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Electronic Health Record Phenotyping of Radionecrosis
No full textRadionecrosis is a serious complication that can occur in patients who have received radiation therapy to the brain. However, the complexity and heterogeneity of radionecrosis presentations pose challenges for manual identification from electronic health records (EHRs). We hypothesized that by leveraging advanced computational methods and clinically relevant curated features, we could develop accurate and efficient phenotyping algorithms for identifying radionecrosis in the EHR. This study aimed to develop and evaluate advanced phenotyping algorithms for the automated identification of radionecrosis in patients who have undergone brain radiation therapy.
We retrospective evaluated a cohort of 865 patients, with a median age of 63 (IQR 71-53), who received brain radiation therapy. Following treatment, 60 patients (7%) developed radionecrosis. We then developed a naive rule-based algorithm, a weighted scoring function, and several machine learning models (including Logistic Regression, Support Vector Machines, and Random Forests) to identify radionecrosis cases based on structured EHR data as well as unstructured clinical notes. These algorithms were then evaluated using performance metrics.
Most (501 patients, 57.9%) received radiation for metastatic disease to the brain, while 195 patients (22.5%) underwent radiation for a primary brain tumor. The weighted scoring function approach, which derived optimal feature weights through logistic regression, achieved a sensitivity of 0.82, specificity, 0.94, accuracy 0.92 and precision 0.74. Machine learning models, particularly Logistic Regression and Support Vector Machines with linear and radial basis function kernels, demonstrated high discriminative ability (AUC> 0.90). Feature importance analysis revealed key predictors of radionecrosis, including never-smoker status and specific patient characteristics.
The development of phenotyping algorithms for the accurate identification of radiation-induced toxicity is crucial for optimizing patient care and advancing precision medicine in oncology. Our developed phenotyping algorithms showcase the potential for automated identification of radionecrosis from EHR data using machine learning approaches. This study lays the foundation for future research and validation efforts to refine these methods. Accurate and efficient curation of large radiation oncology datasets has implications for downstream adverse outcome risk stratification, observational studies, hypothesis-generating, and prospective trial recruitment
Civic Effects of Education Models
No full textPolitical scientists have long argued that schools nurture active citizens by teaching civics. I provide an alternative perspective by viewing schools as a formative social experience: education happens in social settings among teachers and peers, and individuals learn politically relevant self-conceptions from the nature of social interactions in school. I distinguish two models of education. Under teacher-centered models, teachers dominate decision-making and knowledge, placing students in roles that follow decisions made by authority figures. Under student-centered models, students participate in making decisions and knowledge so that they are placed in roles that shape classroom discourse. I argue that by becoming constructors of class content, those learning in student-centered education models take ownership of collective matters and become active citizens in their community beyond school. I find that around the world, those who learn in student-centered models are more likely to engage with social issues and identify with a larger community. Using panel survey data, I find that individuals who learn in student-centered models during childhood are more likely to vote, sign petitions, and attend protests as adults. Data from an original survey in school districts that randomly assigned individuals to education models provide additional support that student-centered education makes more active citizens. I find mixed evidence that these effects are mediated by political efficacy and communal views of self-interest, suggesting that further work is needed to investigate what accounts for the civic effects of education models
We Bring with Us the Strength of Tomorrow: Visions of Future and Resistance in Brazil, and the Caribbean
No full textThe Afrofuturist movement has significantly impacted Latin American artists and scholars who seek to recover alternative understandings of the future and create spaces for counterhegemonic narratives within their nations. Brazilian and Caribbean Afrofuturist artists, in particular, have celebrated the integration of Africa and Afrodiasporic philosophies, mythology, cosmology, and technology through artistic performances that depict Afro-centered futures and alternative realities. By focusing on temporality bending, alternative timelines, the revision of the past, and the speculation of future technologies, these narratives illuminate present anxieties and challenge the constructs behind the discourses of futurity within the Brazilian and Caribbean Afro-diasporas. Most important, they raise questions such as, how do these literary works facilitate an epistemic shift pertinent to the struggles of Afro-Brazilian and Caribbean subjects? How do the structure and content of these narratives challenge official historical constructs? In what ways do these stories break away from Westernized visions of futurity to introduce new epistemes into national narratives
Hippocampal circuit dynamics during learning and sleep in freely behaving macaque monkeys
No full textThe ability of organisms to learn and form memories based on experience and to use these memories flexibly in different situations is a hallmark of cognitive evolutionary processes. The neural basis for this ability, however, is typically studied in laboratory settings with minimal environmental cues and a restricted behavioral repertoire. These limitations have been shown to affect cognitive performance in memory tasks and neural organization that supports memory. To overcome these constraints, we applied two technological developments that were designed to allow the study of the neural circuit dynamics of memory in macaques with improved ecological validity. First, we designed a 3-D enclosure to study cognition in freely moving macaques in a more naturalistic environment. Monkeys flexibly learned multiple unique sequences of objects-in-context, where both the macaques and the object-sequences were fully situated within that 3-D context. Second, Second, we performed wireless recordings using high-density, chronically implanted linear arrays. Contextual memory formation relies on the spatiotemporal dynamics of the hippocampus; therefore, we recorded across layers of the hippocampal area in CA1 as monkeys performed the task and during post-learning sleep. We evaluated for the first time in primates the properties of different cell groups and their relation to oscillatory dynamics in CA1 of the hippocampus. Active wakefulness and sleep states were characterized by distinct modes of oscillation. Theta (4-10Hz) oscillations dominated sleep and strongly entrained spiking activity of different cell groups. During active wakefulness, supra-theta oscillations (15-80Hz) became prominent and spikes preferentially locked to the gamma band. Cross-frequency coupling analysis revealed that theta and gamma oscillations are decoupled in monkey CA1, unlike that described in rodents. Inhibitory cell groups dynamically reconfigured their phase relationship with the pyramidal cell group in a brain-state-dependent manner, which could allow different cell groups to be allocated to the control of oscillations as a function of frequency. As suggested in rodents, but not yet described in primates, the pyramidal cells from superficial and deep substrata differed in their physiological properties and showed selective interactions with the inhibitory cell groups. This included a tightly time-resolved coupling with those cells that decreased firing rates during the sharp-wave ripple oscillation. Finally, these pyramidal cells were biased to form cell assemblies with members of their own strata, and rarely across strata. These results suggest that monkey CA1's oscillatory dynamics differ from rodents, potentially due to differences in the behavioral repertoire and/or underlying circuit mechanisms; but that some of the underlying regulatory mechanisms such as inhibitory timing and cell assembly clustering among populations, may be conserved. As such, theories of learning and memory from rodents that are dependent on oscillatory bands may not readily translate to primates; however, the microcircuit principles including sublayers in the radial axis of CA1 persist in supporting different behavioral-cognitive implementations of a (partially) conserved underlying circuitry
Women’s Responses to a Mindfulness-Based Body Scan
No full textBackground: Mind-body therapies can improve mental and physical health outcomes for women with trauma and posttraumatic stress disorder (PTSD). However, greater awareness of body sensations can lead to adverse responses that interfere with the efficacy and completion of mind-body therapies.
Purpose: The purposes of this study are to (1) explore how women with varying levels of PTSD symptoms respond to one exposure to a mindfulness-based body scan in terms of self-report measures and subjective experience and, (2) identify characteristics of women at risk for adverse responses to mind-body therapies.
Methods: A single-group, pre-post study of a mindfulness-based body scan intervention was conducted to assess changes in state anxiety and affect in a sample of 60 women with a history of trauma and varying levels of PTSD symptoms. The associations of PTSD, depressive, and dissociative symptoms as well as trauma history with changes in outcome measures were examined. A subset of 20 women were interviewed about their experiences during the body scan.
Results: Overall, women had pre-post decreases in anxiety (Median change= -11.0, p.05). Higher levels of total PTSD symptoms and Arousal symptoms were associated with decreases in anxiety (d=0.63, p=.021; d=0.76, p=.006; respectively). Greater total PTSD, Cognitions/Mood, and Arousal symptoms were associated with decreases in negative affect (d=0.54, p=.045; d=0.54, p=.047; d=0.57, p=.034; respectively). Higher levels of depressive symptoms were associated with decreases in anxiety (d=0.61, p=.024), but depressive symptoms were not associated with changes in negative affect or positive affect (both p>.05). Those with a decrease in positive affect had lower levels of dissociative symptoms than those with no change (z= -2.59, p=.009) or increase (z= -2.97, p=.003) in positive affect. No association was observed between dissociative symptoms and change in negative affect or anxiety (p>.05). There were no associations of sexual trauma history with outcomes (all p>.05). Qualitatively, women’s experiences were summarized into four themes: overall positive experiences of the body scan, embodied awareness, perceived benefits, and barriers
Establishing a Training Philosophy at a Performance Consulting Firm
No full textLeadership and Learning in Organizations capstone projectThis capstone project sought to help Performance Consulting Firm (PCF) establish its training philosophy. PCF is a growing consulting firm whose main source of revenue comes from government contracting. The lack of a training philosophy leads to unclear guidelines around what types of training should be created for internal leadership development. This mixed-methods study used interviews, document reviews, and data from the organization’s annual employee engagement survey to investigate the following project questions:
Q1. How do organizational leaders at PCF characterize the nature and quality of internal employee training?
Q2. How do organizational leaders view their role in leadership development of employees?
Q3. How do organizational leaders align and support organizational growth with professional development?
Through our literature review and data analysis, six findings emerged. These included PCF’s leaders not being aligned on the purpose of training, a lack of leadership and manager training in PCF’s learning management system, the leaders’ alignment on needing formal but flexible manager training including more dedicated time, leaders not being fully developed for career advancement, and PCF leaders not thinking beyond the current tuition assistance policy to help develop their employees.
Based on our study’s findings and an understanding of the organization, we have developed recommendations to help PCF establish a training philosophy and a training and development program, repurpose the tuition assistance budget to be used for more impactful training, and develop leaders to be more involved in training and development as well as for career advancement
Optimizing Talent Acquisition Strategies for Effective STEM Onboarding
No full textLeadership and Learning in Organizations capstone projectREGENT, a startup revolutionizing coastal travel with seaglider technology, faces challenges recruiting critical STEM talent to meet production goals. This study aimed to optimize its Talent Acquisition Program (TAP) using a mixed-methods approach, including surveys, interviews, and statistical analyses. The investigation revealed that unmet basic needs, such as competitive compensation and geographic concerns, could hinder REGENT's ability to recruit STEM talent. Recommendations include focusing on employee motivation, strengthening culture branding, addressing relocation barriers, and refining the hiring process to attract top STEM talent effectively
Reovirus enhances egress in extracellular vesicles that protect virus particles and facilitate multiparticle infection
No full textExtracellular vesicles (EVs) are membrane-bound structures that range in size and play a key role in cell-cell communication. Many viruses employ host cell-derived EVs as vehicles of egress. EV-mediated viral transport may be advantageous for viral infection by facilitating multiparticle infection and immune system defense evasion. I wanted to determine how reovirus is released from infected cells, and I wanted to further understand how the mode of reovirus egress influences downstream infection of recipient cells. I show that in two separate cell types, infectious units of two reovirus strains with distinct membrane disruption capacities egress both as free virus particles and associated with large and medium EVs, but not with small EVs. These medium-sized EVs measure, on average, 600-1000 nm in diameter, are resistant to mechanical disruption, and can withstand a variety of storage conditions. Furthermore, I show that medium EVs can protect reovirus particles from antibody neutralization and proteolysis in a cell type- and virus strain-dependent manner. This protection phenotype may be influenced by the capacity of the virus to induce cell death. Such neutralization protection potentially occurs in vivo, as I observe a trend towards reovirus protection by medium EVs harvested from infected mice. Additionally, EVs permit reovirus to be transported between cells in multiparticle infectious units. Finally, reovirus enhances the release of EVs of all sizes during infection. Overall, my work reveals mechanisms by which reovirus may escape immune system defenses and overcome cellular thresholds to infection, enhancing the likelihood of productive infection. These findings, which enhance our field’s current understanding of the effect of egress strategy on virus infection, may apply broadly to other viruses, including highly pathogenic viruses that are released and travel in association with EVs. Further insights into the mechanisms and effects of EV-mediated virus egress may help inform viral vaccination strategies and delivery of viral vectors
Using Molecular Dynamics Simulations to Understand the Molecular Organization of Stratum Corneum Lipids
No full textThe skin serves as the body’s primary barrier against external chemicals and pathogens as well as water loss. This protective function is localized to the skin’s outermost layer, the stratum corneum. The stratum corneum consists of corneocyte cells embedded within an extracellular lipid matrix, comprising ceramides, cholesterol, and free fatty acids. Skin conditions like eczema and psoriasis, that disrupt its barrier function, alter the lipid composition and arrangement within the stratum corneum. Understanding this connection between lipid composition, arrangement and barrier function requires insight into the unique structure of the lipid matrix. Several hypothetical lipid configurations within the stratum corneum have been proposed based upon experimental methods. However, these techniques often lack the molecular-level precision required to achieve a consensus on lipid organization. Molecular dynamics simulations offer a promising solution to bridge this gap, providing a three-dimensional, molecular-level representation of membrane structures.
This dissertation employs molecular dynamics simulations to investigate lipid organization within the short and long periodicity phases, which are the predominant lamellar phases of the stratum corneum lipid matrix. A multiscale approach is utilized, that combines efficient coarse-grained models, capable of exploring extended time scales, with precise atomistic models. First, a combined simulation and experimental approach is employed to explore the phase behavior, in-plane morphology, and the impact of molecular conformation and cholesterol composition on the short periodicity phase. The results of this study emphasize the importance of examining multilayer structures for accurate comparisons with experimental membranes. The feasibility of various lipid arrangements of the short and long periodicity phases is further assessed by comparing atomistic simulations of these structures to experimental data. Finally, the coarse-grained model is extended to simulate self-assembly into the long periodicity phase, which is considered a critical component contributing to the skin's permeability barrier. These findings provide a foundation for future investigations into structural variations in healthy and diseased states, the effects of topical formulations, and permeability of the stratum corneum lipid matrix
Improving Circulating Tumor DNA-based Liquid Biopsy Through Understanding Molecular Regulators of Cell Free DNA Release
No full textLiquid biopsy is a promising technique that is already impacting clinical decision making by supplementing traditional tumor biopsy as a way to derive molecular information about various cancers. However, it has potential to provide much greater impact through avenues such as early detection and minimal disease detection. Most studies attempt to elevate liquid biopsy to the levels of sensitivity and specificity required to be used for these approaches by adding additional analytes or increasing the quality of sequencing performed as part of the assay. However, few have attempted to identify and modify regulators of the cfDNA life cycle to increase the presence of ctDNA and therefore improve liquid biopsy accuracy. We sought to address this gap in knowledge by determining the most relevant mechanisms of cell-free DNA release, of which many have been proposed, including apoptosis, necrosis, and active release.
In chapter II of this dissertation, I include the materials and methods used in this work. Chapters III and IV are data chapters primarily derived from work about to be published in Communications Biology. In Chapter III of this dissertation, we define a model system for the release of cell-free DNA and create and perform a novel screen for mediators of cell-free DNA release in two cell lines. In Chapter IV, we validate the hits identified in our screen using genetic and drug studies and determine that apoptotic processes are the major regulator of cell-free DNA release. Finally, in Chapter V, I discuss limitations, implications, and future directions that could be taken based on this work