IMT was measured successfully using edge-detection in 814 infants, and 290 of these infants also had aIMT measured using manual sonographic calipers. The intra-reader intraclass correlation (ICC) (n = 20) was 0.90 (95%CI 0.76, 0.96), mean difference 1.5 μm (95%LOA -39, 59). The between reader ICC using edge-detection (n = 20) was 0.92 (95%CI 0.82, 0.97) mean difference 2 μm (95%LOA -45.0, 49.0) and with manual caliper measurement (n = 290) the ICC was 0.84 (95%CI 0.80, 0.87) mean difference 5 μm (95%LOA -51.8, 61.8). Edge-detection measurements were greater than those from manual sonographic calipers (mean aIMT 618 μm (50) versus mean aIMT 563 μm (49) respectively; p < 0.001, mean difference 44 μm, 95%LOA -54, 142). With the exception of infant crying (p = 0.001), no associations were observed between individual and environmental variables and image quality. Conclusion In a population-derived cohort of term infants, aIMT measurement has a high level of intra and inter-reader reproducibility. Measurement of aIMT using edge-detection software gives higher inter-reader ICC than manual sonographic calipers. Image quality is not substantially affected by individual and environmental factors. [ABSTRACT FROM AUTHOR]

Objectives We characterized human H1N1 influenza isolate A/Hokkaido/15/02, which has haemagglutinin and neuraminidase mutations that reduce drug susceptibility to oseltamivir, zanamivir and peramivir. Methods One wild-type and three mutant viruses were isolated by plaque purification. Viruses were tested in MUNANA-based enzyme assays, cell culture and receptor binding assays. Results Two viruses had a neuraminidase Y155H mutation that reduced susceptibility in the enzyme inhibition assay to all inhibitors by 30-fold to >100-fold. The Y155H mutation reduced plaque size and affected the stability, Km and pH activity profile of the enzyme. In contrast to previous mutants, this neuraminidase demonstrated a slower rate of inhibitor binding in the IC50 kinetics assay. One virus had both the Y155H mutation and a haemagglutinin D225G mutation that rescued the small-plaque phenotype of the Y155H virus and affected receptor binding and drug susceptibility in cell culture and binding assays. We also isolated a third mutant virus, with both neuraminidase V114I and haemagglutinin D225N mutations, which affected susceptibility in the enzyme inhibition assay and receptor binding, respectively, but to lesser extents than the Y155H and D225G mutations. Conclusions Neither Y155 nor V114 is conserved across neuraminidase subtypes. Furthermore, Y155 is not conserved even among avian and swine N1 viruses. Structurally, both residues reside far from the neuraminidase active site. D225 forms part of the receptor binding site of the haemagglutinin. We believe this is the first demonstration of a specific haemagglutinin mutation correlating with reduced drug susceptibility in plaque assays in both Madin Darby Canine Kidney and SIAT cells. [ABSTRACT FROM AUTHOR]

• Culpability analysis was conducted on 5000 injured drivers in whom drug testing was conducted. • Alcohol gave large increases in the odds of culpability that was concentration-dependent. • Methylamphetamine also showed a large increase in the odds of culpability. • THC gave a modest increase in the odds of culpability • Benzodiazepines also gave a modest increase in the odds of culpability. Culpability analysis was conducted on 5000 drivers injured as a result of a vehicular collision and in whom comprehensive toxicology testing in blood was conducted. The sample included 1000 drivers for each of 5 years from approximately 5000–6000 drivers injured and taken to hospital in the State of Victoria. Logistic regression was used to investigate differences in the odds of culpability associated with alcohol and drug use and other selected crash attributes using the drug-free driver as the reference group. Adjusted odds ratios were obtained from multivariable logistic regression models in which other potentially explanatory driver and crash attributes were included. Drivers with alcohol present showed large increases in the odds of culpability similar to that seen in other studies investigating associations between blood alcohol concentration and crash risk. Methylamphetamine also showed a large increase in the odds of culpability (OR 19) compared to the reference group at both below and above 0.1 mg/L, whereas those drivers with Δ9-tetrahydrocannabinol (THC) present showed only modest increase in odds when all concentrations were assessed (OR 1.9, 95 %CI 1.2–3.1). Benzodiazepines in drivers also gave an increase in odds (3.2, 95 %CI 1.6–6.1), but not other medicinal drugs such as antidepressants, antipsychotics and opioids. Drivers that had combinations of impairing drugs generally gave a large increase in odds, particularly combinations of alcohol with THC or benzodiazepines, and those drivers using both THC and methamphetamine. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Randomised controlled trial of amoxycillin clavulanate in children with chronic wet cough" by J. Marchant, I. B. Masters and A. Champion et al. in the 2012 issue.

Background: Aortic intima-media thickness measured by transabdominal ultrasound (aIMT) is an intermediate phenotype of cardiovascular risk. We aimed to (1) investigate the reproducibility of aIMT in a population-derived cohort of infants; (2) establish the distribution of aIMT in early infancy; (3) compare measurement by edge-detection software to that by manual sonographic calipers; and (4) assess the effect of individual and environmental variables on image quality.Methods: Participants were term infants recruited to a population-derived birth cohort study. Transabdominal ultrasound was performed at six weeks of age by one of two trained operators. Thirty participants had ultrasounds performed by both operators on the same day. Data were collected on environmental (infant sleeping, presence of a sibling, use of sucrose, timing during study visit) and individual (post-conception age, weight, gender) variables. Two readers assessed image quality and measured aIMT by edge-detection software and a subset by manual sonographic calipers. Measurements were repeated by the same reader and between readers to obtain intra-observer and inter-observer reliability.Results: Aortic IMT was measured successfully using edge-detection in 814 infants, and 290 of these infants also had aIMT measured using manual sonographic calipers. The intra-reader intra-class correlation (ICC) (n = 20) was 0.90 (95% CI 0.76, 0.96), mean difference 1.5 μm (95% LOA -39, 59). The between reader ICC using edge-detection (n = 20) was 0.92 (95% CI 0.82, 0.97) mean difference 2 μm (95% LOA -45.0, 49.0) and with manual caliper measurement (n = 290) the ICC was 0.84 (95% CI 0.80, 0.87) mean difference 5 μm (95% LOA -51.8, 61.8). Edge-detection measurements were greater than those from manual sonographic calipers (mean aIMT 618 μm (50) versus mean aIMT 563 μm (49) respectively; p < 0.001, mean difference 44 μm, 95% LOA -54, 142). With the exception of infant crying (p = 0.001), no associations were observed between individual and environmental variables and image quality.Conclusion: In a population-derived cohort of term infants, aIMT measurement has a high level of intra and inter-reader reproducibility. Measurement of aIMT using edge-detection software gives higher inter-reader ICC than manual sonographic calipers. Image quality is not substantially affected by individual and environmental factors. [ABSTRACT FROM AUTHOR]