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Allergy and Pancreatic Cancer: A Mendelian Randomization Analysis
Get PDFIntroduction: Pancreatic cancer remains one of the most lethal malignancies with five-year survival rates ranging from 2-9%. Observational studies have suggested that allergic diseases may offer a protective effect, through mechanisms of enhanced immune surveillance. However, these studies are often limited by confounding and reverse causation. Mendelian Randomization (MR), which uses genetic variants as proxies for exposures, offers an alternative approach less prone to these biases. This study aimed to investigate whether allergic traits causally influence pancreatic cancer risk using a two-sample MR framework.
Methods: Genetic variants for four allergy-related phenotypes, i.e., asthma, allergic reactions, an asthma-allergy cross-trait, and a combined phenotype of asthma, hay fever, and eczema, were selected from two large-scale genome-wide association studies. Pancreatic cancer summary statistics were derived from PanScan and PanC4 meta-analyses. MR methods included inverse-variance weighting, MR-Egger, weighted median, weighted mode, MR-PRESSO, and leave-one-out sensitivity analyses.
Results: Asthma and allergic reactions showed directionally consistent, but statistically non-significant, protective trends. The cross-trait measure yielded null associations. Interestingly, the combined allergy phenotype demonstrated a small but statistically significant positive association with pancreatic cancer risk. Sensitivity analyses detected marginal heterogeneity but little evidence of pleiotropy.
Conclusion: These findings offer limited evidence for a causal protective effect of allergic traits on pancreatic cancer risk. Phenotypic heterogeneity may obscure protective mechanisms within combined allergy phenotypes. Further research using phenotype-specific MR approaches and diverse ancestral populations is needed to clarify the immunogenetic links between allergies and pancreatic cancer
ECONOMIC DECISION-MAKING FOR NATURE-BASED CLIMATE SOLUTIONS IN LATIN AMERICA AND THE CARIBBEAN
Get PDFClimate change presents significant challenges for Latin American countries, particularly in terms of economic losses, ecosystem degradation, and social vulnerability. In response, naturebased solutions (NbS), interventions that harness natural processes for climate resilience and sustainable development, have emerged as a viable means of climate adaptation and mitigation, and can be economic stimulus as well.
This capstone paper explores the development of a cost-benefit analysis tool for the United Nations Development Programme (UNDP) to support the evaluation of economic and environmental effectiveness of climate adaptation nature-based solutions in Latin America and the Caribbean. Through case studies of previously implemented projects, this tool allows for assessment of the cost-effectiveness of various NbS strategies in a warming world by quantifying the economic, social, and environmental benefits of these projects. A literature review of naturebased solutions is also included in this paper, highlighting their benefits for individual nations and the global community. The findings inform future policy decisions and enhance investment strategies for sustainable development through targeted NbS projects
Understanding and Addressing the Decay of Nucleic Acid-Based Electrochemical Sensors in Biofluids
No full textNucleic acid-based electrochemical sensors (NBEs) have emerged as a promising approach to continuous molecular monitoring in vivo. NBEs consist of electrically conducting gold surfaces coated with self-assembled monolayers of a mixture of electrode-passivating alkylthiols and functional alkylthiol-modified oligonucleotides (oligos). The oligos are further modified with redox reporters able to transfer electrons to the underlying electrode. Although sufficiently robust for continuous, multihour sensing of small molecules and proteins in biological fluids both in vitro and in vivo, NBEs decay over periods longer than 12 hours of continuous operation if unprotected, thereby limiting the translation of NBEs to the clinic. To address this issue, here I first report two investigations into why NBEs degrade. Firstly, I show that in cases of patients with afflictions, overexpressed protein biomarkers may act as nucleases and degrade alkylthiol-modified oligos, demonstrated via human cyclophilin B, a marker for pancreatic cancer. Secondly, I performed a fundamental investigation into possible pathways of degradation. I highlighted that voltage-induced desorption of monolayer elements and competitive displacement of alkylthiol-modified oligos by naturally occurring cysteine and glutathione are the two greatest driving forces of NBE decay under continuous sensor operation in biofluids. Leveraging this knowledge and experimental framework, I report strategies to mitigate sensor degradation pathways and improve operational sensor stability, progressing the future development of NBEs towards extended operational lifetimes
Unraveling the zinc-responsive transcriptional regulation by Citrobacter rodentium Zur
No full textThe genus Citrobacter, a member of the family Enterobacteriaceae, is emerging as a potential public health concern in recent years, largely due to its increasing multidrug resistance. Zinc ion interference, aided by advancements in nanomaterials, has garnered attention in antimicrobial research. Understanding zinc homeostasis control in bacteria is therefore of critical biological and biomedical importance.
Despite its significance, the zinc uptake regulator (Zur) in Citrobacter has remained largely unexplored. This dissertation focuses on Zur in Citrobacter rodentium, a versatile model organism within the genus. Using RNA-seq and in vivo transcription reporter assays, we identified the Zur regulon of C. rodentium, uncovering the different regulatory effects of Zur with zinc binding on consensus targets such as znuABC, zinT and ykgO, compared to the new target rpmE, which encodes the zinc-containing ribosomal protein bL31.
We further characterized the in vivo dynamics of C. rodentium Zur on its target promoters and demonstrated the critical role of four specific residues for its full functionality and stability. We also visualized the endogenous Zur concentration change in C. rodentium using immunoblotting. Our study revealed that the concentration of the repressor itself is also likely to be controlled in the cell, making the in vivo turnover of Zur an appealing direction to be further addressed.
Finally, through a forward genetics approach, we identified the DegS pathway as an upstream effector specifically regulating Zur de-repression at the znuA promoter during zinc starvation.
The findings presented in this dissertation contributed to the knowledge of zinc homeostasis control by C. rodentium Zur and provide broader insights into bacterial transcription regulation in general. Collectively, this work offers a comprehensive framework for understanding zinc-responsive transcriptional regulation mechanisms in bacteria
TREATMENT OF TYPE 2 DIABETES AMONG MEDICARE BENEFICIARIES WITH AND WITHOUT ALZHEIMER’S DISEASE: A RETROSPECTIVE COHORT STUDY
Get PDFBackground: While many individuals with Alzheimer’s disease (AD) have type 2 diabetes (T2DM), little is known regarding whether and how the treatment of T2DM varies by AD status.
Objective: To compare T2DM treatment among individuals with and without AD.
Methods: We conducted a retrospective cohort study using 20% Medicare Fee-for-Service (FFS) claims data from January 2017 through January 2019. We included individuals aged ≥66 years who were newly diagnosed with T2DM with continuous enrollment for at least one year prior to their T2DM diagnosis. Individuals with prior diagnoses of type 1 diabetes or T2DM were excluded. AD was identified using the 12 months preceding T2DM diagnosis. We assessed the initiation of antidiabetic therapy within one year of incident T2DM diagnosis and described utilization patterns by drug class. Multivariable logistic regression models were used to estimate adjusted odds ratios for the association between AD status and overall antidiabetic drug initiation, as well as initiation of specific drug classes, controlling for demographic and clinical covariates.
Results: Among 388,359 Medicare beneficiaries newly diagnosed with T2DM, 9,584 had a diagnosis of AD. Patients with AD were older (mean age 83.2 vs. 75.8) and more often female (64.4% vs. 53.4%) compared to those without AD. Antidiabetic treatment initiation within one year was lower in individuals with AD compared to those without AD (41.7% vs. 64.4%). At first treatment initiation, patients with AD were more likely to receive insulin (32.3% vs. 18.6%) but were less likely to initiate metformin (41.9% vs. 53.4%), SGLT2 inhibitors (0.6% vs. 2.1%), and GLP-1 receptor agonists (0.8% vs. 2.4%). In adjusted models, AD was associated with significantly lower odds of antidiabetic treatment initiation (OR 0.55, 95% CI 0.53–0.57) and lower odds of initiating newer drugs like GLP-1 receptor agonists (OR 0.50, 95% CI 0.34–0.71) and SGLT2 inhibitors (OR 0.48, 95% CI 0.31–0.69).
Conclusion: Among this large, diverse cohort of Medicare beneficiaries in the U.S., there were notable differences in diabetes treatment among older adults with and without AD. Insulin use was more common, while metformin and newer agents such as SGLT2 inhibitors and GLP-1 receptor agonists were less frequently prescribed in AD patients. Future work should explore the basis for these differences, which may reflect a combination of patient, provider and system-level factors
Competing risks analysis for a COVID-19 clinical trial
Get PDFIn COVID-19 clinical trials, time to death and time to recovery are both important components to evaluating effectiveness of potential treatments. However, in the presence of competing risks, traditional survival analysis which only considers one event as the outcome of interest may not provide a complete picture of the effect of treatment on patient outcomes. This study applied competing risks analysis to re-examine data from the Adaptive COVID-19 Treatment Trial, evaluating the effect of remdesivir treatment on time to death and time to discharge. We estimated the cumulative incidence functions of time to death and time to discharge, stratified by treatment arm and additionally by ventilation history to understand treatment effect on patients of varying clinical severities. Treatment effect was evaluated using cause-specific proportional hazards and Fine-Gray regression.
Time on ventilation is also an important intermediate outcome, though estimation of cumulative incidence is not available using traditional competing risks methods. By using quality of life-weighted survival, we estimated cumulative incidence functions for time on ventilation.
Our findings show that remdesivir significantly increased cause-specific hazard of recovery (HR: 1.29; 95% CI: 1.12 – 1.49) but did not significantly reduce cause-specific hazard of death (HR: 1.13; 95% CI: 0.76 – 1.38). Under the Fine-Gray model, treatment significantly increased cumulative incidence of recovery (sHR: 1.32; 95% CI: 1.15 – 1.52) but did not significantly impact cumulative incidence of death (sHR: 1.27; 95% CI: 0.98 – 1.48). Cumulative incidence function estimates suggest that treatment was most effective at reducing hospitalization time for patients who recovered without ventilation but did not impact recovery for patients who required ventilation. Remdesivir may have slightly reduced progression to ventilation for those who were eventually discharged but did not impact ventilation duration. Future directions include regression model development for intermediate events and hierarchical analysis to account for clustering within multi-site trials
Evaluating the Influence of Risk Perception, Cultural Worldviews, and HIV Testing on HPV Vaccination Intention among Haitian Migrant Women
No full textBackground: Haitian women have one of the highest incidence rates of cervical cancer in the United States and are disproportionately affected by HIV. This dual disease burden is relevant as HIV significantly increases the risk of cervical cancer. Cervical cancer can be prevented through immunization with the human papillomavirus (HPV) vaccine, however HPV vaccination among Haitian women remains low. Studies have highlighted a key role of affect (i.e. emotions) influenced by cultural worldviews, in the rapid, automatic formulation of cancer risk perceptions and cancer prevention behaviors. Yet, this has been unexplored among Haitian women. This exploratory sequential mixed-methods study assessed the influence of affective cancer risk perception, cultural worldviews, and HIV testing on HPV vaccination intention among Haitian migrant women in South Florida.
Methods: Participants completed qualitative interviews (N=25) exploring cultural worldviews and affective risk perception towards cervical cancer. Qualitative data was subsequently used to develop and test the psychometric properties of a cultural worldviews scale influencing cervical cancer risk and behaviors. Participants completed cross-sectional surveys (N=151) which included cultural worldview items and items measuring sociodemographics, affective risk perception , cervical cancer knowledge, along with other variables influencing HPV vaccination intention commonly cited in the literature.
Results: Women in qualitative interviews described cultural practices and beliefs influencing cervical cancer risk, and endorsed affective risk perception domains which shaped their perceived susceptibility to cervical cancer. The scale measuring cultural worldviews developed from qualitative interviews demonstrated robust validity and reliability (Cronbach’s alpha=0.79). Analysis of survey data revealed statistically significant interactions between HIV testing and affective risk perception (negative affect [OR=1.84 , 95% CI [1.09,3.10], p=0.02], defensive pessimism [OR=4.23, 95% CI [1.39,12.91], p=0.011], cognitive causation [OR=0.67, 95% CI [0.42,1.01], p=0.06] ) and cultural worldviews (OR=0.67, 95% CI [0.48,0.93], p=0.02) on HPV vaccination intention.
Conclusion: Affective risk perception , cultural worldviews , and past HIV testing behaviors may have a significant role in HPV vaccination intention. When there is no prior experience of a disease, and minimal knowledge is available, these constructs can shape an individual’s appraisal of their disease risk and guide their health decisions
Shadowland: The "Russia Problem" in the American Foreign Policy Imagination, 1900-1933
No full textThis dissertation employs historical methods to explain the intellectual, political, and policy motivations that drove the American foreign policy elite to engage repeatedly and intensively with what many of its members termed the “Russia problem” between 1900 and 1933 – despite Russia’s distance from the United States, the relatively low volume of bilateral trade, and the seeming absence of a direct military threat. Drawing on multiple archives around the United States and with an emphasis on the personal papers of senior leaders, this investigation reconstructs this elite’s debates over the nature of the “Russia problem” and critical decisions on U.S. Russia policy from the Boxer Rebellion to FDR’s recognition of the Soviet Union. It challenges the historiographical tendency to define U.S.-Russian relations in this period as a tragic prelude to the Cold War and argues that the elite was serially drawn to the “Russia problem” not merely because of its episodic salience in international affairs but because Russia occupies a special place in a historically inflected American foreign policy imagination. Often interpreted as a shadow version of their own country, Russia’s arc in world history and its relations with the America served as a canvas on which the foreign policy elite could work out their vision for the United States’ role in the world. These findings suggest the importance of explicitly interrogating perceptions, historical analogies, and personal biographies in the conduct of contemporary foreign policy
THE CASE FOR EXPANDING ACCESS TO GLP-1S: SHOULD EVERYONE GET OZEMPIC?
Get PDFOzempic and Wegovy, medications that fall under the class of Glucagon Like Peptide 1 Receptor Agonists (GLP-1RAs), have skyrocketed in popularity. Current use of these drugs is limited to those who would derive a medical benefit from its potent weight loss and hunger curbing effects, such as those who suffer from Type 2 Diabetes or obesity. Although off-label use is rampant, these medications are expensive if insurance does not offer coverage. However, the patent for semaglutide, the active GLP-1RA in Ozempic and Wegovy, is set to expire in 2032. This paper argues that post-expiry, these medications should be offered as a weight loss tool for the general public due to its safe, effective pharmacology and potential to improve food well-being. Such an expansion must be carefully regulated, with guardrails such as mental health screening and regulated access
Leveraging Radio Frequency Interferometric Techniques for a Cooperative Space-Based Space Domain Awareness System: A Systems Engineering Analysis
No full textThe increasing number and density of trackable space objects has made the need for timely and accurate Space Domain Awareness (SDA) acute. This thesis asserts that a directed, distributed space-based SDA system can likely be achieved using cooperative sensing techniques. A novel system of systems is envisioned to perform space domain awareness from a constellation of dedicated space-based platforms. Three test cases’ performance is evaluated for coverage in executing unqueued space observation, with a sun-synchronous plane of SDA spacecraft exhibiting system architecting and commercial strengths. The nonfunctional attributes of such a system, including its resilience, distributed nature, and potential availability in contested and wartime scenarios constitute compelling advantages for supplementing the space surveillance network with additional space-based observation