Memory deficits and executive dysfunction are highly prevalent among HIV-infected adults. These conditions can affect their quality of life, antiretroviral adherence, and HIV risk behaviors. Several factors have been suggested including the role of genetics in relation to HIV disease progression. This dissertation aimed to determine whether genetic differences in HIV-infected individuals were correlated with impaired memory, cognitive flexibility and executive function and whether cognitive decline moderated alcohol use and sexual transmission risk behaviors among HIV-infected alcohol abusers participating in an NIH-funded clinical trial comparing the efficacy of the adapted Holistic Health Recovery Program (HHRP-A) intervention to a Health Promotion Control (HPC) condition in reducing risk behaviors. A total of 267 individuals were genotyped for polymorphisms in the dopamine and serotonin gene systems. Results yielded significant associations for TPH2, GALM, DRD2 and DRD4 genetic variants with impaired executive function, cognitive flexibility and memory. SNPs TPH2 rs4570625 and DRD2 rs6277 showed a risk association with executive function (odds ratio = 2.5, p = .02; 3.6, p = .001). GALM rs6741892 was associated with impaired memory (odds ratio = 1.9, p = .006). At the six-month follow-up, HHRP-A participants were less likely to report trading sex for food, drugs and money (20.0%) and unprotected insertive or receptive oral (11.6%) or vaginal and/or anal sex (3.2%) than HPC participants (49.4%, p

Background: Muscular strengthening activity (MSA) has been shown to be inversely associated with insulin resistance (IR). The associations between quartiles of the homeostatic model assessment of insulin resistance (HOMA-IR) and self-reported MSA in a nationally representative sample of euglycemic U.S. adults were examined. Methods: Sample included adult participants (≥20 years of age [n=2,543]) from the 1999-2004 National Health and Nutrition Examination Survey (NHANES). HOMA-IR was categorized into quartiles based on every 25th percentile. No MSA was the dependent variable. Results: Following adjustment for covariates, those with HOMA-IR values in third (p Conclusions: Having a higher HOMA-IR value is associated with greater odds of reporting no MSA in euglycemic U.S. adults.

Introduction: Ventricular arrhythmias (VAs) are common after an acute coronary syndrome (ACS) and are associated with worse clinical outcomes. However, little is known about recent trends in their occurrence, their association with serum glucose levels, and their psychological impact in ACS setting. Methods: We examined 25-year (1986-2011) trends in the incidence rates (IRs) and hospital case-fatality rates (CFRs) of VAs, and the association between serum glucose levels and VAs in patients with an acute myocardial infarction (AMI) in the Worcester Heart Attack Study. Lastly, we examined the relationship between in-hospital occurrence of VAs and 12-month progression of depression and anxiety among hospital survivors of an ACS in the longitudinal TRACE-CORE study. Results: We found the IRs declined for several major VAs between 1986 and 2011while the hospital CFRs declined in both patients with and without VAs over this period. Elevated serum glucose levels at hospital admission were associated with a higher risk of developing in-hospital VAs. Occurrence of VAs, however, was not associated with worsening progression of symptoms of depression and/or anxiety over a 12-month follow-up period in patients discharged after an ACS. Conclusions: The burden and impact of VAs in patients with an AMI has declined over time. Elevated serum glucose levels at hospital admission may serve as a predictor for in-hospital occurrence of serious cardiac arrhythmias. In-hospital occurrence of VAs may not be associated with worsening progression of symptoms of depression and anxiety in patients with an ACS.

Background: The Veterans Health Administration (VHA) encourages depression screening and treatment for pregnant veterans; however, rates of depression symptoms and treatment utilization during pregnancy have not been well-studied. Methods: We used data from the Maternity Care Coordination for Women Veterans cohort study. Specifically, our aims were to: 1) examine rates and correlates of depression symptoms in a sample of pregnant veterans; 2) understand mental health care treatment utilization and explore the experiences of veterans accessing mental health care at the VHA during pregnancy; and 3) examine VHA mental health provider's perspectives on depression screening and treatment in the perinatal period. Findings: Depression symptoms were present in 28% of pregnant veterans in our sample. Social support and employment decreased odds of symptoms; history of anxiety, antidepressant use, and active duty service resulted in increased odds of symptoms. Nearly 70% of women veterans with prenatal depression symptoms received at least one mental health visit or antidepressant prescription during pregnancy. However, symptomatic pregnant women without a history of depression were less likely to receive care. Mental health providers identified absence of screening protocols and referral procedures and variability in risk/benefit conversations surrounding antidepressant use as areas of weakness for VHA mental health care during the perinatal period. Conclusions: Depression symptoms were present in nearly one in every three pregnant veterans. Depression treatment during pregnancy is complex, requiring individualized care. Policies for depression screening, referrals to providers, and medication review could be better encouraged to improve standardized care across the VHA.

Dengue fever (DF) and dengue hemorrhagic fever (DHF) are emerging infectious diseases which are endemic in many regions of the globe, many of which are resource-poor areas. DHF and DF impose a severe economic health burden in tropical and subtropical areas. Dengue virus causes an acute febrile illness that can be a self-limited febrile illness, as seen in most cases of DF, or a life-threatening illness with plasma leakage and shock, as seen in cases of DHF. A systematic review of the literature revealed gaps in the knowledge base of clinical laboratory findings of dengue illness with regards to longitudinal dynamics and classification and predictive modeling of disease severity. The objective of this thesis was to investigate the utility of clinical laboratory variables for classification and prediction of disease outcomes. The data used in this investigation was derived from a prospective study of Thai children presenting to either of two study hospitals within 72 hours of onset of an acute febrile illness. Systematic data collection, including clinical laboratory parameters, and routine clinical management continued each day until 24 hours after the fever had subsided. A final diagnosis of DHF, DF, or other febrile illness (OFI) was assigned by an expert physician after chart review. The first research objective of this study was to describe the temporal dynamics of clinical laboratory parameters among subjects with DHF, DF, or OFI. Data were analyzed using lowess curves and population-average models. Quadratic functions of clinical variables over time were established and demonstrated significantly divergent patterns between the various diagnostic groups. The second research objective was to establish and validate tools for classification of illness severity using easily obtained clinical laboratory measures. Bivariate logistic regression models were established using data from one hospital in an urban area of Thailand as a training data set and validated with a second data set from a hospital in a rural area of Thailand. The validated models maintained a high sensitivity and specificity in distinguishing severe dengue illnesses without using the hallmark indicators of plasma leakage. The third research objective used classification and regression tree (CART) analysis to established diagnostic decisions trees using data obtained on the day of study enrollment, within the first 3 days of acute illness. Decision trees with high sensitivity were established for severe dengue defined either as: 1) DHF with evidence of shock (dengue shock syndrome, DSS); or 2) DSS or dengue with significant pleural effusion. This study expands existing knowledge of the potential utility of clinical laboratory variables during different phases of dengue illness. The application of the results of these studies should lead to promising opportunities in the fields of epidemiological research and disease surveillance to reduce the health burden, and improve the clinical management, of dengue illness. Future directions involve application of these algorithms to different study populations and age groups. Additionally, other analytical techniques, such as those involving CART analysis, can be explored with these data.

Background: A landmark study suggested that wide excision of intermediate-thickness melanoma with sentinel lymph node biopsy (SLNB) and subsequent completion lymph node dissection (CLND) for regional disease may improve prognostication and disease-free survival (DFS) compared with those undergoing wide excision alone. However, these benefits were relatively small and not associated with an improvement in disease-specific survival (DSS). It remains unknown if SLNB and subsequent treatments are beneficial in elderly patients who have a decreased overall (OS) due to other causes. Methods: Adults ≥ 70 years of age, who underwent surgical intervention for intermediate-thickness cutaneous melanoma from 2000-2013 were identified from a prospectively-maintained database. Clinicopathologic variables measured included age, gender, anatomic site, histologic type, tumor thickness, ulceration, receipt and result of SLNB, completion of CLND, OS, and DFS. Results: Ninety-one patients underwent excision of an intermediate-thickness melanoma. Forty-nine patients (54%) received a SLNB. Seven of these biopsies (14%) were positive, and five patients went on to receive CLND. Five-year OS was 41% in patients who did not receive SLNB and 52% in patients who did receive SLNB (p=0.11). DFS was similar between groups independent of receipt of SLNB. Conclusion: Among elderly patients with intermediate-thickness melanoma, patients who received SLNB had similar 5-year OS and DFS compared with those who did not receive SLNB. Routine SLNB for intermediate-thickness melanoma patients may not significantly change outcomes for this age group, and clinical decision-making should consider individual patient comorbidities and goals of care.

Background. Emerging evidence suggests that youth with attention deficit/hyperactivity disorder (ADHD) may engage in sub-optimal health behaviors including high levels of screen time, low physical activity participation, and consumption of poor diets. These are independent risk factors for adverse health outcomes, and health-related behavior patterns established in childhood can track into adulthood. Thus, identifying and addressing dietary and physical activity habits in sub-populations of youth have important implications for health over the lifespan. The specific aims of this dissertation were to: (1) compare screen time between youth with and without ADHD and to assess its relationship to ADHD symptomatology; (2) compare participation in physical activity (PA) between adolescents with and without ADHD and to assess the relationship of PA participation to ADHD symptomatology; and (3) evaluate the association of diet quality and dietary patterns to ADHD symptomatology among youth ages 8-15 years. Methods. The aforementioned outcomes of interest were analyzed using data from the continuous National Health and Nutrition Examination Survey (NHANES) 2001-2004. These waves of NHANES included a structured DSM-IV-based interview administered to parents that identified youth with ADHD and also yielded symptom counts for hyperactivity/impulsivity and inattention. Screen time and physical activity data were obtained from questionnaires that queried the amount of time spent watching television, playing videos, or using the computer outside of school time, and also surveyed the types, frequency, and duration of PA in which youth participated. Diet quality and dietary patterns, which included consumption of sugar-sweetened beverages (SSBs), total calorie intake, and eating frequency, were obtained by a 24-hour dietary recall using the Automated Multiple Pass Method of interviewing. Linear and logistic regression models adjusted for sociodemographic factors and anxiety/depression were employed to address the specific aims. Results. The findings suggest that youth with ADHD are at the same, if not higher, risk for engaging in suboptimal health behaviors. Overall, youth participating in NHANES engaged in excessive amounts of screen time, failed to acquire sufficient physical activity, and consumed diets of poor quality. However, our findings suggest that ADHD symptomatology places youth at higher risk for sedentary behavior and poor diet quality. Relative to screen time, youth with ADHD showed a trend toward increased screen time, as did youth who took medication. ADHD symptoms were also associated with over two hours of daily TV viewing and overall increased screen time, and this was particularly true for children ages 8-11 years. Relative to physical activity, the outcomes did not differ between youth with and without ADHD, but the majority of youth did not meet the recommended guidelines of 60 minutes or more of moderate-to-vigorous PA each day. Diet quality was poor across the population of youth who participated in NHANES, and hyperactive/impulsive symptoms were associated with an even greater decrease in diet quality in both children and adolescents. In males, the presence of hyperactive/impulsive symptoms was associated with a decrease in diet quality, whereas in females, inattentive symptoms accounted for a decrease in diet quality. No differences in the other dietary patterns (i.e., SSB consumption, total energy intake, and eating frequency) were observed. Conclusions. The diagnosis of ADHD and/or its symptoms are associated with less-than-recommended levels of screen time and poor diet quality, though youth in general were found to be engaging in suboptimal sedentary, physical activity, and dietary behaviors. The mechanisms for why youth with ADHD may have increased vulnerability to poorer health behaviors are not yet well understood. The findings from this dissertation support the need for ongoing efforts to address lifestyle factors among the nation’s youth generally, but may also stimulate new hypotheses about the needs of youth with ADHD from both public health and clinical perspectives, and encourage research on the implications of ADHD symptomatology on health-related behaviors and lifestyle factors.

Background: Major depression is one of the most prevalent, disabling, and costly illnesses worldwide. Despite a 400% increase in antidepressant medication use since 1988, fewer than half of treated depression patients experience a clinically meaningful reduction in symptoms and uncertainty exists regarding how to successfully obtain symptom remission. Identifying homogenous subgroups based on clinically observable characteristics could improve the ability to efficiently predict who will benefit from which treatments. Methods: Latent class analysis and latent transition analysis (LTA) were applied to data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study to explore how to efficiently identify subgroups comprised of the multiple dimensions of depression and examine changes in subgroup membership during treatment. The specific aims of this dissertation were to: 1) evaluate latent depression subgroups for men and women prior to antidepressant treatment; 2) examine transitions in these subgroups over 12 weeks of citalopram treatment; and 3) examine differences in functional impairment between women’s depression subgroups throughout treatment. Results: Four subgroups of depression were identified for men and women throughout this work. Men’s subgroups were distinguished by depression severity and psychomotor agitation and retardation. Severity, appetite changes, insomnia, and psychomotor disturbances characterized women’s subgroups. Psychiatric comorbidities, especially anxiety disorders, were related to increased odds of membership in baseline moderate and severe depression subgroups for men and women. After 12 weeks of citalopram treatment, depression severity and psychomotor agitation were related to men’s chances of improving. Severity and appetite changes were related to women’s likelihood of improving during treatment. When functional impairment was incorporated in LTA models for women, baseline functional impairment levels were related to both depression subgroups at baseline and chances of moving to a different depression subgroup after treatment. Conclusion: Depression severity, psychomotor disturbances, appetite changes, and insomnia distinguished depression subgroups in STAR*D. Gender, functional impairment, comorbid psychiatric disorders, and likelihood of transitioning to subgroups characterized by symptom improvement differed between these subgroups. The results of this work highlight how relying solely on summary symptom rating scale scores during treatment obscures changes in depression that might be informative for improving treatment response.

Background: Migraine headache is a chronic pain condition that affects 20% of women of reproductive age, and is often treated with triptans. Triptans are serotonin 1B, 1D, and 1F receptor agonists that act as vasoconstrictors and inhibitors of the trigeminal cervical complex as well as peripheral neurons; they cross the blood brain barrier and placenta, and as such are plausible neurodevelopmental teratogens. No studies have examined risk of neurodevelopmental problems in children with prenatal triptan exposure. This dissertation had three aims: (1) to examine risk of behavioral problems in children using in the presence of time-varying confounding by concomitant medication use; (2) to examine risk of temperamental, motor, and communication disturbances associated with prenatal triptans exposure, adjusting for unmeasured confounding by migraine type and severity; and (3) to examine changes in neurodevelopment over time associated with prenatal triptan exposure. Methods: This dissertation used data from the Norwegian Mother and Child Cohort Study, a prospective birth cohort including more than 100,000 women recruited during their first prenatal ultrasound visit. Aims 1 and 3 used marginal structural models to assess the risk of (1) neurodevelopmental problems at age 36 months (Aim 1), or (2) change in risk of neurodevelopmental problems from 18 to 36 months (Aim 3) associated with prenatal triptan exposure. Aim 2 used propensity matching and calibration to adjust for unmeasured confounding by migraine type, severity, and attitudes towards medication use in pregnancy. Neurodevelopmental outcome measures included the Child Behavior Checklist (CBCL), the Emotionality, Activity, and Temperament Scale (EAS), and the Ages and Stages Questionnaire (ASQ). Exposure to triptans was ascertained by self-report. Results: Prenatal triptan exposure was associated with greater externalizing behavior problems at 18 and 36 months, as well as greater increases in emotionality and activity from 18 to 36 months. We observed no association between triptan exposure and motor skills or communication problems; triptan use during pregnancy was associated with migraine severity but not migraine type, and adjustment for unmeasured migraine characteristics moved effect estimates towards the null. Conclusions: Prenatal triptan exposure is associated with externalizing-type behaviors and temperament in children, while migraine itself is associated with internalizing-type behaviors and temperament. The use of concomitant medications and the severity of the underlying condition both exerted substantial influence on observed effect estimates, and should be considered in any future studies of triptan medication use in pregnancy.

Background: Venous thromboembolism (VTE), comprising the conditions of deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common acute cardiovascular event associated with increased long-term morbidity, functional disability, all-cause mortality, and high rates of recurrence. Major advances in identification, prophylaxis, and treatment over the past 3-decades have likely changed its clinical epidemiology. However, there are little published data describing contemporary, population-based, trends in VTE prevention and management. Objectives: To examine recent trends in the epidemiology of clinically recognized VTE and assess the risk of recurrence after a first acute episode of VTE. Methods: We used population-based surveillance to monitor trends in acute VTE among residents of the Worcester, Massachusetts, metropolitan statistical area (WMSA) from 1985 through 2009, including in-hospital and ambulatory settings. Results: Among 5,025 WMSA residents diagnosed with acute PE and/or lower-extremity DVT between 1985 and 2009 (mean age = 65 years), 46% were men and 95% were white. Age- and sex-adjusted annual event rates (per 100, 000) of clinically recognized acute first-time and recurrent VTE was 142 overall, increasing from 112 in 1985/86 to 168 in 2009, due primarily to increases in PE occurrence. During this period, non-invasive diagnostic VTE testing increased, vi while treatment shifted from the in-hospital (chiefly with warfarin and unfractionated heparin) to out-patient setting (chiefly with low-molecular-weight heparins and newer anticoagulants). Among those with community-presenting first-time VTE, subsequent 3-year cumulative event rates of key outcomes decreased from 1999 to 2009, including all-cause mortality (41% to 26%), major bleeding episodes (12% to 6%), and recurrent VTE (17% to 9%). Active-cancer (with or without chemotherapy), a hypercoagulable state, varicose vein stripping, and Inferior vena cava filter placement were independent predictors of recurrence during short- (3-month) and long-term (3-year) follow-up after a first acute episode of VTE. We developed risk score calculators for VTE recurrence based on a 3-month prognostic model for all patients and separately for patients without active cancer. Conclusions: Despite advances in identification, prophylaxis, and treatment between 1985 and 2009, the disease burden from VTE in residents of central Massachusetts remains high, with increasing annual events. Declines in the frequency of major adverse outcomes between 1999 and 2009 were reassuring. Still, mortality, major bleeding, and recurrence rates remained high, suggesting opportunities for improved prevention and treatment. Clinicians may be able to use the identified predictors of recurrence and risk score calculators to estimate the risk of VTE recurrence and tailor outpatient treatments to individual patients.