Stroke is the third most common cause of death and a leading cause of disability in the United States. The existing treatments of acute ischemic stroke (AIS) involve pharmaceutical thrombolytic therapy and/or mechanical thrombectomy. The Food and Drug Administration (FDA)-approved recombinant tissue plasminogen activator (tPA) administration for treatment of stroke is efficacious, but has a short treatment time window and is associated with a risk of symptomatic hemorrhage. Other than tPA, the Mechanical Embolus Removal in Cerebral Ischemia (MERCI) retriever system and the Penumbra Aspiration system are both approved by the FDA for retrieval of thromboemboli in AIS patients. However, the previous clinical studies have shown that the recanalization rate of the MERCI system and the clinical outcome of the Penumbra system are not optimal. To identify the variables which could affect the performance of the thrombectomy devices, much effort has been devoted to evaluate thrombectomy devices in model systems, both in vivo and in vitro, of vascular occlusion. The goal of this study is to establish a physiologically realistic, in vitro model system for the preclinical assessment of mechanical thrombectomy devices. In this study, the model system of cerebrovascular occlusion was mainly composed of a human vascular replica, an embolus analogue (EA), and a simulated physiologic mock circulation system. The human vascular replica represents the geometry of the internal carotid artery (ICA)/middle cerebral artery (MCA) that is derived from image data in a population of patients. The features of the vasculature were characterized in terms of average curvature (AC), diameter, and length, and were used to determine the representative model. A batch manufacturing was developed to prepare the silicone replica. The EA is a much neglected component of model systems currently. To address this limitation, extensive mechanical characterization of commonly used EAs was performed. Importantly, the properties of the EAs were compared to specimens extracted from patients. In the preliminary tests of our model system, we selected a bovine EA with stiffness similar to the thrombi retrieved from the atherosclerotic plaques. This EA was used to create an occlusion in the aforesaid replica. The thrombectomy devices tested included the MERCI L5 Retriever, Penumbra system 054, Enterprise stent, and an ultrasound waveguide device. The primary efficacy endpoint was the amount of blood flow restored, and the primary safety endpoint was an analysis of clot fragments generated and their size distribution. A physiologically realistic model system of cerebrovascular occlusion was successfully built and applied for preclinical evaluation of thrombectomy devices. The recanalization rate of the thrombectomy device was related to the ability of the device to capture the EA during the removal of the device and the geometry of the cerebrovasculature. The risk of the embolic shower was influenced by the mechanical properties of the EA and the design of the thrombectomy device.

Objective: Chronic obstructive pulmonary disease (COPD) is a common comorbidity in patients with heart failure, yet little is known about the impact of this condition in patients with acute decompensated heart failure (ADHF), especially from a more generalizable, community-based perspective. The primary objective of this study was to describe the in-hospital and post discharge mortality and treatment of patients hospitalized with ADHF according to COPD status. Methods: The study population consisted of patients hospitalized with ADHF at all 11 medical centers in central Massachusetts during 4 study years: 1995, 2000, 2002, and 2004. Results: Of the 9,748 patients hospitalized with ADHF during the years under study, 35.9% had a history of COPD. The average age of this population was 76.1 years, 43.9% were men, and 93.3% were white. At the time of hospital discharge, patients with COPD were less likely to have received evidence-based heart failure medications, including beta-blockers and ACE inhibitors/angiotensin receptor blockers, than patients without COPD. Multivariable adjusted in-hospital death rates were similar for patients with and without COPD. However, among patients who survived to hospital discharge, patients with COPD had a significantly higher risk of dying at 1 (adjusted RR 1.10; 95% CI 1.06, 1.14) and 5-years (adjusted RR 1.40; 95% CI 1.28, 1.42) after hospital discharge than patients who were not previously diagnosed with COPD. Conclusions: COPD is a common co-morbidity in patients hospitalized with ADHF and is associated with a worse long-term prognosis. Further research is required to understand the complex interactions of these diseases and to ensure that patients with ADHF and COPD receive optimal treatment modalities.

Magnetic resonance imaging (MRI) has emerged as the imaging modality of choice in a wide variety experimental and clinical applications. In this dissertation, I will describe novel MRI techniques for the characterization of neural and pulmonary vascular function in preclinical models of disease. In the first part of this dissertation, experimental results will be presented comparing the identification of ischemic lesions in experimental stroke using dynamic susceptibility contrast (DSC) and a well validated arterial spin labeling (ASL). We show that DSC measurements of an index of cerebral blood flow are sensitive to ischemia, treatment, and stroke subregions. Further, we derived a threshold of cerebral blood flow for ischemia as measured by DSC. Finally, we show that ischemic lesion volumes as defined by DSC are comparable to those defined by ASL. In the second part of this dissertation, a methodology of visualizing clots in experimental animal models of stroke is presented. Clots were rendered visible by MRI through the addition of a gadolinium based contrast agent during formation. Modified clots were used to induce an experimental embolic middle cerebral artery occlusion. Clots in the cerebral vasculature were visualized in vivousing MRI. Further, the efficacy of recombinant tissue plasminogen activator (r-tPA) and the combination of r-tPA and recombinant annexin-2 (rA2) was characterized by clot visualization during lysis. In the third part of this dissertation, we present results of the application of hyperpolarized helium (HP-He) in the characterization of new model of experimental pulmonary ischemia. The longitudinal relaxation time of HP-He is sensitive to the presence of paramagnetic oxygen. During ischemia, oxygen exchange from the airspaces of the lungs to the capillaries is hindered resulting in increased alveolar oxygen content which resulted in the shortening of the HP-He longitudinal relaxation time. Results of measurements of the HP-He relaxation time in both normal and ischemic animals are presented. In the final part of this dissertation, I will present results of a new method to measure pulmonary blood volume (PBV) using proton based MRI. A T1 weighted, inversion recovery spin echo sequence with cardiac and respiratory gating was developed to measure the changes in signal intensity of lung parenchyma before and after the injection of a long acting intravascular contrast agent. PBV is related to the signal change in the lung parenchyma and blood before and after contrast agent. We validate our method using a model of hypoxic pulmonary vasoconstriction in rats.

The overarching goal of this dissertation was to elucidate the psychosocial and behavioral determinants of medication nonadherence among African Americans with hypertension. One in three Americans in the United States has hypertension, and the prevalence of hypertension among African Americans is among the highest in the world. In addition to healthy behaviors such as following a low-salt and low-fat diet, getting regular exercise, and reducing stress, patients with hypertension must also adhere to antihypertensive medications. Poor medication adherence may be driven by psychosocial and behavioral factors; however, the impact of these factors on medication adherence is unclear especially within the African American community. To date, a paucity of research has examined the relationship between psychosocial and behavioral factors such as reported racial discrimination, John Henryism (a measure of active coping and an unhealthy response to stress) and home remedies with medication nonadherence. However, each of these factors has individually been linked with poorer health outcomes among African Americans. Using data from the TRUST study (2006-2008) the association between these constructs and medication adherence was assessed within our sample of 788 African Americans and a comparison group of 137 White participants with hypertension. Ordinal logistic regression was used to assess the association between racial discrimination, John Henryism, home remedies, and medication adherence. The findings from this research indicated more reported racial discrimination, higher John Henryism scores, and greater use of home remedies were associated with lower medication adherence. These findings yield new knowledge about medication adherence and provide practical insights about the psychosocial and behavioral determinants of medication adherence.

During heart valve remodeling, and in many disease states, valvular interstitial cells (VICs) shift to an activated myofibroblast phenotype which is characterized by enhanced synthetic and contractile activity. Pronounced alpha smooth muscle actin (αSMA)-containing stress fibers, the hallmark of activated myofibroblasts, are also observed when VICs are placed under tension due to altered mechanical loading in vivo or during in vitro culture on stiff substrates or under high mechanical loads and in the presence of transforming growth factor-beta1 (TGF-β1). The work presented herein describes three distinct model systems for application of controlled mechanical environment to VICs cultured in vitro. The first system uses polyacrylamide (PA) gels of defined stiffness to evaluate the response of VICs over a large range of stiffness levels and TGF-β1 concentration. The second system controls the boundary stiffness of cell-populated gels using springs of defined stiffness. The third system cyclically stretches soft or stiff two-dimensional (2D) gels while cells are cultured on the gel surface as it is deformed. Through the use of these model systems, we have found that the level of 2D stiffness required to maintain the quiescent VIC phenotype is potentially too low for a material to both act as matrix to support cell growth in the non-activated state and also to withstand the mechanical loading that occurs during the cardiac cycle. Further, we found that increasing the boundary stiffness on a three-dimensional (3D) cell populated collagen gel resulted in increased cellular contractile forces, αSMA expression, and collagen gel (material) stiffness. Finally, VIC morphology is significantly altered in response to stiffness and stretch. On soft 2D substrates, VICs cultured statically exhibit a small rounded morphology, significantly smaller than on stiff substrates. Following equibiaxial cyclic stretch, VICs spread to the extent of cells cultured on stiff substrates, but did not reorient in response to uniaxial stretch to the extent of cells stretched on stiff substrates. These studies provide critical information for characterizing how VICs respond to mechanical stimuli. Characterization of these responses is important for the development of tissue engineered heart valves and contributes to the understanding of the role of mechanical cues on valve pathology and disease onset and progression. While this work is focused on valvular interstitial cells, the culture conditions and methods for applying mechanical stimulation could be applied to numerous other adherent cell types providing information on the response to mechanical stimuli relevant for optimizing cell culture, engineered tissues or fundamental research of disease states.

Background: Guideline-concordant therapies for survivors of an acute coronary syndrome (ACS) hospitalization require healthcare access, something that millions of Americans lack. Methods and Results: Using data from a prospective cohort study of over 2,000 survivors of a hospitalization for an ACS in central Massachusetts and Georgia from 2011 to 2013, the first two aims of this thesis sought to identify the post-discharge consequences for survival and health status of having: 1) financial barriers to healthcare, 2) no usual source of care, and 3) transportation barriers. We found that patients lacking a usual source of care and having a transportation barrier were more likely to have died within two years following hospital discharge compared to those without such barriers. Also, patients with financial barriers to healthcare were more likely to experience clinically meaningful declines in physical and mental health-related quality of life over the six months after hospital discharge. The third aim sought to better understand factors influencing the success of care transitions home after an unplanned hospitalization through a qualitative study of 22 patients. Participants described how adequate healthcare access, particularly having insurance and transportation to clinical appointments, facilitated the receipt of follow-up care and adherence to treatments. Conclusions: Limitations in healthcare access may contribute to poorer survival, health-related quality of life, and survival. Additional research is needed to identify interventions to improve healthcare access and test whether improved access leads to better patient outcomes.

Background Acute coronary syndromes (ACS) are a major cause of mortality and morbidity in the developed world. By 2020, ACS will be the leading cause of morbidity and mortality worldwide, largely due to substantial increases in ACS burden in developing countries. The developing world has been under-represented in international ACS registries. The Arabian Gulf area is a part of the developing world where little is known about the epidemiology of ACS. The first aim of the dissertation is to compare ACS patient characteristics, current practice patterns, and in-hospital outcomes in the Arabian Gulf area to a large multinational sample. Patients with an ACS suffer numerous clinical complications that worsen their prognosis. Cardiogenic shock (CS) is the most serious complication of ACS and the leading cause of in-hospital death. Despite advances in therapies; CS hospital mortality rates continue to exceed 50%. The second aim of the dissertation is to describe the characteristics of patients presenting with ACS complicated by cardiogenic shock, their management, and outcomes in a large multinational sample. In recent years, ACS has been increasingly affecting younger patients. While marked age-related differences have been observed in the risk of developing as well as the prognosis of ACS, few studies however examined time trends in the epidemiology of ACS in young adult patients. The third aim of the dissertation is to examine trends in frequency rates, patient characteristics, treatment practices, and outcomes in young adults hospitalized with an ACS. Methods Data from two large multinational registries of patients hospitalized with an ACS were used for this investigation. Nearly 65,000 patients were enrolled in the Global Registry of Acute Coronary Events (GRACE) between 2000 and 2007, while 6,700 patients participated in the Gulf Registry of Acute Coronary Events (Gulf RACE) in 2007. Results Aim1: Patients in Gulf RACE were significantly younger and were more likely to be male, diabetic, and smoke Compared to GRACE. Patients in Gulf RACE were less likely to receive evidence based therapies. Short-term mortality rates were comparable between the two patient cohorts. Aim2: Compared to patients with no CS, patients with CS were more likely to be older, female, have a history of diabetes, and heart failure. Patients with CS were less likely to receive effective cardiac catheterization and adjunctive cardiac medications. In-hospital case-fatality rate of patients with CS were 59.4%. While in-hospital mortality declines over the study period, incidence rates only showed minor declines. Aim2: Baseline characteristics of patients < 55 years of age did not significantly change, while the use of evidence based therapies increased significantly during the years under study. Rates of short-term adverse outcomes and mortality significantly declined over time. Conclusions We observed marked regional differences in the risk profile, clinical management, and outcomes of patients with an ACS internationally compared to the Arab Middle East. Despite the encouraging trends in the use of evidence based therapies which have likely contributed to the improving trends in the prognosis of ACS, rates of development of ACS, as well as mortality due to ACS complications, remain high.

The Institute for Healthcare Improvement (IHI) has promoted implementing a RRS to provide safer care for hospitalized patients. Additionally, the Joint Commission made implementing a RRS a 2008 National Patient Safety Goal. Although mandated, the evidence to support the effectiveness of a RRS to reduce cardiac arrests on hospital medical or surgical floors and un-anticipated ICU transfers remains inconclusive, partly because of weak study designs and partly due to a failure of published studies to report all critical aspects of their intervention. This study attempted to evaluate the effectiveness and the implementation of a RRS on the two campuses of the UMass Memorial Medical Center (UMMMC). The first study presented was an attempt to identify the preventability and timeliness of floor to ICU transfers. This was done using 3 chief residents who reviewed 100 randomly selected medical records. Using Cohen’s kappa to assess the inter-rater reliability it was determined that 13% of the cases could have possibly been preventable with earlier intervention. The second study was an evaluation of the effectiveness of the Rapid Response System. Outcomes were cardiac arrests, code calls and floor to ICU admissions. There were two study periods 24 months before the intervention and 24 months after. A Spline regression model was used to compare the two time periods. Though there was a consistent downward trend over all 4 years there were no statistically significant changes in the cardiac arrests and ICU transfers when comparing the before and after periods. There was a significant reduction in code calls to the floors on the University campus. The third study was a modified process evaluation of the Rapid Response intervention that will assess fidelity of RRS implementation, the proportion of the intended patient population that is reached by the RRS, the overall number of RRS calls implemented (dose delivered) and the perceptions of the hospital staff affected by the RRS with respect to acceptability and satisfaction with the RRS and barriers to utilization. The process evaluation showed that that the Rapid Response System was for the most part being used as it was designed, though the nurses were not using the specific triggers as a deciding factor in making the call. Staff satisfaction with the intervention was very high. Overall these studies demonstrated the difficulty in clearly defining outcomes and data collection in a large hospital system. Additionally the importance of different study designs and analysis methods are discussed.

Background and Objective: Comorbidity and especially cardiovascular diseases are common among patients with chronic obstructive pulmonary disease (COPD). The primary purpose of this study was to identify drugs for the treatment of cardiovascular diseases in COPD patients. The secondary purpose was to analyze whether the use of cardiovascular drugs differs between patients with mild and severe COPD symptoms.     Method: The study was a retrospective cross-sectional study of 421 COPD patients whose drug lists were analyzed and cardiovascular drugs were identified. These drugs were then divided into eight drug groups, based on the drug's ATC (Anatomic Therapeutic Chemical classification system) codes. Only patients with reported cardiovascular diseases were included in the analysis. Patients with mild and severe COPD symptoms were identified. Thereafter, the patients were divided into two groups based on the COPD symptoms. Chi-squared test was performed to see if the use of cardiovascular drugs differs between patients with mild and severe COPD symptoms.  Setting: Primary and secondary care patients with COPD in Gävle and Dalarna.  Main outcome measures: Identify and analyze the use of cardiovascular drugs in COPD patients with mild and severe symptoms.  Results: The results of the survey showed that cardiovascular drugs were used by 274 (65%) of the COPD patients. Among them, 66 % with severe COPD symptoms and 34 % with mild symptoms. The use of the eight cardiovascular drug groups were similar between patients with mild and severe COPD symptoms. There wasn’t any statistically significant difference in the use of cardiovascular drugs between patients with mild and severe COPD symptoms (p= 0,893).   Conclusions: There wasn’t any difference in the use of cardiovascular drugs among patients with mild and severe COPD symptoms. However, this result needs to be substantiated with a follow-up study with a larger study population and longer study time to be generalizable.

Indiana University-Purdue University Indianapolis (IUPUI) / Noble metal nanostructures display collective oscillation of the surface conduction electrons upon light irradiation as a form of localized surface plasmon resonance (LSPR) properties. Size, shape, and refractive index of the surrounding environment are the key features that control the LSPR properties. Surface passivating ligands on to the nanostructure can modify the charge density of nanostructures. Further, allow resonant wavelengths to match that of the incident light. This unique phenomenon called the “plasmoelectric effect.” According to the Drude model, red and blue shifts of LSPR peak of nanostructures are observed in the event of reducing and increasing charge density, respectively. However, herein, we report unusual LSPR properties of gold triangular nanoprisms (Au TNPs) upon functionalization with para-substituted thiophenols (X-Ph-SH, X = -NH2, -OCH3, -CH3, -H, -Cl, -CF3, and -NO2). Accordingly, we hypothesized that an appropriate energy level alignment between the Au Fermi energy and the HOMO or LUMO of ligands allows the delocalization of surface plasmon excitation at the hybrid inorganic-organic interface. Thus, provides a thermodynamically driven plasmoelectric effect. We further validated our hypothesis by calculating the HOMO and LUMO levels and work function changes of Au TNPs upon functionalization with para-substituted thiol. This reported unique finding then utilized to design ultrasensitive plasmonic substrate for biosensing of cancer microRNA in bladder cancer and cardiovascular diseases. In the discovery of early bladder cancer diagnosis platform, for the first time, we have been utilized to analyze the tumor suppressor microRNA for a more accurate diagnosis of BC. Additionally, we have been advancing our sensing platform to mitigate the false positive and negative responses of the sensing platform using surface-enhanced fluorescence technique. This noninvasive, highly sensitive, highly specific, also does not have false positives techniques that provide the strong key to detect cancer at a very early stage, hence increase the cancer survival rate. Moreover, the electromagnetic field enhancement of Surface-Enhanced Raman Scattering (SERS) and other related surface-enhanced spectroscopic processes resulted from the LSPR property. This dissertation describes the design and development of entirely new SERS nanosensors using a flexible SERS substrate based on the unique LSPR property of Au TNPs. The developed sensor shows an excellent SERS activity (enhancement factor = ~6.0 x 106) and limit of detection (as low as 56 parts-per-quadrillions) with high selectivity by chemometric analyses among three commonly used explosives (TNT, RDX, and PETN). Further, we achieved the programmable self-assembly of Au TNPs using molecular tailoring to form a 3D supper lattice array based on the substrate effect. Here we achieved the highest reported sensitivity for potent drug analysis, including opioids and synthetic cannabinoids from human plasma obtained from the emergency room. This exquisite sensitivity is mainly due to the two reasons, including molecular resonance of the adsorbate molecules and the plasmonic coupling among the nanoparticles. Altogether we are highly optimistic that our research will not only increase the patient survival rate through early detection of cancer but also help to battle the “war against drugs” that together are expected to enhance the quality of human life.