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.

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.

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.

BACKGROUND: Adolescent idiopathic scoliosis (AIS) surgery is the most common reason for elective pediatric orthopaedic surgery. Minimization of adverse events is an important goal. Institute of Medicine (IOM) outlined 6 facets of healthcare quality improvement within the acronym STEEEP. Two of these facets, Safety and Timeliness for AIS surgery in Canada, are examined in this thesis. METHODS: A three - part study, using clinical records at the largest Canadian pediatric hospital and CIHI national administrative data, determined i) the relationship between surgical wait times and rates of adverse events, along with determination of an empirically derived access target, ii) accuracy of ICD-10 coding of surgical AIS cases along with an optimal search strategy to identify surgical AIS cases, and iii) the volume – outcome relationships for scoliosis surgery using hierarchical and conventional single level multi-variate regression analysis. RESULTS: Access target of 3 months minimized the adverse events related to waiting. Optimal search strategy for AIS surgical cases using ICD-10 coding required combination of codes as each code in isolation was inaccurate due to limitations in coding definitions. There was no significant volume – outcome relationship using appropriate modeling strategies. CONCLUSIONS: Ensuring timeliness of surgical treatment of less than 3 months is important in surgical cases of AIS given the potential for curve progression in higher risk individuals who are skeletally immature with large magnitude curves at time of surgical consent. At the administrative database level, knowledge of coding accuracy and optimal search strategies are needed to capture a complete cohort for analysis. In AIS, several ICD-10 codes need to be combined. AIS surgery cases captured through this optimal search strategy, revealed no significant volume-outcome relationships with appropriate modeling. Based on these results, minimum volume thresholds and regionalization of care for AIS surgery does not appear to be justified. However, a larger sample size was needed to determine whether there was a clinically significant difference in wound infection and blood transfusion rates. Furthermore, clinical variables, not part of an administrative database such as curve pattern were not included.

Despite the existence of numerous knee-joint specific patient-reported outcome measures, the content contained within such instruments does not completely capture the spectrum of injury and impairments experienced by multi-ligament knee injured patients. Based on this shortcoming, the overall objective of the current study was to develop, and to test the reliability and validity of a novel disease-specific quality of life instrument for patients with multi-ligament knee injuries. The World Health Organization’s International Classification of Functioning, Disability, and Health was used to guide content development. Using a mixed methods approach (surveys, patient focus groups, expert interviews), the final Multi-ligament Quality of Life (MLQOL) instrument was comprised of 52 items distributed over 4 domains. This instrument demonstrated excellent content validity, test-retest reliability, and construct validity. Future work will evaluate the responsiveness of the MLQOL and will implement its use in randomized trials.

BACKGROUND: Adolescent idiopathic scoliosis (AIS) surgery is the most common reason for elective pediatric orthopaedic surgery. Minimization of adverse events is an important goal. Institute of Medicine (IOM) outlined 6 facets of healthcare quality improvement within the acronym STEEEP. Two of these facets, Safety and Timeliness for AIS surgery in Canada, are examined in this thesis. METHODS: A three - part study, using clinical records at the largest Canadian pediatric hospital and CIHI national administrative data, determined i) the relationship between surgical wait times and rates of adverse events, along with determination of an empirically derived access target, ii) accuracy of ICD-10 coding of surgical AIS cases along with an optimal search strategy to identify surgical AIS cases, and iii) the volume – outcome relationships for scoliosis surgery using hierarchical and conventional single level multi-variate regression analysis. RESULTS: Access target of 3 months minimized the adverse events related to waiting. Optimal search strategy for AIS surgical cases using ICD-10 coding required combination of codes as each code in isolation was inaccurate due to limitations in coding definitions. There was no significant volume – outcome relationship using appropriate modeling strategies. CONCLUSIONS: Ensuring timeliness of surgical treatment of less than 3 months is important in surgical cases of AIS given the potential for curve progression in higher risk individuals who are skeletally immature with large magnitude curves at time of surgical consent. At the administrative database level, knowledge of coding accuracy and optimal search strategies are needed to capture a complete cohort for analysis. In AIS, several ICD-10 codes need to be combined. AIS surgery cases captured through this optimal search strategy, revealed no significant volume-outcome relationships with appropriate modeling. Based on these results, minimum volume thresholds and regionalization of care for AIS surgery does not appear to be justified. However, a larger sample size was needed to determine whether there was a clinically significant difference in wound infection and blood transfusion rates. Furthermore, clinical variables, not part of an administrative database such as curve pattern were not included.

Despite the existence of numerous knee-joint specific patient-reported outcome measures, the content contained within such instruments does not completely capture the spectrum of injury and impairments experienced by multi-ligament knee injured patients. Based on this shortcoming, the overall objective of the current study was to develop, and to test the reliability and validity of a novel disease-specific quality of life instrument for patients with multi-ligament knee injuries. The World Health Organization’s International Classification of Functioning, Disability, and Health was used to guide content development. Using a mixed methods approach (surveys, patient focus groups, expert interviews), the final Multi-ligament Quality of Life (MLQOL) instrument was comprised of 52 items distributed over 4 domains. This instrument demonstrated excellent content validity, test-retest reliability, and construct validity. Future work will evaluate the responsiveness of the MLQOL and will implement its use in randomized trials.

Objectives: The aim of this dissertation was to examine bias in randomized controlled trials (RCTs) and non-randomized studies (NRS) in surgery using the literature evaluating laparoscopy and conventional (i.e. open) surgery for the treatment of colon cancer as a case study. The objectives were 1) to develop a conceptual framework for bias in comparative NRS; 2) to compare effect estimates from NRS with those from RCTs at low risk of bias; 3) to explore the impact of NRS-design attributes on estimates of treatment effect. Methods: The methods included a modified framework synthesis, systematic review of the literature, random-effects meta-analyses, and frequentist and Bayesian meta-regression. The Cochrane Risk of Bias Tool was used to classify trials as Strong RCTs (i.e. low risk of bias) or Typical RCTs (i.e. unclear or high risk of bias). Results: A conceptual framework for bias in comparative NRS was developed and it contains 37 individual sources of bias or “items”. These items were organized within 6 overarching “domains”: selection bias, information bias, performance bias, detection bias, attrition bias, and selective reporting bias. Our analyses revealed that NRS were associated with more extreme estimates of benefit for laparoscopy than Strong RCTs when examining subjective outcomes. The odds ratios from NRS were 36% smaller (i.e. demonstrating more benefit for laparoscopy) than those from Strong RCTs for the outcome post-operative complications (Ratio of Odds Ratios, ROR 0.64, [0.42, 0.97], p=0.04). Similar exaggerated benefit was seen among NRS when assessing length of stay, (Difference in Mean Differences, -2.15 days, [-4.08, -0.21], p=0.03). This pattern was not observed with the objective outcomes peri-operative mortality and number of lymph nodes harvested. Analyses adjusted for period effects and between-study case-mix yielded similar findings. Finally, effect estimates in NRS did not consistently vary according to the presence or absence of nine design characteristics identified from the conceptual framework. Conclusions: We have demonstrated that the results of surgical NRS can be significantly biased as compared with those of low risk of bias RCTs when evaluating subjective outcomes. However, none of the nine NRS-design characteristics examined was consistently associated with biased effect estimates.

Objectives: The aim of this dissertation was to examine bias in randomized controlled trials (RCTs) and non-randomized studies (NRS) in surgery using the literature evaluating laparoscopy and conventional (i.e. open) surgery for the treatment of colon cancer as a case study. The objectives were 1) to develop a conceptual framework for bias in comparative NRS; 2) to compare effect estimates from NRS with those from RCTs at low risk of bias; 3) to explore the impact of NRS-design attributes on estimates of treatment effect. Methods: The methods included a modified framework synthesis, systematic review of the literature, random-effects meta-analyses, and frequentist and Bayesian meta-regression. The Cochrane Risk of Bias Tool was used to classify trials as Strong RCTs (i.e. low risk of bias) or Typical RCTs (i.e. unclear or high risk of bias). Results: A conceptual framework for bias in comparative NRS was developed and it contains 37 individual sources of bias or “items”. These items were organized within 6 overarching “domains”: selection bias, information bias, performance bias, detection bias, attrition bias, and selective reporting bias. Our analyses revealed that NRS were associated with more extreme estimates of benefit for laparoscopy than Strong RCTs when examining subjective outcomes. The odds ratios from NRS were 36% smaller (i.e. demonstrating more benefit for laparoscopy) than those from Strong RCTs for the outcome post-operative complications (Ratio of Odds Ratios, ROR 0.64, [0.42, 0.97], p=0.04). Similar exaggerated benefit was seen among NRS when assessing length of stay, (Difference in Mean Differences, -2.15 days, [-4.08, -0.21], p=0.03). This pattern was not observed with the objective outcomes peri-operative mortality and number of lymph nodes harvested. Analyses adjusted for period effects and between-study case-mix yielded similar findings. Finally, effect estimates in NRS did not consistently vary according to the presence or absence of nine design characteristics identified from the conceptual framework. Conclusions: We have demonstrated that the results of surgical NRS can be significantly biased as compared with those of low risk of bias RCTs when evaluating subjective outcomes. However, none of the nine NRS-design characteristics examined was consistently associated with biased effect estimates.

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.