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1.  The Effect of Massage Therapy on Autonomic Activity in Critically Ill Children 
Objectives. Our main objective was to describe the effect of foot and hand (F&H) massage on the autonomic nervous system (ANS) activity in children hospitalized in a pediatric intensive care unit (PICU); the secondary objectives were to assess the relationship between ANS function and the clinical severity and to explore the effects of repeated massage sessions on the ANS. Methods. Design was a descriptive experimental study. Intervention was single or six session(s) of F&H massage. ANS function was assessed through the frequency-domain analysis of heart rate variability. Main metrics included high and low frequency power (HF and LF), HF + LF, and LF/HF ratio. Results. Eighteen children participated in the study. A strong Spearman's correlation (ρ = −0.77) was observed between HF + LF and clinical severity. During massage, the parasympathetic activity (measured by HF) increased significantly from baseline (P = 0.04) with a mean percentage increase of 75% (95% CI: 20%∼130%). LF increased by 56% (95% CI: 20%∼92%) (P = 0.026). Repeated sessions were associated with a persistent effect on HF and LF which peaked at the second session and remained stable thereafter. Conclusions. HF + LF is positively correlated with clinical severity. F&H massage can improve the ANS activity and the effect persists when repeated sessions are offered.
PMCID: PMC4283436  PMID: 25587344
2.  Anthropometric Measures and the Risk of Endometrial Cancer, Overall and by Tumor Microsatellite Status and Histological Subtype 
American Journal of Epidemiology  2013;177(12):1378-1387.
Obesity is an established risk factor for endometrial cancer, but this association is not well understood for subtypes of endometrial cancer. We evaluated the association of recent and adult-life obesity with subtypes of endometrial cancer based on microsatellite status (microsatellite-stable (MSS) vs. microsatellite-instable (MSI)) and histology (type I vs. type II). Analyses were based on a population-based case-control study (524 cases and 1,032 controls) conducted in Alberta, Canada (2002–2006) and included the following groupings of subtypes: MSS = 337 and MSI = 130; type I = 458 and type II = 66. Logistic and polytomous logistic regression were used to estimate odds ratios and 95% confidence intervals for overall endometrial cancer and subtypes of endometrial cancer, respectively. The risks of all subtypes of endometrial cancer, except type II, increased with an increase in all of the anthropometric characteristics examined. The risks for MSI tumors were suggestively stronger than those for MSS tumors; the risk with high (≥30) body mass index (weight (kg)/height (m)2) was significantly stronger for MSI tumors (odds ratio = 4.96, 95% confidence interval: 2.76, 8.91) than for MSS tumors (odds ratio = 2.33, 95% confidence interval: 1.66, 3.28) (P-heterogeneity = 0.02). Obesity is associated with most subtypes of endometrial cancer, and further studies are warranted to elucidate the biological mechanisms underlying the stronger risk for the MSI subtype with a high body mass index.
PMCID: PMC3732018  PMID: 23673247
DNA mismatch repair; endometrial neoplasms; microsatellite instability; risk factors
3.  Abnormal brain maturation in preterm neonates associated with adverse developmental outcomes 
Neurology  2013;81(24):2082-2089.
Our objective was to determine the association of early brain maturation with neurodevelopmental outcome in premature neonates.
Neonates born between 24 and 32 weeks’ gestation (April 2006 to August 2010) were prospectively studied with MRI early in life and again at term-equivalent age. Using diffusion tensor imaging and magnetic resonance spectroscopic imaging, fractional anisotropy (FA) (microstructure) and N-acetylaspartate (NAA)/choline (metabolism) were measured from the basal nuclei, white matter tracts, and superior white matter. Brain maturation is characterized by increasing FA and NAA/choline from early in life to term-equivalent age. In premature neonates, systemic illness and critical care therapies have been linked to abnormalities of these measures. Of the 177 neonates in this cohort, 5 died and 157 (91% of survivors) were assessed at 18 months’ corrected age (adjusted for prematurity) using the Bayley Scales of Infant and Toddler Development III motor, cognitive, and language composite scores (mean = 100, SD = 15).
Among these 157 infants, white matter injury was seen in 48 (30%). Severe white matter injury, in 10 neonates (6%), was associated with a decrease in motor (−18 points; p < 0.001) and cognitive (−8 points; p = 0.085) scores. With greater severity of adverse neurodevelopmental outcomes, slower increases in FA and NAA/choline were observed in the basal nuclei and brain white matter regions as neonates matured to term-equivalent age, independent of the presence of white matter injury.
In the preterm neonate, abnormal brain maturation evolves through the period of neonatal intensive care and is associated with adverse neurodevelopmental outcomes.
PMCID: PMC3863348  PMID: 24212394
4.  Postnatal infection is associated with widespread abnormalities of brain development in premature newborns 
Pediatric research  2012;71(3):274-279.
Infection is a risk factor for adverse neurodevelopmental outcome in preterm newborns. Our objective was to characterize the association of postnatal infection with adverse microstructural and metabolic brain development in premature newborns. One hundred seventeen preterm newborns (24–32 weeks gestation) were studied prospectively at a median of 32.0 and 40.3 weeks postmenstrual age: MRI (white matter injury, hemorrhage), MR (magnetic resonance) spectroscopy (metabolism) and diffusion tensor imaging (microstructure). Newborns were categorized as having “no infection”, “clinical infection”, or “positive-culture infection.” We compared brain injuries, as well as metabolic and microstructural development across these infection groups. In 34 newborns, clinical signs were accompanied by positive cultures while 17 had clinical signs of sepsis alone. White matter injury was identified in 34 newborns. In multivariate regression models infected newborns had brain imaging measures indicative of delayed brain development: lower N-acetylaspartate/choline, elevated average diffusivity (DAV) and decreased white matter fractional anisotropy. These widespread brain abnormalities were found in both newborns with positive-culture infection and in those with clinical infection. These findings suggest that postnatal infection, even without a positive culture, is an important risk factor for widespread abnormalities in brain. These abnormalities extend beyond brain injuries apparent with conventional MRI.
PMCID: PMC3940469  PMID: 22278180 CAMSID: cams4005
5.  Prenatal and Postnatal Inflammation in Relation to Cortisol Levels in Preterm Infants at 18 Months Corrected Age 
To examine whether early inflammation is related to cortisol levels at 18 months corrected age (CA) in children born very preterm.
Study Design
Infants born ≤ 32 weeks gestational age were recruited in the NICU, and placental histopathology, MRI, and chart review were obtained. At 18 months CA developmental assessment and collection of 3 salivary cortisol samples were carried out. Generalized least squares was used to analyze data from 85 infants providing 222 cortisol samples.
Infants exposed to chorioamnionitis with funisitis had a significantly different pattern of cortisol across the samples compared to infants with chorioamnionitis alone or no prenatal inflammation (F[4,139] = 7.3996, P <.0001). Postnatal infections, necrotizing enterocolitis and chronic lung disease were not significantly associated with the cortisol pattern at 18 months CA.
In children born very preterm, prenatal inflammatory stress may contribute to altered programming of the HPA axis.
PMCID: PMC3819325  PMID: 23558431
preterm; chorioamnionitis; funisitis; premature infants; hypothalamic-pituitary-adrenal axis; infection; cortisol; stress
6.  Brain injury and development in newborns with critical congenital heart disease 
Neurology  2013;81(3):241-248.
To determine the relationship between radiologically identifiable brain injuries and delayed brain development as reflected by brain metabolic and microstructural integrity.
Term newborns with congenital heart disease (CHD) (120 preoperatively and 104 postoperatively) were studied with MRI to determine brain injury severity (BIS), microstructure reflected by fractional anisotropy (FA) and average diffusivity (Dav), and metabolism reflected by N-acetylaspartate (NAA)/choline (Cho) and lactate/Cho. Brain development is characterized by increasing NAA/Cho and white matter FA, and by decreasing Dav and lactate/Cho.
Newly acquired brain injury was common (41% preoperative, 30% postoperative). Lower white matter FA (p = 0.005) and lower NAA/Cho (p = 0.01) were associated with increasing preoperative BIS. Higher neonatal illness severity scores (p = 0.03), lower preoperative oxygen saturation (p = 0.002), hypotension (p < 0.001), and septostomy (p = 0.002) were also predictive of higher preoperative BIS. Preoperative FA, Dav, and NAA/Cho did not predict new postoperative BIS. Increasing preoperative BIS predicted higher postoperative Dav (p = 0.002) and lactate/Cho (p = 0.008). Within the postoperative scan, new brain injuries were associated with lower white matter FA (p = 0.04). Postoperative BIS (new lesions) was associated with lower postoperative systolic (p = 0.03) and mean (p = 0.05) blood pressures.
Brain injuries in newborns with CHD are strongly related to abnormalities of brain microstructural and metabolic brain development, especially preoperatively. Both newly acquired preoperative and postoperative brain injuries are related to potentially modifiable clinical risk factors.
PMCID: PMC3770166  PMID: 23771484
7.  Neonatal Pain-Related Stress and NFKBIA Genotype Are Associated with Altered Cortisol Levels in Preterm Boys at School Age 
PLoS ONE  2013;8(9):e73926.
Neonatal pain-related stress is associated with elevated salivary cortisol levels to age 18 months in children born very preterm, compared to full-term, suggesting early programming effects. Importantly, interactions between immune/inflammatory and neuroendocrine systems may underlie programming effects. We examined whether cortisol changes persist to school age, and if common genetic variants in the promoter region of the NFKBIA gene involved in regulation of immune and inflammatory responses, modify the association between early experience and later life stress as indexed by hair cortisol levels, which provide an integrated index of endogenous HPA axis activity. Cortisol was assayed in hair samples from 128 children (83 born preterm ≤32 weeks gestation and 45 born full-term) without major sensory, motor or cognitive impairments at age 7 years. We found that hair cortisol levels were lower in preterm compared to term-born children. Downregulation of the HPA axis in preterm children without major impairment, seen years after neonatal stress terminated, suggests persistent alteration of stress system programming. Importantly, the etiology was gender-specific such that in preterm boys but not girls, specifically those with the minor allele for NFKBIA rs2233409, lower hair cortisol was associated with greater neonatal pain (number of skin-breaking procedures from birth to term), independent of medical confounders. Moreover, the minor allele (CT or TT) of NFKBIA rs2233409 was associated with higher secretion of inflammatory cytokines, supporting the hypothesis that neonatal pain-related stress may act as a proinflammatory stimulus that induces long-term immune cell activation. These findings are the first evidence that a long-term association between early pain-related stress and cortisol may be mediated by a genetic variants that regulate the activity of NF-κB, suggesting possible involvement of stress/inflammatory mechanisms in HPA programming in boys born very preterm.
PMCID: PMC3774765  PMID: 24066085
8.  Procedural pain and brain development in premature newborns 
Annals of neurology  2012;71(3):385-396.
Preterm infants are exposed to multiple painful procedures in the neonatal intensive care unit (NICU) during a period of rapid brain development. Our aim was to examine relationships between procedural pain in the NICU and early brain development in very preterm infants.
Infants born very preterm (n=86, 24–32 weeks gestational age) were followed prospectively from birth, and studied with MRI, 3D MR spectroscopic imaging (MRSI) and diffusion tensor imaging (DTI): scan 1 early in life (median 32.1 weeks) and scan 2 at term-equivalent age (median 40 weeks). We calculated N-acetylaspartate to choline ratios (NAA/choline), lactate to choline ratios, average diffusivity (DAV) and white matter fractional anisotropy (FA) from up to seven white and four subcortical grey matter regions of interest. Procedural pain was quantified as the number of skin-breaking events from birth to term or scan 2. Data were analysed using generalized estimating equation modelling adjusting for clinical confounders such as illness severity, morphine exposure, brain-injury and surgery.
After comprehensively adjusting for multiple clinical factors, greater neonatal procedural pain was associated with reduced white matter FA (β= −0.0002, p=0.028) and reduced subcortical grey matter NAA/choline (β= −0.0006, p=0.004). Reduced FA was predicted by early pain (before scan 1), whereas lower NAA/choline was predicted by pain exposure throughout the neonatal course, suggesting a primary and early effect on subcortical structures with secondary white matter changes.
Early procedural pain in very preterm infants may contribute to impaired brain development.
PMCID: PMC3760843  PMID: 22374882 CAMSID: cams3350
9.  Comparing the effectiveness of copper intrauterine devices available in Canada. Is FlexiT non-inferior to NovaT when inserted immediately after first-trimester abortion? Study protocol for a randomized controlled trial 
Trials  2012;13:147.
We describe the rationale and protocol for a randomized noninferiority controlled trial (RCT) to determine if the Flexi-T380(+) copper intrauterine contraceptive device (IUD) is comparable in terms of effectiveness and expulsion rates to the most common Canadian IUD currently in use, NovaT-200, when placed immediately after a first-trimester abortion.
Consenting women choosing to use an IUD after an abortion for a pregnancy of less than 12 weeks of gestation will be randomized to device-type groups to receive immediate post-abortion placement of either a Flexi-T380(+) IUD, a device for which no current evidence on expulsion or effectiveness rates is available, or the Nova-T200 IUD, the only other brand of copper IUD available in Canada at the time of study initiation. The primary outcome measure is IUD expulsion rate at 1 year. Secondary outcomes include: pregnancy rate, method continuation rate, complication rates (infection, perforation), and satisfaction with contraceptive method. A non-intervention group of consenting women choosing a range of other post-abortion contraception methods, including no contraception, will be included for comparison of secondary outcomes. Web-based contraception satisfaction questionnaires, clinical records, and government-linked health administrative databases will be used to assess primary and secondary outcomes.
The RCT design, combined with access to clinical records at all provincial abortion clinics, and to information in provincial single-payer linked administrative health databases, birth registry, and hospital records, offers a unique opportunity to determine if a novel IUD has a comparable expulsion rate to that of the current standard IUD in Canada, in addition to the first opportunity to determine pregnancy rate and method satisfaction at 1 year post-abortion for women choosing a range of post-abortion contraceptive options. We highlight considerations of design, implementation, and evaluation of the first trial to provide rigorous evidence for the effectiveness of current Canadian IUDs when inserted after first-trimester abortion.
Trial registration Identifier NCT01174225
PMCID: PMC3495410  PMID: 22920273
Contraception; Intrauterine device; Intrauterine device expulsion; Contraception effectiveness; Abortion-induced; Therapeutic abortion; Non-inferiority trial; Randomized controlled trial; Canada
11.  Identification by families of pediatric adverse events and near misses overlooked by health care providers 
Identifying adverse events and near misses is essential to improving safety in the health care system. Patients are capable of reliably identifying and reporting adverse events. The effect of a patient safety reporting system used by families of pediatric inpatients on reporting of adverse events by health care providers has not previously been investigated.
Between Nov. 1, 2008, and Nov. 30, 2009, families of children discharged from a single ward of British Columbia’s Children’s Hospital were asked to respond to a questionnaire about adverse events and near misses during the hospital stay. Rates of reporting by health care providers for this period were compared with rates for the previous year. Family reports for specific incidents were matched with reports by health care providers to determine overlap.
A total of 544 familes responded to the questionnaire. The estimated absolute increase in reports by health care providers per 100 admissions was 0.5% (95% confidence interval −1.8% to 2.7%). A total of 321 events were identified in 201 of the 544 family reports. Of these, 153 (48%) were determined to represent legitimate patient safety concerns. Only 8 (2.5%) of the adverse events reported by families were also reported by health care providers.
The introduction of a family-based system for reporting adverse events involving pediatric inpatients, administered at the time of discharge, did not change rates of reporting of adverse events and near misses by health care providers. Most reports submitted by families were not duplicated in the reporting system for health care providers, which suggests that families and staff members view safety-related events differently. However, almost half of the family reports represented legitimate patient safety concerns. Families appeared capable of providing valuable information for improving the safety of pediatric inpatients.
PMCID: PMC3255180  PMID: 22105750
12.  The Centre for Healthy Weights—Shapedown BC: A Family-Centered, Multidisciplinary Program that Reduces Weight Gain in Obese Children over the Short-Term 
The objective was to conduct a program evaluation of the Centre for Healthy Weights—Shapedown BC (CHW-SB), a family-centered, multidisciplinary program for obese children, by assessing the change in weight trajectories from program intake to completion. Secondary outcomes included changes in clinical, biochemical and psychological parameters, and in physical activity (PA) levels. The CHW-SB program was evaluated over 10 weeks. Data collection included anthropometric, metabolic, PA and psychological measures. Longitudinal mixed effects regression was performed to evaluate weight change from Phase 1 (before program on waitlist) to Phase 2 (during program). 238 children <18 years of age were referred to the program of which 119 were eligible for participation. There was a significant decrease in weight trajectory in children following program entry. Participants experienced an average .89% monthly increase before program entry, compared to a .37% monthly decline afterwards, a drop of 1.26% (p < 0.0001, 95%CI 1.08 to 1.44). zBMI (2.26 ± 0.33 to 2.20 ± 0.36, p < 0.001), waist circumference (99 ± 15.7 to 97 ± 16 cm, p < 0.0001) and fasting insulin (137 ± 94.8 to 121 ± 83.4 pmol/L, p < 0.001) also decreased in participants who attended the final visit. Significant improvements were seen in all measures of PA, self-concept, and anxiety. CHW-SB, a government-funded program, is the first obesity-treatment program to be evaluated in Canada. While short-term evaluation revealed significant improvements in adiposity, PA, and psychological measures, the lack of full follow-up is a limitation in interpreting the clinical effectiveness of this program, as drop-out may be associated with lack of success in meeting program goals. These data also emphasize the need for ongoing evaluation to assess the long-term implications of this unique program and ultimately optimize utilization of governmental resources.
PMCID: PMC3290977  PMID: 22408595
obesity; weight loss; BMI reduction; children; prevention; treatment; intervention
13.  Extreme Premature Birth is Not Associated with Impaired Development of Brain Microstructure 
The Journal of pediatrics  2010;157(5):726-732.e1.
To assess if birth at less than 26 weeks gestation is an important predictor of brain microstructure maturation as determined by using diffusion tensor imaging.
Study design
We performed serial MRI and diffusion tensor imaging in 176 infants born at < 33 weeks gestation. Diffusion parameters were calculated for white and gray matter regions. Linear regression for repeated measures was used to assess the effect of extremely premature birth on brain maturation.
In white matter, fractional anisotropy increased by 0.008 per week (95% CI 0.007-0.009, p=<0.0001) and mean diffusivity decreased by 0.021 mm2/sec per week, (95% CI -0.24 to -0.018, p=<0.0001). Birth at < 26 weeks was associated with lower white matter fractional anisotropy (-0.01, 95% CI -0.018 to -0.003, p=0.008) but this effect was eliminated when co-morbid conditions were added to the model. Moderate-severe brain injury was associated with decreased mean white matter fractional anisotropy (-0.012, 95% CI -0.02 to -0.004, p=0.002).
Brain microstructure maturation as measured serially in premature infants is independent of extremely premature birth. Brain injury and co-morbid conditions may be the important determinants of microstructure maturation.
PMCID: PMC2957506  PMID: 20598316
Infant, premature; Magnetic resonance imaging; Diffusion tensor imaging
14.  Mediators and moderators of the effects of a year-long exercise intervention on endogenous sex hormones in postmenopausal women 
Cancer Causes & Control  2011;22(10):1365-1373.
To identify factors that mediate or moderate the effects of exercise on postmenopausal sex hormone concentrations.
Postmenopausal women were randomized to 12 months of aerobic exercise for 200 min/week (n = 160) or to a control group (n = 160). Intention-to-treat analyses were performed using general linear models with sex hormone concentrations at 6 and 12 months as the outcome. Mediation by adiposity and insulin was investigated by examining changes in effect estimates after adjustment for changes in these factors over 12 months. Moderation was studied as the interaction between group assignment and eight baseline characteristics.
Intervention effects on sex hormone–binding globulin (SHBG) and estradiol changes were attenuated with adjustment for change in overall body fat, while there was less attenuation adjusting for intra-abdominal fat change. Intervention effects on SHBG levels were unaffected by adjustment for insulin change. Significant interactions were identified between treatment and physical fitness (for SHBG and testosterone) and age (for testosterone), implying subgroup differences in intervention effect.
Our data suggest that overall fat loss partially mediated exercise-induced changes in estradiol and SHBG concentrations. No previous RCT in postmenopausal women has studied moderators of exercise-induced sex hormone changes; therefore, future studies are needed to corroborate our results.
PMCID: PMC3176403  PMID: 21732049
Exercise; Gonadal steroid hormones; Sex hormone–binding globulin; Randomized controlled trial; Breast neoplasms
15.  Immediate vs. delayed insertion of intrauterine contraception after second trimester abortion: study protocol for a randomized controlled trial 
Trials  2011;12:149.
We describe the rationale and protocol for a randomized controlled trial (RCT) to assess whether intrauterine contraception placed immediately after a second trimester abortion will result in fewer pregnancies than current recommended practice of intended placement at 4 weeks post-abortion. Decision analysis suggests the novel strategy could substantially reduce subsequent unintended pregnancies and abortions. This paper highlights considerations of design, implementation and evaluation of a trial expected to provide rigorous evidence for appropriate insertion timing and health economics of intrauterine contraception after second trimester abortion.
Consenting women choosing to use intrauterine contraception after abortion for a pregnancy of 12 to 24 weeks will be randomized to insertion timing groups either immediately (experimental intervention) or four weeks (recommended care) post abortion. Primary outcome measure is pregnancy rate at one year. Secondary outcomes include: cumulative pregnancy rates over five year follow-up period, comprehensive health economic analyses comparing immediate and delayed insertion groups, and device retention rates, complication rates (infection, expulsion) and, contraceptive method satisfaction. Web-based Contraception Satisfaction Questionnaires, clinical records and British Columbia linked health databases will be used to assess primary and secondary outcomes. Enrolment at all clinics in the province performing second trimester abortions began in May 2010 and is expected to complete in late 2011. Data on one year outcomes will be available for analysis in 2014.
The RCT design combined with access to clinical records at all provincial abortion clinics, and to information in provincial single-payer linked administrative health databases, birth registry and hospital records, offers a unique opportunity to evaluate such an approach by determining pregnancy rate at one through five years among enrolled women. We highlight considerations of design, implementation and evaluation of a trial expected to provide rigorous evidence for appropriate insertion timing and health economics of intrauterine contraception after second trimester abortion.
Trial registration
Current Controlled Trials ISRCTN19506752
PMCID: PMC3141529  PMID: 21672213
16.  Changes in insulin resistance indicators, IGFs, and adipokines in a year-long trial of aerobic exercise in postmenopausal women 
Endocrine-Related Cancer  2011;18(3):357-369.
Physical activity is a known modifiable lifestyle means for reducing postmenopausal breast cancer risk, but the biologic mechanisms are not well understood. Metabolic factors may be involved. In this study, we aimed to determine the effects of exercise on insulin resistance (IR) indicators, IGF1, and adipokines in postmenopausal women. The Alberta Physical Activity and Breast Cancer Prevention Trial was a two-armed randomized controlled trial in postmenopausal, inactive, cancer-free women. A year-long aerobic exercise intervention of 225 min/week (n=160) was compared with a control group asked to maintain usual activity levels (n=160). Baseline, 6- and 12-month serum levels of insulin, glucose, IGF1, IGF-binding protein 3 (IGFBP3), adiponectin, and leptin were assayed, and after data collection, homeostasis model assessment of IR (HOMA-IR) scores were calculated. Intention-to-treat analyses were performed using linear mixed models. The treatment effect ratio (TER) of exercisers to controls was calculated. Data were available on 308 (96.3%) women at 6 months and 310 (96.9%) women at 12 months. Across the study period, statistically significant reductions in insulin (TER=0.87, 95% confidence interval (95% CI)=0.81–0.93), HOMA-IR (TER=0.86, 95% CI=0.80–0.93), and leptin (TER=0.82, 95% CI=0.78–0.87), and an increase in the adiponectin/leptin ratio (TER=1.21, 95% CI=1.13–1.28) were observed in the exercise group compared with the control group. No significant differences were observed for glucose, IGF1, IGFBP3, adiponectin or the IGF1/IGFBP3 ratio. Previously inactive postmenopausal women who engaged in a moderate-to-vigorous intensity exercise program experienced changes in insulin, HOMA-IR, leptin, and adiponectin/leptin that might decrease the risk for postmenopausal breast cancer.
PMCID: PMC3111235  PMID: 21482635
17.  Mammographic Density Change with One Year of Aerobic Exercise Among Postmenopausal Women: A Randomized Controlled Trial 
The Alberta Physical Activity and Breast Cancer Prevention (ALPHA) Trial examined the influence of aerobic exercise on biologic factors that are associated with breast cancer risk. Mammographic density, a secondary outcome, is reported here.
The ALPHA Trial was a parallel group randomized controlled trial conducted between May 2003 and July 2007. Postmenopausal, sedentary women aged 50 to 74 years (n = 320) were evenly randomized to aerobic exercise (45 minutes, 5 days per week) or control (usual lifestyle) for one year. Dense fibroglandular tissue and nondense fatty tissue were measured from mammograms at baseline and one year using computer-assisted thresholding software for area measurements and a new technique that relies on the calibration of mammography units with a tissue-equivalent phantom for volumetric measurements.
Nondense volume decreased in the exercise group relative to the control group (difference between groups = −38.5 cm3; 95% confidence interval = −61.6 to 15.4; P = 0.001). Changes in total body fat accounted for this decrease. Changes in dense area and dense volume, measures that have previously been associated with breast cancer risk, were not significantly different between the groups (P ≥ 0.36).
To achieve changes in mammographic measures may require more exercise or a study population with higher baseline levels of sex hormones or a wider range of mammographic density. The data from this study, however, suggest that the protective effect of exercise on breast cancer risk may operate through a mechanism other than mammographic density.
PMCID: PMC2945907  PMID: 20332266
Physical activity; mammographic density; breast cancer; postmenopausal women; randomized controlled trial
18.  Family physicians who provide intrapartum care and those who do not 
Canadian Family Physician  2011;57(4):e139-e147.
To examine FPs’ attitudes toward birth for those providing intrapartum care (IPC) and those providing only antepartum care (APC).
National, cross-sectional Web- and paper-based survey.
A total of 897 Canadian FPs: 503 providing both IPC and APC (FPIs), 252 providing only APC but who previously provided IPC (FPPs), and 142 providing only APC who never provided IPC (FPNs).
Main outcome measures
Respondents’ views (measured on a 5-point Likert scale) on routine electronic fetal monitoring, epidural analgesia, routine episiotomy, doulas, pelvic floor benefits of cesarean section, approaches to reducing cesarean section rates, maternal choice and the mother’s role in her own child’s birth, care providers’ fears of vaginal birth for themselves or their partners, and safety by mode or place of birth.
Results showed that FPIs and FPPs were more likely than FPNs were to take additional training or advanced life support courses. The FPIs consistently demonstrated more positive attitudes toward vaginal birth than did the other 2 groups. The FPPs and FPNs showed significantly more agreement with use of routine electronic fetal monitoring and routine epidural analgesia (P < .001). The FPIs displayed significantly more acceptance of doulas (P < .001) and more disagreement with the pelvic floor benefits of cesarean section than other FPs did (P < .001). The FPIs were significantly less fearful of vaginal birth for themselves or their partners than were FPPs and FPNs (P < .001). All FP groups agreed on rejection of elective cesarean section, in the absence of indications, for themselves or their partners and on support for vaginal birth in the presence of uterine scar. While all FP groups supported licensed midwifery, three-quarters thought home birth was more dangerous than hospital birth and showed ambivalence toward birth plans. Only 7.8% of FPIs would choose obstetricians for their own or their partners’ maternity care.
The FPIs had a more positive, evidence-based view of birth. It is likely that FPs providing only APC are influencing women in their practices toward a relatively negative view of birth before referral to obstetricians, FPIs, or midwives for the actual birth. The relatively negative views of birth held by FPs providing only APC need to be addressed in family practice education and in continuing education.
PMCID: PMC3076498  PMID: 21490345
19.  Alberta Physical Activity and Breast Cancer Prevention Trial: Sex Hormone Changes in a Year-Long Exercise Intervention Among Postmenopausal Women 
Journal of Clinical Oncology  2010;28(9):1458-1466.
We examined how an aerobic exercise intervention influenced circulating estradiol, estrone, sex hormone–binding globulin (SHBG), androstenedione, and testosterone levels, which may be involved in the association between physical activity and breast cancer risk.
A two-center, two-arm randomized controlled trial of exercise was conducted in 320 postmenopausal, sedentary women age 50 to 74 years. Participants were randomly assigned to a 1-year aerobic exercise intervention of 225 min/wk (n = 160) or to a control group who maintained their usual level of activity (n = 160). Baseline, 6-month, and 12-month assessments of estrone, estradiol, androstenedione, and testosterone were quantified by radioimmunoassay after extraction, and SHBG was quantified by an immunometric assay. Intent-to-treat analyses were performed using linear mixed models.
Blood data were available on 309 women (96.6%) at 12 months. Women in the intervention group exercised an average of 3.6 d/wk for 178 min/wk. At 12 months, statistically significant reductions in estradiol (treatment effect ratio [TER] = 0.93; 95% CI, 0.88 to 0.98) and free estradiol (TER = 0.91; 95% CI, 0.87 to 0.96) and increases in SHBG (TER = 1.04; 95% CI, 1.02 to 1.07) were observed in the exercise group compared with the control group. No significant differences in estrone, androstenedione, and testosterone levels were observed between exercisers and controls at 12 months.
This trial found that previously sedentary postmenopausal women can adhere to a moderate- to vigorous-intensity exercise program that results in changes in estradiol and SHBG concentrations that are consistent with a lower risk for postmenopausal breast cancer.
PMCID: PMC2849767  PMID: 20159820
20.  Designing and implementing a longitudinal study of children with neurological, genetic or metabolic conditions: charting the territory 
BMC Pediatrics  2010;10:67.
Children with progressive metabolic, neurological, or chromosomal conditions and their families anticipate an unknown lifespan, endure unstable and often painful symptoms, and cope with erratic emotional and spiritual crises as the condition progresses along an uncertain trajectory towards death. Much is known about the genetics and pathophysiology of these diseases, but very little has been documented about the trajectory of symptoms for children with these conditions or the associated experience of their families. A longitudinal study design will help to close this gap in knowledge.
Charting the Territory is a longitudinal descriptive, correlational study currently underway with children 0-19 years who are diagnosed with progressive neurological, metabolic, or chromosomal conditions and their families. The purpose of the study is to determine and document the clinical progression of the condition and the associated bio-psychosocial-spiritual experiences of the parents and siblings age 7-18 years. Approximately 300 families, both newly diagnosed children and those with established conditions, are being recruited in six Canadian cities. Children and their families are being followed for a minimum of 18 months, depending on when they enroll in the study. Family data collection will continue after the child's death if the child dies during the study period. Data collection includes monthly parental assessment of the child's symptoms; an annual functional assessment of the child; and completion of established instruments every 6 months by parents to assess family functioning, marital satisfaction, health status, anxiety, depression, stress, burden, grief, spirituality, and growth, and by siblings to assess coping and health. Impact of participation on parents is assessed after 1 year and at the end of the study. Chart reviews are conducted at enrollment and at the conclusion of the study or at the time of the child's death.
Knowledge developed from this study will provide some of the first-ever detailed descriptions of the clinical symptom trajectory of these non-curable progressive conditions and the bio-psychosocial-spiritual aspects for families, from diagnosis through bereavement. Information about developing and implementing this study may be useful to other researchers who are interested in designing a longitudinal study.
PMCID: PMC2954926  PMID: 20854664
21.  Effect of angiotensin-converting enzyme inhibition on C-reactive protein levels: The Ramipril C-Reactive pRotein Randomized evaluation (4R) trial results 
The Canadian Journal of Cardiology  2009;25(7):e236-e240.
Plasma levels of the inflammatory biomarker C-reactive protein (CRP) predict cardiovascular risk and may represent a target for treating and/or monitoring risk-reduction strategies. The effect of angiotensin-converting enzyme inhibitors on CRP levels has not been adequately studied.
A total of 264 men and women, with CRP levels of 2 mg/L or greater and no history of cardiovascular disease, were enrolled in a 12-week randomized, double-blind, placebo-controlled study. Participants were randomly assigned to receive 10 mg/day of ramipril (n=132) or placebo (n=132) for 12 weeks. The main outcome measure was the change in CRP levels from baseline to 12 weeks in the ramipril- versus placebo-treated patients.
The mean (± SD) age was 53±9 years (60% men). Baseline demographics were similar between the volunteers allocated to receive either placebo or ramipril. The geometric mean CRP at baseline was 3.84 mg/L (95% CI 3.62 mg/L to 4.06 mg/L). The percentage change in geometric mean CRP values over 12 weeks was −13.2% (95% CI −22.3% to −3.2%) in the placebo group compared with −21.1% (95% CI −29.9% to −11.2%) in the ramipril group (P nonsignificant), indicating no significant reduction in the primary end point of the trial.
A 12-week ramipril treatment protocol for healthy middle-aged volunteers did not lower CRP levels compared with placebo. However, because of the inherent variability of CRP levels, a much larger study is required to exclude a small treatment effect.
PMCID: PMC2723033  PMID: 19584979
ACE inhibitors; CRP; Risk factors
22.  Improving outcomes for ill and injured children in emergency departments: protocol for a program in pediatric emergency medicine and knowledge translation science 
Approximately one-quarter of all Canadian children will seek emergency care in any given year, with the two most common medical problems affecting children in the emergency department (ED) being acute respiratory illness and injury. Treatment for some medical conditions in the ED remains controversial due to a lack of strong supporting evidence.
The purpose of this paper is to describe a multi-centre team grant in pediatric emergency medicine (PEM) that has been recently funded by the Canadian Institutes of Health Research (CIHR). This program of research integrates clinical research (in the areas of acute respiratory illness and injury) and knowledge translation (KT). This initiative includes seven distinct projects that address the objective to generate new evidence for clinical care and KT in the pediatric ED. Five of the seven research projects in this team grant make significant contributions to knowledge development in KT science, and these contributions are the focus of this paper.
The research designs employed in this program include: cross-sectional surveys, randomized controlled trials (RCTs), quasi-experimental designs with interrupted time-series analysis and staggered implementation strategies, and qualitative designs.
This team grant provides unique opportunities for making important KT methodological developments, with a particular focus on developing a better theoretical understanding of the causal mechanisms and effect modifiers of different KT interventions.
PMCID: PMC2754977  PMID: 19772665
23.  Determination of the minimal clinically important difference for seven fatigue measures in rheumatoid arthritis 
Journal of clinical epidemiology  2008;61(7):705-713.
To estimate the minimal clinically important difference (MCID) of seven measures of fatigue in rheumatoid arthritis.
Study Design and Setting
A cross-sectional study design based on inter-individual comparisons was used. Six to eight subjects participated in a single meeting and completed seven fatigue questionnaires (nine sessions were organized and 61 subjects participated). After completion of the questionnaires, the subjects had five one-on-one 10-minute conversations with different people in the group to discuss their fatigue. After each conversation, each patient compared their fatigue to their conversational partner’s on a global rating. Ratings were compared to the scores of the fatigue measures to estimate the MCID. Both non-parametric and linear regression analyses were used.
Non-parametric estimates for the MCID relative to “little more fatigue” tended to be smaller than those for “little less fatigue”. The global MCIDs estimated by linear regression were: FSS 20.2, VT 14.8, MAF 18.7, MFI 16.6, FACIT–F 15.9, CFS 9.9, RS 19.7, for normalized scores (0 to 100). The standardized MCIDs for the seven measures were roughly similar (0.67 to 0.76).
These estimates of MCID will help to interpret changes observed in a fatigue score and will be critical in estimating sample size requirements.
PMCID: PMC2486378  PMID: 18359189
minimal clinically important difference; sample size requirement; fatigue; rheumatoid arthritis; health status; interpretation
24.  Do educational materials change knowledge and behaviour about crying and shaken baby syndrome? A randomized controlled trial 
Shaken baby syndrome often occurs after shaking in response to crying bouts. We questioned whether the use of the educational materials from the Period of PURPLE Crying program would change maternal knowledge and behaviour related to shaking.
We performed a randomized controlled trial in which 1279 mothers received materials from the Period of PURPLE Crying program or control materials during a home visit by a nurse by 2 weeks after the birth of their child. At 5 weeks, the mothers completed a diary to record their behaviour and their infants' behaviour. Two months after giving birth, the mothers completed a telephone survey to assess their knowledge and behaviour.
The mean score (range 0–100 points) for knowledge about infant crying was greater among mothers who received the PURPLE materials (63.8 points) than among mothers who received the control materials (58.4 points) (difference 5.4 points, 95% confidence interval [CI] 4.1 to 6.5 points). The mean scores were similar for both groups for shaking knowledge and reported maternal responses to crying, inconsolable crying and self-talk responses. Compared with mothers who received control materials, mothers who received the PURPLE materials reported sharing information about walking away if frustrated more often (51.5% v. 38.5%, difference 13.0%, 95% CI 6.9% to 19.2%), the dangers of shaking (49.3% v. 36.4%, difference 12.9%, 95% CI 6.8% to 19.0%), and infant crying (67.6% v. 60.0%, difference 7.6%, 95% CI 1.7% to 13.5%). Walking away during inconsolable crying was significantly higher among mothers who received the PURPLE materials than among those who received control materials (0.067 v. 0.039 events per day, rate ratio 1.7, 95% CI 1.1 to 2.6).
The receipt of the Period of PURPLE Crying materials led to higher maternal scores for knowledge about infant crying and for some behaviours considered to be important for the prevention of shaking. ( trial register no. NCT00175422.)
PMCID: PMC2659818  PMID: 19255065
25.  Effects of an enhanced secondary prevention program for patients with heart disease: A prospective randomized trial 
The Canadian Journal of Cardiology  2007;23(13):1066-1072.
Secondary prevention medications in cardiac patients improve outcomes. However, prescription rates for these drugs and long-term adherence are suboptimal.
To determine whether an enhanced secondary prevention program improves outcomes.
Hospitalized patients with indications for secondary prevention medications were randomly assigned to either usual care or an intervention arm, in which an intensive program was used to optimize prescription rates and long-term adherence. Follow-up was 19 months.
A total of 2643 patients were randomly assigned in the study; 1342 patients were assigned to usual care and 1301 patients were assigned to the intervention arm. Prescription rates were near optimal except for lipid-lowering medications. Rehospitalization rates per 100 patients were 136.2 and 132.6 over 19 months in the usual care and intervention groups, respectively (P=0.59). Total days in hospital per patient were similar (10.9 days in the usual care group versus 10.2 days in the intervention group; P not significant). Crude mortality was 6.2% and 5.5% in the usual care and intervention groups, respectively, with no significant difference (P=0.15) in overall survival. Post hoc analysis suggested that after the study team became experienced, days in hospital per patient were reduced by the program (11.1±0.91 and 8.9±0.61 in the usual care and intervention groups, respectively; P<0.05).
The intervention program failed to improve outcomes in the present study. One explanation for these results is the near optimal physician compliance with guidelines in both groups. It is also possible that a substantial learning curve for the staff was involved, as suggested by the reduction in total days in hospital in the intervention patients during the second part of the study.
PMCID: PMC2651931  PMID: 17985009
Guideline adherence; Secondary prevention

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