32,759 research outputs found

    In Silico Techniques to Improve Understanding of Gait in Cerebral Palsy

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    Thesis (Ph.D.)--University of Washington, 2024In this dissertation we focus on utilizing computer-aided engineering techniques to improve our understanding of gait in cerebral palsy (CP). CP is the most common motor disability in children and arises from a non-progressive brain injury at or near the time of birth which alters control (i.e., poor coordination and increased muscle co-contraction). Additionally, individuals with CP often develop secondary, progressive impairments like weakness and contracture. Current treatments to improve mobility in CP primarily target secondary impairments but functional outcomes are inconsistent, leaving treatment efficacy at around 50%. To improve treatment efficacy, clinicians need a better understanding of the complex interactions between, and relative effects of, multi-modal neuromuscular impairments on gait. However, eliciting interactions between, and relative effects of, neuromuscular impairments on gait is difficult or even impossible to do clinically and experimentally. Thus, the goal of this dissertation was to utilize in silico techniques to improve the understanding of gait in CP. Specifically, we use physics-based (i.e., musculoskeletal) modeling, optimal control (i.e., neuromuscular simulation), and data-driven modeling (i.e., machine learning) to investigate the interactions between, and relative effects of, altered control, muscle weakness, and contracture on gait and predict and understand gait energetics in CP which can be used to improve treatment efficacy. The effects of altered motor control on gait are poorly understood because altered control persists post-intervention and its relative effects are difficult to discern amidst secondary impairments, like weakness and contracture. Prior studies have investigated the impacts of weakness, contracture, and altered control on gait, but they have yet to be investigated together. Thus, in this dissertation we sought to understand the effects of, and interactions between, neuromuscular impairments during gait by utilizing a musculoskeletal model and neuromuscular simulation framework. We simulated nondisabled (ND) gait and then perturbed each simulation with altered control, weakness, and contracture of varying severities. We found that altered control exacerbated the restrictions imposed by secondary impairments: ND gait was less robust to, and required more muscle activation to adapt to, weakness and contracture with altered control when compared to unaltered control (Chapter 3). These findings highlight the inimical effects of altered control on gait and emphasize the advantages of in silico techniques to identify specific impairments, such as altered control, that should take treatment precedence (in silico-informed interventions). However, it is unclear if these conclusions extend to different gait patterns like those in CP. Abnormal gait patterns are common for individuals with CP; the most inimical and common of which is crouch gait. Crouch gait is characterized by excessive knee flexion, which increases knee extensor demand while reducing the knee extensor's ability to extend the knee making it inefficient and disadvantageous. In Chapter 4, we extended our prior computational methods to simulate crouch gait of varying severities. By simulating both crouch and ND gait, and incorporating machine learning (ML), we investigated if the interactions between, and relative effects of, neuromuscular impairments are gait pattern-specific. We determined that the interactions between, and relative effects of, neuromuscular impairments are gait pattern-specific highlighting advantages and disadvantages of walking in crouch. Thus, by combining computational techniques like modeling, simulation, and machine learning we elicited rationale for why individuals may select non-normative gait patterns and emphasized the utility of in silico techniques to parse and identify impairments primarily affecting function in CP which could then be used to inform treatment. Individuals with CP consume on average 2x the energy of their ND peers while walking; the origin of which remains unknown. Elevated energy consumption persists post-intervention making it a primary complaint among patients and objective of research in the CP community. We sought to accurately predict and understand energetics in CP with modeling, simulation, and machine learning to reduce clinical collection burden on patients and caregivers and improve identification of effective treatment methods for reducing energetics in CP. In the final study of this dissertation, we first used our modeling and simulation framework to generate and perturb walking simulations from gait data from the largest database of walking data for individuals with CP. Generated simulations then acted as synthetic data within a machine learning algorithm to complement existing clinical data and attempt to improve predictions of energetics in CP. Using simulations generated for 240 children with cerebral palsy we analyzed the energetic discrepancy—difference between measured and predicted—to identify primary mechanisms elevating energetics in CP (Chapter 5). Synthetic data generated from gait simulations marginally improve prediction accuracy of energetics in CP, but augmented discrepancy models—energetic predictions with the reconstructed discrepancy—improved modeling of CP energetics, identifying kinematics at initial contact and contracture as primary mechanisms elevating walking energy in CP. Utilizing in silico techniques can provide additional synthetic data (i.e., data augmentation) to reduce data collection burdens on patients, caregivers, and clinicians while eliciting additional insight in causal mechanisms affecting gait and function. This dissertation supports in silico informed interventions by improving our understanding of gait in CP. By utilizing modeling, simulation, and machine learning we examined the interactions between, and effects of, neuromuscular impairments on gait in both ND and CP individuals and how that information could better predict and understand energetics in CP. This work provides a foundation to utilize modeling, simulation, and machine learning to rapidly evaluate causal mechanisms impacting gait, probe and parse complex relationships between neuromuscular impairments, and incorporate synthetic data to better inform machine learning algorithms and clinical decision making. In conclusion, the work we have completed over the last 4 years highlights the benefits of in silico techniques to understand gait in CP, seeking to support the creation and implementation of in silico informed interventions for individuals with CP

    Centering Washington Tribal Libraries: Establishing the Foundations

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    In this article, we will describe a project called “Centering Washington Tribal Libraries: Building Relationships and Understanding Libraries from the Stories of Their Communities,” hereafter referred to as CWATL, based at the University of Washington Information School (UW iSchool). This one-year project, sponsored by a Mellon Foundation Public Knowledge grant, is designed to establish a foundation for working with Washington tribal communities and listening to the stories these communities tell about their libraries

    A simple model of the hypersonic boundary layer

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    A simple model of the hypersonic boundary layer is proposed. There are three assumptions: The mean velocity profile is linear, the total enthalpy is uniform, and turbulent transport is controlled by sonic eddies, whose rotational Mach number is unity. The model predicts that turbulent transport is slowest at the outer edge of the layer, consistent with the formal assumption of a linear velocity profile. The concentration profile of any conserved scalar is uniform across the boundary layer, matching the boundary condition at the wall. Any difference with the free stream concentration is accommodated by a jump at the outer edge of the layer

    Capacitive Eye Tracker made of Carbon-Nanotube Paper Composite for Human-Machine Interface and Neuroscience Applications

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    Thesis (Ph.D.)--University of Washington, 2023The uniqueness of eyes, facial geometry, and gaze direction make eye tracking a very challenging technological pursuit. The gold standard for an eye-tracking device has been the scleral search coil system. Despite dominant camera-based eye-tracking systems, their bulky equipment's obtrusiveness and high-power consumption are considered challenging for wearable applications. Piezoelectric sensors, electrooculography (EOG), and capacitive sensors have been attempted for eye tracking but failed due to low sensitivity. The capacitive sensors are unique in that eye movement can be monitored in a noncontact manner, but the sensitivity dampens as the number of sensors increases due to enlarged parasitic capacitance. In this dissertation, the capacitive sensors are reviewed with respect to their history, working principles, sensing mechanism, fabrication methods, recent nanoscale and microscale regimes, and current applications. An analytical and numerical study is presented to understand in-plane and fringing capacitances. Single- and differential sensing configurations are analyzed in terms of sensitivity and linearity by analytical equations and numerical simulations. Micro and nanostructured materials to construct capacitive sensors will be assessed in the contexts of target parameters, including pressure, strain, force, liquid level, humidity, temperature, displacement, and acceleration. The applications of capacitive sensors are presented in the emerging fields of wearable sensors, human-machine interface (HMI), biomedical implementation, human health monitoring, robotics, and industrial monitoring. Based on the knowledge, the capacitive interaction between a novel sensor and eye movement for wearable eye-tracking is studied. The capacitive sensors are made of a pair of asymmetric electrodes; one comprising carbon nanotube-paper composite fibers (CPC) and the other being a rectangular metal electrode. The interaction between the asymmetric sensor and a spherical object mimicking an eyeball is analyzed numerically. Using a face simulator, both single- and differential capacitive measurements are characterized with respect to proximity, geometry, and human body charge. Using a prototype eye tracker, multiple sensor locations are studied to determine the optimal configurations. The capacitive responses to vertical and horizontal gaze directions are analyzed in comparison to those of a commercial eye-tracking system. The performance is demonstrated for sensitive eye-movement tracking, closed-eye monitoring, and human-machine interface. Eye tracker performance is validated in comparison to the scleral search coil, the current gold standard in eye tracking. The capacitive interaction between the CPC electrode and a spherical eyeball is analyzed by a numerical study to understand how the shape and scale of the eyeball affect capacitive interaction. A non-human primate (NHP), implanted with a scleral search coil, is utilized to conduct an eyeball interaction study. The CPC eye tracker’s response to smooth pursuit and saccadic movements is investigated and validated against the scleral search coil. This research has important implications for the development of capacitive, wearable eye trackers, which can facilitate fields of human-machine interface, cognitive monitoring, neuroscience research, and rehabilitation

    Bottom-Up Synthesis of Colloidal Systems Using Sequence Defined Molecules

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    Thesis (Ph.D.)--University of Washington, 2023Self-assembled colloidal nanoparticles can be used to deliver vaccines, sense pathogenic materials, and mark tumors. In response to light, they catalyze the formation of clean fuels or help transform it directly into usable energy.Quantum dots are used in commercial displays and will be a key step in new forms of computing and information storage. The performance of nanoparticles is dictated by their structure and composition and can be controlled using sequence defined molecules. The latter include any polymeric or oligomeric materials in which the exact sequence is precisely controlled using enzymatic processes or synthetic chemistry. Their physicochemical diversity and modularity are used to intervene in chemical processes occurring during synthesis, stabilize specific crystal facets, or form templates that guide nanomaterial growth. Yet the multivariate relationship between experimental parameters and intermolecular reactions that govern nanomaterial self-assembly is difficult to study using traditional experimental methods. In this work, gold nanoparticle synthesis in the presence of peptides is used as a model system for developing and integrating experimental automation with computational approaches to extract information for guiding sequence design.Several peptide variants were selected through systematic variations of a gold binding peptide, and nanoparticles were synthesized using a liquid handling robot in a large design space of reagent concentrations. The plasmonic response of nanoparticles was used as a fast proxy for changes in structures and was analyzed using functional data analysis methods. The analysis resulted in a metric for quantifying how changes in peptide design affect nanoparticle synthesis outcomes, and the conclusions were corroborated with small-angle X-ray scattering and electron microscopy. Next, the relationship between substitution of methionine in a peptide sequence and an increase in particle anisotropy was assessed. A programmed liquid handling robot was used to dynamically intervene in nanoparticle synthesis to control the resulting structure and stability of anisotropic nanoparticles. Finally, highlights of how small-angle X-ray scattering can work in parallel with computational methods to study colloidal self-assembly mechanisms are presented

    Understanding recursive splicing in the human genome

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    Thesis (Ph.D.)--University of Washington, 2023Recursive splicing is a non-canonical splicing mechanism that results in an intron being removed in two or more segments. Identifying recursive splicing presents technical challenges due to the lack of evidence in mRNA and the instability of splicing intermediates and byproducts. Few recursive splice sites have been identified with high confidence in human introns and largely have been located within long introns. Using a stringent approach to map lariat reads, I identified recursive splicing genome-wide, finding evidence for 100 new recursive splice sites in a broader range of intron sizes than previously reported and characterizing a new location for recursive splicing at the distal end of cassette exons. These data demonstrate the unappreciated prevalence of recursive splicing, the potential for finding additional sites as appropriately enriched RNA sequencing datasets become available, and its possible influence on gene expression through alternative exon isoforms. In addition, I discuss the evidence for intronic and distal exonic recursive splice sites as a mechanism of exon birth

    Development of a Novel Gene Therapy & Investigation of Synthetic Gene Therapy Delivery Systems

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    Thesis (Ph.D.)--University of Washington, 2023Dystroglycanopathies are a family of neuromuscular disorders, in which enzymes that glycosylate the protein dystroglycan and therefore play a key role in muscle structure, have reduced or nonexistent activity. For example, Limb-girdle muscular dystrophy type R9 is caused by a mutation in the FKRP gene, that encodes one of various enzymes that glycosylates the muscle membrane protein dystroglycan. The result is muscle degeneration and weakness, and palliative care is presently the only available treatment for dystroglycanopathy patients. We approached the need for treatment from a gene therapy perspective, focusing on two main ideas: 1) the development of a novel AAV gene therapy with which to treat limb-girdle muscular dystrophy type R9, and 2) the evolution of a synthetic nanoparticle with a long-range goal of improving tissue targeting and therapeutic gene delivery. Our research into AAV gene therapy led us to determine that removal of the untranslated regions of the FKRP gene increases protein expression. Following these in vitro results, we further verified the restoration of muscle strength and health in a 10-month-old LGMDR9 mouse model. Additionally, potential deleterious effects of AAV-FKRP gene therapy has created controversy in the field, and our data suggest that this is not an issue at the doses and vectors tested, as treated WT mice show no physiological evidence of harmful effects. However, AAVs are unavailable as a treatment for patients with preexisting immunity to the vector, such that alternative gene therapy delivery systems must be considered. Using customizable synthetic nanoparticles bearing a library of surface miniproteins that encapsulate their own mRNA, we selected for desired characteristics (i.e. tissue tropism) over multiple rounds of selection in vivo. This genetically coded library consisted of millions of nanoparticles, which we injected into mice for two rounds of in vivo selection for binding to specific cell types, such as skeletal muscle. Following each round, we sequenced nanoparticle mRNA in desired tissues, from which we then created a new library to be evaluated in vivo again. The results of this suggest common binding moieties in mini-protein binders on the surface of the nanoparticles. The goal is to identify synthetic particles bearing surface proteins that have high affinity for selected tissues that could eventually be used as gene therapy delivery mechanisms for neuromuscular disorders

    Tuberculosis Risk and Prevention: Findings from Domestic and Global Cohorts

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    Thesis (Ph.D.)--University of Washington, 2023Tuberculosis is a highly infectious disease, leading to disproportionate morbidity and mortality amongst vulnerable populations such as immigrants, adolescents and young adults (AYA), and people living with HIV (PLWHIV). Approximately one quarter of the global population is infected with TB, which can develop into TB disease due to a myriad of factors. There has been an increasing proportion of TB cases in the U.S. attributed to non-U.S. born individuals, particularly among individuals from countries with high TB burden. Individuals who are immunocompromised, such as PLWHIV, are particularly susceptible to TB disease due to the weakened status of their immune system. Additionally heightened risk of TB during the adolescent and young adult period (age 10-24) has been linked to changes in environmental and physiological factors. There have been changes in approaches to TB screening in the U.S; however, new screening recommendations do not account for variations of TB risk by country of origin. Additionally, gaps in knowledge persist regarding TB risk particularly among adolescents and young adults with HIV (YWHIV). TB diagnosis is particularly difficult among children and knowledge of TB risk among YWHIV has been further hampered by dichotomized data reporting among children (less than 15) and adults (15 years of age and older). TB prevention therapy (TPT) can significantly decrease TB, especially among PLHIV on ART. TPT should be available to all PLHIV, however reporting has been prone to missingness and overlooked among YWHIV. Understanding other factors associated with TPT use and TB disease among YWHIV is of utmost importance to achieving global TB targets. In this dissertation, we evaluate TB risk among non-U.S. born individuals, quantify TPT use among YWHIV, and evaluate TPT utilization and TB risk among YWHIV to address the current gaps in research. In Chapter 2, we estimated TB risk among non-U.S. born individuals in Washington state utilizing region of origin, World Health Organization (WHO) incidence categories, and time since entry into the U.S. In Chapters 3, we conducted the largest retrospective cohort analyses among 10,000 YWHIV in our study cohort. We estimated the TPT cascade of care, quantifying the number of YWHIV who initiated and completed TPT during our study period. We also evaluated clinic level and individuals level co-factors associated with TPT initiation and completion. Lastly in Chapter 4, we estimated the TB risk among YWHIV in Kenya and calculated TB incidence among individuals newly initated on ART and those previously on ART and evaluated co-factors for TB. Cumulatively these findings emphasize the continued need for tailored screening guidelines for non-U.S. born individuals and identified deficiencies in TPT utilization and the particularly high risk of TB among YWHIV in Kenya

    Barriers and Facilitators to Staying on Peritoneal Dialysis from the Perspective of Black and Latino Patients with Kidney Failure – A Qualitative Study

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    Thesis (Master's)--University of Washington, 2023Introduction: Despite being associated with better quality of life, lower cost, and longer preservation of residual kidney function compared to hemodialysis (HD), peritoneal dialysis (PD) is underutilized for Black and Latino patients with kidney failure. The objective of this study was to identify barriers and facilitators to dialysis retention among Black and Latino patients with kidney failure. Methods: We conducted a qualitative study using in-depth, semi-structured interviews of adult Black and Latino patients currently on PD. Interviews were conducted in English and Spanish, transcribed verbatim, and analyzed using constant comparison method,1 guided by Andersen’s behavioral model for health services use.2 Results: Our sample consisted of 2 Black English-speaking and 7 Latino Spanish-speaking participants (mean age 48 years, 67% female, mean duration on PD 38 months). Facilitators to PD retention included positive attitudes towards PD, self-efficacy to perform dialysis at home, access to a supportive and readily available dialysis team, and family support. Barriers to PD retention included lack of Spanish-speaking dialysis providers, and underuse of professional medical interpreters for Spanish-speaking participants. The initiation of PD was noted to have a negative impact on mental health and mobility and required unanticipated adaptation to both work and social schedules for patients and their caregivers. Despite reporting PD-associated complications and symptoms, almost all participants reported an overall positive change in their health and quality of life since starting PD. All participants reported that they would still choose PD over other dialysis modalities if given the choice. Conclusions: Provision of high-quality language assistance services or bilingual providers and preparation for transitioning to home PD may improve patient experience and PD retention. This work leverages patient experience to identify areas for future interventions aimed at addressing the equity gap in home dialysis for Black and Latino patients with kidney failure. 1. Miles MB, Huberman AM, Saldaña J. Qualitative Data Analysis : A Methods Sourcebook. Fourth ed. Los Angeles: SAGE, 2020.2. Andersen R, Newman JF. Societal and individual determinants of medical care utilization in the United States. Milbank Mem Fund Q Health Soc 1973;51(1):95-124. (https://www.ncbi.nlm.nih.gov/pubmed/4198894)

    Characterizing blood protein surface interactions for the development of thromboresistant fluoropolymer coatings

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    Thesis (Ph.D.)--University of Washington, 2023Patients with long term blood-contacting medical devices will continue to require risky systemic anticoagulant administration until the effects of device thrombogenicity can be adequately addressed. Adsorption of the protein, fibrinogen, to biomaterials is broadly acknowledged as the primary mediator of platelet adhesion and aggregation, yet fibrinogen in its native soluble form is inactive and circulates harmoniously with platelets in the bloodstream. Therefore, the adsorption process induces a structural change to the protein that exposes platelet-binding epitopes. Complete elimination of protein adsorption on biomaterial surfaces for extended durations has proven a significant challenge, and even ultralow levels of surface fibrinogen can initiate full platelet activation and thromboembolism formation. However, a body of evidence suggests that platelet membranes themselves are inert against continued exposure to blood after initial degranulation. Thus, perhaps a more realistic approach to developing long-term blood contacting materials is to engineer surfaces that adsorb fibrinogen in a layer that rapidly promotes uniform platelet adhesion and spreading to form a smooth passivating layer against further activation by circulating blood components. Separately, fluoropolymers hold a long history of delivering favorable outcomes for blood-contacting applications. Our group possesses expertise in glow-discharge plasma polymerized fluorocarbons, which have historically demonstrated exceptionally high patency rates, high blood flow, and low embolization rates in in vitro studies and ex vivo primate shunt models compared to other materials of their class. However, the mechanism behind their favorable adsorption of blood protein constituents or conformations to resist long-term activation of blood cellular components deserves more investigation to properly characterize their mode of action. In this dissertation, we present several studies of blood protein interactions on a custom plasma-polymerized fluorocarbon (ppC3F6) developed in our research group in comparison with standard commercial fluoropolymer counterparts to further explore the platelet membrane passivation mechanism. We begin with an overview of the historical challenges in addressing hemocompatibility and the viability of engineered fluoropolymers to fulfill long-term blood contacting needs (Chapter 1). We then delve into preparation and characterization of a small selection of fluoropolymers (Chapter 2), followed by assessments on differential total protein adsorption using quartz crystal microbalance with dissipation (Chapter 3). Given that the origins of thrombus formation depend on adsorption-induced structural changes of fibrinogen in addition to total adsorption, we pursued a series of studies investigating these changes across our fluoropolymer materials (Chapter 4). We then discuss our effort to better understand structurally sensitive regions in the fibrinogen platelet-binding domain that give rise to bleeding disorders including thrombosis through molecular dynamics simulations (Chapter 5). Finally, we assess platelet adhesion and activation in relation to our fluoropolymers preadsorbed with fibrinogen to identify relationships between fluoropolymer surface chemistry, adsorbed blood protein surface composition and structural bioactivity, and cellular response (Chapter 6), concluding with proposed mechanisms of improved blood compatibility and remarks on future directions for the application of plasma-polymerized fluoropolymers in blood-contacting devices (Chapter 7)
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