22689 research outputs found
Sort by
THE BIOECONOMY’S ROLE IN BOLSTERING HEALTH SECURITY AND BIODEFENSE IN THE U.S.
Get PDFThis dissertation investigates the role of the U.S. bioeconomy in bolstering national health security and biodefense capabilities. Through three complementary research aims, it explores the ethical foundations, historical contributions, and future trajectories of biotechnology and life science innovation in the context of biological threat preparedness and response.
The first manuscript examines how bioindustrial manufacturing leaders understand and integrate principles of safety, security, sustainability, and social responsibility ("4S principles") into their operations. Drawing on qualitative interviews, it identifies opportunities for policymakers to advance ethically aligned, socially beneficial biomanufacturing through targeted policy and norm-setting interventions.
The second manuscript presents a comparative analysis of technological innovation across three recent public health emergencies - Ebola, Zika, and COVID-19. Through a structured integrative review, it highlights enabling factors such as public-private partnerships, regulatory flexibility, and platform technologies, as well as barriers to medical countermeasure (MCM) deployment, such as manufacturing constraints and equity gaps. The findings emphasize the potential of the bioeconomy to drive outbreak response, while underscoring structural limitations hindering preparedness.
The third manuscript builds on expert interviews to assess the post-COVID trajectory of the U.S. bioeconomy, identifying critical risks and policy gaps influencing long-term biodefense readiness. While innovation in MCM platforms continues, there are concerns about federal funding stability, private-sector disengagement, regulatory rigidity, and erosion of institutional knowledge. Experts consistently point to the need for sustained investment, stable public-private coordination, and regulatory modernization to avoid continued "panic-and-neglect" cycles.
These studies provide a multifaceted assessment of the strategic conditions required to align biotechnology innovation with long-term health security objectives. The final chapter situates these findings alongside the April 2025 release of the National Security Commission on Emerging Biotechnology (NSCEB) report. While developed independently, the dissertation and the Commission report converge on several themes, including the importance of workforce development, interagency coordination, and robust public-private collaboration.
This research advances a forward-looking perspective on how biotechnology can serve as both a driver of innovation and a pillar of national resilience. It offers insights for decision-makers seeking to build a coherent, equitable, and sustainable biodefense architecture in the years ahead
EVALUATION OF POLYGENIC RISK SCORES AS A VALID INSTRUMENT TO CONDUCT MENDELIAN RANDOMIZATION IN DIVERSE ANCESTRY POPULATIONS
No full textCoronary artery disease (CAD) is a leading cause of death in the US, with high LDL cholesterol as a key risk factor, though its causal role in diverse populations remains unclear. Differences in study design, study population makeup and diversity, and underlying health disparities in CAD contribute to uncertainty about LDL’s effect on CAD across racial and ethnic groups. This dissertation aimed to evaluate the validity of using a polygenic risk score for LDL (PRSLDL) as a causal instrument in Mendelian randomization (MR) across diverse U.S. populations, with the overarching goal of understanding if PRSLDL can serve as a valid tool in this use case, and when incorporating sensitivities to race, ethnicity, individual smoking status, and area-level air pollution exposure measured via exposure to PM2.5. Our three aims were (1) to characterize differences in the performance of PRSLDL as a predictive tool for LDL across racial and ethnic groups, (2) to understand the possible confounding or modifying effect of smoking and air pollution exposure on the PRSLDL-LDL relationship, and (3) to conduct MR using PRSLDL and quantify the causal effect between LDL and CAD overall and when stratified by aforementioned demographic and environmental variables. We used data from the All of Us Research Program (AoU) (n=71,678) and the Population Architecture Using Genomics and Epidemiology (PAGE) Study (n=22,810), applying a multi-ancestry PRS for LDL developed by the Global Lipid Genetics Consortium as a genetic instrument. The addition of PRSLDL into a basic clinical risk model for LDL yielded a significant improvement in model performance, though the extent of LDL variance explained by PRSLDL varied substantially between racial and ethnic groups in both studies. We found significant differences in the effect of PRSLDL on LDL between groups, with a statistically higher effect in African-American AoU participants. Incorporating smoking status as a modifier of the PRSLDL-LDL relationship further improved the performance of our prediction model for LDL, and we identified that the variance in LDL explained by PRSLDL was highest in never smokers in AoU and PAGE. PRSLDL-PM2.5 interactions only improved model performance in Non-Hispanic White AoU participants, and PRSLDL explained a higher proportion of LDL variance in lower tertiles of PM2.5 exposure. We found that every unit increase in PRSLDL- predicted LDL caused a 1.01 times higher odds of CAD in AoU, accounting for confounding due to race, ethnicity, individual smoking status, and PM2.5 exposure. Stratified MR estimates yielded overlapping and statistically significant causal estimates in AoU, though no significant estimate was identified in a smaller subset of PAGE participants. The use of PRSLDL as an instrumental variable replicated known epidemiologic evidence of the directionally positive causal effects of LDL on CAD in AoU, across all strata of demographic and environmental factors, though lack of replication in PAGE demonstrates the importance of study context and heterogeneity in using genetic epidemiology tools for causal inference applications. Altogether, this dissertation aimed to assess the possibility of using a genome-wide PRS as an instrument to conduct a causal inference MR study of LDL and CAD in diverse US populations in order to better understand methods to characterize health disparities in complex traits and diseases
STRUCTURAL INTERSECTIONALITY: A POLICY-BASED MEASURE OF STATE-LEVEL DISCRIMINATION
No full textBackground: Identifying methods to measure structural determinants of health including structural discrimination is key to advancing health equity research. However, few structural measures of discrimination consider policy contexts nor the synergistic effects of racism, sexism, and classism on health inequities. The overarching goal of this dissertation is to apply an intersectional framework and state policy contexts to improve our understanding and measurement of structural discrimination.
Methods: In Aim 1, we used a theory-driven confirmatory factor analysis approach to develop the Policy-Based State Discrimination (PBSD) measure, using cross-sectional policy data from 2012. In Aim 2, we assessed the construct validity of the PBSD and conducted an empirical evaluation of existing state-level discrimination measures using a nomological net approach. In Aim 3, we used a cross-sectional ecological design and nested negative binomial regression models to evaluate the relationship between the PBSD and maternal mortality from 2015-2019.
Results: We identified two models of intersectional structural discrimination with theoretical and empirical support: a 3-factor model that specifies factors for structural racism, sexism, and classism, and a unidimensional model that specifies one intersectional factor with the same policy indicators as the 3-factor model. Top policy-drivers of intersectional structural discrimination were domains related to social safety net, criminal justice, and sexual and reproductive health. Our nomological net indicated that existing measures of structural discrimination cluster based on measurement conceptualizations (e.g., policy-based, inequity-based etc.). Additionally, we provide evidence for segregation and incarceration as two contemporary racializing regimes that operate differently in different state contexts. Finally, we found that the PBSD was associated with a 17% increase in maternal mortality. Although Black populations had more than double the risk of maternal mortality, the effect of PBSD-I on maternal mortality was significantly attenuated in Black populations compared to White populations.
Conclusions: Policies are modifiable drivers of health inequity and are an important tool to measuring structural discrimination at the state-level. An intersectional approach, a historical perspective, and a critical assessment of measures of structural discrimination are central to advancing health equity
Oral History Interview with Rueben C. Warren
No full textThis interview with Rueben Warren, DDS, DrPH, is part of “Moral Histories: Voices and Stories from the Founding Figures of Bioethics,” an oral history project of the Johns Hopkins Berman Institute of Bioethics. Dr. Warren is Dean Emeritus, School of Dentistry, Meharry Medical College and former Director of the National Center for Bioethics and Professor Emeritus of Bioethics at Tuskegee University. He also spent many years working at the Department of Health and Human Services and the Centers for Disease Control. His expertise includes dental health, access to oral healthcare, public health, faith communities, and environmental justice. He is the author of over one hundred journal articles.
Dr. Warren discussed the close-knit community of his childhood in the Watts neighborhood of South Central Los Angeles and his higher education experiences at San Francisco State University, Meharry Medical College, Harvard University, and the Interdenominational Theological Center. He described being on the Tuskegee Syphilis Study Legacy Committee, the 1997 apology from President Bill Clinton, and the subsequent establishment of the National Center for Bioethics in Research and Healthcare at Tuskegee University. While director, he shared how he focused on engaging descendants of the U.S. Public Health Service Syphilis Study, established programming with Black church leaders, and developed a bioethics honors program. He described the need for institutions to prove their trustworthiness to gain community trust, particularly in healthcare settings.
He discussed working in the Office of Minority Health and the Agency for Toxic Substances and Disease Registry, where he investigated environmental harms and the disproportionate impact on low-income and minority communities. The Covid-19 pandemic occurred during his last years at Tuskegee and he shares that experience as why medical providers and bioethicists should examine the trustworthiness of institutions versus implicating vaccine-hesitant communities. The conversation ends with a comparison of the Human Genome Project to the work of the Diaspora Human Genomic Institute, emphasizing the importance of involving Black scientists and communities in data collection, preservation, and analysis
Amour Noir: France, Love, and the Making of the Modern Black American Woman, 1884-1925
Get PDFBetween the 1880s and 1920s, France and the French language became a critical part of the training, leisure, and intellectual lives of educated Black women in the U.S. The love of France served many purposes. Some used French literature and history alongside Greek and Latin to prove their academic abilities, thus challenging Jim Crow’s racial hierarchies and pseudoscience painting them as unintelligent and uncivilized. Others claimed a familial connection to France and used associations with the French language to protect themselves from Jim Crow segregation. Using the ideals of French interracial republicanism, some made renewed claims to full citizenship and national belonging. France also served as a site of pleasure and personal development, through the consumption of material goods and experiences, often concentrated in Paris. Navigating the playground of transatlantic elites, educated Black women affirmed their status as representatives of “the race” and their belonging to a leadership class. Back home, connections to France were used as a form of social and cultural capital that allowed these representatives to speak to audiences from a place of authority and climb the ladder of professional success—from classical music to visual arts and more. World War One offered another chapter in the relationship between France and Black America. African American women served in the war camps of France and participated in the political aftermath of the war both as advocates of Peace and as champions of Pan African solidarity. In the 1920s, the “New Negro” movement embraced connections to the francophone world once more.
This project shows that the love of France and all things French was a central ideology among educated African American women at the turn of the twentieth century, which deeply shaped their understanding of racial, national and gendered identities. From an intellectual and linguistic exercise to a cultural marker, a source of joy, and a weapon of political organizing, France and its language loomed large in the world of Black female representatives of the turn of the twentieth century and informed the making of a modern Black American woman
DISSECTING THE MECHANISMS OF TUMOR PROGRESSION AND RESISTANCE TO TARGETED THERAPY IN ACRAL MELANOMA
Get PDFAcral melanoma (AM), a rare and aggressive cutaneous melanoma subtype with
5-year survival rates below 16%, exhibits limited durable responses to CDK4/6
inhibitors (CDK4i/6i) despite frequent genetic alterations in this pathway. Here, we
identify rapid rewiring of AKT-mTOR signaling as a critical escape mechanism
following CDK4/6 inhibition. Using a genetically diverse panel of AM cell lines, we
demonstrate that CDK4i/6i induces Rb dephosphorylation within 1–3 hours,
concurrent with hyperactivation of AKT (pS473) and mTORC1 (pS6 S240/244).
Mechanistically, CDK4/6 inhibition disrupts cytoplasmic Rb interactions with the
mTORC2 subunit SIN1, as evidenced by proximity ligation assays showing
elevated Rb-SIN1 puncta at 3–6 hours post-treatment. This dissociation correlates
with loss of Rb-mediated suppression of mTORC2 activity, enabling AKT-driven
mTORC1 activation.
Pharmacological co-targeting of CDK4/6 and mTOR pathways synergistically
enhances anti-tumor efficacy, reducing clonogenic survival and increasing
annexin+ cytotoxicity relative to single-agent therapies. Dual inhibition ablates
mTORC1 activity and elevates cleaved PARP levels, as confirmed by immunoblot
and immunofluorescence assays. Long-term colony formation assays reveal
sustained suppression of proliferative recovery only under combination conditions.
In vivo, catalytic mTORC1/2-inhibition with TAK228 significantly reduces tumor
volume and multi-organ metastases in AM xenograft models.
These findings establish the Rb-SIN1-mTORC2 axis as a novel mediator of
intrinsic CDK4i/6i resistance and provide preclinical rationale for co-targeting
CDK4/6 and mTORC1/2 to improve AM outcomes
Causal inference with benefit-risk analysis, non-adherence and bivariate missing data, and large-scale observational studies
No full textThis thesis is a collection of three studies on causal inference. Chapter 2 is a study protocol on performance evaluation of several causal survival methods in large-scale observational data under realistic simulation settings with computationally feasible algorithm implementations. Chapter 3 develop efficient estimation methods for the joint distribution of benefit and risk in settings of observational studies when outcome missingness is independent of outcome given treatment and baseline covariates. Chapter 4 focus on studies in which adherence status is measured at a single time point and a binary outcome is measured at a subsequent time point. We develop efficient estimation methods for the counterfactual probabilities of the outcome under adherence when there is missing information on adherence status and on the outcome
DSRNA SENSING & SIGNALING DURING SKIN REGENERATION
No full textMammalian skin wound healing is a tightly regulated and complex orchestration involving hemostasis, inflammation, cellular proliferation, and tissue remodeling. While acute wound healing often leads to tissue repair, chronic wounds and excessive scarring remain significant clinical challenges, particularly in the context of comorbidities such as diabetes and obesity. Current therapies often fail to promote true regeneration, underscoring the need to better understand the molecular mechanisms underlying wound repair. Recent research has highlighted the critical role of endogenous double-stranded RNA (dsRNA) and non-coding RNAs (ncRNAs) in regulating skin regeneration and immune responses. Non-coding RNAs have emerged as key modulators of wound healing, influencing inflammation, cell migration, and re-epithelialization. In this thesis work I explore the role of dsRNA sensing and signaling, typically associated with antiviral defense, its abundance in basal keratinocytes under homeostatic conditions and its upregulation during periods of high cellular turnover, such as wound healing and hair follicle cycling. Activation of the dsRNA sensor TLR3 has been shown to be essential for initiating regenerative responses, including wound-induced hair neogenesis (WIHN) in mice. Loss of the RNase L gene, which negatively regulates dsRNA-TLR3 signaling via caspase-1-mediated cleavage of TRIF, leads to enhanced regeneration, suggesting a trade-off between antiviral immunity and tissue repair. Despite these insights, the precise identities, sources, and mechanisms of action of pro-regenerative dsRNAs and ncRNAs remain largely undefined. Therefore, understanding the regulatory networks involved in dsRNA sensing, TLR3 activation, and dsRNA mediated signaling may provide new therapeutic targets for promoting functional skin regeneration, mitigating fibrosis, and addressing the burden of chronic wounds
EQUITABLE INDICATORS? EXAMINING HOW WELL EARLY-WARNING INDICATORS DISTINGUISH EDUCATIONAL OUTCOMES ACROSS DISTRICTS AND SCHOOLS
No full textEarly warning indicators (EWIs) have become widespread as a way to help identify students who need support early in their high school career so that schools may intervene and help students achieve on-time high school graduation. While EWIs are typically implemented with a consistent definition across districts or schools, the measures that underly EWIs vary substantially across district and school contexts. This dissertation examines how well early high school measures that are commonly used in EWIs can distinguish educational outcomes across districts and schools. Using receiver operating characteristic (ROC) analysis and data from multiple cohorts of first-time, ninth-grade students in Maryland, I examined three different aspects of EWIs across districts and schools: i) signal strength which relates to how well the underlying measures can distinguish on-time graduation status, ii) optimal thresholds which are empirically derived cut-points at which measures perform best as early warning classifiers, and iii) classification errors which focus on the cases when EWIs provide signals that differ from outcomes. Results show that these three aspects of EWIs vary substantially at the school level, suggesting differential EWI performance. Policy implications and directions for future research are discussed
Robot-Assisted 3D Endoscopy for Neurosurgical Guidance
Get PDFNeuroendoscopy is utilized for minimally invasive access to deep brain structures, but is limited by restricted field of view, challenging spatial orientation, and brain deformation that compromises conventional neuronavigation. Current approaches lack accurate visualization beyond the direct endoscopic view, making it difficult to localize critical structures and surgical targets. The research in this dissertation aimed to develop a Robot-Assisted Ventriculoscopy (RAV) system that integrates precise robotic positioning with advanced vision-based guidance techniques to provide accurate, real-time tracking and visualization of anatomical targets in support of emerging neurosurgical techniques.
An experimental RAV platform was established as a foundation for the development of algorithms that combine robotic precision with endoscopic imaging to overcome the limitations of conventional neuronavigation. Structure from Motion (SfM) methods were developed and evaluated for offline reconstruction of endoscopic scenes, achieving sub-millimeter accuracy with significant runtime advantages when integrated with robotic assistance. Real-time Simultaneous Localization and Mapping reconstruction methods were implemented to enable compatibility with freehand endoscopy, maintaining robust performance even with up to 40% feature loss while achieving a 16× speedup over SfM.
A self-supervised feature detection approach (R2D2-E) was adapted to the neuroendoscopy context and shown to outperform classical feature detection methods. A Neural Radiance Fields (NeRF) approach was developed for dense volumetric reconstruction in neuroendoscopy, demonstrating sub-millimeter accuracy across different endoscope trajectories with superior robustness to visual artifacts. The methods were validated through phantom studies and retrospective clinical data, demonstrating the feasibility of augmenting endoscopic views with planning data from preoperative MR images.
Such advances in 3D video reconstruction could elevate the functionality of neuroendoscopes from that of passive visualization to one of active 3D guidance, potentially improving the safety, precision, and effectiveness of deep-brain neurosurgical procedures even in the presence of brain deformation