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Cohen J.M.,Montreal Childrens Hospital Research Institute | Hutcheon J.A.,Biostatistics and Occupational Health | Kramer M.S.,Biostatistics and Occupational Health | Kramer M.S.,McGill University | And 3 more authors.
Ultrasound in Obstetrics and Gynecology | Year: 2010

Objectives To explore the effects of ultrasound-todelivery interval and maternal-fetal characteristics on the distribution of measurement error in estimated fetal weights (EFWs), and to determine the predictive ability of EFW for diagnosis of small-for-gestational age (SGA) and large-for-gestational age (LGA) among infants delivered within 1 day of an ultrasound examination. Methods Percentage differences between EFW and birth weights were calculated in 3697 pregnancies. Linear regression was used to compare the accuracy of EFW for births on each of the 6 days after an ultrasound scan with the accuracy observed among births on the same day. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value for diagnosis of SGA and LGA according to EFW was assessed. Results The mean ±} SD percentage difference among deliveries within 1 day of the last ultrasound scan was 0.2 ±} 9.0%. Mean percentage differences were not significantly different from day 0 on days 1, 2 and 3; however, combining the data from these 4 days obscured a slight bias towards an overestimation of weight evident on day 0 and day 1. Among deliveries within 1 day of an ultrasound scan, the PPV was 61% for SGA diagnosis and 54% for LGA diagnosis. Conclusion Combining data from births>1 day after the last ultrasound examinationmay lead to a false conclusion that there is systematic underestimation of weight. EFW tended to underestimate the weight of macrosomic fetuses and overestimate that of small fetuses which limitedsensitivity and PPV. Maternal-fetal characteristics are weak predictors of individual errors in EFW. Copyright ©2010 ISUOG. Published by John Wiley & Sons, Ltd.

Itzkovitz B.,Montreal Childrens Hospital Research Institute | Jiralerspong S.,Montreal Childrens Hospital Research Institute | Nimmo G.,Montreal Childrens Hospital Research Institute | Loscalzo M.,University of South Florida | And 7 more authors.
Human Mutation | Year: 2012

Rhizomelic chondrodysplasia punctata (RCDP) is a disorder of peroxisome metabolism resulting from a deficiency of plasmalogens, a specialized class of membrane phospholipids. Classically, patients have a skeletal dysplasia and profound mental retardation, although milder phenotypes are increasingly being identified. It is commonly caused by defects in the peroxisome transporter, PEX7 (RCDP1), and less frequently due to defects in the peroxisomal enzymes required to initiate plasmalogen synthesis, GNPAT (RCDP2) and AGPS (RCDP3). PEX7 transports AGPS into the peroxisome, where AGPS and GNPAT partner on the luminal membrane surface. The presence of AGPS is thought to be required for GNPAT activity. We present six additional probands with RCDP2 and RCDP3, and the novel mutations identified in them. Using cell lines from these and previously reported patients, we compared the amounts of both AGPS and GNPAT proteins present for the first time. We used protein modeling to predict the structural consequences of AGPS mutations and transcript analysis to predict consequences of GNPAT mutations, and show that milder RCDP phenotypes are likely to be associated with residual protein function. In addition, we propose that full GNPAT activity depends not only on the presence of AGPS, but also on the integrity of substrate channeling from GNPAT to AGPS. © 2011 Wiley Periodicals, Inc.

Platt R.W.,McGill University | Platt R.W.,Montreal Childrens Hospital Research Institute | Delaney J.A.C.,University of Florida | Suissa S.,McGill University | Suissa S.,McGill Pharmacoepidemiology Research Unit
European Journal of Epidemiology | Year: 2012

Estimates of the average causal effect (ACE) of warfarin on the risk of bleeding may be confounded by indication as patients at high risk of bleeding are unlikely to be prescribed warfarin. One approach to estimating the ACE is inverse probability of treatment weighting (IPTW). This study was designed to examine the use of IPTW in this setting, and to demonstrate problems with the violation of the positivity assumption. We analyzed a case-control study on 4,028 cases of gastro-intestinal bleeding and 79,239 controls set in the United Kingdom's General Practice Research Database. Warfarin exposure was defined as a prescription issued in the 90 days before the index date. Secondary analyses were conducted restricted to patients more likely to receive warfarin and with a truncated weight distribution, to exclude subjects highly unlikely to be treated. The estimated association between warfarin use and bleeding was stronger with IPTW [odds ratio (OR): 17.2; 95% confidence interval (CI): 6.5-37.7] than with a standard logistic regression model (OR: 2.1; 95% CI: 1.7-2.5). The presence of large weights (five subjects with stabilized weight >500) indicated a potential violation of the positivity assumption. In the restricted analysis, both IPTW (OR: 2.0; 95% CI: 0.4-9.6) and standard regression (OR: 1.6; 95% CI: 1.3-2.0) were compatible with a meta-analysis of randomized trials inverse probability of treatment weighting is sensitive to the positivity assumption; however, such sensitivity may assist in diagnosing off-support inference. © Springer Science+Business Media B.V. 2011.

Gaskins A.J.,National Health Research Institute | Wilchesky M.,Montreal Childrens Hospital Research Institute | Mumford S.L.,National Health Research Institute | Whitcomb B.W.,University of Massachusetts Amherst | And 4 more authors.
American Journal of Epidemiology | Year: 2012

C-reactive protein (CRP) is one of the most commonly used markers of acute phase reaction in clinical settings and predictors of cardiovascular risk in healthy women; however, data on its physiologic regulation in premenopausal women are sparse. The objective of this study was to evaluate the association between endogenous reproductive hormones and CRP in the BioCycle Study (2005-2007). Women aged 18-44 years from western New York were followed prospectively for up to 2 menstrual cycles (n = 259). Serum levels of CRP, estradiol, progesterone, luteinizing hormone, and follicle-stimulating hormone were measured up to 8 times per cycle, timed by fertility monitors. CRP levels varied significantly across the cycle (P < 0.001). More women were classified as being at elevated risk of cardiovascular disease (CRP, >3 mg/L) during menses compared with other phases (12.3% vs. 7.4%; P < 0.001). A 10-fold increase in estradiol was associated with a 24.3% decrease in CRP (95% confidence interval: 19.3, 29.0). A 10-fold increase in luteal progesterone was associated with a 19.4% increase in CRP (95% confidence interval: 8.4, 31.5). These results support the hypothesis that endogenous estradiol might have antiinflammatory effects and highlight the need for standardization of CRP measurement to menstrual cycle phase in reproductive-aged women. © The Author 2012.

Almodhen F.,McGill University | He X.,Montreal Childrens Hospital Research Institute | Loutochin O.,McGill University | Jednak R.,McGill University | And 2 more authors.
Urology | Year: 2011

Objectives To assess the role of hypothermia in testicular ischemic injury in a prepubertal rat model. Methods The study included 24 male, prepubertal Sprague-Dawley rats. Of the 24 rats, 20 were subjected to right testicular ischemia with and without hypothermia for 30 and 60 minutes, 5 in each group. The remaining 4 rats underwent sham operation and were used as controls. A vascular clamp was used to clamp the spermatic cord for the specified time. Hypothermic treatment consisted of placing the testicle in ice slush. At 8 weeks postoperatively, both testicles were harvested. The left testicle was used as the control. A pathologist, who was unaware of the groups, examined all the slides. The mean seminiferous tubular diameter (STD) and mean number of germinal cell layers (GCLs) were obtained. Results When the contralateral testicle was used as the control, the mean GCL and STD in the ipsilateral operated sides were significantly worse in all ischemic groups. When the sham-operated testicles were used as the control, no significant differences were found between the cold ischemia groups and the sham group. In the warm ischemia groups, the mean GCL and STD were significantly worse than those in the sham group. We compared the operated sides among the groups. At 30 minutes, the mean GCL and STD showed a trend toward preservation with cold ischemia, although the difference was insignificant. At 60 minutes, the mean GCL and STD were significantly worse with warm than with cold ischemia. Conclusions The results of our study have shown that permanent ipsilateral ischemic testicular damage occurred as early as 30 minutes in prepubertal rats. The damage might be reduced with hypothermia. © 2010 Elsevier Inc.

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