Digital Commons Network^™

Characterizing Populations Living Near Concentrated Animal Feeding Operations: Implications For Health Equity And Environmental Justice, Leah Salzano

Public Health Theses

Current literature has highlighted that concentrated animal feeding operations (CAFOS) are associated with adverse health outcomes among populations living in close proximity to the farms and that, in certain states, vulnerable populations may be disproportionately exposed to CAFOs. However, none of the existing studies have assessed the sociodemographic makeup of areas highly exposed to CAFOs across a diverse geographic range. Using locations of CAFOs across six states with robust operations, we conducted logistic regression models assessing the likelihood of high exposure vs. low exposure at the census tract level for each 10% increase in sociodemographic variables (percent unemployed, percent minority, …

From Theory To Practice: Zoonotic Spillover, One Health And The Role Of Local Indigenous Communities, Pranav Prabhu Savanur

Public Health Theses

This paper discusses the impact of zoonotic spillovers on public health and the need for a One Health approach to preventing future pandemics. Zoonotic spillovers occur when pathogens are transmitted from animals to humans, facilitated by anthropogenic land changes, migration or trade, increased human-animal contact, and poor biosafety. However, anthropogenic land use change is the primary driver for zoonotic spillovers. Most emerging infectious diseases in humans are of zoonotic origin, and the impact of these spillovers on public health is significant. The paper emphasizes the need to prevent spillover events for primary pandemic prevention, which requires a coordinated and collaborative …

The Immunologic And Epigenomic Regulation Of Hiv-1 Persistence, Jack A. Collora

Yale Graduate School of Arts and Sciences Dissertations

Curing HIV-1 is challenging due to the presence and persistence of CD4+ T cells harboring HIV-1 proviruses. Understanding the epigenetic and transcriptional regulation that enables HIV-1 to persist despite antiretroviral therapy (ART) and immune pressure is critical to counteracting this latent reservoir. A first chapter consists of an edited published review and preview covering a relevant subset of known features of HIV-1 persistence and HIV-1-T cell interaction biology. The remaining three chapters are parallel projects to understand the multifaceted nature of HIV-1: the interrogation and longitudinal tracking of HIV-1 RNA+ cells from infected individuals, the identification HIV-1 silencing host factors …

Identifying Immunological Biomarkers In Massive Public Data, Daniel G. Chawla

Yale Graduate School of Arts and Sciences Dissertations

Recent advances in high-throughput experiments and systems biology approaches have resulted in hundreds of publications profiling immune responses to exposures such as pathogens and vaccines. Immune profiling is important for an emerging class of disease diagnostic technologies, as well as for understanding the mechanisms underlying disease pathogenesis and vaccine response. Massive amounts of public data are available for biomarker discovery and mechanistic profiling, including both datasets capturing transcriptional profiles of the immune system as well as published signatures describing changes that occur (e.g., in gene expression or cellular phenotypes) following infection or vaccination. This wealth of public data presents both …

Neoantigen-Driven B Cell And Cd4 T Cell Collaboration Promotes Anti-Tumor Cd8 T Cell Responses In Lung Adenocarcinoma, Can Cui

Yale Graduate School of Arts and Sciences Dissertations

Lung cancer is the leading cause of cancer-related mortality worldwide, accounting for ~1.8 million deaths annually. Lung adenocarcinoma (LUAD) is the most common form of non-small cell lung cancer (NSCLC; 40% of cases) and is most frequently associated with mutations in KRAS proto-oncogene (30% of cases). Traditionally, therapeutic options for KRAS-mutant LUAD have been limited, but the successful application of immune checkpoint blockade (ICB) targeting the PD-1 pathway has changed the therapeutic landscape. The success of PD-1-blockade therapy has also changed the perception that LUAD is a non-immunogenic cancer type because anti-PD-1/PD-L1 treatment potentiates the function of previously activated T …

The Role And Production Of Gut Food-Specific Immunoglobulin A, Elise Liu

Yale Graduate School of Arts and Sciences Dissertations

Immunoglobulin A (IgA) is the predominant antibody isotype in the gut, where it regulates commensal flora and neutralizes toxins and pathogens. The function of food-specific IgA in the gut is unknown but is presumed to protect from food allergy. Specifically, it has been hypothesized that food-specific IgA binds ingested allergens and promotes tolerance by immune exclusion; however, the evidence to support this hypothesis is indirect and mixed. While it is known that healthy adults make gut peanut-specific IgA, it is unclear whether children also have gut peanut-specific IgA. We found that in a cohort of non-food allergic infants (n=112), there …

Impact And Cost-Effectiveness Of Human Papillomavirus Vaccination Policies In The United States Uniformed Armed Forces, Noel Dickens

Yale Graduate School of Arts and Sciences Dissertations

Background. Virtually all cervical cancers and cases of recurrent respiratory papillomatosis (RRP) are caused by human papillomavirus (HPV) as well as a large proportion of anal, penile, oropharyngeal, vulvar, and vaginal cancers and anogenital warts (AGW). Vaccination with the nonvalent HPV vaccine (9vHPV) is proven to prevent a significant proportion of HPV-associated diseases. Adoption of large-scale HPV vaccination programs by US public institutions requires careful consideration of the cost to benefit ratio of each program through economic evaluations. US Uniformed Armed Forces (USUAF) HPV vaccination policy would benefit from economic evaluations that consider the unique population and institutional characteristics of …

Immunology, Immunopathology, And Immunopharmacology Of Covid-19, Tianyang Mao

Yale Graduate School of Arts and Sciences Dissertations

Respiratory viruses represent a continuous and growing threat to humanity. This is exemplified by the ongoing global COVID-19 pandemic, which is caused by a newly emerged coronavirus SARS-CoV-2. The immune system provides a formidable barrier to viral pathogens, while dysregulated immunity leads to deleterious infection outcomes. Understanding the involvement of immune responses in viral infections will provide crucial insights into disease pathogenesis and shed light on potential targets for therapeutic interventions. In this thesis, we interrogate the components of the immune response that control SARS-CoV-2 and contribute to its pathogenesis. Based on these insights, we develop distinct immunopharmacological strategies to …

Computerized Cognitive Behavioral Therapy For Patients With Post-Treatment Lyme Disease Syndrome, Katherine Fry

Yale School of Medicine Physician Associate Program Theses

Lyme disease is the most common vector-borne illness in North America. Post-treatment Lyme disease syndrome is defined as a subset of patients appropriately treated for Lyme disease who continue to experience generalized symptoms, such as depression. However, treatment options for depressive symptoms in post-treatment Lyme disease syndrome largely remain unknown. The objective of this study is to examine whether computerized cognitive behavioral therapy, an internet-delivered form of traditional cognitive behavioral therapy, can reduce depressive symptoms in patients with post-treatment Lyme disease syndrome. Here, we conduct a parallel randomized controlled trial to evaluate whether computerized cognitive behavioral therapy can reduce depressive …

Spatial And Prediction Models For Addressing Challenges In Pediatric Tuberculosis Control And Care, Kenneth Suranga Gunasekera

Yale Graduate School of Arts and Sciences Dissertations

Tuberculosis (TB) is among the leading causes of global mortality among children <5 years. Each year, over 1 million TB cases occur among children <15 years worldwide, and nearly one quarter of those children die; approximately 80% of those deaths occur among children <5 years. Alleviating the burden of pediatric TB and mortality requires 1) enhanced efforts to prevent transmission to children and 2) treating more children for TB. Targeting resources to children with a known TB exposure has been a cornerstone of the public health response to prevent transmission and detect cases early. Infectious adults must be diagnosed and treated earlier to prevent transmission to their child contacts. Modeling studies suggest that targeting community-level active case-finding to areas with high local transmission intensity may demonstrate population-level reductions in TB incidence. However, obtaining conclusive evidence of concentrated transmission requires access to spatial and genomic data, which is often only available under research conditions in high TB-incidence settings. In chapter 1, I use Bayesian spatial modeling methods to probe routinely collected, age-disaggregated TB notification data to demonstrate that overrepresentation of young child cases co-locate with areas of high local transmission intensity, identified by molecular evidence of transmission from a prospective cohort study in the same setting. This finding suggests that the use of models that leverage widely available notification data should be explored as tools to target case-finding and treatment efforts in high-transmission locations to maximize the direct and indirect benefits of active screening approaches. In chapter 2, I leverage data from a large prevalence survey to investigate a poorly understood form of TB that may frustrate symptom-based active case-finding efforts. Given that modeling estimates suggest that 96% of global childhood mortality due to TB occurs among children not receiving antituberculosis treatment, identifying and treating more cases of pediatric TB provide an opportunity to reduce child mortality. Diagnostic tools for pediatric pulmonary TB are limited by paucibacillary disease in children as well by resource constraints in many high TB-incidence settings. This contributes to poorer treatment outcomes through missed diagnoses and treatment delays. In chapter 3, I describe the analysis of a cohort of children being evaluated for TB from Cape Town, South Africa to demonstrate that a majority of antituberculosis treatment-decisions could be made using clinical evidence alone, without the need for additional diagnostic testing. In chapter 4, I describe the assembly of a large cohort of pediatric TB diagnostic evaluation data sourced from multiple geographically diverse, high TB-incidence settings to develop a prediction model for TB and investigate its validity and generalizability. As part of this work, I describe efforts in partnership with the World Health Organization to operationalize the prediction model as a treatment-decision algorithm to guide the evaluation of children with presumptive pulmonary TB.

Investigating The Impact Of Maternal Antiviral Responses On Pregnancy And Fetal Development, Alice Lu-Culligan

Yale Graduate School of Arts and Sciences Dissertations

The maternal-fetal interface during pregnancy is an underexplored environment rich in immunological factors that must propel developmental processes while simultaneously providing protection from invading pathogens such as viruses. Almost half of all cells in the maternal decidua in pregnancy are leukocytes, which are required for successful pregnancy, and the placenta has increasingly become recognized as an immunological organ. Viral infections during pregnancy are associated with significant mortality and morbidity, both for the pregnant female and the developing fetus. Notably, impacts on fetal development have typically been attributed to direct viral damage to cells and tissues during the course of infection, …

Applications Of Dynamic Modeling And Statistical Analysis To Infectious Diseases, Alyssa Sholeh Parpia

Yale Graduate School of Arts and Sciences Dissertations

In this dissertation, I explore the disproportionate burden of infectious disease outbreaks, epidemics, and pandemics and the projected impact of interventions for mitigating their harm on populations in Cameroon and the United States. The spatial heterogeneity in vaccination coverage and access to care in Cameroon creates areas that are highly susceptible to measles transmission. In the US, the HIV epidemic is increasingly concentrated in the southern states in addition to larger cities with variable levels of prevention and linkage to sustained treatment. Disparities in COVID-19 burden exist by race and geography across Michigan, in part due to systemic racism and …

Contact Tracing In The Era Of Covid-19: Implementation Of Traditional Strategies In Novel Contexts And Innovative Approaches To Address Existing Barriers, Tyler James Shelby

Yale Graduate School of Arts and Sciences Dissertations

Background: Contact tracing is an evidence-based intervention that became a core component of many COVID-19 response plans throughout the globe. Despite its demonstrated success within other disease contexts, early studies of COVID-19 contact tracing have reported mixed results regarding the effectiveness and impact of contact tracing on ultimate pandemic objectives such as case incidence or mortality. Yet, there remains a knowledge gap regarding contextual factors that influence implementation outcomes of contact tracing that may in turn influence its ultimate impact. The primary objective of this dissertation is to address this knowledge deficit by evaluating an emergency contact tracing program developed …

Dissecting The Impact Of Clonal Hematopoiesis On Age-Related Disease, Seyedeh Maryam Zekavat

Yale Graduate School of Arts and Sciences Dissertations

Aging is the strongest risk factor for a number of diseases. Despite current risk prediction, prevention, and therapeutic strategies, age-related diseases including coronary artery disease (CAD), cancer, and now COVID-19, are the leading causes of death in the US and worldwide. The aging hematopoietic system is characterized by increased prevalence of acquired somatic variants predisposing to clonal expansion. Carriers of somatic mutations predisposing to clonal expansion in hematopoietic stem cells (clonal hematopoiesis of indeterminate potential, CHIP) are at increased risk for not only hematologic cancer but also atherosclerosis. Other classes of somatic variation besides CHIP, including larger somatic structural variants …

Discovery Of Novel Cancer Immunotherapy Targets With Next Generation Genome Engineering Methods, Jonathan Joon-Young Park

Yale Graduate School of Arts and Sciences Dissertations

Recent advances in immuno-oncology have led to remarkable clinical benefits in a variety of different cancers; however, a large fraction of patients encounter resistance. Identifying novel targets that can improve T cell functionality can therefore broaden the potential of cancer immunotherapy. We developed methods for discovering such targets using CRISPR gene editing technology. First, we created a hybrid genetic screening system where Sleeping Beauty (SB) transposons and single guide RNA cassettes are nested in an adeno-associated virus (AAV) to enable in vivo AAV-SB-CRISPR screens for membrane protein targets in CD8+ T cells in mouse models of glioblastoma. Second, we developed …

On The Surveillance And Spread Of Drug Resistant Malaria In Sub-Saharan Africa, Hanna Y. Ehrlich

Yale Graduate School of Arts and Sciences Dissertations

Artemisinin-based combination therapies (ACTs) are among the most important tools in our arsenal to treat and control malaria. ACTs and other antimalarial drugs have contributed to significant declines in global malaria-attributed morbidity and mortality over the past few decades. However, progress is the effort to eradicate the disease has not been equally distributed: sub-Saharan Africa continues to experiences the vast majority of the burden of the disease. Recent reports of ACT resistance in Rwanda and Uganda confirm longstanding expectations that artemisinin-resistant parasites will eventually emerge in Africa. To delay the spread of artemisinin resistance across the malaria endemic sub-continent, it …

Ion Transport In Membranes With Sub-Nanometer Pores: Material Design And Selectivity Mechanisms, Xuechen Zhou

Yale Graduate School of Arts and Sciences Dissertations

As of 2017, over 800 million people around the world still lacked the access to safe drinking water. With over 97% of the earth’s water stored in the ocean, reverse osmosis (RO) seawater desalination has been proposed as a promising solution to boost the water supply and alleviate the water shortage. Polyamide (PA) thin-film composite (TFC) membranes are the state-of-the-art membranes for RO separation and a typical PA TFC membrane can reject over 99% of the sodium chloride (NaCl) in the feed stream. Despite their exceptional water-salt separation capability, current PA membranes have two major limitations: 1) they are highly …

Synthesizing Epidemiological Evidence Of Respiratory Syncytial Virus To Predict The Potential Effectiveness Of Three Rsv Prevention Strategies, Zhe Zheng

Yale Graduate School of Arts and Sciences Dissertations

Respiratory syncytial virus (RSV) is the leading cause of respiratory infection and hospitalization for infants, children, and the elderly [1]. In this dissertation, I present five quantitative studies aimed at improving our understanding of the disease burden, epidemic timing, geographic spread, and prevention of RSV. Specifically, I applied statistical and mathematical models to (1) estimate respiratory hospitalizations attributable to RSV across age and socioeconomic groups; (2) identify drivers that impact RSV epidemic spatiotemporal patterns in a typical winter season; (3) estimate the timing and intensity of RSV reemergence following the COVID-19 pandemic; (4) compare the geographic spread of RSV epidemics …

Assessment Of Emergency Care Services In Nigerian Hospitals: A Cross-Sectional Study, Kelechi Herbert Umoga

Yale Medicine Thesis Digital Library

The Accident and Emergency (A&E) unit in Nigeria is a key entry point to access health care for patients with various diseases. Currently there are limited data assessing the functionality of these units and their capacity for care. This study aims to evaluate the functional capacity of A&Es in Nigeria and to identify factors impeding optimal care.We conducted a cross-sectional study of seven hospitals in Nigeria, randomly selecting one hospital from each of the six geopolitical zones, and purposively including National Hospital Abuja. We used a universal sampling technique interviewing all doctors and nurses identified as routine A&E staff. We …

Is Risk Compensation Real? The Effect Of Perceived Level Of Hiv Acquisition On Risk Behavior In A Pilot Pre-Exposure Prophylaxis Demonstration Project In Men Who Have Sex With Men In Malaysia, Kelsey Rankin

Yale Medicine Thesis Digital Library

Pre-exposure prophylaxis (PrEP) is highly effective in human immunodeficiency virus (HIV) prevention for key populations, including men who have sex with men (MSM). In Malaysia, human immunodeficiency virus (HIV) prevalence among MSM is 22%, and is even higher in key urban areas, including Kuala Lumpur. Despite nationwide campaigns committed to address HIV, scale-up of PrEP for MSM in Malaysia has been suboptimal. This limitation can be attributed partially to concerns that PrEP will lead to increased sexual risk behaviors, based on the controversial theory of risk compensation.

A 2018 PrEP demonstration study of MSM in Malaysia (n=150) was used to …

Medicine@Yale May/June 2022 Volume 17, Issue 1, Yale School Of Medicine Office Of Communications

Medicine@Yale - development newsletter

Medicine@Yale : advancing biomedical science, education and health care was a print and online newsletter which published news about academics, research and philanthropy for alumni, donors, faculty, students and the general public. It was initially published 6 times a year and then changed to a quarterly schedule. The first issue came out June/Jul. 2005. The final issue was published in May/June 2022, vol. 17, issue 1. Published by Yale School of Medicine, Office of Communications.

Role Of Covid-19 Attributions In Inciting Violence Toward Older Asian Individuals, Emily Zhen Ning Hwang

Public Health Theses

Older adults in the Asian Americans and Pacific Islanders (AAPI) community faced heightened levels of violence and discrimination during the COVID-19 pandemic. Yet, little is known about the factors driving Asian-specific violence. This study investigated if individuals who attributed COVID-19 to stable factors and anything related to China were more likely to commit violence against older Asian adults. From April 23 to May 5 2020, a survey was conducted with 1498 American individuals (M = 55.19 years, SD = 17.97 years) using two online platforms. Participants who made stable attributions about the origin of COVID-19 were significantly more likely to …

Trends In Recurrent Clostridioides Difficile Infection In New Haven County, Chinenye Maryanne Okafor

Public Health Theses

Background: Recurrent Clostridioides difficile infection (CDI) is a cause of increased burden on the healthcare system and factors associated with this disease merit understanding. This study aimed to determine the incidence rate and to describe the factors associated with recurrent CDI cases in New Haven County from 2015 to 2020. It also examined the trends in annual recurrent CDI cases across epidemiological classes. Methods: This study utilized data from a population-based surveillance program of the Healthcare-Associated Infectious Community Interface (HAIC) Program within the Connecticut Emerging Infectious Program (CT EIP) at Yale School of Public Health which served all residents of …

A Scoping Review Comparing Sustainable Diet Indices, Natalie Henning

Public Health Theses

Interest in environmentally sustainable diets (i.e., diets beneficial for both human and planetary health) has increased as the role of food systems in climate change and population health has become better understood. Sustainable diet indices have been proposed as a holistic approach to assessing diets around the world with regards to human and planetary outcomes. The aim of this scoping review was to summarize and compare sustainable diet indices and their applicability to various populations.A literature search of three databases (Scopus, PubMed, and the Climate Change and Human Health Literature Search Portal) was conducted to identify articles that developed, validated, …

Comprehensive West Nile Virus Phylogenetic Analysis: Europe And Beyond, Robert T. Koch

Public Health Theses

ABSTRACT West Nile virus (WNV) inhabits a unique position in the infectious disease landscape. It is both the most widespread arbovirus in the world, and yet is one of the least known. WNV is spread by mosquitoes and has high morbidity and mortality in birds, humans are dead-end hosts of the virus but can develop a serious neuroinvasive form of the disease (WNND). The incidence of such cases is on the rise around the world. To explore WNV, we created a comprehensive phylogenetic analysis with all available WNV genomes in genbank database using Nextstrain to identify use cases for increasing …

Identification Of An In Vitro Medium For Leptospira Spp. As A Surrogate For Host Environment, Using Rna-Seq Transcriptome Analysis, Zitong Lin

Public Health Theses

Pathogenic Leptospira species causes millions of leptospirosis cases around the world and is an urgent public health issue that needs to be properly addressed. The infection leads to clinical manifestations ranging from self-limiting febrile illness to severe life-threatening symptoms. Currently, there is a lack of sensitive assay for early diagnosis of leptospirosis, and there is no FDA-approved vaccine for human use in the United States. Despite the worldwide occurrence of this zoonotic disease, low and middle-income countries are disproportionately affected by it. A better understanding of the pathogenesis of Leptospira is a crucial step for the development of better diagnostic …

Longitudinal Modeling Of Early Hiv Burden In The Central Nervous System, Victor Diego Armengol

Yale Medicine Thesis Digital Library

The dynamics of plasma HIV replication during early infection including establishment of a viral set-point are well-known. However, the course of HIV in the central nervous system (CNS) after initial entry of HIV into this compartment is less understood. Using longitudinal samples, we modeled the natural history of HIV RNA in the cerebrospinal fluid (CSF) and plasma during early HIV prior to initiation of antiretroviral treatment (ART). Participants with primary HIV infection (PHI, within 12 months of initial infection) were enrolled in prospective studies with paired longitudinal sampling of blood and CSF conducted in San Francisco, USA, and Gothenburg, Sweden …

Predictors Of Very Late Onset Infection In Kidney Transplant Recipients At Least Ten Years Post Transplant, Harry Cheung

Yale Medicine Thesis Digital Library

Although there have been improved outcomes for kidney transplant recipients, infection is still a leading cause of morbidity and mortality for long-term kidney transplant survivors (LTKS). This thesis and study aims to investigate the epidemiology of very late onset infections (>10 years post-transplant), or VLOI and clinical markers that can predict these infections.

A single-center, retrospective study of a cohort of patients (≥18 years old) who underwent kidney transplantation between 2003-2009 and survived for at least 10 years post transplantation was conducted. The primary outcome studied was the occurrence of VLOI. The data collected included transplant data, patient co-morbidities, …

Sleep Apnea In Veterans With Schizophrenia: Estimating Prevalence And Impact On Cognition, Stephen Edward Ghazikhanian

Yale Medicine Thesis Digital Library

The cognitive impairments of schizophrenia drive the functional disability of the illness but are difficult to treat. One barrier to effective cognitive interventions may be medical illnesses that compromise cognition and are over-represented in people with schizophrenia. Obstructive sleep apnea (OSA) is treatable, causes reversible impairments in many cognitive domains also affected by schizophrenia, and is likely under-diagnosed in people with schizophrenia. We have estimated the prevalence of OSA in schizophrenia, both by self-report and with a predictive model, and characterized the associations between OSA and cognition and functional capacity in schizophrenia, using a large dataset of 3942 patients with …

Pre-Operative Urinary Tract Infection And 30-Day Outcomes In Neurosurgery, James Yoon

Yale Medicine Thesis Digital Library

Urinary tract infections (UTIs) are the most common bacterial infection in the United States, placing significant demands on our healthcare system already constrained by rising costs and limited resources. While patient complications occur in all areas of surgery, the issue around neurosurgical patients deserves special attention as treatment of surgical site infections in neurosurgery is the most expensive among all surgical specialties. Complication rates are also disproportionately higher in patients over 65 years old, which are noteworthy in caring for our aging patient population.

While the adverse effects of a post-operative UTI have been well described in the surgical literature, …