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1.  Exposure to Beta-(1,3)-D-Glucan in House Dust at Age 7–10 Is Associated with Airway Hyperresponsiveness and Atopic Asthma by Age 11–14 
PLoS ONE  2014;9(6):e98878.
Mould exposure has been linked to childhood asthma and bronchial hyper-responsiveness. Few studies have assessed beta-(1,3)-d-glucan (beta-glucan), a significant fungal cell wall constituent, in relation to asthma in adolescence.
To determine whether house dust-derived beta-glucan exposure at age 7–10 is associated with the development and persistence of atopic and non-atopic asthma, and bronchial hyper-responsiveness (BHR) by age 11–14.
Dust samples were collected from the 1995 Study of Asthma, Genes, and Environment (SAGE) birth cohort. This cohort was derived from Manitoba provincial healthcare administrative records of children high and low risk for asthma. Samples were collected from the homes of 422 children at age 7–10 and analyzed using beta-glucan and endotoxin-specific Limulus Amoebocyte Lysate assays. Asthma, atopy, and BHR status of each child were also assessed at ages 7–10 and 11–14.
At age 7–10, beta-glucan dust levels in the home were associated with persistent atopic asthma at age 11–14 (OR 1.79 for each unit increase in levels, 95% CI 1.14–2.81), independent of endotoxin exposure, and Alternaria or Cladosporium sensitization. The likelihood of BHR almost doubled with unit increases in dust beta-glucan in asthmatic children. In children without asthma, exposure to high beta-glucan levels at age 7–10 also elevated risk for BHR in adolescence (OR 1.74, 95% CI 1.05–2.89). New-onset atopic asthma was twice more likely following high beta-glucan exposure in children without asthma but the association did not reach statistical significance. No associations were evident with concurrent asthma phenotype at age 7–10 or non-atopic asthma at age 11–14.
These findings implicate home beta-glucan exposure at school-age as a risk factor for persistent atopic asthma and new-onset BHR. The higher prevalence of BHR in urban adolescents may be propagated by this home exposure.
PMCID: PMC4048218  PMID: 24905346
2.  A Meta-analysis of Genome-wide Association Studies for Serum Total IgE in Diverse Study Populations 
Immunoglobulin E (IgE) is both a marker and mediator of allergic inflammation. Despite reported differences in serum total IgE levels by race-ethnicity, African American and Latino individuals have not been well represented in genetic studies of total IgE.
To identify the genetic predictors of serum total IgE levels.
We used genome wide association (GWA) data from 4,292 individuals (2,469 African Americans, 1,564 European Americans, and 259 Latinos) in the EVE Asthma Genetics Consortium. Tests for association were performed within each cohort by race-ethnic group (i.e., African American, Latino, and European American) and asthma status. The resulting p-values were meta-analyzed accounting for sample size and direction of effect. Top single nucleotide polymorphism (SNP) associations from the meta-analysis were reassessed in six additional cohorts comprising 5,767 individuals.
We identified 10 unique regions where the combined association statistic was associated with total serum IgE levels (P-value <5.0×10−6) and the minor allele frequency was ≥5% in two or more population groups. Variant rs9469220, corresponding to HLA-DQB1, was the most significantly associated SNP with serum total IgE levels when assessed in both the replication cohorts and the discovery and replication sets combined (P-value = 0.007 and 2.45×10−7, respectively). In addition, findings from earlier GWA studies were also validated in the current meta-analysis.
This meta-analysis independently identified a variant near HLA-DQB1 as a predictor of total serum IgE in multiple race-ethnic groups. This study also extends and confirms the findings of earlier GWA analyses in African American and Latino individuals.
PMCID: PMC3596497  PMID: 23146381
meta-analysis; genome wide association study; total immunoglobulin E; race-ethnicity; continental population groups
3.  Genome-wide association study of body mass index in 23,000 individuals with and without asthma 
Both asthma and obesity are complex disorders that are influenced by environmental and genetic factors. Shared genetic factors between asthma and obesity have been proposed to partly explain epidemiological findings of co-morbidity between these conditions.
To identify genetic variants that are associated with body mass index (BMI) in asthmatic children and adults, and to evaluate if there are differences between the genetics of BMI in asthmatics and healthy individuals.
In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23,000 individuals with predominantly European descent, of whom 8,165 are asthmatics.
We report associations between several DENND1B variants (p=2.2×10−7 for rs4915551) on chromosome 1q31 and BMI from a meta-analysis of GWAS data using 2,691 asthmatic children (screening data). The top DENND1B SNPs were next evaluated in seven independent replication data sets comprising 2,014 asthmatics, and rs4915551 was nominally replicated (p<0.05) in two of the seven studies and of borderline significance in one (p=0.059). However, strong evidence of effect heterogeneity was observed and overall, the association between rs4915551 and BMI was not significant in the total replication data set, p=0.71. Using a random effects model, BMI was overall estimated to increase by 0.30 kg/m2 (p=0.01 for combined screening and replication data sets, N=4,705) per additional G allele of this DENND1B SNP. FTO was confirmed as an important gene for adult and childhood BMI regardless of asthma status.
Conclusions and Clinical Relevance
DENND1B was recently identified as an asthma susceptibility gene in a GWAS on children, and here we find evidence that DENND1B variants may also be associated with BMI in asthmatic children. However, the association was overall not replicated in the independent data sets and the heterogeneous effect of DENND1B points to complex associations with the studied diseases that deserve further study.
PMCID: PMC3608930  PMID: 23517042
Association; Asthma; BMI; Genetics; Genome-wide; Obesity
4.  GSTP1 and TNF Gene Variants and Associations between Air Pollution and Incident Childhood Asthma: The Traffic, Asthma and Genetics (TAG) Study 
Environmental Health Perspectives  2014;122(4):418-424.
Background: Genetics may partially explain observed heterogeneity in associations between traffic-related air pollution and incident asthma.
Objective: Our aim was to investigate the impact of gene variants associated with oxidative stress and inflammation on associations between air pollution and incident childhood asthma.
Methods: Traffic-related air pollution, asthma, wheeze, gene variant, and potential confounder data were pooled across six birth cohorts. Parents reported physician-diagnosed asthma and wheeze from birth to 7–8 years of age (confirmed by pediatric allergist in two cohorts). Individual estimates of annual average air pollution [nitrogen dioxide (NO2), particulate matter ≤ 2.5 μm (PM2.5), PM2.5 absorbance, ozone] were assigned to each child’s birth address using land use regression, atmospheric modeling, and ambient monitoring data. Effect modification by variants in GSTP1 (rs1138272/Ala114Val and rs1695/IIe105Val) and TNF (rs1800629/G-308A) was investigated.
Results: Data on asthma, wheeze, potential confounders, at least one SNP of interest, and NO2 were available for 5,115 children. GSTP1 rs1138272 and TNF rs1800629 SNPs were associated with asthma and wheeze, respectively. In relation to air pollution exposure, children with one or more GSTP1 rs1138272 minor allele were at increased risk of current asthma [odds ratio (OR) = 2.59; 95% CI: 1.43, 4.68 per 10 μg/m3 NO2] and ever asthma (OR = 1.64; 95% CI: 1.06, 2.53) compared with homozygous major allele carriers (OR = 0.95; 95% CI: 0.68, 1.32 for current and OR = 1.20; 95% CI: 0.98, 1.48 for ever asthma; Bonferroni-corrected interaction p = 0.04 and 0.01, respectively). Similarly, for GSTP1 rs1695, associations between NO2 and current and ever asthma had ORs of 1.43 (95% CI: 1.03, 1.98) and 1.36 (95% CI: 1.08, 1.70), respectively, for minor allele carriers compared with ORs of 0.82 (95% CI: 0.52, 1.32) and 1.12 (95% CI: 0.84, 1.49) for homozygous major allele carriers (Bonferroni-corrected interaction p-values 0.48 and 0.09). There were no clear differences by TNF genotype.
Conclusions: Children carrying GSTP1 rs1138272 or rs1695 minor alleles may constitute a susceptible population at increased risk of asthma associated with air pollution.
Citation: MacIntyre EA, Brauer M, Melén E, Bauer CP, Bauer M, Berdel D, Bergström A, Brunekreef B, Chan-Yeung M, Klümper C, Fuertes E, Gehring U, Gref A, Heinrich J, Herbarth O, Kerkhof M, Koppelman GH, Kozyrskyj AL, Pershagen G, Postma DS, Thiering E, Tiesler CM, Carlsten C, TAG Study Group. 2014. GSTP1 and TNF gene variants and associations between air pollution and incident childhood asthma: the traffic, asthma and genetics (TAG) Study. Environ Health Perspect 122:418–424;
PMCID: PMC3984232  PMID: 24465030
6.  Infant gut microbiota and the hygiene hypothesis of allergic disease: impact of household pets and siblings on microbiota composition and diversity 
Multiple studies have demonstrated that early-life exposure to pets or siblings affords protection against allergic disease; these associations are commonly attributed to the “hygiene hypothesis”. Recently, low diversity of the infant gut microbiota has also been linked to allergic disease. In this study, we characterize the infant gut microbiota in relation to pets and siblings.
The study population comprised a small sub-sample of 24 healthy, full term infants from the Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort. Mothers reported on household pets and siblings. Fecal samples were collected at 4 months of age, and microbiota composition was characterized by high-throughput signature gene sequencing.
Microbiota richness and diversity tended to be increased in infants living with pets, whereas these measures were decreased in infants with older siblings. Infants living with pets exhibited under-representation of Bifidobacteriaceae and over-representation of Peptostreptococcaceae; infants with older siblings exhibited under-representation of Peptostreptococcaceae.
This study provides new evidence that exposure to pets and siblings may influence the early development of the gut microbiota, with potential implications for allergic disease. These two traditionally protective “hygiene hypothesis” factors appear to differentially impact gut microbiota composition and diversity, calling into question the clinical significance of these measures. Further research is required to confirm and expand these findings.
PMCID: PMC3655107  PMID: 23607879
Infants; Gut microbiota; Gut microbiome; Hygiene hypothesis; Microflora hypothesis; Pets; Siblings; Atopy; Allergic disease; Environmental exposures
7.  Gut microbiota of healthy Canadian infants: profiles by mode of delivery and infant diet at 4 months 
The gut microbiota is essential to human health throughout life, yet the acquisition and development of this microbial community during infancy remains poorly understood. Meanwhile, there is increasing concern over rising rates of cesarean delivery and insufficient exclusive breastfeeding of infants in developed countries. In this article, we characterize the gut microbiota of healthy Canadian infants and describe the influence of cesarean delivery and formula feeding.
We included a subset of 24 term infants from the Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort. Mode of delivery was obtained from medical records, and mothers were asked to report on infant diet and medication use. Fecal samples were collected at 4 months of age, and we characterized the microbiota composition using high-throughput DNA sequencing.
We observed high variability in the profiles of fecal microbiota among the infants. The profiles were generally dominated by Actinobacteria (mainly the genus Bifidobacterium) and Firmicutes (with diverse representation from numerous genera). Compared with breastfed infants, formula-fed infants had increased richness of species, with overrepresentation of Clostridium difficile. Escherichia–Shigella and Bacteroides species were underrepresented in infants born by cesarean delivery. Infants born by elective cesarean delivery had particularly low bacterial richness and diversity.
These findings advance our understanding of the gut microbiota in healthy infants. They also provide new evidence for the effects of delivery mode and infant diet as determinants of this essential microbial community in early life.
PMCID: PMC3602254  PMID: 23401405
9.  Influence of Socioeconomic Status Trajectories on Innate Immune Responsiveness in Children 
PLoS ONE  2012;7(6):e38669.
Lower socioeconomic status (SES) is consistently associated with poor health, yet little is known about the biological mechanisms underlying this inequality. In children, we examined the impact of early-life SES trajectories on the intensity of global innate immune activation, recognizing that excessive activation can be a precursor to inflammation and chronic disease.
Stimulated interleukin-6 production, a measure of immune responsiveness, was analyzed ex vivo for 267 Canadian schoolchildren from a 1995 birth cohort in Manitoba, Canada. Childhood SES trajectories were determined from parent-reported housing data using a longitudinal latent-class modeling technique. Multivariate regression was conducted with adjustment for potential confounders.
SES was inversely associated with innate immune responsiveness (p = 0.003), with persistently low-SES children exhibiting responses more than twice as intense as their high-SES counterparts. Despite initially lower SES, responses from children experiencing increasing SES trajectories throughout childhood were indistinguishable from high-SES children. Low-SES effects were strongest among overweight children (p<0.01). Independent of SES trajectories, immune responsiveness was increased in First Nations children (p<0.05) and urban children with atopic asthma (p<0.01).
These results implicate differential immune activation in the association between SES and clinical outcomes, and broadly imply that SES interventions during childhood could limit or reverse the damaging biological effects of exposure to poverty during the preschool years.
PMCID: PMC3369855  PMID: 22685596
10.  The Association Between Community Stressors and Asthma Prevalence of School Children in Winnipeg, Canada 
It is generally surmised that community stressors have an incubating effect for a variety of diagnoses on maternal and child health. This is of public health significance, as children of mothers facing long-term distress were found to have a 60% higher risk for asthma diagnosis at age 7 in Manitoba, Canada. Our objective was to determine the association of community stressors with childhood asthma prevalence in Winnipeg, Canada from participants who completed the Study of Asthma, Genes and the Environment (SAGE) survey administered in 2002–2003 to a birth cohort from 1995. Measures of community socioeconomic makeup and community disorder with rank ordinalized by quintile at the census tract level were obtained from the 1996 Canada Census. Crime data (annual incidence per 10,000 persons) by neighbourhood profile for 2001 was provided by the Winnipeg Police Service. Dichotomous caregiver report of child asthma along with other indicators from the geocoded SAGE survey allowed linkage to 23 neighbourhood profiles. Multilevel logistic regression analyses were performed to estimate the effect of community stressors on childhood asthma prevalence for birth and non-birth home children (N = 1472) and children resident of birth homes at age 7 or 8 (N = 698). After adjusting for individual risk factors, children resident of birth homes in a high thefts over $5,000 neighbourhood profile were twice as likely (Adjusted OR, 2.05; 95% CI, 1.11–3.81) to have report of asthma compared to children in a lower thefts over $5,000 profile, with community thefts over $5,000 explaining over half of the observed neighbourhood variation in asthma.
PMCID: PMC3315265  PMID: 22470311
childhood asthma; community stressors; multilevel modelling
15.  TLR4 Asp299Gly and Thr399Ile Polymorphisms: No Impact on Human Immune Responsiveness to LPS or Respiratory Syncytial Virus 
PLoS ONE  2010;5(8):e12087.
A broad variety of natural environmental stimuli, genotypic influences and timing all contribute to expression of protective versus maladaptive immune responses and the resulting clinical outcomes in humans. The role of commonly co-segregating Toll-like receptor 4 (TLR4) non-synonymous single nucleotide polymorphisms Asp299Gly and Thr399Ile in this process remains highly controversial. Moreover, what differential impact these polymorphisms might have in at risk populations with respiratory dysfunction, such as current asthma or a history of infantile bronchiolitis, has never been examined. Here we determine the importance of these polymorphisms in modulating LPS and respiratory syncytial virus (RSV) - driven cytokine responses. We focus on both healthy children and those with clinically relevant respiratory dysfunction.
To elucidate the impact of TLR4 Asp299Gly and Thr399Ile on cytokine production, we assessed multiple immune parameters in over 200 pediatric subjects aged 7–9. Genotyping was followed by quantification of pro- and anti-inflammatory cytokine responses by fresh peripheral blood mononuclear cells upon acute exposure to LPS or RSV.
Principal Findings
In contrast to early reports, neither SNP influenced immune responses evoked by LPS exposure or RSV infection, as measured by the intermediate phenotype of pro- and anti-inflammatory cytokine responses to these ubiquitous agents. There is no evidence of altered sensitivity in populations with “at risk” clinical phenotypes.
Genomic medicine seeks to inform clinical practice. Determination of the TLR4 Asp299Gly/Thr399Ile haplotype is of no clinical benefit in predicting the nature or intensity of cytokine production in children whether currently healthy or among specific at-risk groups characterized by prior infantile broncholitis or current asthma.
PMCID: PMC2919413  PMID: 20711470
16.  Asthma and genes encoding components of the vitamin D pathway 
Respiratory Research  2009;10(1):98.
Genetic variants at the vitamin D receptor (VDR) locus are associated with asthma and atopy. We hypothesized that polymorphisms in other genes of the vitamin D pathway are associated with asthma or atopy.
Eleven candidate genes were chosen for this study, five of which code for proteins in the vitamin D metabolism pathway (CYP27A1, CYP27B1, CYP2R1, CYP24A1, GC) and six that are known to be transcriptionally regulated by vitamin D (IL10, IL1RL1, CD28, CD86, IL8, SKIIP). For each gene, we selected a maximally informative set of common SNPs (tagSNPs) using the European-derived (CEU) HapMap dataset. A total of 87 SNPs were genotyped in a French-Canadian family sample ascertained through asthmatic probands (388 nuclear families, 1064 individuals) and evaluated using the Family Based Association Test (FBAT) program. We then sought to replicate the positive findings in four independent samples: two from Western Canada, one from Australia and one from the USA (CAMP).
A number of SNPs in the IL10, CYP24A1, CYP2R1, IL1RL1 and CD86 genes were modestly associated with asthma and atopy (p < 0.05). Two-gene models testing for both main effects and the interaction were then performed using conditional logistic regression. Two-gene models implicating functional variants in the IL10 and VDR genes as well as in the IL10 and IL1RL1 genes were associated with asthma (p < 0.0002). In the replicate samples, SNPs in the IL10 and CYP24A1 genes were again modestly associated with asthma and atopy (p < 0.05). However, the SNPs or the orientation of the risk alleles were different between populations. A two-gene model involving IL10 and VDR was replicated in CAMP, but not in the other populations.
A number of genes involved in the vitamin D pathway demonstrate modest levels of association with asthma and atopy. Multilocus models testing genes in the same pathway are potentially more effective to evaluate the risk of asthma, but the effects are not uniform across populations.
PMCID: PMC2779188  PMID: 19852851
17.  Should Younger Siblings of Peanut-Allergic Children Be Assessed by an Allergist before Being Fed Peanut? 
The objective of this study was to determine the risk of peanut allergy in siblings of peanut-allergic children. In 2005-2006, 560 households of children born in 1995 in the province of Manitoba, Canada, were surveyed. The index children (8-to 10-year-olds) were assessed by a pediatric allergist and had skin-prick testing and/or capRAST for peanut allergy. Surveys were completed by parents for siblings to determine the presence of peanut allergy. Of 560 surveys, 514 (92%) were completed. Twenty-nine (5.6%) index children were peanut allergic. Fifteen of 900 (1.7%) siblings had peanut allergy. Four of 47 (8.5%) were siblings of peanut-allergic children and 11 of 853 (1.3%) were siblings of non-peanut-allergic children. The risk of peanut allergy was markedly increased in siblings of a peanut-allergic child (odds ratio 6.72, 95% confidence interval 2.04-22.12). Siblings of peanut-allergic children are much more likely to be allergic to peanut. An allergy assessment by a qualified allergist should be routinely recommended before feeding peanut to these children.
PMCID: PMC2868888  PMID: 20525137
allergy tests; cohort study; odds ratio; peanut allergy; siblings
18.  Asthma is not enough: Continuation of smoking among parents with an asthmatic child 
Ideally, on diagnosis of asthma in a child, parents are counselled to decrease environmental tobacco smoke exposure to their children.
To determine whether a diagnosis of asthma in children altered parental smoking behaviour toward a reduction in environmental tobacco smoke exposure.
In 2002/2003, a survey was sent to 12,556 households with children born in 1995 in Manitoba. Parents were asked whether their seven-year-old child had asthma, and whether smokers were present in the home in 1995 and/or currently. The likelihood (OR) of a change in parental smoking behaviour was determined according to the presence of asthma in their child, a family history of asthma, the location of residence (rural or urban) and their socioeconomic status.
A total of 3580 surveys (28.5%) were returned. The overall prevalence of parental smoking in 1995 and 2002/2003 was 32.2% and 23.4%, respectively (31.9%/23.2% and 32.3%/23.6% in rural and urban environments, respectively). In 2002/2003, the prevalence of parental smoking in homes with asthmatic children was 29.8%. Parents were not more likely to quit smoking (OR=1.01, 95% CI 0.66 to 1.54) or smoke outside (OR=1.02, 95% CI 0.56 to 1.83) if their child developed asthma. Parental smoking behaviour (quit smoking or smoked outside) did not change if there was a positive family history of asthma (OR=1.04, 95% CI 0.78 to 1.37), if they lived in a rural or urban location (OR=0.94, 95% CI 0.71 to 1.23), or if they were from a low- or high-income household (OR=1.12, 95% CI 0.85 to 1.47).
The likelihood of altering parental smoking behaviour occurred independently of a diagnosis of asthma in their child, a family history of asthma, the location of residence and their socioeconomic status.
PMCID: PMC2676408  PMID: 17885695
Asthma; Children; Environmental tobacco smoke; Parents; Smoking cessation
19.  Effect of regulatory warnings on antidepressant prescription rates, use of health services and outcomes among children, adolescents and young adults 
Regulatory bodies worldwide, including Health Canada, have issued warnings about prescribing antidepressants to children and adolescents. We sought to determine whether the Health Canada warning had the desired effects on prescribing patterns and outcomes and whether it had any unintended health consequences.
We examined data from prescription and health care databases representing more than 265 000 children, adolescents and young adults annually to determine changes in the rates of antidepressant prescription, use of health services and outcomes in these populations in the 9 years before and the 2 years after the Health Canada warning. We also examined the data for unintended changes in these rates among patients with anxiety disorders. We used young adults as the comparison group because they were not targeted by the warning.
Following the warning, the rate of antidepressant prescriptions decreased among children and adolescents (relative risk [RR] 0.86, 95% confidence interval [CI] 0.81–0.91) and among young adults (RR 0.90, 95% CI 0.86–0.93). Ambulatory visits because of depression decreased among children and adolescents (RR 0.90, 95% CI 0.85–0.96) and young adults (RR 0.91, 95% CI 0.87–0.96). The rate of completed suicides among children and adolescents rose significantly after the warning (RR 1.25, 95% CI 1.08–1.44; annual rate per 1000 = 0.04 before and 0.15 after the warning). There was no equivalent change in the rate of completed suicides among young adults (RR 1.01, 95% CI 0.93–1.10; annual rate per 1000 = 0.15 before and 0.22 after the warning). Among patients with an anxiety disorder, the prescription rates did not change among children and adolescents, except for a decrease in the use of selective serotonin reuptake inhibitors other than fluoxetine, but the rates among young adults changed similar to the pattern of changes in the overall prescribing of antidepressants. There was also a significant decrease in the rate of physician visits because of anxiety disorders among young adults after the warning.
Health advisories and warnings issued by regulatory bodies may have unintended consequences on the provision of care, delivery of health services and clinical outcomes. Further efforts are required to ensure that health warnings do not result in unexpected harm.
PMCID: PMC2276558  PMID: 18390943
20.  Evidence-based prescribing of antibiotics for children: role of socioeconomic status and physician characteristics 
Evidence-based guidelines for antibiotic use are well established, but nonadherence to these guidelines continues. This study was undertaken to determine child, household and physician factors predictive of nonadherence to evidence-based antibiotic prescribing in children.
The prescription and health care records of 20 000 Manitoba children were assessed for 2 criteria of nonadherence to evidence-based antibiotic prescribing during the period from fiscal year 1996 (April 1996 to March 1997) to fiscal year 2000: receipt of an antibiotic for a viral respiratory tract infection (VRTI) and initial use of a second-line agent for acute otitis media, pharyngitis, pneumonia, urinary tract infection or cellulitis. The likelihood of nonadherence to evidence-based prescribing, according to child demographic characteristics, physician factors (specialty and place of training) and household income, was determined from hierarchical linear modelling. Child visits were nested within physicians, and the most parsimonious model was selected at p < 0.05.
During the study period, 45% of physician visits for VRTI resulted in an antibiotic prescription, and 20% of antibiotic prescriptions were for second-line antibiotics. Relative to general practitioners, the odds ratio for antibiotic prescription for a VRTI was 0.51 (95% confidence interval [CI] 0.42–0.62) for pediatricians and 1.58 (95% CI 1.03–2.42) for other specialists. The likelihood that an antibiotic would be prescribed for a VRTI was 0.99 for each successive $10 000 increase in household income. Pediatricians and other specialists were more likely than general practitioners to prescribe second-line antibiotics for initial therapy. Both criteria for nonadherence to evidence-based prescribing were 40% less likely among physicians trained in Canada or the United States than among physicians trained elsewhere.
The links that we identified between nonadherence to evidence-based antibiotic prescribing in children and physician specialty and location of training suggest opportunities for intervention. The independent effect of household income indicates that parents also have an important role.
PMCID: PMC450362  PMID: 15262882
21.  Decrease in antibiotic use among children in the 1990s: not all antibiotics, not all children 
Decreases in antibiotic use were widely reported in the 1990s. This study was undertaken to determine trends in the use of antibiotics from fiscal year (FY) 1995 (April 1995 to March 1996) to FY 2001 in a complete population of Manitoba children.
Using Manitoba's health care databases, we determined annual population-based rates of antibiotic prescription among children by antibiotic class (narrow-spectrum and broader-spectrum antibiotics), age group, physician diagnosis (e.g., otitis media or bronchitis) and neighbourhood income in urban areas (derived from the 1996 census). Antibiotic prescription rates were generated within a generalized linear model framework with general estimating equations, and differences between FY 2001 and FY 1995 were tested. Differences in antibiotic use over time were compared across antibiotic classes, age groups, diagnoses and income neighbourhoods.
The overall antibiotic prescription rate decreased by almost one-third, from 1.2 prescriptions per child in FY 1995 to 0.9 prescriptions in FY 2001. Total antibiotic use declined for all respiratory tract infections; decreases were greatest for the sulfonamides (decrease to less than one-third the FY 1995 rate) and narrow-spectrum macrolides (decrease to less than half the FY 1995 rate). In contrast, the FY 2001 rate for broader-spectrum macrolides was as much as 12.5 times the FY 1995 rate. Otitis media accounted for one-quarter of the use of the latter agents. Preschool children and low-income children received the greatest number of antibiotic prescriptions. Declines in antibiotic prescriptions were of a lesser magnitude for low-income children (for whom rates in FY 2001 were four-fifths the rates in FY 1995) than for higher-income children (for whom rates in FY 2001 were about two-thirds the rates in FY 1995).
Overall, antibiotic use declined over the late 1990s in this population of Canadian children, but the increasing use of broader-spectrum macrolides and higher rates of antibiotic use among preschool and low-income children may have implications for antibiotic resistance.
PMCID: PMC450361  PMID: 15262881
22.  Income-based drug benefit policy: impact on receipt of inhaled corticosteroid prescriptions by Manitoba children with asthma 
Drug benefit policies are an important determinant of a population's use of prescription drugs. This study was undertaken to determine whether a change in a provincial drug benefit policy, from a fixed deductible and copayment system to an income-based deductible system, resulted in changes in receipt of prescriptions for inhaled corticosteroids by Manitoba children with asthma.
Using Manitoba's health care administrative databases, we identified a population-based cohort of 10 703 school-aged children who met our case definition for asthma treatment before and after the province's drug benefit policy was changed in April 1996. The effects of the program change on the probability of receiving a prescription for an inhaled corticosteroid and on the mean number of inhaled corticosteroid doses dispensed were compared between a group of children insured under other drug programs (the comparison group) and 2 groups of children insured under the deductible program: those living in low-income neighbourhoods and those living in higher-income neighbourhoods. All analyses were adjusted for a measure of asthma severity.
For higher-income children with severe asthma who were covered by the deductible program, the probability of receiving an inhaled corticosteroid prescription and the mean annual number of inhaled corticosteroid doses declined after the change to the drug policy. A trend toward a decrease in receipt of prescriptions was also observed for low-income children, but receipt of prescriptions was unaltered in the comparison group. Before the policy change, among children with severe asthma, the mean annual number of inhaled corticosteroid doses was lowest for low-income children, and this pattern persisted after the change. Among children with mild to moderate asthma, those covered by the deductible program (both low income and higher income) were less likely to receive prescriptions for inhaled corticosteroids than those in the comparison group, and this difference was statistically significant for the higher-income children.
The change to an income-based drug benefit policy was associated with a decrease in the use of inhaled corticosteroids by higher-income children with severe asthma and did not improve use of these drugs by low- income children.
PMCID: PMC81497  PMID: 11599328
23.  Probiotic supplementation during pregnancy or infancy for the prevention of asthma and wheeze: systematic review and meta-analysis 
Objective To evaluate the association of probiotic supplementation during pregnancy or infancy with childhood asthma and wheeze.
Design Systematic review and meta-analysis of randomised controlled trials.
Data sources Medline, Embase, and Central (Cochrane Library) databases from inception to August 2013, plus the World Health Organization’s international clinical trials registry platform and relevant conference proceedings for the preceding five years. Included trials and relevant reviews were forward searched in Web of Science.
Review methods Two reviewers independently identified randomised controlled trials evaluating probiotics administered to mothers during pregnancy or to infants during the first year of life. The primary outcome was doctor diagnosed asthma; secondary outcomes included wheeze and lower respiratory tract infection.
Results We identified 20 eligible trials including 4866 children. Trials were heterogeneous in the type and duration of probiotic supplementation, and duration of follow-up. Only five trials conducted follow-up beyond participants’ age of 6 years (median 24 months), and none were powered to detect asthma as the primary outcome. The overall rate of doctor diagnosed asthma was 10.7%; overall rates of incident wheeze and lower respiratory tract infection were 33.3% and 13.9%, respectively. Among 3257 infants enrolled in nine trials contributing asthma data, the risk ratio of doctor diagnosed asthma in participants randomised to receive probiotics was 0.99 (95% confidence interval 0.81 to 1.21, I2=0%). The risk ratio of incident wheeze was 0.97 (0.87 to 1.09, I2=0%, 9 trials, 1949 infants). Among 1364 infants enrolled in six trials, the risk ratio of lower respiratory tract infection after probiotic supplementation was 1.26 (0.99 to 1.61, I2=0%). We adjudicated most trials to be of high (ten trials) or unclear (nine trials) risk of bias, mainly due to attrition.
Conclusions We found no evidence to support a protective association between perinatal use of probiotics and doctor diagnosed asthma or childhood wheeze. Randomised controlled trials to date have not yielded sufficient evidence to recommend probiotics for the primary prevention of these disorders. Extended follow-up of existing trials, along with further clinical and basic research, are needed to accurately define the role of probiotics in the prevention of childhood asthma.
Systematic review registration PROSPERO (CRD42013004385).
PMCID: PMC3898421  PMID: 24304677

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