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Caring For Actively Dying Children And Their Parents In The Pediatric Icu:a Mixed Methods Study
No full textA child’s death upends a family’s anticipated life cycle and embodied parental roles; resulting in a profound grieving process. Though most children die in the pediatric intensive care unit (PICU) following a planned withdrawal of life-sustaining treatments, little is known about how nursing care at end-of-life shapes parents’ bereavement. This dissertation examined how nursing care at end-of-life in the PICU shapes parents’ long-term bereavement using a sequential explanatory (QUAN -\u3e qual) mixed methods design that integrated quantitative clinical information with qualitative parent interview data. Mixed-effects models were used to identify associations between patient characteristics (age, illness trajectory, length of stay, circumstances of death) and patterns of daily outcomes (pain, sedation, and nursing care requirements). Patients’ pain and sedation scores were generally comfortable but showed episodic discomfort. Patients with cancer demonstrated higher peak daily pain scores than patients with acute illness trajectories. Patients with longer length of stay more frequently had pain and pain with agitation on day of death. Most patients continued with multiple invasive devices in place until death, regardless of illness trajectory or circumstances of death (i.e., withdrawal of life-support, failed resuscitation, brain death). Qualitative analysis revealed four domains that shifted in priority and intersected to amplify one another; (1) Being together, (2) Tending to evolving clinical needs, (3) Managing institutional, situational, and structural factors, and (4) Navigating an array of emotions in an unwelcome context. These data were integrated to explain and contextualize quantitative findings and examine similarities and differences between parents’ perceptions and documented nursing care. Parents of children with varying illness trajectories used different priorities and terminology when recalling their child’s comfort and symptoms at end-of-life. Parents’ memories of their child’s suffering more closely corresponded with peaks in clinical scores, rather than overarching averages. The findings from this dissertation show that the end-of-life and grief experience is unique for each child and family, but opportunities exist for nurses to tailor their caring actions to promote a meaningful death experience that grieving parents remember for a lifetime
Policy Implementation And Engineering For Tagged Architectures
Get PDFTagged architectures have seen renewed interest as a means to improve the security and reliability of computing systems. Rich, programmable tag-based hardware security monitors like the PUMP allow software-defined security policies to benefit from hardware acceleration. The thesis of this work is that policies for programmable tagged architectures (1) can be engineered to enforce critical security properties at low cost, (2) can protect real programs running on real ISAs, and (3) can be applied automatically to programs—that is with compilation passes or automatic analysis—so that the benefits of such an architecture can be brought to existing and new software with minimal human intervention.
To support this claim, I have constructed a range of security policies that run on real workloads automatically, modeled their overheads using architectural simulations, explored tradeoffs in policy design and engineering to reduce their costs, and finally characterized them by their security properties. As examplar policies, I have created stack and heap memory protection policies that can thwart traditional memory corruption vulnerabilities. Additionally, I have built a compartmentalization framework that allows a security engineer to automatically generate and evaluate a wide range of tag-based compartmentalization strategies. To generate compartments automatically, the framework includes algorithms for quantitatively minimizing overprivilege and packing the rules required for those policies into manageable sets that can be cached favorably for high performance. Across these three categories of policies, I present the following policy engineering contributions: (1) lazy tagging, an optimization that reduces the cost of tagging memory objects, (2) rule packing, a technique for relaxing policies in key ways to improve their performance, and (3) rule prefetching, a technique that can exploit predictable rule sequences by preemptively fetching and installing rules before they are needed
A Computational Approach To The Study Of Trauma
Get PDFTrauma with hypovolemic shock is an extreme pathological state that challenges the body to maintain blood pressure and oxygenation in the face of hemorrhagic blood loss. In conjunction with surgical actions and transfusion therapy, survival requires the patient’s blood to maintain hemostasis to stop bleeding. The physics of the problem are multiscale: (1) the systemic circulation sets the global blood pressure in response to blood loss and resuscitation therapy, (2) local tissue perfusion is altered by localized vasoregulatory mechanisms and bleeding, and (3) altered blood and vessel biology resulting from the trauma as well as local hemodynamics control the assembly of clotting components at the site of injury. Building upon ongoing modeling efforts to simulate arterial or venous thrombosis in a diseased vasculature, we have developed models of trauma (both multiscale and machine-learning based) to understand patient risk and predict response. Key results were: (1) the upstream vascular network rapidly depressurizes to reduce blood loss, (2) wall shear rates at the hemorrhaging wound exit are sufficiently high (~10,000 s-1) to drive von Willebrand Factor unfolding, (3) full coagulopathy results in \u3e2L blood loss in 2 hours for severing all vessels of 0.13 to 0.005 mm diameter within the bifurcating network, whereas full hemostasis limits blood loss to \u3c100 mL within 2 min, and (4) hemodilution from transcapillary refill increases blood loss and could be implicated in trauma induced coagulopathy. Machine learning based methods were also implemented to understand trauma patient outcomes. A 400-estimator gradient boosting classifier was trained to predict survival probability and the model is able to predict a survival probability for any trauma patient and accurately distinguish between a deceased and survived patient in 92.4% of all cases. Partial dependence curves (Psurvival vs. feature value) obtained from the trained model revealed the global importance of Glasgow coma score, age, and systolic blood pressure while pulse rate, respiratory rate, temperature, oxygen saturation, and gender had more subtle single variable influences. Shapley values, which measure the relative contribution of each of the 8 features to individual patient risk, were computed for several patients and quantified patient-specific warning signs
Vβ Recombination Signal Sequences Mediate Monoallelic and Monogenic TCRβ Gene Assembly: Implications for the TCRβ Repertoire and Allelic Exclusion in Health and Disease
No full textMonoallelic expression of antigen receptor (AgR) genes is assumed to be critical for the proper development and function of T and B lymphocytes. AgR loci are composed of variable (V), joining (J), and sometimes diversity (D) gene segments that must be cleaved and assembled by RAG-endonuclease mediated V(D)J recombination to form a functional gene. TCRβ, IgH, and Igκ allelic exclusion is achieved by: assembly of an in-frame gene on one allele, transient inhibition of V(D)J recombination signaled by RAG DNA double stranded breaks (DSBs), and the resulting protein sending feedback signals to permanently inhibit V-to-(D)J recombination of the non-functional allele. Any definitive mechanisms that promote asynchronous AgR gene assembly in developing lymphocytes remain unknown. V segment recombination signal sequences (RSSs) of Tcrb and Igh loci that target RAG have been proposed to render V recombination inefficient and mediate monoallelic V-to-DJ recombination. To test the role of Vβ RSSs in promoting Tcrb allelic exclusion, I created and studied mice harboring particular Vβ RSS replacements with the stronger 3’Dβ1 RSS. I demonstrate a substantial role for weak Vβ RSSs in limiting: Vβ recombination frequency, biallelic Vβ-to-DJβ recombination before the onset of transient and permanent feedback mechanisms, biallelic TCRβ expression, and unexpectedly dual TCRβ chain expression from a single Tcrb allele. These data indicate that weak Vβ RSSs limit Vβ recombination to promote monogenic Tcrb assembly within the time window before feedback inhibition halts Vβ rearrangements. I also establish a role for ATM, a key factor in the DNA damage response that promotes DNA repair and mediates transient feedback inhibition, in guarding against the formation of promoting Tcrb allelicnonfunctional deletions for V segments that rearrange by inversion and cooperating with weak Vβ RSSs to impose TCRβ allelic exclusion. AgR allelic exclusion is most stringently applied to Tcrb and Igh, whose assembly, expression, and signaling through pre-AgR complexes drive cellular proliferation. As I am able to drive biallelic recombination of Tcrb genes, I introduce preliminary data that supports the model that mechanisms directing monoallelic induction of RAG DSBs evolved at Tcrb and Igh loci in part to suppress DSBs from entering S phase and forming oncogenic AgR translocations. Finally, as the Vβ RSS replacements result in dramatic shifts in the Vβ repertoire, I present data that suggests the composition of the TCRβ repertoire may affect antigen-specific immune responses by defining the frequency of naïve antigen-reactive cells. Together, these studies reveal mechanisms in developing thymocytes that promote: monoallelic Tcrb assembly and allelic exclusion, repertoire diversity, and perhaps T cell immune responses and genome stability
Structural and Mechanical Responses to Intermittent Parathyroid Hormone Treatment, Discontinuation and Cyclic Administration Regimens
No full textBone mineral density rapidly decreases upon withdrawal from intermittent parathyroid hormone (PTH) treatment despite its potent effect of promoting bone formation. To better understand this adverse phenomenon, this study first aimed to investigate the phenotype of PTH withdrawal in both intact and estrogen-deficient rat model by using a well-designed experiment combined with innovative longitudinal imaging techniques and localized cellular activities. Due to observing a continuous anabolic window upon early discontinuation of PTH treatment in estrogen-deficient animals, we propose a potential effective treatment strategy, the short cycles of PTH and antiresorptive treatment regimen, which could extend the anabolic windows by increasing the number of newly activated modeling-based bone formation (MBF) sites. Lastly, to understand the structure-function relationships of bone tissue formed through MBF compared to the remodeling-based bone formation (RBF), we developed an innovative imaging platform with a mechanical testing platform to determine the mechanical properties of MBF and RBF and their long-term contributions in intact animals
Scale-Dependent Coupling between Aeolian Form and Flow
No full textWhere there are erodible and durable grains and sufficiently strong winds to move them, erosion and deposition produces dunes. Dune fields are a coarsening pattern that defines large swaths of planetary landscapes. They exchange momentum and heat with the atmosphere, which in turn alters winds, creating a coupling between flow and form at the planetary surface. In this dissertation I investigate how surface properties of dune fields alter the winds that produce them, what conditions are necessary for dune growth and if it saturates, and how dune fields may respond to changing climate in the near future. These studies use a blend of scientific methods and are framed as problems in dynamics; investigations of non-uniformity, non-stationarity, saturation and thresholds. I show how the atmospheric boundary layer’s response to the roughness and low thermal inertia of dune fields creates spatial and temporal heterogeneity in dune-field activity, respectively. I argue that Earth’s dune coarsen indefinitely, predict that they will become less active during this century, and put bounds on the requisite winds and grain properties for their existence on bodies in the Solar System. This dissertation offers novel and generic contributions to the field of aeolian geomorphology applicable at the dune-field scale
Reading and Writing a Garden, Materials of a Garden Made in Germantown, Pennsylvania (1683–1719)
No full textThis dissertation describes and interprets an example of a relationship between belief, imagination, reading, writing, and the art of gardening in colonial Pennsylvania. The chapters analyze and interpret the role and influence of Francis Daniel Pastorius’ art of gardening in early American garden culture as it was based on his own Christian Humanist and polyglot demeanor, German Pietism, early modern natural science, and the multilingual culture of the newly forming Quaker colony. The garden in question was made behind his home at, what is now, 6019 Germantown Avenue, between 1683 and 1719. His garden and garden art are reconstructed based on a close reading of his own plant prints, botanical and devotional poetry, literal descriptions, and didactic writing about plants and horticulture. This writing is found in several of his notebooks that survive at the Historical Society of Pennsylvania, The German Society of Pennsylvania, and the Kislak Center at the University of Pennsylvania. His writing documents a garden of over two hundred and twenty species of exotic, ornamental, culinary, and medicinal plants that he cultivated in his garden, orchard, vineyard, and fields and a productive apiary of four to five hives. It also reveals his deeply felt, mystical intimacy with bees and plants. He celebrated this intimacy in his writing, and in the manner that he arranged, cultivated, and propagated plants in his garden beds. His art was a lyrical and didactic, multilingual hortenses poesis: a garden poem that celebrated the creative act of making a garden in a Pennsylvania woods
Parents’ Insights About At-Home Learning During the Covid-19 Pandemic
No full textThis research study sought to develop systematic ways for surfacing parents’ knowledge and insights about how a neighborhood elementary charter school in a large east coast city has been responding to the COVID-19 pandemic and the challenges of systemic racism. As practitioner research, the study conceptualized parents as practitioners with whom school leaders could collaboratively theorize about providing a high-quality experience for all students. In my position as assistant principal, I conducted interviews and inquiry meetings with parents and staff. We co-generated knowledge about the ways in which stakeholder relationships and school planning impacted the experiences of students during the pandemic. I used emic coding approaches to foreground parents’ perspectives on their children’s experiences, their roles as parents during at-home learning, and their perspectives on the school’s response to the pandemic. Their analysis presented empirical evidence that teachers fulfilled “deep equity roles” (Pollock et al., 2019) at the intersections of classroom life and online coursework. The parents’ stance as practitioners, who are doing the deliberative, metatheoretical work of teaching and learning (Campano, 2009), showed their important role in school planning that prioritizes community-based epistemologies (Khalifa, 2018) and a shared responsibility for students’ well-being (Cochran-Smith & Lytle, 2009) in high accountability contexts, within and beyond the pandemic
Vaccine Mediated Immunity to Malaria
No full textMalaria infects millions of people every year, and despite recent advances in controlling disease spread, it remains a global health concern. Decades of research into both naturally acquired and vaccine mediated immunity have given a broad range of correlates of protection. RTS,S, the only licensed anti-malarial vaccine, has implicated antibodies against the circumsporozoite protein (CSP) as a key correlate. Not to be discounted, CD8+ T cells targeting liver-stage (LS) antigens were associated with protection in attenuated sporozoite vaccination. Clearly there is no panacea for malarial immunity, and a broad range of responses against multiple antigens is crucial. In this work we develop novel synthetic DNA vaccines targeting antigens in multiple Plasmodium pre-erythrocytic life cycle stages, and evaluate the immunity elicited by each in the context of murine models of malaria. To further evaluate protection mediated by Liver stage antigens, we focused on the exported pre-erythrocytic proteins EXP1, PFN, EXP2, ICP, TMP21, and UIS3. SynDNA antigen cocktails were tested with and without the molecular adjuvant plasmid IL-33. Immunized animals developed robust T cell responses including induction of antigen-specific liver-localized CD8+ T cells, which were enhanced by the co-delivery of plasmid IL-33. In total, 100% of mice in adjuvanted groups and 71%–88% in nonadjuvanted groups were protected from disease following Plasmodium yoelii challenge. To further evaluate protection mediated by sporozoite antigens, five synDNA vaccines encoding variations of CSP were designed and studied: 3D7, GPI1, ΔGPI, TM, and DD2. ΔGPI generated the most robust immunity, and was the most efficacious in an IV sporozoite challenge. We then compared the immunity generated by ΔGPI vs synDNA mimics for two leading malaria vaccine candidates (RTS,S and R21). They demonstrated similar anti-CSP antibody responses, however ΔGPI induced a more focused T cell response. In an infectious mosquito challenge all three of these constructs generated potent inhibition of liver stage infection, with ΔGPI appearing to also provide the best sterilizing immunity from blood stage parasitemia. Together these studies demonstrated that synDNA vaccines encoding malaria immunogens can provide substantial protection from disease, and highlighted the importance of targeting the pre-erythrocytic life cycle stages to combat malaria
Modeling Genetic, Neural and Behavioral Correlates of Substance Use Disorders in Mice
No full textOver the past several decades, research in animal models has advanced our understanding of the neurobiological underpinnings of substance use disorders. Influences on drug abuse liability are broad and multifaceted, and include environmental, genetic and epigenetic factors. A history of chronic drug use may also induce persistent changes in the brain that contribute to high rates of relapse. The collection of studies described herein serves to further our understanding of substance dependence across genetic, neural and behavioral scales. First, we apply systems approaches to characterize changes in the functional architecture of the brain following chronic opiate exposure. We relate these changes to patterns of interregional gene expression and identify regions of the brain that may drive opiate-induced alterations in the state of the brain. We then examine the influence of a common genetic variant on cellular physiology and behavior relevant to opiate abuse liability. Finally, we identify a potential novel therapeutic target for treating symptoms of withdrawal in a mouse model of nicotine dependence. This body of work contributes to our understanding of how genetics, behavior, and neural circuitry contribute to the initiation and maintenance of drug dependence and demonstrates the utility of a mouse model of nicotine dependence for assessing novel treatment approaches for substance use disorders