The implementation of Electronic Medical Records (EMRs) may lead to improved quality of primary health care. To investigate this, we conducted a mixed methods study of eighteen Toronto family physicians who implemented EMRs in 2006 and nine comparison family physicians who continued to use paper records. We used a controlled before-after design and two focus groups. We examined five preventive services with Pay for Performance incentives: Pap smears, screening mammograms, fecal occult blood testing, influenza vaccinations and childhood vaccinations. There was no difference between the two groups: after adjustment, combined preventive services for the EMR group increased by 0.7% less than for the non-EMR group (p=0.55, 95% CI -2.8, 3.9). Physicians felt that EMR implementation was challenging.

Background and objectives Evidence suggests that circulating IGF-I levels increase mammographic density (a breast cancer risk factor) and breast cancer risk in premenopausal women. The objective of this thesis was to examine the association of genetic variation at the IGF1 gene with IGF-I concentration, mammographic density, breast cancer risk, and related anthropometric measures in premenopausal women. Methods Three IGF1 CA repeat polymorphisms (at the 5′ and 3′ ends, and in intron 2) were genotyped. A cross-sectional design was used to investigate their associations with IGF-I levels, mammographic density, BMI, weight, and height. Families from registries in Ontario and Australia were used to investigate associations with breast cancer risk and also BMI, weight and height. Results In the cross-sectional study, greater number of copies of the 5′ 19 allele were associated with lower circulating IGF-I levels. Greater number of 3′ 185 alleles were associated with greater percentage breast density, smaller amount of non-dense tissue, and lower BMI. Including BMI in regression models removed the association of the 3′ 185 allele with percentage breast density. In the family based study, nominally significant associations (5′ 21 allele, intron 2 212 allele, intron 2 216 allele) with breast cancer risk were observed, but significance was lost after multiple comparison adjustment. There was a stronger association between the intron 2 216 allele and risk under a recessive model, and 5′ allele groupings of length 18 to 20 and 20 or more repeats produced significant positive and negative associations respectively. These associations were not strongly supported in analyses stratified by registry. Results from the family based study did not support an association between genetic variation at IGF1 with BMI, weight or height. Conclusions No specific IGF1 variant influenced each of circulating IGF-I levels, mammographic density, and breast cancer risk. The failure to replicate the association of the 3′ 185 allele with BMI in the family based study suggests that the association of the 3′ 185 allele with percentage breast density is spurious, since this association was mediated through the relationship with BMI (suggesting IGF-I action on body fat). Evidence for an association between IGF1 and breast cancer risk was limited.

This dissertation involved linking a clinical cystic fibrosis (CF) data registry with administrative databases to evaluate clinical, demographic, and geographical predictors of hospitalization in CF patients living in Ontario over a 10 year period. In addition, this work assessed the ability of administrative data to identify individuals with CF using the clinical registry as the reference standard. Sex was an independent predictor of hospitalization rates for individuals with CF. Females had a significantly higher hospitalization rate compared to males even after adjusting for important clinical factors suggesting that this finding is not simply due to worse CF disease. In those between 7 and 19 years of age, the adjusted hospitalization rate was 38% higher in females (rate ratio[RR] 1.38, 95% confidence interval [CI] 1.11-1.73). Similarly in those over the age of 19, females had a 30% higher hospitalization rate compared to males (RR 1.30, 95% CI 1.06-1.59). Other significant predictors associated with higher hospitalization rates in both age groups were lower lung function, worse nutritional status, pancreatic insufficiency, and the presence of CF-related diabetes. The presence of Burkholderia cepacia complex in the sputum was a significant predictor in those over the age of 19 years (RR 1.54, 95% CI 1.26-1.89). Distance to CF centre, community size and socioeconomic status were not significant predictors of hospitalization rates in either age group. There was no significant trend in hospitalization rates over time once rates were adjusted for markers of disease severity (p=0.08). Comparing administrative data with the CF registry data, administrative data captured hospitalizations more comprehensively. Despite CF being a specific diagnosis, health administrative databases alone were insufficient to reliably and accurately identify individuals with CF unless they had been hospitalized. The reason for the gender disparity seen within this dissertation is likely multifactorial. There may be differences in outpatient management between the sexes, hormonal influences may modulate disease severity causing higher hospitalization rates, and patient and provider-level influences may affect the decision to hospitalize a patient. Further research is needed in this area to elucidate the factors contributing to this gender gap.

Background and Objectives: Little is known about the impact of nicotine replacement therapy (NRT) use duration on smoking cessation in the general population. This study determines whether duration of NRT use is associated with smoking cessation. Methods: Data were from the Ontario Tobacco Survey longitudinal study of a population-based cohort of baseline smokers who made serious quit attempts during 18 months of follow-up. The association between NRT (any NRT, patches, or gum) use duration and smoking cessation outcomes (short-term abstinence ≥1 month and long-term abstinence ≥12 months) was estimated by Poisson regression, adjusting for all confounding variables. Results: Among the 1,590 eligible smokers, 933 (59%) did not use any NRT, 535 (34%) used NRT <8 weeks, and 112 (8%) used NRT ≥8 weeks at follow-up. The median duration of NRT use was 14 days. A consistent “J” shape of associations between quit aid use duration and smoking cessation outcomes (quit rates) was found. Using any NRT, patches, or gum <8 weeks was generally associated with a lower likelihood of quitting, but using them ≥8 weeks was generally associated with a higher likelihood of quitting, compared to not using them. Only using patches for the recommended duration (≥8 weeks) was associated with a higher likelihood of short-term (relative risk, RR 1.74, 95% confidence interval, CI 1.21-2.50) and long-term (RR 2.62, 95% CI 1.25-5.50) abstinence at the end of 18 months of follow-up, compared to not using patches. Using gum ≥8 weeks was not associated with short- or long-term abstinence at the end of 18 months of follow-up. Conclusions: Using nicotine patches for the recommended duration is associated with successful short- and long-term abstinence in the general population. More efforts are needed to encourage smokers to use nicotine patches for eight or more weeks when attempting to quit.

The implementation of Electronic Medical Records (EMRs) may lead to improved quality of primary health care. To investigate this, we conducted a mixed methods study of eighteen Toronto family physicians who implemented EMRs in 2006 and nine comparison family physicians who continued to use paper records. We used a controlled before-after design and two focus groups. We examined five preventive services with Pay for Performance incentives: Pap smears, screening mammograms, fecal occult blood testing, influenza vaccinations and childhood vaccinations. There was no difference between the two groups: after adjustment, combined preventive services for the EMR group increased by 0.7% less than for the non-EMR group (p=0.55, 95% CI -2.8, 3.9). Physicians felt that EMR implementation was challenging.

GB virus C (GBV-C) is a common, apathogenic virus that can inhibit human immunodeficiency virus (HIV) replication in vitro. Persistent coinfection with GBV-C has been associated with improved survival among HIV-infected adults while loss of GBV-C viremia has been associated with poor survival. If GBV-C does inhibit HIV replication, it is possible that GBV-C infection may reduce mother-to-child-transmission (MTCT) of HIV. This study investigated whether maternal or infant GBV-C infection was associated with reduced MTCT of HIV infection. The study population consisted of 1,783 pregnant women from three Bangkok perinatal HIV transmission studies (1992-94, 1996-7, 1999-2004). We tested plasma collected at delivery for GBV-C RNA, GBV-C antibody, and GBV-C viral genotype. If maternal GBV-C RNA was detected, the four- or six-month infant specimen was tested for GBV-C RNA. Rates of MTCT of HIV in GBV-C-infected and GBV-C-uninfected women and infants were compared using multiple logistic regression as were associations with MTCT of GBV-C and prevalence of GBV-C infection. The prevalence of GBV-C infection (i.e. presence of RNA or antibody) was 33% among HIV-infected women and 15% among HIV-uninfected women. Forty-one percent of GBV-C-RNA-positive women transmitted GBV-C to their infants. Only two of 101 (2.0%) GBV-C-RNA-positive infants acquired HIV infection compared to 162 (13.2%) of 1,232 of GBV-C-RNA-negative infants (RR 0.15, p<0.0001). This association remained after adjustment for maternal HIV viral load, antiretroviral prophylaxis, CD4+ count and other covariates. MTCT of HIV was not associated with presence of maternal GBV-C RNA or maternal GBV-C antibody. Maternal receipt of antiretroviral therapy was associated with increased MTCT of GBV-C, as was high GBV-C viral load, vaginal delivery and absence of infant HIV infection. GBV-C infection among women was independently associated with more than one lifetime sexual partner, intravenous drug use and HIV-infection. We observed a higher prevalence of GBV-C infection among HIV-infected compared to HIV-uninfected pregnant women in Thailand, likely due to common risk factors. Antiretroviral therapy appears to increase MTCT of GBV-C. Infant GBV-C acquisition, but not maternal GBV-C infection, was significantly associated with reduced MTCT of HIV. Mechanisms for these later two associations are unknown. / Bhanich Supapol W, Remis RS, Raboud J, Millson M, Tappero J, Kaul R, Kulkarni P, McConnell MS, Mock PA, Culnane M, McNicholl J, Roongpisuthipong A, Chotpitayasunondh T, Shaffer N, Butera S. 2008. Reduced mother-to-child transmission of HIV associated with infant but not maternal GB virus C infection. J Infect Dis 197(10):1369-1377. Bhanich Supapol W, Remis RS, Raboud J, Millson M, Tappero JW, Kaul R, Kulkarni P, McConnell MS, Mock PA, McNicholl JM, Vanprarar N, Asavapiriayanont S, Shaffer N, Butera ST. 2009. Mother-to-child transmission of GB virus C in a cohort of women coinfected with GB virus C and HIV in Bangkok, Thailand. J Infect Dis 200:227-235.

Tamoxifen and aromatase inhibitors are treatment options for women with breast cancer and evidence on the risk of stroke is important in choosing between these two options. A systematic review of two randomized controlled trials and their nine related trial reports showed different methods for adverse event reporting and inconsistent estimates of stroke risk. In an observational cohort study of 5443 Ontario women, aged 66 years or older with early stage breast cancer, 86 ischemic stroke events (1.6%) occurred during follow-up of 5 years. There was no statistically significant difference in the risk of stroke between the hormone therapy groups [adjusted HR for tamoxifen compared to AI 1.330 (0.810, 2.179)]. Results were similar across cardiovascular disease risk groups and were robust to different follow up periods and analytic methods. This study suggests that there is no significant difference in stroke between these treatment options.

In this cross-sectional study, the sensibility, reliability, and validity of the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire were assessed in patients who underwent neck dissection for head and neck cancer. A sensibility questionnaire was used to assess face and content validity. Test-retest reliability was tested by re-mailing the questionnaire; validity, by evaluating differences in scores between patients undergoing different types of neck dissections and by correlating DASH scores with Neck Dissection Impairment Index (NDII) scores. The DASH was considered sensible by both patients and surgeons. The DASH was reliable with an intraclass coefficient of 0.91. The DASH showed differences between patients who underwent accessory nerve-sacrifice and nerve-sparing neck dissection. DASH scores strongly correlated with NDII scores. Thus, the DASH is a sensible, reliable, and valid instrument for assessing shoulder impairments and activity limitations following neck dissection.

Doctor of Philosophy / Department of Diagnostic Medicine/Pathobiology / H. Morgan Scott / Copper, as copper sulfate, is often used as an alternative to in-feed antibiotics for growth promotion in both swine and cattle diets. Gut bacteria exposed to copper can acquire resistance, which among enterococci is conferred by a plasmid-borne transferable copper resistance gene (tcrB). The plasmid also carries tetracycline [tet(M)] and macrolide [erm(B)] resistance genes. Because of the genetic link between acquired copper (tcrB) and antibiotic resistance in Enterococcus spp., we hypothesized that copper supplementation may exert selection pressure for enterococci to become resistant to macrolides and tetracyclines, and possibly to other antibiotics. We conducted studies in cattle and swine to investigate the relationship between copper supplementation and the fecal prevalence of tcrB-positive enterococci, as well as its potential co-selection for macrolide and tetracycline resistance. The prevalence was higher in animals fed diets supplemented with elevated level of copper compared to normal level (P < 0.05). The tcrB-positive isolates belonged to either E. faecium or E. faecalis; the majority was E. faecium. All tcrB-positive isolates also contained both erm(B) and tet(M) genes; however, none of them harbored the vanA gene. Median minimum inhibitory concentrations (MIC) of copper for tcrB-positive and tcrB-negative enterococci were 22 mM and 4 mM, respectively (P < 0.0001). The overall prevalence of erm(B) and tet(M) genes among enterococcal isolates of cattle were 46.8 % and 57.5%, respectively; in contrast,100% of the swine isolates were positive for both erm(B) and tet(M) genes. The transferability of the tcrB gene was demonstrated by filter mating assay. Multi-locus variable number tandem repeat analysis revealed a genetically diverse population of enterococci. The finding of a strong association between the copper resistance gene and other antibiotic (tetracycline and tylosin) resistance determinants is significant because enterococci are potential pathogens and have the propensity to transfer resistance genes to other bacteria in the gut. The occurrence of vancomycin resistant enterococci in swine in the US is very rare. Strains of E. faecium positive for vanA, that confers resistance to vancomycin, were isolated and characterized from swine feces. The swine strains belonged to clonal complex 17, a well-adapted hospital clone throughout the world.

Doctor of Philosophy / Department of Diagnostic Medicine/Pathobiology / Wenjun Ma / Influenza A virus (IAV) is an enveloped, segmented, negative-sense RNA virus that infects avian species and mammals. Its segmented feature enables antigenic shift which can generate novel IAVs that pose a threat to animal and public health due to lack of immunity to these viruses. Pigs have been considered the “mixing vessels” of influenza A viruses to generate novel reassortant viruses that may threaten animal and public health. Therefore, it is necessary to understand the pathogenicity and transmissibility of newly emerged reassortant viruses in swine. Adding to this complexity is the newly identified bat influenza A-like viruses which have roused interest in understanding the evolutionary history and pandemic potential of bat influenza. At least 10 different genotypes of novel reassortant H3N2 IAVs with gene(s) from 2009 pandemic H1N1 [A(H1N1)pdm09] have been identified in pigs in the United States. To date, only three genotypes of these viruses have been evaluated in animal models leaving the pathogenicity and transmissibility of the other seven genotype viruses unknown. We showed that reassortant viruses with genes from A(H1N1)pdm09 are pathogenic and transmissible in pigs. Further studies showed that avian-like glycine at position 228 of the HA receptor binding site is responsible for inefficient transmission of the reassortant H3N2 IAV with five A(H1N1)pdm09 genes. Studying the recently discovered IAV-like sequences from bats has been hindered by the lack of live virus isolation or culturing. Using synthetic genomics, we successfully rescued modified bat influenza viruses that had the HA and NA coding regions replaced with two classical IAVs. Additional studies were performed with truncations on NS1 protein and substitution of a putative virulence mutation in bat influenza PB2. Virus reassortment experiments demonstrated that bat influenza has limited genetic and protein compatibility with other influenza viruses; however, it readily reassorts with another divergent bat influenza virus. Taken together, our results provide insights into the pathogenicity and transmissibility of novel reassortant H3N2 IAVs in pigs. It also indicates that the bat influenza viruses recently identified are viable viruses that pose little pandemic threat to humans. Moreover, they provide new insights into the evolution and basic biology of influenza viruses.