Reactive oxygen species are formed internally through cellular metabolism and through external sources including radiation and pollutants. They play an important role in physiologic functions; however, when reactive oxygen species exceed our body’s antioxidant defense system, oxidative stress can occur. Oxidative stress has been implicated in aging and aging-related diseases including cancer and cardiovascular disease. Numerous oxidative stress genes produce antioxidative enzymes to mitigate the effects of reactive oxygen species. Single nucleotide polymorphisms within these genes may impact the functionality of antioxidant enzymes produced leaving the body more susceptible to damage from oxidative stress. The Iowa 65+ Rural Health Study was one of the four study populations in the Established Population for Epidemiologic Studies of the Elderly (EPESE) project initiated by the intramural Epidemiology, Demography and Biometry Program of the National Institute on Aging in 1980. The Iowa cohort was comprised of Iowa county and Washington county residents aged 65 and older at the time of the baseline interview in 1982. Participants completed three in-person interviews and five telephone interviews over eight years which collected data on habits, lifestyle and disease. During the in-person Year 06 interview participants were asked to donate a blood sample. The DNA extracted from the samples was used in each of the three aims of this project. The first aim evaluated single nucleotide polymorphisms in selected oxidative stress genes and their association with lifespan while controlling for aging-associated risk factors such as body mass index, comorbidity, alcohol consumption, smoking, and physical activity. Multivariable linear regression models were fit in the framework of the co-dominant genetic model. The oxidative stress genes selected for this project included the sirtuin family of genes (SIRT1-7), two of the forkhead box genes (FOXO1 and FOXO3), superoxide dismutase 2 and 3 (SOD2 and SOD3), glutathione peroxidase (GPX1), AKT, TP53, and CAMK4. A model was fitted with the risk factors before assessing the impact of each single nucleotide polymorphism. The q-value was used to control for the multiple hypothesis tests. Significant associations were detected between human lifespan and SNPs in genes SIRT3, SIRT5, SIRT6, FOXO3, and SOD3; gender modified the effect of SNPs in SIRT3, SIRT5, and AKT1. The second aim of this project evaluated single nucleotide polymorphisms in selected oxidative stress genes and their association with blood pressure measures while controlling for known risk factors including body mass index, alcohol consumption, smoking, and physical activity. Blood pressure was measured at the baseline and Year 06 interviews. Systolic pressure and diastolic pressure were used to calculate mean arterial pressure and pulse pressure at baseline and Year 06. Multivariable linear regression was used within the co-dominant genetic framework to determine if single nucleotide polymorphisms in SIRT1-7, FOXO1, FOXO3, SOD2-3, GPX1, AKT, TP53, and CAMK4 were associated with systolic, diastolic, mean arterial, or pulse pressure at baseline or Year 06. To examine longitudinal effects, the difference between each measure (i.e., Year 06 systolic – baseline systolic) was calculated for each individual and used to evaluate if any of the single polymorphisms was associated with change in blood pressure measures over time. Significant associations were detected between SIRT1 and SIRT3 and for males in SIRT1 and various blood pressure measures for females. Gender modified the effect of SIRT1, SIRT3, SIRT6, and FOXO1 variants. The third aim of this project evaluated if these genetic variants were associated with incident stroke while controlling for known risk factors including blood pressure, diabetes, body mass index, alcohol consumption, smoking, and physical activity. Multivariable logistic regression within the framework of the co-dominant genetic model was used. Individuals with the GPX1 genotype TT had 2.76 times the risk of an incident stroke compared to the CC genotype. This project identified several associations between single nucleotide polymorphisms within oxidative stress genes and lifespan, blood pressure measures, and incident stroke. Gender modified the association of several single nucleotide polymorphisms and lifespan as well as blood pressure measures. These results suggest genetic variation within oxidative stress genes may play a role in aging, blood pressure and incident stroke.

Prior research has pointed to an association between a history of traumatic events and premenstrual syndrome (PMS) in women. The objective of this study was to further investigate the relationship between trauma and PMS among female veterans, a population with high rates of sexual and physical abuse, as well as combat-related exposures. We conducted a case-control study of 502 women veterans under the age of 52 who were associated with the Iowa City Veterans Affairs Medical Center. Trauma history, gynecological health, mental health (including posttraumatic stress disorder), and other variables were obtained through telephone interview. Cases were women who had moderate to severe PMS as defined by validated criteria and controls were women without PMS. The prevalence of PMS was 14.3%. Thirty-three percent of subjects reported a completed sexual assault, 29% a combat-related trauma, and 86% a non-combat related trauma. Factors significantly associated with PMS (p<0.05) in the univariate analysis were: attempted, completed, and number of rapes during a woman's lifetime; rape before age 18; rape during military service; childhood sexual abuse; and number of non-combat related traumas. Childhood physical abuse and combat-related trauma were not associated with PMS in univariate analyses. In our final multivariate model, lifetime completed sexual assault was associated with PMS (odds ratio =2.42, 95% confidence interval = 1.33-4.40). Findings from this study among female veterans indicate that a history of trauma, particularly sexual trauma, is associated with moderate to severe PMS. Further study is warranted to confirm temporal relationships and causal mechanisms.

This project was designed to develop a method for the collection of environmental samples during prolonged Norovirus (NoV) outbreak investigations, and to develop real-time RT-PCR assays to analyze environmental samples for GI and GII noroviruses. The collection and processing of environmental samples could provide epidemiological data to facilitate investigations of prolonged NoV outbreaks and could guide public health NoV intervention strategies. Real-time RT-PCR assays for the detection of GI and GII NoVs were developed by adapting the State Hygienic Laboratory clinical GI and GII assays to the AB 7500 Fast platform. Analysis of the GI assay performance yielded a dilution curve slope = 3.28, R2 = 0.999 and a calculated amplification efficiency of 102%. The GII assay yielded a dilution curve slope = 3.39, R2 = 0.999 and a calculated amplification efficiency of 97%. Amplification efficiencies determine the sensitivity and the limit of detection of real-time RT-PCR assays. Optimum efficiencies range from 95%-105%, with a 100% efficiency indicating exponential amplification of targeted nucleic acid. To develop a method for the collection of environmental samples, multiple swab types were tested to determine their ability to recover NoV from laboratory spiked environmental surfaces. It was determined that foam swabs moistened with viral transport media were most effective in recovering NoV from spiked surfaces. A field test of the environmental sampling method was conducted by sampling environmental surfaces in four restaurants in one Iowa community. NoVs were not detected in the environmental samples. The collection and processing of environmental samples when conducting an investigation of a prolonged NoV outbreak could provide additional information on the epidemiology of NoV transmission and infection.

Hypospadias is a congenital malformation that occurs in 0.3-1% of live births, in which the meatus (the urethral opening) is dorsally malpositioned. Uncorrected hypospadias can cause difficulties in urination, abnormal sexual function, and adverse psychological consequences; surgical correction, though generally successful, constitutes an economic burden for families. Several common classes of pesticides have demonstrated potential to disrupt normal endocrine hormones that regulate fetal genitourinary development. Past epidemiologic studies of pesticide exposure and risk of hypospadias have been limited by limited available data, small sample sizes, or poor ascertainment of pesticide exposure. The objective of this study was to examine the relationship between parental occupational pesticide exposure and risk of hypospadias in their offspring; and further, to assess whether addition of residential pesticide exposure data is feasible and contributes to overall pesticide exposure. We began by conducting a meta-analysis of the current literature, in which summary measures of occupation (such as census occupation code) had been used to assign pesticide exposure. We found elevated but marginally significant risks of hypospadias were associated with maternal occupational exposure (PRR of 1.36, CI = 1.04-1.77), and paternal occupational exposure (PRR of 1.19, CI= 1.00-1.41) in the previously published literature. We then used industrial hygienist review of occupational histories to estimate the relationship between pesticide exposure and risk of hypospadias. We found that maternal occupational exposure to any pesticides (yes/no) was not associated with an increased risk of hypospadias (OR = 0.83, 95% CI = 0.6-1.1), cumulative insecticide (OR = 1.09; 95% CI = 0.9- 1.3), herbicide (OR = 1.05; 95% CI = 0.9- 1.2), or fungicide (OR = 0.91; 95% CI = 0.7-1.2) exposure. These negative findings might be explained by a lack of relationship at the low levels of exposure observed in this study population, in which case another farm exposure could be related to hypospadias; or this negative finding may be due to exposure misclassification. Finally, we evaluated the feasibility and relevance of collecting residential pesticide exposure and direct reports of occupational exposure from fathers. Residential pesticide use during the six months prior to pregnancy and during pregnancy was common among control mothers: 45% reported that their home had been treated for insect or rodent pests; 47% reported that their lawn or garden had been treated for weeds or insect pests; 16% used a lawn service; 26% reported that a pet had been treated for fleas, ticks, or mites (including flea and tick preventives); 17% reported community-wide sprayings for pests; and 16% reported that their workplaces were treated for pests. Case mothers were more likely to report that their home had been treated of insect or rodent pests (50%) or that a pet had been treated for fleas, ticks, or mites (36.5%). Our results suggest that collection of information on residential pesticide use is feasible, and the impact of residential pesticide use on birth defects risk should be assessed in future studies.

Background: Knee osteoarthritis (OA) is the most common type of OA and is a major cause of pain and thus results in disability for daily activities among persons living in the community. OA currently has no cure. In addition to the conflicting recommendations from clinical guidelines, evidence about the extent to which long-term use of intra-articular injections improves patient outcomes is also lacking. Methods: Using data from the Osteoarthritis Initiative (OAI), marginal structural models (MSMs) applying inverse probability treatment weights (IPTW) were used to examine the effectiveness of intra-articular injections and changes in symptoms over time. The specific aims of this dissertation were to: 1) evaluate longitudinal use of intra-articular injections after treatment initiation among persons with radiographic knee OA; 2) quantify the extent to which intra-articular injection relieves symptoms among persons with radiographic knee OA; and 3) evaluate the performance of missing data techniques under the setting of MSMs. Results: Of those initiating injections, ~19% switched, ~21% continued injection type, and ~60% did not report any additional injections. For participants initiating corticosteroid (CO) injections, greater symptoms post-initial injection rather than changes in symptoms over time were associated with continued use compared to one-time use. Among participants with radiographic evidence of knee OA, initiating treatments with either CO or hyaluronic acid (HA) injections was not associated with reduced symptoms compared to non-users over two years. Compared to inverse probability weighting (IPW), missing data techniques such as multiple imputation (MI) produced less biased marginal causal effects (IPW: -2.33% to 15.74%; -1.88% to 4.24%). For most scenarios, estimates using MI had smaller mean square error (range: 0.013 to 0.024) than IPW (range: 0.027 to 0.22). Conclusions: Among participants with radiographic evidence of knee OA living in the community, the proportion of those switching injection use and one-time users was substantial after treatment initiation. In addition, initiating injection use was not associated with reduced symptoms over time. With respect to issues of missing data, using MI may confer an advantage over IPW in MSMs applications. The results of this work highlight the importance of using comparative effectiveness research with non-experimental data to study these commonly used injections and may help to understand the usefulness of these treatments for patients with knee OA.

Background: During the past 50 years, novel diagnostic tools, interventional approaches, and population-wide changes in the major coronary risk factors have occurred. However, few studies have examined relatively recent trends in the demographic characteristics, clinical profile, and the short-term outcomes of patients hospitalized for acute myocardial infarction (AMI) from the more generalizable perspective of a population-based investigation. Methods:We examined decade long trends (2001 to 2011) in patient’s demographic and clinical characteristics, treatment practices, and hospital outcomes among residents of the Worcester metropolitan area hospitalized with a validated initial AMI (n = 3,730) at all 11 greater Worcester medical centers during 2001, 2003, 2005, 2007, 2009, and 2011. Results:The average age of the study population was 68.5 years and 56.9% were men. Patients hospitalized with a first AMI during the most recent study years were significantly younger (mean age = 69.9 in 2001/03; 65.2 in 2009/11), had lower serum troponin levels, and experienced a shorter hospital stay compared to patients hospitalized during the earliest study years. Hospitalized patients were more likely to received evidence-based medical management practices during the years under study. Multivariable-adjusted regression models showed a considerable decline over-time in the hospital death rate (9.6% in 2001/03; 6.5% in 2009/11), and a significant reduction in the proportion of patients who developed atrial fibrillation, heart failure, and ventricular fibrillation during their acute hospitalization. Conclusions: These results highlight the changing nature of patients hospitalized with an incident AMI, and reinforce the need for surveillance of AMI at the community level.

First, this study examined the association of perfluorinated chemicals with 1) cardio-metabolic health outcomes and 2) the association of phthalates with cardiometabolic health outcomes, and 3) cardio-metabolic health outcomes while assessing the possibility of additive interactions between perfluorinated chemicals (PFCs) and phthalates. Second, association with markers of chronic inflammation and oxidative stress were explored. Finally, this study examined the association of these chemicals with estrogenic cancers- Breast cancer, prostate cancer, uterine cancer and ovarian cancer. Using data from the National Health and Nutrition Examination Survey (NHANES), logistic regression models were used to investigate the relationship between PFCs and the cardio-metabolic health outcomes adjusting for covariates. An interaction term between PFCs and phthalates was added to the main effect model to assess the possibility of effect modification. Generalized linear models were used to examine associations between PFCs and inflammatory and oxidative stress markers per unit increase in exposure to PFCs while adjusting for covariates. Binomial logistic regression was used in investigating the association between quartiles of PFCs and presence or absence of cancer while also adjusting for covariates. Discriminant analysis was used to assess the correlation between individual PFCs compounds and individual cancer categories. Perfluorononanoic acid (PFNA) was associated with increased odds of central obesity in females, odds ratio (OR): 1.10; 95% confidence interval (CI): (1.01, 1.21). Perfluorohexane sulfonic acid (PFHS), Perfluorononanoic acid (PFNA), Perfluorooctanoic acid (PFOA), Perfluorooctane sulfonic acid (PFOS), and Perfluorodecanoic acid (PFDE) were all significantly associated with lymphocyte counts. Beta (95% CI); 0.03(0.02,0.05), 0.04(0.02,0.05), 0.05(0.03, 0.07), 0.04(0.03,0.05), 0.03(0.01,0.04) and with serum iron 0.07(0.05,0.09), 0.04(0.02,0.07), 0.10(0.07,0.12), 0.05(0.03,0.07), 0.04(0.02,0.06) and serum albumin 0.02(0.02,0.02), 0.02(0.02,0.03), 0.03(0.03,0.04), 0.02(0.02, 0.023), 0.01 (0.01, 0.05). Only PFHS, PFNA, PFOA and PFOS were associated with serum total bilirubin 0.04(0.03,0.05), 0.02(0.00,0.03), 0.06(0.04,0.08), 0.03(0.02,0.05). PFCs studied were associated with increased odds of breast, prostate, uterine and ovarian cancers, p

Background: The initial systolic blood pressure (SBP) in patients with acute heart failure (AHF) can be used as a guide when choosing specific pharmacologic treatments by helping identify the underlying type of HF (e.g., HF with preserved ejection fraction). Clinical experience and research data from our medical center suggests that AHF with elevated SBP may be presenting less frequently than in the past. This may call into question the utility of initial SBP as a clinical guide. The goal of this Master’s Thesis is to test the hypothesis that the frequency of AHF patients with a SBP>160mmhg has declined over time. Methods: This observational study compares data from 4 cohorts of adult patients admitted with AHF in central MA. Data were obtained from a contemporary (2011-2013) study of patients with AHF as well as from the 1995, 2000, 2006 Worcester Heart Failure Study (WHFS) cohorts. The Framingham criteria the diagnostic criterion for AHF. The main outcome was the proportion of patients with AHF with a SBP > 160 mmHg who presented in each of the 4 study cohorts and was examined by multivariate logistic regression. Results: 2,366 patients comprised the study population. The average age was 77 years, 55% were female, 94% white, and 75% had prior HF. In 1995 33.6% of AHF patients had a SBP >160 mmHg compared to 19.5% in 2011-2013 (p160 mmHg in 2006 (0.64, (0.42-0.96)) and 2011-13 (0.46, (0.28-0.74)). Conclusion: The proportion of patients with AHF and an initial SBP >160 mmHg has significantly declined over time. This may warrant a reexamination of the utility of SBP to inform diagnosis and treatment in patients with AHF.

The purpose of this study was to evaluate the prevalence of child psychosocial concerns in rural primary care, hypothesized to be greater than national averages due to lacking mental health services in rural areas. This study was an examination of the role of SES, various definitions of “rural,” and the interaction of SES and rurality, in predicting parent-reported child psychosocial concerns in Appalachian primary care clinics. Caregivers presenting with their child at one of 8 pediatric primary care sites (n=2,672) were recruited to complete a measure assessing demographics and the Pediatric Symptom Checklist (PSC). Results showed that while rural status was not associated with PSC scores, higher parental education was associated with lower rates of clinically significant psychosocial concerns. The present study failed to replicate prior preliminary findings that child psychosocial concerns are more prevalent in rural primary care. SES, rather than rurality, appeared to be the primary predictor of such concerns.

Severe liver and kidney dysfunction are prevalent in 10%-30% of the Southeast Asian population. Dengue virus infection has been reported as a modifiable risk factor for liver and kidney dysfunction, especially among children in Southeast Asia. Epidemiologic studies assessing this relationship are sparse, often failed to include children, and did not adjust for important covariates. Therefore, we evaluated the relationship between dengue virus infection and liver and kidney dysfunction among hospitalized children in Cambodia (n=551). Participants with a serologically confirmed dengue virus infection were categorized according to increasing severity of infection (i.e. dengue fever, dengue hemorrhagic fever, or dengue shock syndrome) using clinical assessment. Laboratory assays were used to assess liver (i.e. albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total protein) and kidney protein levels (i.e. creatinine and urea). Descriptive statistics were used to assess the impact of severity of dengue virus infection on kidney dysfunction. Additionally, descriptive statistics and linear mixed modeling were used to assess the impact of severity of dengue virus infection on liver dysfunction while adjusting for important risk factors. Approximately 75% of all participants had abnormal liver or kidney protein level(s) over the first four days of follow-up. Overall, a negative association was observed between increasing dengue disease severity and albumin (ßadj = -0.08, 95% CI = -0.45 to 0.29), ALT (ßadj = -18.02, 95% CI = -51.59 to 15.55), and AST (ßadj = -7.18, 95% CI = -49.57 to 35.21) protein levels. A positive association was observed between increasing dengue disease severity and total protein levels (ßadj = 7.14, 95% CI = 1.15 to 13.13). While abnormal liver function (increases in ALT and/or AST levels and decreases in albumin and/or total protein levels) is a common clinical finding in dengue infections, we did not find evidence for a significant association with more severe forms of dengue virus infection (i.e. dengue hemorrhagic fever or dengue shock syndrome) and greater liver dysfunction as compared to patients with dengue fever in pediatric populations in Cambodia.