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A TYPE II IMPLEMENTATION-EFFECTIVENESS HYBRID STUDY OF A COLLABORATIVE MODEL OF CARE BETWEEN ORTHOPAEDICS AND ALLIED HEALTHCARE PROFESSIONALS (CONNACT) PLUS IN KNEE OSTEOARTHRITIS IN SINGAPORE
No full textBackground: Knee osteoarthritis is a leading cause of disability globally, with exercise and self-management recommended as first-line treatments. However, most evidence comes from Western populations, leaving a critical gap in understanding intervention effectiveness in Asian contexts with distinct sociocultural norms and healthcare systems. This thesis addresses this gap by evaluating the effectiveness and implementation of a Collaborative Model of Care between Orthopaedics and Allied Healthcare Professionals (CONNACT) Plus, a community-based, Health Coach (HC)-led program in Singapore.
Methods: Using a Type 2 hybrid implementation-effectiveness design, this thesis integrated three components: (1) a non-equivalent control group design (n=108 enrollees vs. 457 usual care controls) assessing clinical effectiveness using the Knee Injury and Osteoarthritis Outcome Score (KOOS-12) and secondary outcomes (pain reduction, health-related quality of life (QoL) and psychological wellbeing); (2) semi-structured interviews (n=20) exploring user experiences; and (3) a mixed-methods evaluation of contextual factors, barriers and facilitators to implementation across Reach, Effectiveness, Adoption, Implementation and Maintenance domains. Quantitative data were analyzed using mixed effects models with propensity score matching; qualitative data employed inductive-deductive thematic analysis.
Results: There were no significant treatment group differences in KOOS-12 scores at 4 or 12 months. The average 4-month scores were 68.95±15.15 and 64.98±18.26 for the CONNACT plus and usual care groups (adjusted difference=2.57, 95% CI: [-1.3, 6.44], while the average 12-month scores were 72.28±16.66 and 68.33±19.43 respectively (adjusted difference=2.45, 95% CI: [-2.79, 9.90]). Secondary outcomes showed no significant treatment effects except in QoL: EQ-5D Visual Analog Scale scores were higher in CONNAC Plus at 4 months (77.80±11.14 vs. 72.63±16.64; adjusted difference=4.36, 95% CI: [0.18, 8.54]). Implementation outcomes revealed limited reach (19.1% enrollment) and post-intervention maintenance challenges. Key barriers included HC training gaps, balancing group/individual needs, and limited referrals. User experiences identified five themes: pre-existing knowledge disparities, motivational diversity, variable skill development, group composition effects, and maintenance challenges post-program.
Conclusion: While CONNACT Plus showed limited effectiveness, it demonstrates the viability of HC-led models in community osteoarthritis care. By synthesizing effectiveness, user experience and implementation insights, this work advances implementation science in non-Western contexts and offers a blueprint for culturally adapted chronic disease management in aging populations globally
UBI JUS IBI REMEDIUM?: AN EXAMINATION OF INTERNATIONAL LAW REMEDIES FOR US CORPORATIONS THAT ARE VICTIMS OF INTERNATIONAL CYBERATTACKS
No full textThis thesis is a doctrinal study that analyses relevant international law, US domestic laws, and publicly available data on international cyber operations to demonstrate that applying international law to matters in cyberspace does not translate into meaningful remedies for US corporations adversely affected by international cyberattacks. It employs a theoretical framework that synthesizes the concepts of international cyberattacks and Hart's legal positivism and argues that although domestic US law could complement international law to provide remedies to US corporations that are affected by state-sponsored cyberattacks, significant limitations, and challenges militate against access to those remedies.
The study finds four main challenges that impede US corporations’ effective access to remedies for state-sponsored cyberattacks: (1) limited agency of corporations and difficulty in attributing cyberattacks to States, (2) jurisdictional and sovereignty issues, (3) political and diplomatic factors, and (4) legal interpretation and enforcement difficulties. In light of these challenges, the study proposes legal reform and policy development recommendations to (a) advocate for corporate rights and remedies in international law, (b) strengthen legal mechanisms for attribution and accountability, and (c) enhance international cooperation
Studies in Multivariate Pareto Records
Full text linkThe natural and important notion of multivariate Pareto record is defined based on the dominance relation in and generalizes the classical notion of one-dimensional record in probability theory. Given a sequence of independent and identically distributed random vectors taking values in with continuous distribution function, we first investigate how the probability that the th observation sets a record varies with their common distribution. Then, for observations with independent coordinates, we study the asymptotic behavior (as ) of the Pareto frontier, defined simply in terms of the remaining records (i.e., maxima, or undominated points) at a given epoch , by deriving distributional and almost sure extreme results. These results are then extended to observations that follow a certain class of marginalized Dirichlet distributions, which exhibit negative dependence among the coordinates. For such marginalized Dirichlet observations, we also prove Berry--Esseen bounds for both the total number of records set and the number of remaining records using Stein's method. Finally, for the two models, we introduce a probabilistic approach to identify, with proofs, the asymptotic conditional distribution of the number of Pareto records broken by the th observation conditionally given that the observation sets a record
Development of an Electronics Platform for the Keck Adaptive Secondary Mirror
Full text linkIn this paper we discuss the development of an electronics platform for the Keck Adaptive Secondary Mirror (KASM). KASM is an ongoing project headed by the Laboratory for Adaptive Optics at UC Santa Cruz to mount an adaptive secondary mirror onto the 10-meter Keck 1 telescope. When completed, KASM will be the largest single Adaptive Secondary Mirror (ASM) in the world, measuring 1.5 meters across and carrying over 2300 voice coil actuators. The actuators for the system will be driven by a constellation of 100 Actuator Printed Circuit Board Assemblies (PCBAs), developed for this thesis. Most Actuator PCBAs will drive 26 actuators each with a 10 Nanometer (nm) position resolution and 10 Micrometer (um) full-scale displacement. With position update rates in the Kilohertz (kHz), the Actuator PCBAs require fast and low-latency communications to the controller. This is accomplished with a custom differential Serial Peripheral Interface (SPI) driver, also developed for the purposes of this thesis. Position feedback for the mirror comes from 2 separate sources - a wavefront sensor positioned within the optical path, and an array of eddy current sensors which monitor the displacement of the back of the mirror. Testing and development of these eddy current sensors represents another area of effort in this thesis. During the course of this thesis, the project scope expanded to include an installation for the ASM at the 2.2-meter UH88 telescope at UH Hilo. This ASM has 208 actuators, and a new Actuator PCBA was specifically designed for it. This Rev 2 PCBA incorporates the eddy current sensors onto the Actuator PCBA and will be installed at the UH88 telescope to support their ASM development
Understanding the biophysical principles that drive efficient protein self-assembly
Full text linkThis dissertation explores the self-assembly and binding thermodynamics of macromolecular complexes, with a focus on proteins containing BAR domains, which play crucial roles in membrane binding and remodeling. In Chapter 1, we investigate the kinetics of self-assembly for diverse subunits, emphasizing how variation in subunit types can improve the efficiency and yield of self-assembly processes. By using mass-action kinetic models and automatic differentiation algorithms, we identify optimal protocols that avoid kinetic traps, either through internal design of rate constants or external control via subunit titration. These protocols offer valuable insights into achieving robust self-assembly, applicable to both synthetic and biological systems.
Chapter 2 examines the homodimerization of LSP1 BAR domain proteins in solution, using molecular dynamics (MD) simulations. By employing the MARTINI coarse-grained model and enhanced sampling techniques, we construct a free energy surface that characterizes the stability of dimerized ensembles. The results reveal a heterogeneous set of dimers, with a specific dimer aligning strongly with the membrane’s binding patches. This finding suggests a mechanism for preferential selection of specific dimers during membrane binding, providing a foundation for further studies on BAR domain protein interactions on membrane surfaces.
In Chapter 3, we extend the investigation to dimerization in two-dimensional (2D) environments, such as membrane surfaces. We show how configurational sampling in 2D can alter the free energy landscape of dimerization, comparing it with three-dimensional (3D) dimerization. Simulations of BAR domain proteins reveal that the membrane-bound state favors more enthalpically stable dimer configurations. This study underscores the evolutionary significance of membrane-bound dimerization for membrane remodeling, as it predicts more favorable dimer formation at physiological volume-to-surface-area ratios.
Overall, this dissertation offers valuable insights into protein self-assembly and dimerization, contributing to a deeper understanding of molecular mechanisms in biological and synthetic systems
DISSIPATIVE PARTICLE DYNAMICS MODELS OF PROTEIN, LIPID, AND NANOPARTICLE INTERACTIONS
No full textThe interaction between nanoparticles and biomolecules, particularly proteins, is a critical factor influencing the behavior and fate of nanoparticles in biological systems. Uncovering the mechanisms underlying these interactions is essential for the design of nanoparticles with desired functionalities in medical, environmental, and industrial applications. This thesis employs computational simulations, particularly Dissipative Particle Dynamics (DPD) and other coarse-grained models, to reveal the dynamics and structural characteristics of nanoparticle-biomolecule interactions. Theoretical insights assessing protein conformational changes upon adsorption have been validated by experiments, including circular dichroism (CD) spectroscopy, performed through collaboration. In addition, simulations of nanoparticle-protein and nanoparticle-lipid interactions in model environments of plant-based systems have revealed molecular scale mechanisms in ecological contexts. The integration of theoretical simulations with experimental validation offers a robust framework for predicting and controlling nanoparticle-biomolecule interactions, thereby enhancing the development of nanoparticle-based applications
BACTERIAL COMPOSITION AND FUNCTION OF BIOFILMS IN HUMAN COLORECTAL CANCER AND PAIRED NORMAL TISSUES FROM THE UNITED STATES AND MALAYSIA
No full textColonic biofilms (BF) are bacterial aggregates that invade the typically sterile inner mucus layer of the colon, adhere to colonic epithelial cells, and promote colorectal cancer (CRC), a leading cause of cancer death globally and in the United States (US). Importantly, BF may predate or co-evolve with polyps – abnormal colonic growths that are precancerous but increase one’s risk of cancer – in at least a subset of CRC cases. Therefore, determining whether an individual is biofilm positive (BF+) is critical for identifying those at an increased risk of developing CRC and for preventing disease onset and progression. BF are currently identified using a fluorescent in situ hybridization (FISH) universal 16S rRNA gene probe. However, this method requires invasive tissue sampling and is time-intensive, and is therefore not ideal as a clinical diagnostic tool. Furthermore, prior sequencing analyses suggest that most bacteria in BF+ and BF- tissues are similar and have not identified any bacteria that are unique to or predictive of BF. Additionally, the mechanisms by which BF contribute to tumorigenesis remain unclear. Identifying such bacteria and their functions could aid in the discovery of BF biomarkers and thus improve CRC detection and prevention efforts. This dissertation lays the groundwork for these advancements. We examine the bacterial composition and predicted functions of BF in CRC in globally diverse human cohorts using 16S rRNA amplicon sequencing, a targeted sequencing approach specific to bacteria. We show that BF+ and BF- tissues have distinct bacterial compositions and are predicted to differ in their functional profiles. Further, we identify Sutterella spp. as a candidate biomarker of BF+ tissues. Sutterella spp. was present in more BF+ than BF- tissues, had a significantly higher relative abundance in BF+ compared to BF- tissues, and, alone, showed good discriminatory ability for distinguishing BF status. We also demonstrate the importance of methodological choices like tissue fixation type, the removal of contaminants, and differential analysis methods on bacterial detection and relative abundance. We show that each of these choices impacts the observed bacterial composition, thus highlighting a need to normalize the extensive reporting of methods in microbiome studies
POLY(BETA-AMINO ESTER) NANOPARTICLES FOR CELLULAR REPROGRAMMING AND CANCER THERAPY
No full textGene delivery is a promising therapeutic strategy for treating a wide array of diseases, but improved reagents that can safely and effectively deliver genes to their target sites are needed. Viral gene delivery vectors, though clinically proven, come with a variety of risks and challenges, including insertional mutagenesis, immunogenicity, and expensive production. Nonviral approaches are attractive due to their improved biocompatibility, increased cargo capacity, and relative ease of manufacture. Poly(beta-amino esters) (PBAEs) are polymers that represent an exciting class of nonviral gene delivery vector. PBAEs complex with nucleic acids such as DNA, mRNA, siRNA, and miRNA through electrostatic interactions forming biodegradable nanoparticles. These nanoparticles can be used in the development of novel therapeutics and to aid in development and production of research tools.
The goal of this thesis is to develop and explore (PBAE)-based nanoparticles as safe and effective gene delivery vectors in a variety of contexts. The first aim of this thesis focuses on using PBAE nanoparticles as transfection reagents for recombinant protein production that demonstrate improved transfection efficacy compared to polyethyleneimine, as well as discovery and optimization of novel PBAE structures for improved gene delivery. The second aim applies an optimized PBAE nanoparticle for cancer cell reprogramming, explores various immunostimulatory plasmid combinations, and demonstrates the utility of PBAE nanoparticles for generation of systemic immune responses from local administration. The third aim explores therapeutic miRNA delivery to glioblastoma via lipophilic PBAE nanoparticles, which resulted in improved survival in a model of orthotopic glioblastoma. Together, this work advances PBAE-based technologies and gives insight into future clinical translation of therapeutic PBAE nanoparticles
A PROGRESS TOWARDS UNDERSTANDING THE IMPACT OF STRESS FACTORS ON MRNA LIPID NANO-PARTICLE CRITICAL QUALITY ATTRIBUTES
Full text linkThis study explored the impact of various stress factors on the critical quality attributes (CQAs) of messenger ribonucleic acid (mRNA) lipid nanoparticles (LNPs). Aiming to improve robustness and scalability of the manufacturing process, we evaluated mRNA-LNP product quality impact at the laboratory scale. Key unit operations included thawing, dilution, filtration, mixing/stirring, vialling, automated visual inspection, and freezing for long-term storage. By building representative scale-down models to mimic plant-scale unit operations, we analyzed key risk areas and knowledge gaps on methods, processes, equipment, materials, manufacturing environment, and sample handling. Focusing on quality attributes such as encapsulation efficiency (%EE), particle size, lipid concentration and purity, and nucleic acid concentration and purity, we investigated the impact of air-water interfacial shear stresses during mixing and automated visual inspection, and thermal stresses during long-term storage. This comprehensive approach allowed us to systematically identify and mitigate potential stress factors, filling critical gaps in process knowledge and providing deeper insights into how stress factors impact LNP CQAs, ultimately contributing to ongoing process monitoring and deviation support
PROCESS MODELING AND ITS APPLICATIONS IN THE MANUFACTURE OF ALLOGENEIC CELL THERAPIES
Full text linkCell therapies are a relatively novel innovation in medicine that allows for the treatment of diseases at their root cause. Allogeneic cell therapies, while not specifically targeted to each patient, present some advantages over their autologous counterparts. Due to their generalized nature, allogeneic cell therapies can be produced on a much larger scale. To this end, models can be used in the process of facility and process design to evaluate possible benefits and
shortcomings of various processes. We have developed a model that forecasts yields, costs, and material needs for various processes being considered for commercialization. Using the model, we compared three processes and their key changes to determine the magnitude of improvement and places where more could be done