When the delicate hormonal balance in early pregnancy is disrupted, the consequences can be significant. We have a poor understanding of the "cross-talk" in the fetal/placental/ovarian axis that occurs throughout pregnancy and is essential for normal fetal development. This lack of knowledge challenges our ability to recognize disruptions in this axis that may be a signal for future disease. As a result, our ability to apply preventive measures against adverse obstetric outcomes, such as preterm birth (PTB), are quite limited. Attempts to predict PTB using biomarkers of feto-placental health have been largely unsuccessful, but no one has considered the inclusion of ovarian biomarkers in these models. Anti-Mullerian hormone (AMH) is a biomarker of ovarian activity that has recently been found to decline in early pregnancy at a time that corresponds to the involution of the corpus luteum (CL). The signal for CL involution is believed to originate from the placenta; therefore, the AMH levels in pregnancy may reflect the degree of ovarian up or down-regulation based on feto-placental needs. As the major function of the CL in pregnancy is the production of progesterone, which acts as an anti-inflammatory agent in the placental bed, changes in CL-derived progesterone could result in higher or lower degrees of placental inflammation. Therefore, monitoring the changes in AMH levels may provide insight into the inflammatory state of the placenta which could then be used as a signal for possible adverse obstetric outcomes resulting from a pro-inflammatory state, such as PTB. The first aim of this project was to test the hypothesis of an association between AMH levels in early pregnancy and PTB risk. When the differences in AMH levels between the 1st and 2nd trimesters of pregnancy were stratified by the level of maternal serum alpha-fetoprotein (MSAFP) and controlled for maternal weight gain between trimesters, small or absent decreases in AMH levels were associated with a higher probability of preterm birth. However, when AMH was modeled alone, no significant associations were found. The need for changes in multiple biomarkers in the fetal/placental/ovarian axis suggests that a change is only significant if it can impact multiple axis points. Therefore, models that included two biomarkers from different part of the axis would find stronger associations than two biomarkers from a single point (e.g. two feto-placental biomarkers), and monitoring these changes may help identify women at risk for PTB. The strategy of the second aim was to determine if the changes in AMH levels in early pregnancy could be used to predict time to delivery. Again, only when the risks of AMH and MSAFP were combined was a significant, dose-dependent relationship found with time to delivery. In women with an MSAFP of >1 multiple of the median (MoM), smaller declines and/or elevations in AMH levels were significantly associated with shorter times to delivery. In fact, 19% of women in the highest risk group delivered prior to 32 weeks gestation compared to 7% in the lowest risk group, and all infants who delivered prior to 24 weeks gestation were in the highest risk category. Thus, the amount of change in the AMH level when MSAFP is elevated may reflect the level of disruption in the fetal/placental/ovarian axis, which can then be used to predict time to delivery. Finally, the third aim of this study was to determine if AMH levels were associated with a pro-inflammatory placental state other than PTB. The degree of placental inflammation is known to vary by fetal gender, with male placentas having higher levels of inflammation compared to female placentas. When AMH levels were compared between women with male vs. female fetuses in early pregnancy, 1st trimester AMH levels were found to be lower when carrying a male fetus. Further, sexually-dimorphic patterns in AMH levels were seen between genders when stratified by birth outcome (term vs. preterm delivery). The stronger ovarian response seen in women with female fetuses suggests a better survival function and may account for the discrepancies between PTB rates in males and females. This also strengthens our hypothesis that the dynamic changes in AMH levels reflect the degree of placental inflammation and the need for CL-derived progesterone. This project demonstrates that the changes in AMH levels may be representative of the cross-talk occurring in the fetal/placental/ovarian axis in early pregnancy. Further, changes in AMH levels may be an indication of the amount of inflammation in the placenta and the physiologic need for higher levels of progesterone to control this inflammatory state when considered along with MSAFP. Therefore, the consideration of AMH levels as a biomarker of ovarian activity along with biomarkers of feto-placental health may provide clinically useful information about the development of future diseases such as preterm birth.

Lymphedema of the arm is a complication that occurs in about 10-20% of women treated for breast cancer. Breast cancer treatment can damage or disrupt normal lymphatic pathways, causing fluid to accumulate in the arm. This condition is called lymphedema. Swelling of the arm can be painful and disfiguring, negatively impacting the quality of life of afflicted individuals. Lymphedema is a progressive disorder that requires prompt diagnosis and treatment to prevent the occurrence of more serious complications, such as infection or severe disability of the arm. Past research have attempted to identify risk factors that influenced the development of lymphedema, however conflicting results were observed between studies. Therefore, a comprehensive literature review was conducted to identify studies that examined the effect of prognostic and/or personal factors on lymphedema. In the meta-analyses, results from each independent study were abstracted and pooled with other studies using the random-effects model. In an effort to examine additional factors that were not widely studied, a retrospective cohort study was conducted on women diagnosed with breast cancer in Iowa during 2004. A questionnaire was developed to collect information on arm activities, co-morbidity, and lymphedema-related symptoms. Eligible women were identified from the State Health Registry of Iowa and data were collected through computer-assisted telephone interviews. At the end of the interview, each woman was asked to measure the circumference of her right and left arm one hand width above and below the elbow crease. The meta-analysis found that mastectomy (as opposed to a lumpectomy), axillary dissection (as opposed to sentinel node biopsy), radiation therapy, presence of positive nodes, obesity (body mass index >30), low education (less than high school), presence of any co-morbidity, injury and infection increased the risk of developing lymphedema. The cohort study found that the presence of axillary dissection and radiation, cancer stage, positive nodes, large tumor size, high body mass index, and younger women increased the risk of lymphedema.

Leishmaniasis is a parasitic disease that affects humans and animals in more than 98 countries across the globe placing more than 1 billion people at risk for the disease and killing more than 20,000 people per year. In the United States the disease is enzootic within the hunting dog population and vertical transmission has been identified as the primary route of transmission in this population. In Brazil the disease is endemic in the human population and enzootic in the dog population with vector and vertical transmission having been reported. In many diseases reports have found there is increased disease severity when an individual is co-infected with another organism. Case reports have suggested this may also occur with tick borne diseases and leishmaniosis in dogs but there is limited longitudinal data to support this relationship. Even less is known and understood regarding the risk factors and basic reproduction number, number of secondary cases one infected individual can cause in a susceptible population, of leishmaniosis in regards to vertical transmission. The goal of the work presented in this thesis is to address host factors related to the transmission of L. infantum and the way in which co-infections affect the progression of the disease both in the U.S. and in Brazil. Understanding the risk factors associated with the transmission of the parasite Leishmania infantum, the causative agent of the disease, are necessary to controlling and potentially elimination the disease. Utilizing a large prospective cohort and both active and passive surveillance it was identified that leishmaniosis can be maintained in a population via vertical transmission at prevalence rates similar to other endemic countries, 20%. With this knowledge an additional study examining a longitudinal cohort and assessing the impact of tick borne disease co-infections upon disease transmission was performed. It was identified that dogs exposed to three or more tick borne diseases were 11x more likely to progress to clinical disease (Adjusted RR: 11.64 95% CI: 1.22-110.99 p-value: 0.03) than dogs with no tick borne disease exposures. Furthermore, dogs with Leishmania and tick borne disease were 5x more likely to die within the study (RR: 4.85 95% CI: 1.65-14.24 p-value: 0.0051). When examining this relationship in a cross-sectional study in Brazil it was found that dogs with multiple tick borne disease exposures had 1.68x greater risk of being positive for Leishmania (Adjusted RR: 1.68 95% CI: 1.09-2.61 p-value: 0.019). Using a retrospective cohort of dogs and information regarding their dam’s diagnostic status near the time of pregnancy risk factors associated with vertical transmission and the basic reproduction number were calculated. It was found that dogs who were born to dams that were ever diagnostically positive for exposure and/or infection with L. infantum were 13.84x more likely become positive for L. infantum within their lifetime (RR: 13.84 95% CI: 3.54-54.20 p-value < 0.0001). The basic reproduction number for vertically transmitted L. infantum within this cohort was 4.16. The results of these studies suggest that leishmaniosis can be maintained in a population through vertical transmission. Furthermore, the studies show the risk factors associated with vertical transmission relate to the mother’s diagnostic status at time of pregnancy. The results of the co-infection studies highlight the importance of tick prevention in order to reduce disease progression. With increased disease severity associated with increased transmission to potential vectors these studies underline the need for immunotherapies and prevention measures to reduce disease progression in order to reduce transmission. Furthermore, these studies highlight the need for public health control and prevention programs to address vertical transmission if elimination of the disease is to ever be successful.

Staphylococcus aureus (S. aureus) is a ubiquitous bacterium that has the potential to cause severe disease in children and adults. Asymptomatic carriage of S. aureus is an important risk factor for developing infection, as well as a key contributor to transmission. Despite the fact that child care workers are at risk of infections, little research has focused on asymptomatic carriage of S. aureus in this occupational group. We collected samples from 110 employees, 81 children, and 214 surfaces at twelve child care facilities, as well as 111 age- and gender-matched adults not employed at child care centers. After adjusting for age, a household contact with a recent influenza-like illness, and a household contact with exposure to cattle, the odds ratio for S. aureus carriage in child care employees was 0.68 (95% CI 0.31 - 1.50, p-value 0.34). The odds of MRSA carriage was 3.09 times higher in child care employees than unexposed adults after adjusting for a history of cigarette smoking (95% CI 1.04 - 9.17, p-value 0.042). Colonization rates of all S. aureus and MRSA in children were 19.8% and 1.23%, respectively. S. aureus and MRSA were isolated from 9.80% and 0.90% of surfaces. Washing children's hands upon arrival had a protective effect among employees (adjusted OR 0.17, 95% CI 0.095 - 0.32, p < 0.0001). Molecular characterization suggested transmission of S. aureus among children, employees, and environmental surfaces. While the overall prevalence of MRSA is low at child care facilities, employees may be at increased risk of carrying this organism.

This thesis is composed of three studies pertaining to the quality of care for radical cystectomy in Ontario between 1992 and 2004. In the first paper, the associations between provider volume and both operative and overall mortality were assessed. In the second paper, potential factors that could explain the association between volume and outcome were explored. In the final paper, the impact of waiting for cystectomy on survival outcomes was evaluated. Methods: A total of 3296 patients undergoing cystectomy for bladder cancer in Ontario between 1992 and 2004 were identified using the Canadian Institute for Health Information Discharge Abstract Database and the Ontario Cancer Registry. The effects of hospital and surgeon volume on operative mortality and overall survival were assessed using random effects logistic regression and marginal Cox Proportional Hazards modeling, respectively. To elucidate the factors underlying the volume-outcome association, the ability of a number of structure and process of care variables to attenuate the impact of volume was assessed. The effect of waiting for care, from transurethral resection to cystectomy, on overall survival was also assessed using marginal Cox models. Results: Neither hospital nor surgeon volume was significantly associated with operative mortality; however, both were associated with overall mortality. Of the measured structure/process measures, hospital factors caused the greatest attenuation of the volume hazard ratios, albeit to a limited degree. The wait time between the decision for surgery and cystectomy was also significantly associated with overall survival. The impact of delayed care was greatest for patients with lower stage disease. The data suggested a maximum wait time of 40 days for cystectomy. Conclusions: In this thesis, gaps in the quality of care for radical cystectomy in Ontario were identified. Patients treated by low volume hospitals and surgeons or those with long wait times all experienced worse outcomes. Since the underlying measures responsible for provider volume remain elusive, additional work is required to understand what these factors are. Initiatives to decrease wait times, however, are under way in Ontario. Whether these interventions decrease wait times and benefit patients remains to be seen.

This thesis is composed of three studies pertaining to the quality of care for radical cystectomy in Ontario between 1992 and 2004. In the first paper, the associations between provider volume and both operative and overall mortality were assessed. In the second paper, potential factors that could explain the association between volume and outcome were explored. In the final paper, the impact of waiting for cystectomy on survival outcomes was evaluated. Methods: A total of 3296 patients undergoing cystectomy for bladder cancer in Ontario between 1992 and 2004 were identified using the Canadian Institute for Health Information Discharge Abstract Database and the Ontario Cancer Registry. The effects of hospital and surgeon volume on operative mortality and overall survival were assessed using random effects logistic regression and marginal Cox Proportional Hazards modeling, respectively. To elucidate the factors underlying the volume-outcome association, the ability of a number of structure and process of care variables to attenuate the impact of volume was assessed. The effect of waiting for care, from transurethral resection to cystectomy, on overall survival was also assessed using marginal Cox models. Results: Neither hospital nor surgeon volume was significantly associated with operative mortality; however, both were associated with overall mortality. Of the measured structure/process measures, hospital factors caused the greatest attenuation of the volume hazard ratios, albeit to a limited degree. The wait time between the decision for surgery and cystectomy was also significantly associated with overall survival. The impact of delayed care was greatest for patients with lower stage disease. The data suggested a maximum wait time of 40 days for cystectomy. Conclusions: In this thesis, gaps in the quality of care for radical cystectomy in Ontario were identified. Patients treated by low volume hospitals and surgeons or those with long wait times all experienced worse outcomes. Since the underlying measures responsible for provider volume remain elusive, additional work is required to understand what these factors are. Initiatives to decrease wait times, however, are under way in Ontario. Whether these interventions decrease wait times and benefit patients remains to be seen.

Withdrawal of life support therapy involves controlled removal of life support modalities including artificial respiration and circulation with intent to provide a comfortable death. Withdrawal of life support therapy is necessary prior to procedures such as organ donation after cardio-circulatory death, but remains poorly explored in current literature. To enhance the current evidence, we conducted a thorough structured review, an observational study, and a qualitative comparison of components comprising withdrawal of life support therapy in both donor and non-donor patient groups. At all stages, we considered how results impacted donation after cardio-circulatory death. Withdrawal of life support therapy processes vary between countries, hospitals, practitioners, and patients. Variability in practice impacts care and outcomes for both donor and non-donor patients. Improved definitions and consensus about the process of withdrawal of life support therapy may improve patient care, success of organ donation after cardio-circulatory death, and uptake of donation protocols.

The most commonly attributed causes of failure of smoking cessation are non-adherence to treatment, experiencing severe nicotine withdrawal symptoms and post-cessation weight gain. However, there is a lack of information regarding these factors among smokers who attempt to quit in low-income country settings. The main objective of this study was to identify predictors of: 1) adherence to cessation treatment; 2) severity of withdrawal symptoms: and 3) post-cessation changes in body mass index among 269 smokers who attempted to quit in a randomized smoking cessation trial in a low-income country setting (Aleppo, Syria). All participants received behavioral counseling and were randomized to receive either 6 weeks of nicotine or placebo patch and were followed for one year. Findings from logistic regression showed that lower adherence to cessation treatment was associated with higher daily smoking, greater withdrawal symptoms, waterpipe use, being on placebo patch and the perception of receiving placebo patch. Generalized estimating equation (GEE) analyses indicated that throughout the study, lower total withdrawal score was associated with greater education, older age of smoking initiation, higher confidence in ability to quit, higher adherence to patch, lower nicotine dependence, lower reported depression, waterpipe use and the perception of receiving nicotine patches rather than placebo. Further, smoking abstainers gained 1.8 BMI units (approximately 4.8kg) greater than non-abstainers over one year post quitting. In addition, greater BMI was associated with being female, smoking to control weight and having previously failed to quit due to weight gain. In conclusion, nicotine dependence, waterpipe use and expectancies regarding cessation treatment are important factors that influence adherence to cessation treatment and severity of nicotine withdrawal symptoms. Moreover, targeted interventions that take into consideration the prevailing local and cultural influences on diet and levels of physical activity are recommended especially for females and smokers with weight concerns prior to quitting. Collectively, these findings will help in conducting future tailored effective cessation programs in Syria and other low-income countries with similar levels of developments and tobacco use patterns.

Withdrawal of life support therapy involves controlled removal of life support modalities including artificial respiration and circulation with intent to provide a comfortable death. Withdrawal of life support therapy is necessary prior to procedures such as organ donation after cardio-circulatory death, but remains poorly explored in current literature. To enhance the current evidence, we conducted a thorough structured review, an observational study, and a qualitative comparison of components comprising withdrawal of life support therapy in both donor and non-donor patient groups. At all stages, we considered how results impacted donation after cardio-circulatory death. Withdrawal of life support therapy processes vary between countries, hospitals, practitioners, and patients. Variability in practice impacts care and outcomes for both donor and non-donor patients. Improved definitions and consensus about the process of withdrawal of life support therapy may improve patient care, success of organ donation after cardio-circulatory death, and uptake of donation protocols.

Background: Cesarean delivery rates have been increasing since 1996, and Cesarean delivery is now the most common major operative procedure performed in the United States. Identifying risk factors for wound complications following Cesarean delivery is necessary to prevent unnecessary maternal morbidity. Methods: A case-control study was carried out and data was collected via a medical record review for patients undergoing a Cesarean delivery at the UIHC between 10/1/2011 and 12/31/2012. Results: Several modifiable risk factors were identified, and models based on patient and surgical factors performed better than the current standard NHSN risk index model. Conclusion: More robust prediction models can be created using patient and surgical factors.