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Alzheimer’s disease is the most common type of dementia that currently affects over 6.5 million people in the U.S. Currently there is no cure and the existing drug therapies attempt to delay the mental decline and improve cognitive abilities. Two of the most commonly prescribed such drugs are Donepezil and Memantine. We formally tested and confirmed the presence of a beneficial drug-drug interaction of Donepezil and Memantine using a causal inference analysis. We applied doubly robust estimators to one of the largest and high-quality medical databases to estimate the effect of two commonly prescribed Alzheimer’s disease (AD) medications, Donepezil and Memantine, on the average number of hospital or emergency department visits per year among patients diagnosed with AD. Our results show that, compared to the absence of medication scenario, the Memantine monotherapy, and the Donepezil monotherapy, the combined use of Donepezil and Memantine treatment significantly reduces the average number of hospital or emergency department visits per year by 0.078 (13.8%), 0.144 (25.5%), and 0.132 days (23.4%), respectively. The assessed decline in the average number of hospital or emergency department visits per year is consequently associated with a substantial reduction in medical costs. As of 2022, according to the Alzheimer’s Disease Association, there were over 6.5 million individuals aged 65 and older living with AD in the US alone. If patients who are currently on no drug treatment or using either Donepezil or Memantine alone were switched to the combined used of Donepezil and Memantine therapy, the average number of hospital or emergency department visits could decrease by over 613 thousand visits per year. This, in turn, would lead to a remarkable reduction in medical expenses associated with hospitalization of AD patients in the US, totaling over 940 million dollars per year.

Initially, our medical centers faced planning for inpatient, ER, and critical care surge capacity, cohorting COVID-positive patients, modeling case numbers, counting ventilators and estimating utilization rates of PPE.2 While the numbers increased across the Unites States of America, we began to plan for the surge capacity at our hospital, the University of Alabama at Birmingham. A positive screening test resulted in case postponement for two weeks with planned retesting. Since the initiation of this pre-operative COVID-19 process until May 5, we have tested 2437 asymptomatic patients and have found 18 positive results. Several tangible benefits of presurgical testing include PPE conservation and the protection of healthcare workers from inadvertent exposure to COVID-19.5 A known COVID-19 status provides considerable reassurance to the perioperative team and therefore a safer working environment. Testing also provides an element of additional patient safety and reduction in healthcare expense and resource utilization, as performing surgery on asymptomatic COVID-19 positive patients is associated with a 44% increase in postoperative ICU admissions and a 20.5% mortality rate.6 Our process involves surgeons posting cases to the operating room schedule at least 72-h in advance of the desired surgery date.

This dissertation documents an investigation into Parkinson’s Disease utilizing machine learning and causal inference methods. I will cover a descriptive analysis of Parkinson’s Disease (PD) in a vast, high-quality database and present costs associated with Parkinson’s Disease medications. I also researched a causal inference method assessing the Carbidopa-Levodopa effect on two-year survival and a causal survival analysis on a one-to-five-year survival comparing no drug use and Carbidopa-Levodopa in Parkinson’s Disease patients. For my classification with Parkinson’s gait, patients were monitored with a smartphone and an additional 6 Inertial Measurement Unit (IMU) sensors to collect clinical gait measures. I used classical machine learning algorithms on raw smartphone data to distinguish between ON and OFF times. With an average accuracy of 92.5%, this work demonstrates the feasibility of using smartphone data to distinguish between ON versus OFF walking and lays the groundwork for a real-world, corrective feedback system.I also researched the causal effect of the most prevalent PD medication in terms of survival. In particular, I focused on the probability of two-year survival with PD patients taking Carbidopa-Levodopa and no drug use and assessing whether there was an effect on survival utilizing the doubly robust method. My results with the differences of causal effects showed a 0.013 positive increase taking Carbidopa-Levodopa indicating this medication had a significant positive effect on the two-year survival of PD patients.I then furthered this study and conducted a causal survival analysis from one-to-five-year survival with two treatments, no drug use and Carbidopa-Levodopa. The results showed that Carbidopa-Levodopa had a significant effect on survival when the drug was prescribed within three years from first diagnosis and no drug use had a significant effect at four and five years of survival. In the process of better using the current data, a descriptive statistical analysis was conducted. As such, I studied a vast and high-quality database Cerner Real-World Data and focused on people who were diagnosed with Parkinson’s Disease from 2016 to 2022. I researched the demographics, comorbidities, and medications of PD patients. After cleaning the database, my final cohort size was 110,037 subjects.

Mucosal viruses cause a diverse array of diseases in humans that are typically restricted to the initial anatomic site of infection but may progress to cause systemic disease if they overcome local immune responses. Even in the absence of progression to systemic disease, these viruses may act on host immune cells in a manner favorable to other pathogens. Herein we consider two predominantly mucosal viruses that direct a complex web of interactions with host immune cells: the evolutionarily ancient Herpes Simplex Virus type 2 (HSV-2) and the newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For HSV-2 we present novel insights into its interactions with CD4+ T cells and how these interactions create an environment that is favorable to human immunodeficiency virus (HIV) reactivation and replication. For SARS-CoV-2 we present differences in pediatric and adult immune responses and discuss the contribution of these differential responses to the epidemiologic observation of reduced disease severity in pediatric COVID-19 patients. Primary HSV-2 infection is typically limited to genital mucosae and is followed by the establishment in sensory ganglia of latency from which the virus will frequently reactivate. Strong epidemiologic data have demonstrated that prior infection with HSV-2 increases the risk of HIV acquisition several fold and worsens HIV disease. Most studies of the mechanisms underlying these observations have focused on local immune responses to HSV-2 lesions and have uncovered mechanisms contributing to increased HIV acquisition risk but have not yielded insights into the observed systemic effects of HSV-2 on HIV, namely the increased HIV plasma viral loads and expanded tissue reservoirs. We hypothesized that HSV-2 modulates systemic measures of HIV disease through direct interactions of HSV-2 with CD4+ T cells. We tested this hypothesis using both primary CD4+ T cells from HIV+ donors and the Jurkat 2D10 cell line model of HIV latency and found that HSV-2 infection of these cells promoted HIV reactivation and replication. Through a combination of bulk and single-cell RNA sequencing and the application of recently-developed computational analysis techniques we identify transcriptional changes in HSV-2 infected cells that promote HIV replication. To better define host mechanisms driving this increase in HIV replication we focused on the long non-coding (lnc)RNA MALAT1 which was significantly increased in our bulk RNAseq dataset, and analysis of our scRNAseq data indicated that MALAT1 expression was significantly coregulated with HSV gene expression. We hypothesized that, consistent with its recently reported role in releasing epigenetic silencing of the HIV ltr promoter, induction of MALAT1 expression contributed to HSV-induced enhancement of HIV replication. CRISPR/Cas9-mediated deletion of MALAT1 abrogated the HSV-induced enhancement of HIV ltr expression. We also found that HIV replication in response to the histone deacetylase (HDAC) inhibitor Romidepsin was reduced in the absence of MALAT1, but there was no effect on the response to TNF, which reactivates HIV via the NFkB pathway. We further found that MALAT1 expression was significantly increased in response to both HSV-2 and Romidepsin, but not TNF, suggesting that HSV-2 acts as an HDAC inhibitor in this context. We subsequently found the HSV-2 protein VP16 to be a significant driver of these observations. These studies highlight a previously underappreciated mechanism by which HSV-2 infection of CD4+ T cells promotes HIV reactivation and replication. The emergence of the novel coronavirus SARS-CoV-2 and the observation that it tended to cause milder clinical disease in children prompted us to hypothesize that discrete differences in the immune responses to SARS-CoV-2 infection in children and adults were responsible for these observations. We identified several differences in pediatric and adult immune responses to infection, namely reduced functional antibody responses in children, and a negative correlation between age and serum levels of the cytokines TNF and IFN-, as well as a weaker memory T cell response in convalescent pediatric patients. These observations led us to hypothesize that a stronger innate immune response in children led to milder clinical disease and poor development of immune memory. We tested this hypothesis by obtaining nasopharyngeal swabs from the pediatric and adult patients at the time of presentation to the emergency department, and quantifying antibodies, cytokines, and performing RNAseq on cells isolated from the swabs. While total and SARS-CoV-2 specific antibodies were similar in children and adults, Type I and II interferons were elevated in fluid from pediatric swabs compared to adults, and transcriptome analysis suggested a stronger innate immune response in the pediatric nasal mucosa. These findings suggest adult COVID-19 patients experience more severe disease as a consequence of weaker innate immune responses failing to restrain SARS-CoV-2 infection.

An essay from the Institute for National Security Ethics and Leadership identifies the traits of strategic leaders and outlines the challenges to be overcome in the exercise of strategic leadership. Six characteristics are particularly relevant to strategic leaders in the future: intellectual openness, nuance, intellectual agility, integration, teamwork, and ethics. Figures. Adapted from the source document.