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1.  Reproducibility of aortic intima-media thickness in infants using edge-detection software and manual caliper measurements 
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.
doi:10.1186/1476-7120-12-18
PMCID: PMC4061507  PMID: 24894574
Aortic intima-media thickness; Edge-detection software; Newborn; Atherosclerosis; Fetal origins of disease
2.  Cardiovascular Disease Risk in the Offspring of Diabetic Women: The Impact of the Intrauterine Environment 
Experimental Diabetes Research  2012;2012:565160.
The incidence of gestational diabetes is increasing worldwide, exposing large numbers of infants to hyperglycaemia whilst in utero. This exposure may have a long-term negative impact on the cardiovascular health of the offspring. Novel methods to assess cardiovascular status in the neonatal period are now available—including measuring arterial intima-media thickness and retinal photography. These measures will allow researchers to assess the relative impact of intrauterine exposures, distinguishing these from genetic or postnatal environmental factors. Understanding the long-term impact of the intrauterine environment should allow the development of more effective health policy and interventions to decrease the future burden of cardiovascular disease. Initiating disease prevention aimed at the developing fetus during the antenatal period may optimise community health outcomes.
doi:10.1155/2012/565160
PMCID: PMC3485506  PMID: 23133443
3.  Objectively Measured Physical Activity and the Subsequent Risk of Incident Dysglycemia 
Diabetes Care  2011;34(7):1497-1502.
OBJECTIVE
To investigate pedometer-measured physical activity (PA) in 2000 and change in PA over 5 years with subsequent risk of dysglycemia by 2005.
RESEARCH DESIGN AND METHODS
This prospective cohort study in Tasmania, Australia, analyzed 458 adults with normal glucose tolerance and a mean (SD) age of 49.7 (12.1) years in 2000. Variables assessed in 2000 and 2005 included PA, by pedometer and questionnaire, nutrient intake, and other lifestyle factors. Incident dysglycemia was defined as the development of impaired fasting glucose or impaired glucose tolerance revealed by oral glucose tolerance testing in 2005, without type 2 diabetes.
RESULTS
Incident dysglycemia developed in 26 participants during the 5-year period. Higher daily steps in 2000 were independently associated with a lower 5-year risk of incident dysglycemia (adjusted odds ratio [AOR] 0.87 [95% CI 0.77–0.97] per 1,000-step increment). Higher daily steps in 2005, after controlling for baseline steps in 2000 (thus reflecting change in steps over 5 years), were not associated with incident dysglycemia (AOR 1.02 [0.92–1.14]). Higher daily steps in 2000 were also associated with lower fasting blood glucose, but not 2-h plasma glucose by 2005. Further adjustment for BMI or waist circumference did not remove these associations.
CONCLUSIONS
Among community-dwelling adults, a higher rate of daily steps is associated with a reduced risk of incident dysglycemia. This effect appears to be not fully mediated through reduced adiposity.
doi:10.2337/dc10-2386
PMCID: PMC3120195  PMID: 21562319
4.  Phenotypic and environmental factors associated with elevated autoantibodies at clinical onset of paediatric type 1 diabetes mellitus 
Results in Immunology  2012;2:125-131.
To examine possible determinants of autoantibody levels at type 1 diabetes mellitus (T1DM) onset.
We assessed levels of glutamic acid decarboxylase 65 islet cell antigen (GADA) and anti-insulin antibodies (IAA) in 247 incident T1DM cases presenting <15 years of age in Melbourne from 1st March 2008 to 30th June 2010.
58.9% (142/241) of cases were GADA seropositive and 42.3% (94/222) were IAA seropositive. Factors associated with elevated IAA antibodies included younger age and red hair phenotype. Factors associated with elevated GAD antibodies included lower birthweight and recent eczema. Intriguingly, low recent or past sun exposure was only associated with elevated GADA levels among children presenting at age <5 years, not older (difference in effect, p<0.05 for 4 of 5 associations).
These findings show that environmental and phenotypic factors are associated with autoantibody levels at time of presentation for T1DM. We recommend such environmental and phenoytypic factors should be examined in further detail.
doi:10.1016/j.rinim.2012.06.002
PMCID: PMC3862385  PMID: 24371576
Peadiatric; Type 1 diabetes; Autoantibodies; Phenotype; Environment
5.  Independent replication analysis of genetic loci with previous evidence of association with juvenile idiopathic arthritis 
Background
Over the last five years, there have been numerous reports of association of juvenile idiopathic arthritis with single nucleotide polymorphisms (SNPs) at various loci outside the major histocompatibility complex (MHC) region. However, the majority of these association findings have been generated using a limited number of international cohorts, and thus there is benefit in further independent replication. To address this, we examined a total of 56 SNPs in 42 non-MHC gene regions previously reported to be associated with JIA, in the ChiLdhood Arthritis Risk factor Identification sTudY (CLARITY), a new Australian collection of cases and healthy child controls.
Findings
Genotyping was performed on a total of 324 JIA cases (mean age 9.7 years, 67.3% female) and 568 controls (mean age 7.8 years, 40.7% female). We demonstrated clear evidence for replication of association of JIA with SNPs in or around c12orf30, c3orf1, PTPN22, STAT4, and TRAF1-C5, confirming the involvement of these loci in disease risk. Further, we generated evidence supportive of replication of association of JIA with loci containing AFF3, CD226, MBL2, PSTPIP1, and RANTES (CCL5). These results were robust to sensitivity analyses for ethnicity.
Conclusion
We have provided valuable independent data as to the underlying genetic architecture of this understudied pediatric autoimmune disease, further confirming five loci outside the MHC, and supporting a role for a further five loci in determining disease risk.
doi:10.1186/1546-0096-11-12
PMCID: PMC3606368  PMID: 23506417
Juvenile idiopathic arthritis; Genetic association; Independent replication
6.  CLARITY – ChiLdhood Arthritis Risk factor Identification sTudY 
Background
The aetiology of juvenile idiopathic arthritis (JIA) is largely unknown. We have established a JIA biobank in Melbourne, Australia called CLARITY – ChiLdhood Arthritis Risk factor Identification sTudY, with the broad aim of identifying genomic and environmental disease risk factors. We present here study protocols, and a comparison of socio-demographic, pregnancy, birth and early life characteristics of cases and controls collected over the first 3 years of the study.
Methods
Cases are children aged ≤18 years with a diagnosis of JIA by 16 years. Controls are healthy children aged ≤18 years, born in the state of Victoria, undergoing a minor elective surgical procedure. Participant families provide clinical, epidemiological and environmental data via questionnaire, and a blood sample is collected.
Results
Clinical characteristics of cases (n = 262) are similar to those previously reported. Demographically, cases were from families of higher socio-economic status. After taking this into account, the residual pregnancy and perinatal profiles of cases were similar to control children. No case-control differences in breastfeeding commencement or duration were detected, nor was there evidence of increased case exposure to tobacco smoke in utero. At interview, cases were less likely to be exposed to active parental smoking, but disease-related changes to parent behaviour may partly underlie this.
Conclusions
We show that, after taking into account socio-economic status, CLARITY cases and controls are well matched on basic epidemiological characteristics. CLARITY represents a new study platform with which to generate new knowledge as to the environmental and biological risk factors for JIA.
doi:10.1186/1546-0096-10-37
PMCID: PMC3551677  PMID: 23153063
Juvenile idiopathic arthritis; Epidemiology; Demographics; Early life; Risk factors
7.  Genome-scale case-control analysis of CD4+ T-cell DNA methylation in juvenile idiopathic arthritis reveals potential targets involved in disease 
Clinical Epigenetics  2012;4(1):20.
Background
Juvenile Idiopathic Arthritis (JIA) is a complex autoimmune rheumatic disease of largely unknown cause. Evidence is growing that epigenetic variation, particularly DNA methylation, is associated with autoimmune disease. However, nothing is currently known about the potential role of aberrant DNA methylation in JIA. As a first step to addressing this knowledge gap, we have profiled DNA methylation in purified CD4+ T cells from JIA subjects and controls. Genomic DNA was isolated from peripheral blood CD4+ T cells from 14 oligoarticular and polyarticular JIA cases with active disease, and healthy age- and sex-matched controls. Genome-scale methylation analysis was carried out using the Illumina Infinium HumanMethylation27 BeadChip. Methylation data at >25,000 CpGs was compared in a case-control study design.
Results
Methylation levels were significantly different (FDR adjusted p<0.1) at 145 loci. Removal of four samples exposed to methotrexate had a striking impact on the outcome of the analysis, reducing the number of differentially methylated loci to 11. The methotrexate-naive analysis identified reduced methylation at the gene encoding the pro-inflammatory cytokine IL32, which was subsequently replicated using a second analysis platform and a second set of case-control pairs.
Conclusions
Our data suggests that differential T cell DNA methylation may be a feature of JIA, and that reduced methylation at IL32 is associated with this disease. Further work in larger prospective and longitudinal sample collections is required to confirm these findings, assess whether the identified differences are causal or consequential of disease, and further investigate the epigenetic modifying properties of therapeutic regimens.
doi:10.1186/1868-7083-4-20
PMCID: PMC3536591  PMID: 23148518
Epigenetics; Juvenile idiopathic arthritis; DNA methylation; Autoimmunity; Methylome; Methotrexate
8.  Measurement of Epstein-Barr virus DNA load using a novel quantification standard containing two EBV DNA targets and SYBR Green I dye 
Virology Journal  2010;7:252.
Background
Reactivation of Epstein-Barr virus (EBV) infection may cause serious, life-threatening complications in immunocompromised individuals. EBV DNA is often detected in EBV-associated disease states, with viral load believed to be a reflection of virus activity. Two separate real-time quantitative polymerase chain reaction (QPCR) assays using SYBR Green I dye and a single quantification standard containing two EBV genes, Epstein-Barr nuclear antigen-1 (EBNA-1) and BamHI fragment H rightward open reading frame-1 (BHRF-1), were developed to detect and measure absolute EBV DNA load in patients with various EBV-associated diseases. EBV DNA loads and viral capsid antigen (VCA) IgG antibody titres were also quantified on a population sample.
Results
EBV DNA was measurable in ethylenediaminetetraacetic acid (EDTA) whole blood, peripheral blood mononuclear cells (PBMCs), plasma and cerebrospinal fluid (CSF) samples. EBV DNA loads were detectable from 8.0 × 102 to 1.3 × 108 copies/ml in post-transplant lymphoproliferative disease (n = 5), 1.5 × 103 to 2.0 × 105 copies/ml in infectious mononucleosis (n = 7), 7.5 × 104 to 1.1 × 105 copies/ml in EBV-associated haemophagocytic syndrome (n = 1), 2.0 × 102 to 5.6 × 103 copies/ml in HIV-infected patients (n = 12), and 2.0 × 102 to 9.1 × 104 copies/ml in the population sample (n = 218). EBNA-1 and BHRF-1 DNA were detected in 11.0% and 21.6% of the population sample respectively. There was a modest correlation between VCA IgG antibody titre and BHRF-1 DNA load (rho = 0.13, p = 0.05) but not EBNA-1 DNA load (rho = 0.11, p = 0.11).
Conclusion
Two sensitive and specific real-time PCR assays using SYBR Green I dye and a single quantification standard containing two EBV DNA targets, were developed for the detection and measurement of EBV DNA load in a variety of clinical samples. These assays have application in the investigation of EBV-related illnesses in immunocompromised individuals.
doi:10.1186/1743-422X-7-252
PMCID: PMC2958162  PMID: 20860842
9.  Low maternal exposure to ultraviolet radiation in pregnancy, month of birth, and risk of multiple sclerosis in offspring: longitudinal analysis 
Objectives To investigate the distribution of month of birth in people with multiple sclerosis in Australia. To use the large regional and seasonal variation in ambient ultraviolet radiation in Australia to explore the association between exposure to ultraviolet radiation during pregnancy and subsequent risk of multiple sclerosis in offspring.
Design Data were gathered on birth month and year (1920-1950), sex, and state of birth for all patients surveyed in 1981 in Queensland, Western Australia, New South Wales (including Australian Capital Territory), South Australia, and Hobart (Tasmania). Population denominators were derived from the 1981 census and supplementary birth registration data. A variable for exposure to ambient ultraviolet radiation “at birth” was generated from monthly averages of daily total ambient ultraviolet radiation for each region. Negative binomial regression models were used to investigate exposure to ambient ultraviolet radiation at birth and at various intervals before birth.
Setting Patient data from multiple sclerosis prevalence surveys carried out in 1981; 1981 Australian census (giving the total number of people born in Australia and still alive and living in Australia in 1981 by year of birth 1920-50); supplementary Australian birth registration data covering the same birth years by month and state.
Participants 1524 patients with multiple sclerosis born in Australia 1920-50 from total population of 2 468 779.
Main outcome measure Cumulative incidence rate of multiple sclerosis.
Results There was a pattern of risk of multiple sclerosis with month of birth (adjusted incidence rate ratio 1.32, 95% confidence interval 1.10 to 1.58, P<0.01, for those born in November-December compared with those born in May-June). This pattern mirrored that previously reported in the northern hemisphere. Region of birth was related to risk. After adjustment for region of birth and other factors, there was an inverse association between ambient ultraviolet radiation in the first trimester and risk of multiple sclerosis (with ≥25 erythemal (skin reddening) dose units as reference (that is, adjusted incidence rate ratio=1.00), the rates were 1.54 (1.10 to 2.16) for 20-<25 units; 1.58 (1.12 to 2.22) for 15-<20 units; 1.65 (1.17 to 2.33) for 10-<15 units; 1.65 (1.18 to 2.29) for 5-<10 units; and 1.67 (1.18 to 2.37) for <5 units). After adjustment for this exposure during early pregnancy, there was no residual association between month of birth and multiple sclerosis.
Conclusion Region of birth and low maternal exposure to ultraviolet radiation in the first trimester are independently associated with subsequent risk of multiple sclerosis in offspring in Australia.
doi:10.1136/bmj.c1640
PMCID: PMC2862149  PMID: 21030361
10.  A Novel Approach for Prediction of Vitamin D Status Using Support Vector Regression 
PLoS ONE  2013;8(11):e79970.
Background
Epidemiological evidence suggests that vitamin D deficiency is linked to various chronic diseases. However direct measurement of serum 25-hydroxyvitamin D (25(OH)D) concentration, the accepted biomarker of vitamin D status, may not be feasible in large epidemiological studies. An alternative approach is to estimate vitamin D status using a predictive model based on parameters derived from questionnaire data. In previous studies, models developed using Multiple Linear Regression (MLR) have explained a limited proportion of the variance and predicted values have correlated only modestly with measured values. Here, a new modelling approach, nonlinear radial basis function support vector regression (RBF SVR), was used in prediction of serum 25(OH)D concentration. Predicted scores were compared with those from a MLR model.
Methods
Determinants of serum 25(OH)D in Caucasian adults (n = 494) that had been previously identified were modelled using MLR and RBF SVR to develop a 25(OH)D prediction score and then validated in an independent dataset. The correlation between actual and predicted serum 25(OH)D concentrations was analysed with a Pearson correlation coefficient.
Results
Better correlation was observed between predicted scores and measured 25(OH)D concentrations using the RBF SVR model in comparison with MLR (Pearson correlation coefficient: 0.74 for RBF SVR; 0.51 for MLR). The RBF SVR model was more accurately able to identify individuals with lower 25(OH)D levels (<75 nmol/L).
Conclusion
Using identical determinants, the RBF SVR model provided improved prediction of serum 25(OH)D concentrations and vitamin D deficiency compared with a MLR model, in this dataset.
doi:10.1371/journal.pone.0079970
PMCID: PMC3841172  PMID: 24302994
11.  Breast-Feeding and Childhood-Onset Type 1 Diabetes 
Diabetes Care  2012;35(11):2215-2225.
OBJECTIVE
To investigate if there is a reduced risk of type 1 diabetes in children breastfed or exclusively breastfed by performing a pooled analysis with adjustment for recognized confounders.
RESEARCH DESIGN AND METHODS
Relevant studies were identified from literature searches using MEDLINE, Web of Science, and EMBASE. Authors of relevant studies were asked to provide individual participant data or conduct prespecified analyses. Meta-analysis techniques were used to combine odds ratios (ORs) and investigate heterogeneity between studies.
RESULTS
Data were available from 43 studies including 9,874 patients with type 1 diabetes. Overall, there was a reduction in the risk of diabetes after exclusive breast-feeding for >2 weeks (20 studies; OR = 0.75, 95% CI 0.64–0.88), the association after exclusive breast-feeding for >3 months was weaker (30 studies; OR = 0.87, 95% CI 0.75–1.00), and no association was observed after (nonexclusive) breast-feeding for >2 weeks (28 studies; OR = 0.93, 95% CI 0.81–1.07) or >3 months (29 studies; OR = 0.88, 95% CI 0.78–1.00). These associations were all subject to marked heterogeneity (I2 = 58, 76, 54, and 68%, respectively). In studies with lower risk of bias, the reduced risk after exclusive breast-feeding for >2 weeks remained (12 studies; OR = 0.86, 95% CI 0.75–0.99), and heterogeneity was reduced (I2 = 0%). Adjustments for potential confounders altered these estimates very little.
CONCLUSIONS
The pooled analysis suggests weak protective associations between exclusive breast-feeding and type 1 diabetes risk. However, these findings are difficult to interpret because of the marked variation in effect and possible biases (particularly recall bias) inherent in the included studies.
doi:10.2337/dc12-0438
PMCID: PMC3476923  PMID: 22837371
13.  Maternal Alcohol Intake and Offspring Pulse Wave Velocity 
Neonatology  2009;97(3):204-211.
Background
Intrauterine exposure to alcohol may affect cardiovascular development, increasing risk of cardiovascular malformations. Intrauterine exposure to light maternal alcohol intake has been reported to affect human umbilical arterial contractility, and adult sheep exposed in utero have had altered cerebrovascular reactivity. In human adults, alcohol intake affects arterial stiffness.
Objectives
We investigated whether intrauterine exposure to alcohol was associated with childhood pulse wave velocity (PWV), a measure of arterial stiffness.
Methods
On postnatal day 4, mothers of 147 twin pairs born in Tasmania from 1991 to 1993 reported alcohol intake during each trimester of pregnancy. At 9 years, child PWV was assessed over carotid-femoral and femoral-dorsalis pedis arterial segments by applanation tonometry.
Results
Carotid-femoral PWV was 0.2 m/s (95% CI 0.06, 0.4) higher (indicating stiffer vessels) in children whose mothers drank alcohol in the 2nd trimester rather than abstained, after adjusting for potential confounding factors. A similar effect was not seen for femoral-dorsalis pedis PWV. Findings were independent of child blood pressure which correlated strongly with PWV. Alcohol intake varied little between trimesters, so it was not possible to assess the effect of timing of exposure.
Conclusions
Carotid-femoral PWV in adults is predictive of cardiovascular morbidity and mortality. The degree of continuity between childhood and adulthood PWV is unknown, but as we found an association between prenatal alcohol exposure and carotid-femoral PWV at 9 years, a permanent change in vessel wall structure or function is possible. These findings need to be confirmed in other and larger cohorts, and mechanistic animal studies are needed.
doi:10.1159/000252973
PMCID: PMC3701444  PMID: 19864927
Fetus; Ethanol; Pulse wave velocity; Blood pressure
14.  Decline in Physical Fitness From Childhood to Adulthood Associated With Increased Obesity and Insulin Resistance in Adults 
Diabetes Care  2008;32(4):683-687.
OBJECTIVE
To examine how fitness in both childhood and adulthood is associated with adult obesity and insulin resistance.
RESEARCH DESIGN AND METHODS
A prospective cohort study set in Australia in 2004–2006 followed up a cohort of 647 adults who had participated in the Australian Schools Health and Fitness Survey in 1985 and who had undergone anthropometry and cardiorespiratory fitness assessment during the survey. Outcome measures were insulin resistance and obesity, defined as a homeostasis model assessment index above the 75th sex-specific percentile and BMI ≥30 kg/m2, respectively.
RESULTS
Lower levels of child cardiorespiratory fitness were associated with increased odds of adult obesity (adjusted odds ratio [OR] per unit decrease 3.0 [95% CI 1.6–5.6]) and insulin resistance (1.7 [1.1–2.6]). A decline in fitness level between childhood and adulthood was associated with increased obesity (4.5 [2.6–7.7]) and insulin resistance (2.1 [1.5–2.9]) per unit decline.
CONCLUSIONS
A decline in fitness from childhood to adulthood, and by inference a decline in physical activity, is associated with obesity and insulin resistance in adulthood. Programs aimed at maintaining high childhood physical activity levels into adulthood may have potential for reducing the burden of obesity and type 2 diabetes in adults.
doi:10.2337/dc08-1638
PMCID: PMC2660487  PMID: 19106381
15.  The High Prevalence of Vitamin D Insufficiency across Australian Populations Is Only Partly Explained by Season and Latitude 
Environmental Health Perspectives  2007;115(8):1132-1139.
Background
Inadequate sun exposure and dietary vitamin D intake can result in vitamin D insufficiency. However, limited data are available on actual vitamin D status and predictors in healthy individuals in different regions and by season.
Methods
We compared vitamin D status [25-hydroxyvitamin D; 25(OH)D] in people < 60 years of age using data from cross-sectional studies of three regions across Australia: southeast Queensland (27°S; 167 females and 211 males), Geelong region (38°S; 561 females), and Tasmania (43°S; 432 females and 298 males).
Results
The prevalence of vitamin D insufficiency (≤ 50 nmol/L) in women in winter/spring was 40.5% in southeast Queensland, 37.4% in the Geelong region, and 67.3% in Tasmania. Season, simulated maximum daily duration of vitamin D synthesis, and vitamin D effective daily dose each explained around 14% of the variation in 25(OH)D. Although latitude explained only 3.9% of the variation, a decrease in average 25(OH)D of 1.0 (95% confidence interval, 0.7–1.3) nmol/L for every degree increase in latitude may be clinically relevant. In some months, we found a high insufficiency or even deficiency when sun exposure protection would be recommended on the basis of the simulated ultraviolet index.
Conclusion
Vitamin D insufficiency is common over a wide latitude range in Australia. Season appears to be more important than latitude, but both accounted for less than one-fifth of the variation in serum 25(OH)D levels, highlighting the importance of behavioral factors. Current sun exposure guidelines do not seem to fully prevent vitamin D insufficiency, and consideration should be given to their modification or to pursuing other means to achieve vitamin D adequacy.
doi:10.1289/ehp.9937
PMCID: PMC1940076  PMID: 17687438
25(OH)D; behavior; latitude; UV index; UVR; vitamin D; vitamin D index
16.  Proactive asthma care in childhood: general practice based randomised controlled trial 
BMJ : British Medical Journal  2003;327(7416):659.
Objectives To assess the feasibility and effectiveness of a general practice based, proactive system of asthma care in children.
Design Randomised controlled trial with cluster sampling by general practice.
Setting General practices in the northern region of the Australian Capital Territory.
Participants 174 children with moderate to severe asthma who attended 24 general practitioners.
Intervention System of structured asthma care (the 3+ visit plan), with participating families reminded to attend the general practitioner.
Main outcome measures Process measures: rates for asthma consultations with general practitioner, written asthma plans, completion of the 3+ visit plan; clinical measures: rates for emergency department visits for asthma, days absent from school, symptom-free days, symptoms over the past year, activity limitation over the past year, and asthma drug use over the past year; spirometric lung function measures before and after cold air challenge.
Results Intervention group children had significantly more asthma related consultations (odds ratio for three or more asthma related consultations 3.8 (95% confidence interval 1.9 to 7.6; P = 0.0001), written asthma plans (2.2 (1.2 to 4.1); P = 0.01), and completed 3+ visit plans (24.2 (5.7 to 103.2); P = 0.0001) than control children and a mean reduction in measurements of forced expiratory volume in one second after cold air challenge of 2.6% (1.7 to 3.5); P = 0.0001) less than control children. The number needed to treat (benefit) for one additional written asthma action plan was 5 (3 to 41) children. Intervention group children had lower emergency department attendance rates for asthma (odds ratio 0.4 (0.2 to 1.04); P = 0.06) and less speech limiting wheeze (0.2 (0.1 to 0.4); P = 0.0001) than control children and were more likely to use a spacer (2.8 (1.6 to 4.7); P = 0.0001). No differences occurred in number of days absent from school or symptom-free day scores.
Conclusions Proactive care with active recall for children with moderate to severe asthma is feasible in general practice and seems to be beneficial.
PMCID: PMC196449  PMID: 14500440
17.  Ecologic analysis of some immune-related disorders, including type 1 diabetes, in Australia: latitude, regional ultraviolet radiation, and disease prevalence. 
Environmental Health Perspectives  2003;111(4):518-523.
The apparent immune-suppressive effect of ultraviolet radiation (UVR) has suggested that this environmental exposure may influence the development of immune-related disorders. Self-reported prevalence rates of type 1 diabetes mellitus, rheumatoid arthritis (RA), eczema/dermatitis, and asthma, from the 1995 Australian National Health Survey, were therefore examined by latitude and ambient level of UVR. A positive association of type 1 diabetes mellitus prevalence was found with both increasing southern latitude of residence (r = 0.77; p = 0.026) and decreasing regional annual ambient UVR (r= -0.80; p = 0.018); a 3-fold increase in prevalence from the northernmost region to the southernmost region was evident. In contrast, asthma correlated negatively with latitude (r = -0.72; p = 0.046), although the change in asthma prevalence from the north to the south of Australia was only 0.7-fold. For both RA and eczema/dermatitis, there were no statistically significant associations between latitude/UVR and disease prevalence. These ecologic data provide some support for a previously proposed beneficial effect of UVR on T-helper 1-mediated autoimmune disorders such as type 1 diabetes. The inverse association of type 1 diabetes prevalence with UVR is consistent with that previously reported for another autoimmune disease, multiple sclerosis, in Australia, and also with type 1 diabetes latitudinal gradients in the Northern Hemisphere. The finding also accords with photoimmunologic evidence of UVR-induced immunosuppression and may suggest a beneficial effect of UVR in reducing the incidence of such autoimmune conditions. In light of this study, analytic epidemiologic studies investigating risk of immune disorders in relation to personal UVR exposure in humans are required.
PMCID: PMC1241438  PMID: 12676609
18.  Within pair association between birth weight and blood pressure at age 8 in twins from a cohort study 
BMJ : British Medical Journal  1999;319(7221):1325-1329.
Objectives
To study the association between birth weight and blood pressure in children from multiple pregnancies (multiplets), mostly twins, to determine whether maternal or genetic factors are responsible for the association.
Design
Cohort study.
Setting
Southern Tasmania.
Subjects
888 children including 104 multiplets (32 monozygotic, 72 dizygotic).
Main outcome measure
Systolic blood pressure (mm Hg).
Results
Blood pressure decreased with birth weight and increased with current body mass. After adjustment for age and body mass, systolic blood pressure changed by −1.94 mm Hg (95% confidence interval −2.89 to –0.98) per 1 kg increase in birth weight of singletons. For multiplets, blood pressure changed by −7.0 mm Hg (−10.1 to −3.9) for each 1 kg increase in birth weight. This was little altered in within pair analyses (−5.3, −13.8 to 3.2) and was similar for both monozygotic (−6.5, −22.5 to 9.4) and dizygotic (−4.9, −15.8 to 6.0) pairs.
Conclusion
Because the association between birth weight and blood pressure was largely unchanged in within pair analyses, exposures originating in the mother (such as nutritional status) cannot be wholly responsible. The association also remained within monozygotic pairs, suggesting that genetic predisposition is not wholly responsible either. The principal causal pathway must concern mechanisms within the fetoplacental unit. The stronger association in multiplets suggests that factors adversely influencing both blood pressure and birth weight are more prevalent in multiple pregnancies.
Key messagesLow birthweight is associated with high blood pressure from an early ageMaternal factors, including diet during pregnancy, cannot wholly explain the association between fetal development and later risk of cardiovascular diseaseBecause the association between blood pressure and birthweight remained in monozygotic twins, genetic factors are unlikely to be responsible for the associationImportant causes of the association seem to be operating within the fetoplacental unit during fetal lifeFurther research should now focus on placental function and fetal exposures
PMCID: PMC28277  PMID: 10567134

Results 1-18 (18)