Effects of aqueous extract from Baiyedancong-Oolong tea on cytochrome P450 enzymes activities, P-gp and OATs transport abilities and transcription levels in mice.

Introduction: Recent studies have been conducted on its influence on drug metabolism and its potential mechanisms, among which the most studies have been focused on CYP3A enzymes. Methods: In this study, Baiyedancong Oolong tea (BOT) was processed by freeze- and hot air-drying techniques separately to obtain the aqueous extracts of freeze-and hot-dried BOT (FBOT and HBOT, respectively). High and low doses of FBOT (1463.7 and 292.74 mg/kg/d, respectively) and HBOT (1454.46 mg/kg/d, 290.89, respectively) were administered to mice for 7 days. Results: Aqueous extracts from BOT simultaneously improved liver CYP3A, CYP2E1, and CYP2C37 activities and weakened the transport ability of P-gp and OATs in a dose-dependent manner, thus affecting multiple links of oral drug metabolism in liver, intestinal absorption and metabolism, and renal excretion. Moreover, aqueous extracts from BOT significantly increased the mRNA expressions of liver CYP3A11 and CYP2C37 as well as intestinal CYP3A11. Decreased transcription levels of MDR1 encoding P-gp in small intestine and renal OAT1 and OAT3, which was in the same direction as the regulation of the above enzyme activities and transport capacities. Besides, the transcription level of liver CYP2E1 was weakened, which was inconsistent with its corresponding enzyme activity, suggesting that the increased CYP2E1 activity may be caused by other mechanisms. Conclusion: Daily consumption or high dose administration of BOT and its related products may affect drug absorption, metabolisms, and excretion.

Validation of Canproj for projecting Canadian cancer incidence data. / Validation de Canproj pour les projections de données sur l'incidence du cancer au Canada.

INTRODUCTION: Cancer projections can provide key information to help prioritize cancer control strategies, allocate resources and evaluate current treatments and interventions. Canproj is a cancer-projection tool that builds on the Nordpred R-package by adding a selection of projection models. The objective of this project was to validate the Canproj R-package for the short-term projection of cancer rates. METHODS: We used national cancer incidence data from 1986 to 2014 from the National Cancer Incidence Reporting System and Canadian Cancer Registry. Cross-validation was used to estimate the accuracy of the projections generated by Canproj and relative bias (RB) was used as validation measure. The Canproj automatic model selection decision tree was also assessed. RESULTS: Five of the six models had mean RB between 5% and 10% and median RB around 5%. For some of the cancer sites that were more difficult to project, a shorter time period improved reliability. The Nordpred model was selected 79% of the time by Canproj automatic model selection although it had the smallest RB only 24% of the time. CONCLUSIONS: The Canproj package was able to provide projections that closely matched the real data for most cancer sites.

Survival of metastatic colorectal cancer patients treated with chemotherapy in Alberta (1995-2004).

GOALS OF WORK: Clinical trials have suggested that advances in chemotherapy significantly improve the survival of patients with metastatic colorectal cancer. Comparable evidence from clinical practice is scarce. This study aims to investigate the survival of patients with metastatic colorectal cancer treated with chemotherapy in Alberta, Canada. PATIENTS AND METHODS: Trends of relative survival of patients diagnosed in 1994-2003 were assessed using Alberta Cancer Registry (ACR) data. The median overall survival (OS) of patients diagnosed in 2004 was determined by linking Cancer Registry data with Electronic Medical Records (EMR). Cox regression models were fitted to calculate the hazard ratio for patients treated with chemotherapy. RESULTS: The 2-year relative survival for patients with metastatic colorectal cancer who received chemotherapy increased significantly from 29% to 41% over the 10 years (1994-2003, p < 0.015). A 69% reduction in the risk of mortality was observed in the 168 patients who received chemotherapy compared to the 87 patients who did not, after adjusting for age, gender, and number of metastases. The median OS of patients who received chemotherapy was 17.5 months. This is comparable to the 18-20 months seen in recently published clinical trials, considering the patients in this study were from the real clinical practice, nearly half of them were older than 70, and many of them might have important co-morbidities. CONCLUSIONS: The survival of patients diagnosed with metastatic colorectal cancer in Alberta has improved in recent years; this is most likely attributable in large part to the use of chemotherapy.

Prevalence, trend, and sociodemographic association of five modifiable lifestyle risk factors for cancer in Alberta and Canada.

OBJECTIVES: To examine the 12-year trend, in Alberta and Canada, of five modifiable lifestyle risk factors for cancer, and their associations with sociodemographic factors. METHODS: Six surveys collected data from Canadians aged > or =12 years. The prevalence, trends, and sociodemographic association of five lifestyle risk factors (smoking, inactivity, excessive drinking, overweight/obesity, and insufficient fruit/vegetable intake) were examined. RESULTS: Smoking and inactivity decreased significantly: by 5.4% and 2.7% (Alberta men) and 4.9% and 12.1% (Alberta women); by 7.5% and 8.5% (Canada men) and 7.7% and 11.9% (Canada women). Excessive drinking increased significantly: by 3.6% (men) and 0.9% (women), Alberta; by 2.5% (men) and 0.9% (women), Canada. Overweight/obesity significantly increased by 6.0% (Alberta) and 4.1% (Canada) in women. Being female, single, highly educated, or having higher income decreased the likelihood of exposure to multiple lifestyle risk factors; being middle aged, widowed/separated/divorced, or in poor health condition increased the likelihood. CONCLUSIONS: The downward trends for smoking and physical inactivity were in a direction that may help reduce cancer burden. The excessive drinking and overweight/obesity trends did not change in desired direction and deserve attention. The clustering of the lifestyle risk factors in specific social groups provides useful information for future intervention planning.

A prospective study of iodine status, thyroid function, and prostate cancer risk: follow-up of the First National Health and Nutrition Examination Survey.

Few studies have investigated the association between iodine status, thyroid disease, and cancer risk despite evidence that thyroid function impacts many organs, including the prostate. We investigated iodine status and prostate cancer risk prospectively using data from the NHANES I Epidemiologic Follow-up Study. Participants were stratified into tertiles according to the urinary iodine/creatinine ratio, as a marker of iodine exposure. As iodine is an integral constituent of thyroid hormones, we also examined the relationship between thyroid disease and prostate cancer risk. Relative to the group with low urinary iodine, the age-adjusted hazard ratio was higher (although marginally insignificant) in the moderate group, hazard ratio 1.33 (95% confidence interval 1.00-1.78), and significantly lower in the high group, 0.71 (0.51-0.99). Thyroid disease was associated with an increased prostate cancer risk, 2.34 (1.24-4.43). Similarly, > 10 yr since thyroid disease diagnosis was associated with an elevated risk, 3.38 (1.66-6.87). After adjusting for other confounding factors, only a history of thyroid disease, 2.16 (1.13-4.14), and > 10 yr since diagnosis of thyroid disease, 3.17 (1.54-6.51) remained significant. Although the role of dietary iodine remains speculative, a role for thyroid disease and/or factors contributing to thyroid disease as a risk factor for prostate carcinogenesis warrants additional investigation.

Neonatal intensive care unit characteristics affect the incidence of severe intraventricular hemorrhage.

OBJECTIVES: The incidence of intraventricular hemorrhage (IVH), adjusted for known risk factors, varies across neonatal intensive care units (NICU)s. The effect of NICU characteristics on this variation is unknown. The objective was to assess IVH attributable risks at both patient and NICU levels. STUDY DESIGN: Subjects were <33 weeks' gestation, <4 days old on admission in the Canadian Neonatal Network database (all infants admitted in 1996-97 to 17 NICUs). The variation in severe IVH rates was analyzed using Bayesian hierarchical modeling for patient level and NICU level factors. RESULTS: Of 3772 eligible subjects, the overall crude incidence rates of grade 3-4 IVH was 8.3% (NICU range 2.0-20.5%). Male gender, extreme preterm birth, low Apgar score, vaginal birth, outborn birth, and high admission severity of illness accounted for 30% of the severe IVH rate variation; admission day therapy-related variables (treatment of acidosis and hypotension) accounted for an additional 14%. NICU characteristics, independent of patient level risk factors, accounted for 31% of the variation. NICUs with high patient volume and high neonatologist/staff ratio had lower rates of severe IVH. CONCLUSIONS: The incidence of severe IVH is affected by NICU characteristics, suggesting important new strategies to reduce this important adverse outcome.

Chorioamnionitis with a fetal inflammatory response is associated with higher neonatal mortality, morbidity, and resource use than chorioamnionitis displaying a maternal inflammatory response only.

OBJECTIVE: This study was undertaken to evaluate whether the proximity of infection of the chorion/amnion and fetal vessels affects neonatal outcomes. STUDY DESIGN: We examined all (n=2012) infants admitted to the British Columbia's Children's Hospital Neonatal Intensive Care Unit, from January 1996 to October 1997. We included infants with a placental examination (n=1296), and stratified those with histologic chorioamnionitis into cases displaying a maternal inflammatory response only and cases also displaying a fetal inflammatory response (funisitis and/or fetal surface vessel angiitis). RESULTS: Histologic evidence of chorioamnionitis was present in 31% of placentas. Of those, 38% exhibited maternal inflammation only, whereas 62% also exhibited fetal inflammation. Neonatal mortality (9.2% vs 7.2%), morbidity, and resource use were significantly (P < .05) higher when fetal inflammation was present compared with when only maternal inflammation was present. CONCLUSION: Chorioamnionitis with a fetal inflammatory response is associated with higher neonatal mortality, morbidity, and resource use than when only a maternal inflammatory response is present.

Variations in rates of nosocomial infection among Canadian neonatal intensive care units may be practice-related.

BACKGROUND: Nosocomial infection (NI), particularly with positive blood or cerebrospinal fluid bacterial cultures, is a major cause of morbidity in neonatal intensive care units (NICUs). Rates of NI appear to vary substantially between NICUs. The aim of this study was to determine risk factors for NI, as well as the risk-adjusted variations in NI rates among Canadian NICUs. METHODS: From January 1996 to October 1997, data on demographics, intervention, illness severity and NI rates were submitted from 17 Canadian NICUs. Infants admitted at < 4 days of age were included. NI was defined as a positive blood or cerebrospinal fluid culture after > 48 hrs in hospital. RESULTS: 765 (23.5%) of 3253 infants < 1500 g and 328 (2.5%) of 13228 infants > or = 1500 g developed at least one episode of NI. Over 95% of episodes were due to nosocomial bacteremia. Major morbidity was more common amongst those with NI versus those without. Mortality was more strongly associated with NI versus those without for infants > or = 1500 g, but not for infants < 1500 g. Multiple logistic regression analysis showed that for infants < 1500 g, risk factors for NI included gestation < 29 weeks, outborn status, increased acuity on day 1, mechanical ventilation and parenteral nutrition. When NICUs were compared for babies < 1500 g, the odds ratios for NI ranged from 0.2 (95% confidence interval [CI] 0.1 to 0.4) to 8.6 (95% CI 4.1 to 18.2) when compared to a reference site. This trend persisted after adjustment for risk factors, and was also found in larger babies. CONCLUSION: Rates of nosocomial infection in Canadian NICUs vary considerably, even after adjustment for known risk factors. The implication is that this variation is due to differences in clinical practices and therefore may be amenable to interventions that alter practice.

Improved outcomes of outborn preterm infants if admitted to perinatal centers versus freestanding pediatric hospitals.

OBJECTIVES: To examine whether admission hospital type (13 perinatal centers vs 4 freestanding pediatric hospitals) was associated with differences in risk and illness severity adjusted mortality and morbidity among outborn preterm infants. STUDY DESIGN: Records of singleton outborn infants < or =32 weeks' gestational age (n = 605) admitted to 17 tertiary level neonatal intensive care units participating in the Canadian Neonatal Network for the period 1996 to 1997 were examined. RESULTS: Outborn infants admitted to freestanding pediatric hospitals were at higher risk of death (adjusted odds ratio [AOR], 2.25; 95% confidence interval [CI], 1.20, 4.20), nosocomial infection (AOR, 2.48; 95% CI, 1.64, 3.73), and oxygen dependency at 28 days of age (AOR, 1.77; 95% CI, 1.14, 2.75) when compared with outborn infants admitted to perinatal centers. CONCLUSIONS: After adjustment for perinatal risks and admission illness severity, outborn infants had better outcomes if they were admitted to perinatal centers compared with freestanding pediatric hospitals.

SNAP-II predicts mortality among infants with congenital diaphragmatic hernia.

OBJECTIVE: Outcomes analysis in congenital diaphragmatic hernia (CDH) requires a validated risk-adjustment tool. The purpose of this study was to use the Canadian Neonatal Network (CNN) database to validate the Score for Neonatal Acute Physiology, Version II (SNAP-II) for prediction of mortality among CDH infants admitted to a neonatal intensive care unit (NICU), and to compare this to the predictive equation recently developed by the Congenital Diaphragmatic Hernia Study Group (CDHSG). STUDY DESIGN: Infants with CDH in the CNN database were identified. Bivariate and multivariable logistic regression models were used to identify risk factors predictive of mortality. Model predictive performance and calibration were assessed using the area under the receiver operator characteristic curve and the technique of Hosmer-Lemeshow, respectively, and compared with the CDHSG predictive equation. RESULTS: There were 88 patients with CDH among 19,507 admissions to CNN hospitals. The mortality rate among CDH patients surviving to NICU admission was 17%, and 12.5% received extracorporeal membrane oxygenation therapy. Gestational age and admission SNAP-II score predicted mortality. Model predictive performance and calibration were optimized with these variables combined. The CDHSG equation was equally predictive of mortality, but was only marginally calibrated. CONCLUSIONS: SNAP-II is highly predictive of mortality among patients with CDH, and can be used to risk-adjust these patients.

Variations in incidence of necrotizing enterocolitis in Canadian neonatal intensive care units.

OBJECTIVES: Necrotizing enterocolitis (NEC) is the most common acquired intestinal disease of neonates. Previous reports on incidence have generally examined small cohorts of extremely low-birth-weight infants and have not examined risk-adjusted variations among neonatal intensive care units (NICUs). The authors examined risk-adjusted variations in the incidence of NEC in a large group of Canadian NICUs and explored possible therapy-related risks. METHODS: The authors obtained data on 18,234 infants admitted to 17 tertiary level Canadian NICUs from January 1996 to October 1997. They used multivariate logistic regression analysis to examine the inter-NICU variation in incidence of NEC, with adjustment for population risk factors and admission illness severity, and explored therapy-related variables. RESULTS: The incidence of NEC was 6.6% (n = 238) among 3,628 infants with birth weight < or = 1,500 g (VLBW), and 0.7% (n = 98) among 14,606 infants with birth weight > 1,500 g (HBW). Multivariate logistic regression analysis showed that for VLBW infants, NEC was associated with lower gestational age and treatment for hypotension and patent ductus arteriosus. Among HBW infants, NEC was associated with lower gestational age, presence of congenital anomalies (cardiovascular, digestive, musculoskeletal, multiple systems) and need for assisted ventilation. There was no significant variation in the risk-adjusted incidence of NEC among NICUs, with the exception of one NICU reporting no cases of NEC. CONCLUSIONS: Risk factors for NEC were different in VLBW and HBW infants. There was no significant variation in the risk-adjusted incidence of NEC among Canadian NICUs, with one possible exception.

Bayesian hierarchical models for multi-level repeated ordinal data using WinBUGS.

Multi-level repeated ordinal data arise if ordinal outcomes are measured repeatedly in subclusters of a cluster or on subunits of an experimental unit. If both the regression coefficients and the correlation parameters are of interest, the Bayesian hierarchical models have proved to be a powerful tool for analysis with computation being performed by Markov Chain Monte Carlo (MCMC) methods. The hierarchical models extend the random effects models by including a (usually flat) prior on the regression coefficients and parameters in the distribution of the random effects. Because the MCMC can be implemented by the widely available BUGS or WinBUGS software packages, the computation burden of MCMC has been alleviated. However, thoughtfulness is essential in order to use this software effectively to analyze such data with complex structures. For example, we may have to reparameterize the model and standardize the covariates to accelerate the convergence of the MCMC, and then carefully monitor the convergence of the Markov chain. This article aims at resolving these issues in the application of the WinBUGS through the analysis of a real multi-level ordinal data. In addition, we extend the hierarchical model to include a wider class of distributions for the random effects. We propose to use the deviance information criterion (DIC) for model selection. We show that the WinBUGS software can readily implement such extensions and the DIC criterion.