[Show abstract][Hide abstract] ABSTRACT: Background:
In recent years the role of vitamin D status in early life on the development of allergic disease has generated much interest. The aim of this study was to determine whether cord blood vitamin D concentrations were associated with risk of early childhood allergic disease.
Measurements of cord blood 25-hydroxyvitamin D [25(OH)D] concentrations were available in 270 mother-child pairs who were participating in the allergy follow-up (n = 706) of the Docosahexaenoic Acid to Optimise Mother Infant Outcome randomised controlled trial. All of the children had a hereditary risk of allergic disease. The diagnosis of allergic disease was made during medical assessments at 1 and 3 years of age.
The mean (standard deviation) standardised cord blood 25(OH)D concentration was 57.0 (24.1) nmol/L. The cumulative incidence of eczema to 3 years of age, n = 101/250 (40 %) was associated with standardised cord blood 25(OH)D concentration, with a 10 nmol/L rise in 25(OH)D concentration reducing the risk of eczema by 8 % (relative risk 0.92, 95 % confidence interval 0.86-0.97; P = 0.005). This association was stronger at 1 year of age, when a 10 nmol/L rise in standardised cord blood 25(OH)D concentration reduced the risk of eczema by 12 % (relative risk 0.88, 95 % confidence interval 0.81-0.96; P = 0.002). No associations between cord blood 25(OH)D concentrations and development of allergic sensitisation, allergic rhinitis or asthma in early childhood were found.
In children with a family history of allergic disease, a higher cord blood 25(OH)D concentration appears to be associated with reduced risk of eczema in early childhood.
Australian New Zealand Clinical Trials Registry ACTRN12610000735055 (DOMInO trial: ACTRN12605000569606).
Full-text · Article · Dec 2015 · World Allergy Organization Journal
[Show abstract][Hide abstract] ABSTRACT: Background
Informative birth size occurs when the average outcome depends on the number of infants per birth. Although analysis methods have been proposed for handling informative birth size, their performance is not well understood. Our aim was to evaluate the performance of these methods and to provide recommendations for their application in randomised trials including infants from single and multiple births.Methods
Three generalised estimating equation (GEE) approaches were considered for estimating the effect of treatment on a continuous or binary outcome: cluster weighted GEEs, which produce treatment effects with a mother-level interpretation when birth size is informative; standard GEEs with an independence working correlation structure, which produce treatment effects with an infant-level interpretation when birth size is informative; and standard GEEs with an exchangeable working correlation structure, which do not account for informative birth size. The methods were compared through simulation and analysis of an example dataset.ResultsTreatment effect estimates were affected by informative birth size in the simulation study when the effect of treatment in singletons differed from that in multiples (i.e. in the presence of a treatment group by multiple birth interaction). The strength of evidence supporting the effectiveness of treatment varied between methods in the example dataset.Conclusions
Informative birth size is always a possibility in randomised trials including infants from both single and multiple births, and analysis methods should be pre-specified with this in mind. We recommend estimating treatment effects using standard GEEs with an independence working correlation structure to give an infant-level interpretation.
No preview · Article · Sep 2015 · Paediatric and Perinatal Epidemiology
[Show abstract][Hide abstract] ABSTRACT: A randomised controlled trial (RCT) of high-dose v. low-dose fish oil in recent-onset rheumatoid arthritis (RA) demonstrated that the group allocated to high-dose fish oil had increased remission and decreased failure of disease-modifying anti-rheumatic drug (DMARD) therapy. This study examines the relationships between plasma phospholipid levels of the n-3 fatty acids in fish oil, EPA and DHA, and remission and DMARD use in recent-onset RA. EPA and DHA were measured in blood samples from both groups of the RCT. The data were analysed as a single cohort, and Cox proportional hazards models were used to examine relationships between plasma phospholipid (PL) EPA and DHA and various outcome measures. When analysed as a single cohort, plasma PL EPA was related to time to remission, with a one unit increase in EPA (1 % total fatty acids) associated with a 12 % increase in the probability of remission at any time during the study period (hazard ratio (HR)=1·12; 95 % CI 1·02, 1·23; P=0·02). Adjustment for smoking, anti-cyclic citrullinated peptide antibodies and 'shared epitope' HLA-DR allele status did not change the HR. Plasma PL EPA, adjusted for the same variables, was negatively related to time to DMARD failure (HR=0·85; 95 % CI 0·72, 0·99; P=0·047). The HR for DHA and time to remission or DMARD failure were similar in magnitude to those for EPA, but not statistically significant. Biomarkers of n-3 status, such as plasma PL EPA, have the potential to predict clinical outcomes relevant to standard drug treatment of RA patients.
Full-text · Article · Aug 2015 · The British journal of nutrition
[Show abstract][Hide abstract] ABSTRACT: Background:
The intention-to-treat principle states that all randomised participants should be analysed in their randomised group. The implications of this principle are widely discussed in relation to the analysis, but have received limited attention in the context of handling errors that occur during the randomisation process. The aims of this article are to (1) demonstrate the potential pitfalls of attempting to correct randomisation errors and (2) provide guidance on handling common randomisation errors when they are discovered that maintains the goals of the intention-to-treat principle.
The potential pitfalls of attempting to correct randomisation errors are demonstrated and guidance on handling common errors is provided, using examples from our own experiences.
We illustrate the problems that can occur when attempts are made to correct randomisation errors and argue that documenting, rather than correcting these errors, is most consistent with the intention-to-treat principle. When a participant is randomised using incorrect baseline information, we recommend accepting the randomisation but recording the correct baseline data. If ineligible participants are inadvertently randomised, we advocate keeping them in the trial and collecting all relevant data but seeking clinical input to determine their appropriate course of management, unless they can be excluded in an objective and unbiased manner. When multiple randomisations are performed in error for the same participant, we suggest retaining the initial randomisation and either disregarding the second randomisation if only one set of data will be obtained for the participant, or retaining the second randomisation otherwise. When participants are issued the incorrect treatment at the time of randomisation, we propose documenting the treatment received and seeking clinical input regarding the ongoing treatment of the participant.
Randomisation errors are almost inevitable and should be reported in trial publications. The intention-to-treat principle is useful for guiding responses to randomisation errors when they are discovered.
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to quantify the magnitude of association between incremental increases in body mass index (BMI) and the development of incident, post-operative, and post-ablation atrial fibrillation (AF).
No preview · Article · Jun 2015 · JACC Clinical Electrophysiology
[Show abstract][Hide abstract] ABSTRACT: Six Year Follow Up of Children at High Hereditary Risk of Allergy, Born To Mothers Supplemented With Docosahexaenoic Acid (DHA) in the DOMInO Trial
Best K1,2, Sullivan T6,Gold M1, Kennedy D4,5, Martin J4,5, Palmer D1,7, Makrides M1,2,3
1Women’s & Children’s Health Research Institute, University of Adelaide, North Adelaide, Australia
2School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, Australia
³Healthy Mothers, Babies and Children, South Australian Health and Medical Research Institute, Adelaide, Australia
4Discipline of Paediatrics, University of Adelaide, Adelaide, Australia
5 Department of Respiratory and Sleep Medicine, Women’s & Children’s Hospital, North Adelaide, Australia
6 School of Population Health, University of Adelaide, Adelaide, Australia
7 School of Paediatrics and Child Health, University of Western Australia, Subiaco, Australia
Background: Dietary omega-3 (n-3) long chain polyunsaturated fatty acids (LCPUFA) modulate neonatal markers of the immune response but there is uncertainty regarding the effect on clinical allergy outcomes. This double blind, randomised controlled trial aimed to determine whether supplementation with DHA rich fish oil during pregnancy to women with a fetus at high risk of allergic disease, will reduce the risk of allergy in the child.
Method: Between 2005 and 2008, pregnant women between 18-21 weeks gestation were randomly assigned to consume capsules containing ~1 g/d of DHA or a blended vegetable oil (no DHA) until birth, the DOMInO trial. From 2012-2014, 603 children (90% of eligible) born to mothers in the DOMInO trial, with a family history of allergic disease completed a six year of age follow up assessment . History of asthma, allergic rhinitis and eczema were assessed, along with food and aero-allergen sensitisation by skin prick testing.
Results: Preliminary results show no difference in the overall percentage of children with IgE-mediated allergic disease between the DHA and control groups (75/279 (26.8%) vs 79/263 (30.0%); RR 0.95; 95% CI 0.73,1.23; P=0.69), although there were fewer children with parent reported hay fever in the DHA group (68/314 (21.6%) vs 84/289 (29.1%); RR 0.75; 95%CI 0.57, 0.99; P=0.04) and fewer children were sensitised to house dust mite, D.Farinae, in the DHA group 31/246 (12.6%) vs 49/231 (21.2%) control; RR 0.61 (0.41, 0.92); P=0.019.
Conclusions: DHA supplementation in pregnancy did not reduce the overall incidence of IgE-mediated allergies at six years of age although parent reported hay fever and D.Farinae sensitisation were lower.
[Show abstract][Hide abstract] ABSTRACT: Obesity is associated with decreased pregnancy rates due, in part, to compromised oocyte quality. The aim of the present cross-sectional study of 84 women undergoing oocyte aspiration was to: (1) compare insulin, lipids and glucose in follicular fluid with serum; (2) determine whether increased body mass index (BMI) and waist circumference, hyperinsulinaemia, dyslipidaemia or metabolic syndrome altered follicular fluid metabolites; and (3) determine relative lipid content in oocytes to reveal any influence of these parameters on oocyte quality and IVF outcomes. Insulin, glucose, triglyceride and free fatty acids were lower in follicular fluid than blood and not strictly correlated between compartments. Insulin, glucose and triglyceride positively correlated with increasing BMI and waist circumference in blood and follicular fluid. Insulin increased in follicular fluid in association with metabolic syndrome. Free fatty acid composition analysis showed saturated fatty acids, particularly palmitic and stearic acid, to be more prevalent in follicular fluid than blood. There were no associations between follicular fluid metabolites or oocyte lipid content and clinical outcomes; however, oocyte immaturity correlated with follicular fluid glucose and fatty acid levels, as well as metabolic syndrome. The present study confirms that the human ovarian follicular environment surrounding the oocyte exhibits a unique metabolite profile compared with blood, with distinct localisation of lipids within follicular fluid and oocytes.
No preview · Article · Mar 2015 · Reproduction Fertility and Development
[Show abstract][Hide abstract] ABSTRACT: Objective: To determine if improvements in cognitive outcome detected at 18 months' corrected age (CA) in infants born <33 weeks' gestation receiving a high-docosahexaenoic acid (DHA) compared with standard-DHA diet were sustained in early childhood. Design: Follow-up of a multicentre randomised controlled trial. Randomisation was stratified for sex, birth weight (<1250 vs >= 1250 g) and hospital. Setting: Five Australian tertiary hospitals from 2008 to 2013. Participants: 626 of the 657 participants randomised between 2001 and 2005 were eligible to participate. Interventions: High-DHA (approximate to 1% total fatty acids) enteral feeds compared with standard-DHA total fatty acids) from age 2-4 days until term CA. Primary outcome: Full Scale IQ of the Wechsler Abbreviated Scale of Intelligence (WASI) at 7 years CA. Prespecified subgroup analyses based on the randomisation strata (sex, birth weight) were conducted. Results: 604 (92% of the 657 originally randomised) consented to participate (291 high-DHA, 313 standard-DHA). To address missing data in the 604 consenting participants (22 for primary outcome), multiple imputation was performed. The Full Scale IQ was not significantly different between groups (high-DHA 98.3, SD 14.0, standard-DHA 98.5, SD 14.9; mean difference adjusted for sex, birthweight strata and hospital -0.3, 95% Cl -2.9 to 2.2; p=0.79). There were no significant differences in any secondary outcomes. In prespecified subgroup analyses, there was a significant sex by treatment interaction on measures of parent-reported executive function and behaviour. Scores were within the normal range but girls receiving the high-DHA diet scored significantly higher (poorer outcome) compared with girls receiving the standard-DHA diet. Conclusions: Supplementing the diets of preterm infants with a DHA dose of approximately 1% total fatty acids from days 2-4 until term CA showed no evidence of benefit at 7 years' CA.
[Show abstract][Hide abstract] ABSTRACT: Objectives Multiple births are an important subgroup to consider in trials aimed at reducing preterm birth or its consequences. Including multiples results in a unique mixture of independent and clustered data, which has implications for the design, analysis and reporting of the trial. We aimed to determine how multiple births were taken into account in the design and analysis of recent trials involving preterm infants, and whether key information relevant to multiple births was reported.
Design We conducted a systematic review of multicentre randomised trials involving preterm infants published between 2008 and 2013. Information relevant to multiple births was extracted.
Results Of the 56 trials included in the review, 6 (11%) excluded multiples and 24 (43%) failed to indicate whether multiples were included. Among the 26 trials that reported multiples were included, only one (4%) accounted for clustering in the sample size calculations and eight (31%) took the clustering into account in the analysis of the primary outcome. Of the 20 trials that randomised infants, 12 (60%) failed to report how infants from the same birth were randomised.
Conclusions Information on multiple births is often poorly reported in trials involving preterm infants, and clustering due to multiple births is rarely taken into account. Since ignoring clustering could result in inappropriate recommendations for clinical practice, clustering should be taken into account in the design and analysis of future neonatal and perinatal trials including infants from a multiple birth.
No preview · Article · Nov 2014 · Archives of Disease in Childhood - Fetal and Neonatal Edition
[Show abstract][Hide abstract] ABSTRACT: Objective:
The origins of cardiovascular and renal disease in type 1 diabetes begin during childhood. We aimed to evaluate carotid (cIMT) and aortic intima-media thickness (aIMT) and their relationship with cardiovascular risk factors and urinary albumin excretion in adolescents with type 1 diabetes in the Adolescent Type 1 Diabetes cardio-renal Intervention Trial (AdDIT).
Research design and methods:
A total of 406 adolescents with type 1 diabetes, who were 14.1 ± 1.9 years old with type 1 diabetes duration of 6.7 ± 3.7 years, and 57 age-matched control subjects provided clinical and biochemical data and ultrasound measurements of vascular structure (cIMT and aIMT). Vascular endothelial and smooth muscle function was also measured in 123 of 406 with type 1 diabetes and all control subjects.
In type 1 diabetic subjects, mean/maximal aIMT (P < 0.006; <0.008), but not mean/maximal cIMT, was greater than in control subjects. Mean/maximal aIMT related to urinary albumin-to-creatinine ratio (multiple regression coefficient [SE], 0.013 [0.006], P = 0.03; 0.023 [0.007], P = 0.002), LDL cholesterol (0.019 [0.008], P = 0.02; 0.025 [0.011], P = 0.02), and age (0.010 [0.004], P = 0.004; 0.012 [0.005], P = 0.01), independent of other variables. Mean/maximal cIMT was greater in males (0.023 [0.006], P = 0.02; 0.029 [0.007], P < 0.0001), and mean cIMT related independently to systolic blood pressure (0.001 [0.001], P = 0.04). Vascular smooth muscle function related to aIMT and cIMT but not to urinary albumin excretion.
aIMT may be a more sensitive marker of atherosclerosis than cIMT in type 1 diabetes during mid-adolescence. Higher urinary albumin excretion, even within the normal range, is associated with early atherosclerosis and should direct clinical attention to modifiable cardiovascular risk factors.
[Show abstract][Hide abstract] ABSTRACT: Randomised controlled trials (RCT) examining the effects of fish oil supplementation on cardiac outcomes have yielded varying results over time. Although RCT are placed at the top of the evidence hierarchy, this methodology arose in the framework of pharmaceutical development. RCT with pharmaceuticals differ in important ways from RCT involving fish oil interventions. In particular, in pharmaceutical RCT, the test agent is present only in the intervention group and not in the control group, whereas in fish oil RCT, n-3 fats are present in the diet and in the tissues of both groups. Also, early phase studies with pharmaceuticals determine pharmacokinetics and pharmacodynamics to design the dose of the RCT intervention so that it is in a predicted linear dose-response range. None of this happens in fish oil RCT, and there is evidence that both baseline n-3 intake and tissue levels may be sufficiently high in the dose-response range that it is not possible to demonstrate a clinical effect with a RCT. When these issues are considered, it is possible that the changing pattern of fish consumption and fish oil use over time, especially in cardiac patients, can explain the disparity where benefit was observed in the early fish oil trials but not in the more recent trials.
Full-text · Article · Jun 2014 · British Journal Of Nutrition
[Show abstract][Hide abstract] ABSTRACT: Partial weight bearing is often prescribed for patients with orthopedic injuries. Patients’ ability to accurately reproduce partial weight bearing orders is variable, and its impact on clinical outcomes is unknown. This observational study measured patients’ ability to reproduce partial weight bearing orders, factors influencing this, patients’ and physiotherapists’ ability to gauge partial weight bearing accuracy, and the effect of partial weight bearing accuracy on long-term clinical outcomes. Fifty-one orthopedic inpatients prescribed partial weight bearing were included. All received standard medical/nursing/physiotherapy care. Physiotherapists instructed patients in partial weight bearing using the hand-under-foot, bathroom scales, and/or verbal methods of instruction. Weight bearing was measured on up to 3 occasions during hospitalization using a force-sensitive insole. Factors that had the potential to influence partial weight bearing accuracy were recorded. Patients and their physiotherapists rated their perception of partial weight bearing accuracy. Three-month clinical follow-up data were retrieved from medical records. The majority of patients (72% or more) exceeded their target load, with mean peak weight bearing as high as 19.3 kg over target load (285% of target load). Weight bearing significantly increased over the 3 measurement occasions (P<.001) and was significantly associated with greater body weight (P=.04). Patients and physiotherapists were unable to accurately gauge partial weight bearing accuracy. The incidence of clinically important complications at 3 months was 9% and not significantly associated with partial weight bearing accuracy during hospitalization (P≥.45). Patients are unable to accurately reproduce partial weight bearing orders when trained with the hand-under-foot, bathroom scales, or verbal methods of instruction.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND A recent review concluded that general health checks fail to reduce mortality in adults. AIM This review focuses on general practice-based health checks and their effects on both surrogate and final outcomes. DESIGN AND SETTING Systematic search of PubMed, Embase, and the Cochrane Central Register of Controlled Trials. METHOD Relevant data were extracted from randomised trials comparing the health outcomes of general practice-based health checks versus usual care in middle-aged populations. RESULTS Six trials were included. The end-point differences between the intervention and control arms in total cholesterol (TC), systolic and diastolic blood pressure (SBP, DBP), and body mass index (BMI) were -0.13 mmol/l (95% confidence interval [CI] = -0.19 to -0.07), -3.65 mmHg (95% CI = -6.50 to -0.81), -1.79 mmHg (95% CI = -2.93 to -0.64), and -0.45 kg/m(2) (95% CI = -0.66 to -0.24), respectively. The odds of a patient remaining at 'high risk' with elevated TC, SBP, DBP, BMI or continuing smoking were 0.63 (95% CI = 0.50 to 0.79), 0.59 (95% CI = 0.28 to 1.23), 0.63 (95% CI = 0.53 to 0.74), 0.89 (95% CI = 0.81 to 0.98), and 0.91 (95% CI = 0.82 to 1.02), respectively. There was little evidence of a difference in total mortality (OR 1.03, 95% CI = 0.90 to 1.18). Higher CVD mortality was observed in the intervention group (OR 1.30, 95% CI = 1.02 to 1.66). CONCLUSION General practice-based health checks are associated with statistically significant, albeit clinically small, improvements in surrogate outcome control, especially among high-risk patients. Most studies were not originally designed to assess mortality.
Preview · Article · Feb 2014 · British Journal of General Practice
[Show abstract][Hide abstract] ABSTRACT: -Surviving myocytes within scar may form channels that support ventricular tachycardia (VT) circuits. There is little data on the properties of channels that comprise VT circuits and those which are non-VT supporting channels.
-In 22 patients with ischemic cardiomyopathy and VT, high-density mapping was performed with the PentaRay™ catheter and Ensite NavX™ system during sinus rhythm. A channel was defined as a series of matching pace-maps with a stimulus (S) to QRS time of ≥40ms. Sites were determined to be part of a VT channel if there were matching pace-maps to the VT morphology. This was confirmed with entrainment mapping when possible. Of the 238 channels identified, 57 channels corresponded to an inducible VT. Channels that were part of a VT circuit were more commonly located within dense scar than non-VT channels (97% vs 82%, p=0.036). VT supporting channels were of greater length (mean±SEM 53±5 vs 33±4mm), had higher longest S-QRS (130±12 vs 82±12ms), longer conduction time (103±14 vs 43±13ms) and slower conduction velocity (0.87±0.23 vs 1.39±0.21m/s) than non-VT channels (p<0.001). Of all the fractionated, late and very late potentials located in scar, only 21%, 26% and 29% respectively were recorded within VT channels.
-High-density mapping shows substantial differences among channels in ventricular scar. Channels supporting VT are more commonly located in dense scar, longer than non-VT channels, and have slower conduction velocity. Only a minority of scar related potentials participate in the VT supporting channels.
Full-text · Article · Feb 2014 · Circulation Arrhythmia and Electrophysiology
[Show abstract][Hide abstract] ABSTRACT: The safety and nutritional adequacy of goat milk infant formulas have been questioned. The primary aim of the present study was to compare the growth and nutritional status of infants fed a goat milk infant formula with those of infants fed a typical whey-based cow milk infant formula. The secondary aim was to examine a range of health- and allergy-related outcomes. A double-blind, randomised controlled trial with 200 formula-fed term infants randomly assigned to receive either goat or cow milk formula from 2 weeks to at least 4 months of age was conducted. A cohort of 101 breast-fed infants was included for comparison. Weight, length and head circumference were measured at 2 weeks and 1, 2, 3, 4, 6 and 12 months of age. Nutritional status was assessed from serum albumin, urea, creatinine, Hb, ferritin, and folate and plasma amino acid concentrations at 4 months. Z-scores for weight, length, head circumference and weight for length were not different between the two formula-fed groups. There were differences in the values of some amino acids and blood biomarkers between the formula-fed groups, but the mean values for biomarkers were within the normal reference range. There were no differences in the occurrence of serious adverse events, general health, and incidence of dermatitis or medically diagnosed food allergy. The incidence of parentally reported blood-stained stools was higher in the goat milk formula-fed group, although this was a secondary outcome and its importance is unclear. Goat milk formula provided growth and nutritional outcomes in infants that did not differ from those provided by a standard whey-based cow milk formula.
Full-text · Article · Feb 2014 · The British journal of nutrition