<p><strong>Background </strong></p> <p>Integrated care programs are collaborations to improve health services delivery for patients with multiple conditions.</p> <p><strong>Objectives</strong></p> <p>This thesis investigated three issues in evaluation of integrated care programs: (1) quantifying integration for integrated care programs, (2) analyzing integrated care programs with substantial non-compliance, and (3) assessing bias when evaluating integrated care programs under different non-compliant scenarios.</p> <p><strong>Methods</strong></p> <p>Project 1: We developed a method to quantity integration through service providers’ perception and expectation. For each provider, four integration scores were calculated. The properties of the scores were assessed.</p> <p>Project 2: A randomized controlled trial (RCT) compared the Children’s Treatment Network (CTN) with usual care on managing the children with complex conditions. To handle non-compliance, we employed the intention-to-treat (ITT), as-treated (AT), per-protocol (PP), and instrumental variable (IV) analyses. We also investigated propensity score (PS) methods to control for potential confounding.</p> <p>Project 3: Based on the CTN study, we simulated trials of different non-compliant scenarios. We then compared the ITT, AT, PP, IV, and complier average casual effect methods in analyzing the data. The results were compared by the bias of the estimate, mean square error, and 95% coverage.</p> <p><strong>Results and conclusions</strong></p> <p>Project 1: We demonstrated the proposed method in measuring integration and some of its properties. By bootstrapping analyses, we showed that the global integration score was robust. Our method has extended existing measures of integration and possesses a good extent of validity.</p> <p>Project 2: The CTN intervention was not significantly different from usual care on improving patients’ outcomes. The study highlighted some methodological challenges in evaluating integrated care programs in a RCT setting.</p> <p>Project 3: When an intervention had a moderate or large effect, the ITT analysis was considerably biased under non-compliance and alternative analyses could provide unbiased results. To minimize the bias, we make some recommendations for the choice of analyses under different scenarios.</p> / Doctor of Philosophy (PhD)

In the last few years, engagement in medical care among individuals living with HIV has become a major priority among HIV medical providers and public health researchers. Engagement in medical care is an important concept as it involves the process of linking newly diagnosed individuals into medical care and retaining those individuals in care throughout the course of their infection. Although there have been major advances in the management of HIV, like the advent of Highly Active Antiretroviral Therapy, morbidity and mortality due to HIV cannot be fully reduced if the individual does not optimally retain in care. Retention in HIV medical care has become an emerging topic in HIV research, but there still remains a scarce amount of research on how to properly define retention, understand its predictors, and how it impacts HIV outcomes. The purpose of this dissertation was to evaluate retention in HIV medical care among individuals diagnosed with HIV and seeking care at an urban infectious disease clinic in Kentucky. The three specific aims of this dissertation were to: (1) compare methods in measuring retention in HIV medical care; (2) determine the predictors of poor retention in care and assess the effect of non-HIV related comorbidities have on retention over time; and (3) determine the impact early retention to medical care has on time to viral load suppression and rebound among individuals initiating Highly Active Antiretroviral Therapy. A retrospective cohort study was conducted employing a medical chart review, and patients who sought HIV care at the Bluegrass Care Clinic between January 1st 2003 and May 1st 2011 were eligible for the study. There were 1,358 patients included in the study and these individuals were followed until December 31st, 2011. The results suggested that individuals living with HIV should seek care at least once every six months (visit constancy) and that only 48.6% of the study population obtained optimal retention over time. Over time the rate of retention decreased among the study sample and those with optimal retention were more likely to suppress their viral loads compared to poor retainers.

<b>Background</b>: Fever is often the initial feature of infectious diseases, which remains a major cause of morbidity and an important cause of mortality in children in the UK, and is one of the most common reasons for children to be taken to a general practitioner. Febrile illness therefore places a considerable burden on children, their families and health care services. The initial disease identification and diagnostic challenge starts at home, with parents and carers differentiating children with suspected serious illness from the vast majority who have self-limiting or minor infections. This thesis aims to understand caregivers’ knowledge, beliefs and actions in the existence of a fever in comparison with NICE guideline advice, and suggests some recommendations to improve their knowledge and management of fever. <b>Method</b>: Four studies were conducted for this thesis. First, a systematic review of 47 studies, including 20,427 participants, was used to understand parents’ knowledge regarding interpretation of temperature measurements, actions to manage a fever, and their beliefs. Second, two focus group interviews in primary care, with 9 parents, were used to explore parental views and beliefs on the management of fever and temperature measurement. Third, a thermometer survey, with 123 thermometers, was used to assess the consistency of advice from information contained in commercially available thermometers, with respect to evidence-based guidelines for feverish illness in children. Fourth, a questionnaire survey, in primary care, with 309 participants, was used to find out carer knowledge of temperature measurement and fever management in children 5 years or younger. <b>Results</b>: Carer knowledge about normal body temperature and fever in children was poor: mild fever was misclassified by many as high. Understanding of what actually constitutes fever ranged widely; carers actively reduced mild fever with antipyretics, used non-recommended methods, and most learned to use a thermometer from its instructions. Most parents did not know what a fever was and believed that it was a harmful condition that may be linked to a more serious disease. Parents wanted to be provided with specific and practical information on the identification of fever and its management. Most of the thermometer information did not include guidance on fever management or thermometer use, did not take into account parental and carer interpretation of fever and disease, however, incorporated unnecessary referrals into health services. Thermometer cost had no influence on the quality of the information provided. <b>Conclusions</b>: The research presented in this thesis suggests that caregivers often lack basic knowledge on temperature measurement and fever care. The study proposes that a simple NICE guideline based educational intervention may help them to correctly take a temperature measurement while assessing other signs of illness, and allow them to provide appropriate management methods at home, and more importantly, seek further referral where necessary. This may help towards decreasing unnecessary attendances in primary and secondary care.

Staphylococcus aureus has been extensively studied, yet it remains unclear why certain individuals continually carry the bacteria while others do not. Livestock workers are known to be at an increased risk of S. aureus colonization, but have not been as studied as other high risk groups, including hospitalized patients, have been. Culture based studies have shown other bacteria may decrease the likelihood of S. aureus colonization. Here, we utilize 16s rRNA sequencing to better characterize the ecologic relationships between S. aureus and the other microbes in the nares and oropharynx in a population of livestock workers. A cross-sectional, epidemiological study was conducted enrolling 59 participants (26 of which had livestock contact) in Iowa. Participants were enrolled in one of four ways: from an existing prospective cohort study (n=38), from the Iowa Department of Natural Resources Animal Feeding Operations database (n=17), through Iowa county fairs (n=3), and through snowball sampling (n=1). We collected two sets of swabs from the nares and oropharynx of each participant. The first set of swabs was used to assess the microbiome via 16s rRNA sequencing and the second was used to culture S. aureus. We observed livestock workers to have greater diversity in their microbiomes compared to those with no livestock contact. In the nares, there were 26 operational taxonomic units found to be different between livestock workers and non-livestock workers with the greatest difference seen with Streptococcus and Proteobacteria. In the oropharynx, livestock workers with swine exposure were more likely to carry several pathogenic organisms. We also observed colonized livestock workers to be more likely to carry P. gingivalis which may act as a bridge allowing S. aureus to adhere to Streptococcus in the oral cavity. While we observed no significant differences when comparing colonized persons to non-colonized persons in either the nares or oropharynx, Corynebacterium was more abundant in the colonized persons. Colonized individuals also had greater diversity in their nasal microbiome compared to non-colonized individuals. However, when comparing persistently colonized persons to intermittently colonized persons, we found Corynebacterium argentorantense to be more abundant in the persistently colonized individuals. We hypothesized the genera present in the nares and oropharynx of S. aureus carriers would be different from that of non-carriers and there would be differences in the nasal and oropharyngeal microbiomes based on livestock contact and carrier state (persistent, intermittent, and non-carrier). While there were no significant differences between carriers and non-carriers, we were able to identify several operational taxonomic units that were different between livestock worker carrier and non-carriers as well as differences by carrier state. The results of this study are the first to characterize the livestock worker nasal and oropharyngeal microbiomes. Additionally, the results shed light onto several organisms that may be influential in S. aureus carriage. However, further studies are needed to better understand these relationships and determine causality.

Cystic fibrosis (CF) is the most common life-restricting, genetically inherited disease among Caucasians affecting approximately 30,000 people in the United States. Lung disease is the major cause of morbidity and mortality in CF. A number of oral, inhaled, and intravenous therapies are available to combat CF lung disease. Of these, this research project focused on inhaled dornase alfa, oral azithromycin, inhaled tobramycin, and inhaled aztreonam. Data to address three research aims were requested and obtained from the Cystic Fibrosis Foundation Patient Registry (CFFPR). The first aim examined the use of inhaled dornase alfa in younger children with CF. With no clinical efficacy data of dornase alfa in children ≤ 6 years of age, the study utilized subsequent forced expiratory volume in 1 second (FEV₁) measured between 6 - 7 years of age, to assess the effectiveness of long-term dornase alfa use ≤ 6 years of age. Propensity score methods were used to reduce the likelihood of treatment indication bias. The results suggested that receiving treatment with dornase alfa before 6 years of age did not improve FEV₁ between 6 - 7 years. Unmeasured covariates leading to treatment indication bias were likely one of the key explanations for these results. Additionally, lack of a more sensitive outcome than FEV₁ to assess lung function in young patients with early lung damage was thought to be another reason for the failure to reject the null hypothesis. The second aim assessed the long-term clinical effectiveness of chronic azithromycin use on the rate of FEV₁ decline in CF patients between 6 - 20 years of age. This study was novel in that the rate of FEV₁ decline, rather than change in FEV₁ from baseline, was the primary outcome, which was characterized using propensity score matching followed by a linear mixed model analysis. The results of the analysis suggested that the rate of FEV₁ decline was slower in patients who did not receive chronic treatment with azithromycin. Treatment indication bias was thought to play an important role in the direction of the association between treatment and outcome. Associations between FEV₁ % predicted and many of the other study variables included in the analysis were consistent with previous studies. The final aim compared the clinical effectiveness of a combination of inhaled tobramycin and aztreonam with inhaled tobramycin alone on the rate of FEV₁ decline in CF patients between 6 - 20 years of age. This aim was novel in that the effect of this combination treatment on rate of decline in FEV₁ has never been assessed. A linear mixed model analysis was used after matching patients in the two treatment groups on their propensity scores. Once again, the results were contrary to the alternative hypothesis with the combination group having a steeper rate of FEV₁ decline than the group that was treated with tobramycin alone. An important reason for this result was thought to be unresolved treatment indication bias that could not be eliminated even with the use of the propensity score methods used to test the associated hypothesis. The use of validated methods of analysis, i.e., propensity scores, to counter treatment indication bias using the largest available observational dataset for CF, was one of the key strengths of this study. Moreover, this study highlighted important weaknesses in the CFFPR with regards to lack of data on patient and physician-level variables - an area of active interest for the Cystic Fibrosis Foundation.

Prosthetic joint infection (PJI) is an emergent concern given the wide usage of prosthetic joints in old and young population to assist with activities of daily living. While the public health burden of PJI appears to be relatively low compared with other potentially fatal infections such as blood stream infections, PJI is associated with excess morbidity and steep healthcare costs. Appropriate and timely diagnosis and management are crucial in preventing poor clinical outcomes and restoring adequate function in patients with PJI. There is lack of studies using robust epidemiologic methods to evaluate effectiveness of existing treatment protocols for PJI. We conducted retrospective studies using the Veterans Affairs (VA) database using data from 123 VA hospitals between 2003 and 2012. We also abstracted clinical data from VA medical records to achieve the objectives of this research. The effectiveness of an antibiotic — rifampin and a surgical management – exchange arthroplasty was assessed in separate studies. These treatments were adjudicated based on their effectiveness in prevention of PJI recurrence and two-year postoperative mortality, respectively. Seven hundred thirty-one of the 2838 patients with first episode of PJI were treated with surgery and medical management for Staphylococcus aureus PJI and were retained in the thesis dataset. In the first study, we compared 300 patients treated with rifampin for the first 42 days of treatment period to 364 patients treated with antibiotics other than rifampin during the 42 days (unexposed). Overall, 255 patients (38.4%) were observed to have a treatment failure defined as recurrence of S. aureus PJI with or without a repeat surgery or death in the 90 days after surgery for the PJI. The rifampin-treated and unexposed groups did not differ on time to treatment failure (p=0.92). It was noted that patients treated with a less invasive surgery that resulted in retention of the infection prosthesis with removal of infected tissue and rifampin treatment had lower risk for treatment failure compared to patients with similar surgery but not treated with rifampin (HR=0.79, 95%CI 0.52-1.20). We also observed that patients who had surgery for removal of the infected prosthesis and were treated with rifampin had significantly greater risk for treatment failure compared to those treated with the prosthesis removal surgery but no rifampin. In our second study we further analyzed this research question in depth using advanced epidemiologic methods to attenuate any bias in our previous findings. We noted that the groups did not differ in their risk for treatment failure after matching patients on their probability of receiving rifampin treatment (HR=1.08, 95%CI 0.71-1.65). In addition, we observed that patients whose treatment decision with rifampin was determined by the rifampin prescription rate in the treating facility substantially benefited with use of rifampin antibiotic for S. aureus PJI. In the third study we assessed the effectiveness of a surgery — exchange arthroplasty (involves removal of infected prosthesis and insertion of new prosthesis) to reduce the risk of death two years after surgery in a sample of 566 S. aureus PJI patients. Patients with this procedure were compared to patients treated with retention of their infected prosthesis and removal of infected tissue (DAIR). Overall, 90 patients (15.9%) died in the 2 years after surgery. Of these, 14 (9.9%) died after exchange surgery while 76 (17.9%) died after the DAIR procedure. We observed that the exchange surgery reduced the risk for death by almost 60% compared to the DAIR (OR=0.42, 95%CI 0.19-0.89). In conclusion, epidemiological studies conducted as part of this thesis identified considerable burden of treatment failure (38.4%) and all-cause mortality (15.9%) among veterans treated for S. aureus PJI. Rifampin combination antibiotic regimen was not observed to be effective in reducing the burden of the infection, in comparison to other antibiotics. Exchange arthroplasty reduced the risk for death in old veteran patients compared to a less invasive but potentially life-threatening procedure such as DAIR. Choice of treatment should be made on a case-by-case basis for patients with S. aureus PJI after thorough consideration of patient characteristics.

Clostridium difficile (C. difficile) is a gram positive, anaerobic, spore forming bacterium. C. difficile infections are triggered by dysbiosis of the intestinal microbiome linked to age, immune status, and medication; particularly use of antibiotics and proton pump inhibitors (PPI). The spore forming nature of the bacteria gives it the ability to persist in the environment for long periods of time and makes it impervious to many commonly-used hospital cleaning and disinfection products. C. difficile, along with Methicillin-resistant Staphylococcus aureus (MRSA) and Vancomycin-resistant Enterococcus (VRE) are some of the leading multi-drug resistant hospital acquired infections in the United States. Environmental contamination and patient susceptibility are hypothesized as major contributors to infection transmission in a healthcare setting. We conducted a cross-sectional pilot study aimed at determining the bioaerosol concentration of C. difficile present in the toilet plume of C. difficile infected patients’ rooms. Patient rooms within the University of Iowa Hospital and Clinics (UIHC) were sampled using a customized bioaerosol air impactor device. Environmental samples were collected before and after flushing the toilet to determine the pre-flush and post-flush levels of aerosolized bacteria. Particle density was collected during both pre and post-flush sampling. Activity levels in the rooms were recorded as a potential confounding variable. A total of 144 environmental samples were collected in 24 rooms. Clostridium difficile was detected in two of the twenty-four rooms (8%). There was a 12% (9/72) positive culture rate pre-flush compared to 23% (19/72) post-flush. Wilcoxon rank sum tests revealed a significant increase in particle concentration at the 5.0µm and 10.0µm size between rooms that produced a bacterial culture compared to rooms that did not (p-values 0.0095 and 0.0082 respectively). There was no significant association between the amount of activity in the room and detectable bioaerosol production (p-value=0.605). Next, we performed a randomized control trial of hospital privacy curtains with antimicrobial properties to determine their ability to resist pathogenic bacterial contamination in an intensive care unit setting. Rooms within the surgical and neurological intensive care unit at UIHC were randomized to receive impregnated curtains, impregnated curtains plus Fuzion hypochlorite spray, or standard control curtains. MRSA, VRE, Pseudomonas spp. and Acinetobacter spp. were the four most frequently cultured pathogenic species. Time to event (contamination) analysis identified a significant difference in time to pathogenic contamination between the control curtains and the impregnated curtains post spray (p-value<0.001). The impregnated curtains post Fuzion spray also grew significantly less colonies of bacteria compared to the control curtains (p-value<0.001). After evaluating environmental risk factors that contribute to Clostridium difficile infection, patient related risk factors for infection were evaluated. Proton pump inhibitors are a class of gastric acid reducers that work by reducing the amount of hydrogen ions produced in the stomach. Recent evidence suggests that prolonged use could negatively affect the intestinal microbiome making it more susceptible to enteric pathogens. A nested case control study was done to determine the association between PPI medication duration and C. difficile infection. Fecal microbiome diversity was analyzed via logistic regression in relation to the development of Clostridium difficile infection. A co-morbidity score was created to adjust for other microbiome altering conditions. PPI duration remained a significant predictor of infection after adjusting for the microbiome influence (p-value=0.0123). Environmental contamination remains a significant risk factor for the transmission of hospital acquired infections including C. difficile. Toilets flushing has been shown to produce pathogenic bioaerosols in the healthcare setting. Hospital privacy curtains have been shown to routinely be contaminated with pathogenic bacteria including other gastrointestinal bacteria that could increase susceptibility to C. difficile infection. PPI medication, which is frequently prescribed in the hospital, has been shown to increase the risk of C. difficile infection, although specific microbiome changes could not be identified.

Chronic pulmonary diseases include a wide range of illnesses that differ in etiology, prevalence, symptomatology and available therapy. A common link among these illnesses is their impact on patients’ vital function of breathing, high symptom burden and significantly impaired quality of life. This dissertation research evaluates disease severity, symptom burden and health behaviors of patients with three different chronic pulmonary conditions. First, alpha-1 antitrypsin deficiency (AATD) is an inherited condition that typically is associated with an increased risk of early onset pulmonary emphysema. This study examines differences in demographic, health, and behavioral characteristics and compares clinical outcomes and health related behaviors and attitudes between two severe genotypes of AATD - ZZ and SZ. The findings of the study suggest that patients with SZ genotype and less severe form of deficiency report higher number of exacerbations, comorbidities, as well as unhealthy behaviors such as lack of exercise and current smoking. In addition, individuals with the more severely deficient ZZ genotype are more adherent to disease management and prevention program recommendations and maintain a healthier lifestyle than individuals with SZ genotype. Second chronic lung disease examined in this research was chronic obstructive pulmonary disease (COPD), the fourth leading cause of death and second leading cause of disability in the United States. Prevalence and burden of cough and phlegm, two of the most common symptoms of the COPD, were assessed among participants of the COPD Foundation’s Patient-Powered Research Network (COPD PPRN). In addition, association between patient-reported levels of phlegm and cough, clinical outcomes and patients’ quality of life were evaluated. Participants’ quality of life was assessed using Patient Reported Outcome Measurement Information System instrument PROMIS-29. Association between changes in symptom severity over time and patient-reported quality of life were examined. Findings of this study indicated that severity of cough and phlegm were associated with higher number of exacerbations, greater dyspnea, and worsened patient-reported quality of life including physical and social functioning. Improvement in cough and phlegm severity over time was associated with better patient-reported quality of life. Third pulmonary illness described in this dissertation is non-cystic fibrosis bronchiectasis (NCFB), a rare and etiologically diverse condition characterized by dilated bronchi, poor mucus clearance and susceptibility to bacterial infection. Association between presence of Pseudomonas aeruginosa (PA), one of the most frequently isolated pathogens in patients with NCFFB, and disease severity was assessed utilizing enrollment data from the Bronchiectasis and NTM Research Registry (BRR). NCFB disease severity was evaluated using modified versions of validated in large international cohorts instruments, the Bronchiectasis Severity Index (BSI) and FACED. The findings of this study indicate that PA infection is common in NCFB patients, and presence of PA in patients’ sputum is associated with having moderate and high severity of bronchiectasis. In addition, the results of this study suggest that the two severity assessment instruments classify patients with NCFB differently which may be attributed to a greater number of severity markers utilized in the calculation of the BSI compared to FACED. In conclusion, the proposed dissertation aims to enhance understanding of differences in health outcomes between genotypes of AATD within AlphaNet registry, and to guide future health-promoting behaviors. It highlights the burden of common symptoms such as cough and phlegm in patients with COPD within COPD PPRN and their association with patients’ quality of life. In addition, it introduces modified indices of NCFB severity and emphasizes high burden of the disease in patients with presence of PA within the US BRR.

To see if aggressive diuresis in first twenty four hours is associated with a comparable number of total days in the hospital as compared to non-aggressive diuresis. In this retrospective cohort study, we compared the length of hospital stay of consecutive patients admitted in one year based on their diuresis during the first twenty-four hours of hospitalization: aggressive diuresis (group 1) i.e. > 2400mL versus non-aggressive diuresis (group 2) i.e. ≤ 2400mL urine output. Patients were excluded if in cardiogenic shock, had creatinine level above 3 mg/dL on admission, or on dialysis. A total of 194 patients were enrolled (29 in group 1 and 165 in group 2 respectively). The Kaplan-Meier estimate of the median cumulative proportion of patients still hospitalized for the group 1 was 4 days and in group 2 was 5 days (log-rank test; P=0.67). In univariate analysis, Cox PH regression showed unadjusted hazard rate of discharge from hospital was slightly higher in group 1 than group 2 but was statistically non-significant (HR=1.08; P=0.70). In multivariate Cox model analysis, creatinine at the time of admission when greater than 1.6mg/dL (P=0.75), LVEF (P= 0.14), total twenty-four hours dose of intravenous Furosemide given (P=0.98) and interaction between Furosemide dose and Creatinine level (P=0.79) were not significant predictor of hospital discharge. Adjusted hazard rate for discharge from hospital was 12% higher in group 1 than group 2 but still statistically non-significant (HR=1.12; P=0.60). Since the length of hospital stay is similar between two groups, we suggest the goal of diuresis to be less than 2400mL in first twenty-four hours to prevent excessive dehydration.

Background: Diabetic foot ulcers are the result of multiple complications from hyperglycemia and lead to poor quality of life and high healthcare costs. The annual diabetes foot screening exam (ADFSE) and prevention interventions can reduce DFUs up to 75%. In 2015, 71% of the US population received the ADFSE. Objectives: The main objectives of this dissertation were: 1) to determine the association between adherence to diabetes self-management behaviors and the ADFSE, 2) to determine the association between concordant and discordant comorbidities and the ADFSE and 3) to determine the association between the performance of diabetes preventive care processes, number of office visits for diabetes and the completion of the ADFSE. Methods: Three cross-sectional studies used data from the 2015 Behavioral Risk Factor Surveillance System. Logistic regression models were evaluated to assess the association between the self-management behaviors and the ADFSE. Structural equation modeling (SEM) was used to assess the simultaneous, direct effects of concordant and discordant comorbidity loads on the ADFSE and the performance of diabetes preventive care processes and the number of office visits for diabetes care on the ADFSE. Results: In 2015, between 78.2% and 80.4% of the US population with diabetes received the ADFSE. Performance of the ADFSE was 77% less likely (OR: 0.33, 95%CI: 0.25-0.44) in those who do not perform self-foot inspections and 40% (OR: 0.59, 95%CI: 0.45-0.76) less likely in those who have never received the pneumococcal vaccination. Receiving the ADFSE was 50-80% less likely in patients who do not self-monitor blood glucose at least one time per day, depending on insulin use and receipt of diabetes education. Neither concordant comorbidities (β=0.226, p=0.086) nor discordant comorbidities (β=0.080, p=0.415) had a direct association with the performance of the ADFSE. The collection of preventive care processes demonstrated a 7% (OR: 1.07, 95% CI: 1.05-1.10) increase in the likelihood the ADFSE was performed Conclusions: Performance of the ADFSE may be improved through multiple types of interventions. Patient-based interventions to increase adherence to self-management behaviors is one route. Programs to improve overall diabetes care in the clinical setting may also help to further improve completion of the ADFSE.