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Cerebrospinal fluid draining lymphatics in health and disease: advances and controversies
Get PDFThe meninges, consisting of the dura, arachnoid and pia mater that surround the brain and spinal cord, have been recognized from the earliest anatomical studies. First identified in 1787, lymphatic vessels in the dura are now receiving greater attention as their contribution to cerebrospinal fluid (CSF) clearance in diverse neurological conditions is being investigated. New methods have increased the understanding of dural lymphatics, but much is still being learned about their heterogeneity, intracranial and extracranial connections, and factors that govern their functions and maintenance. Current research is striving to understand the regulation of CSF drainage and influence of brain antigen and immune cell transit through dural lymphatics on aging impairments and the severity of neurodegenerative and neuroimmune diseases, traumatic brain injury, stroke and other neurological disorders. Achieving these goals should lead to safe and effective methods for manipulating CSF clearance through dural lymphatics for therapeutic benefit
Multiscale impacts of urbanization and avian pathogens on a songbird
Get PDFAs the world changes, we are confronted with unexpected challenges which require unique, potentially unorthodox solutions. This framework defines my research into urban birds and their parasites. Urbanization is a powerful force that changes local environments and has direct impacts on wildlife, including the biology and community composition of birds. We examine how urbanization affects the body feathers of Dark-eyed Juncos (Junco hyemalis). In this case, the indirect effects of urbanization, specifically urban heat island effects, have a subtle but measurable effect on feather structures. Subtle effects are also reflected in the parasites of the juncos. I then examine how the bloodborne parasites of Junco hyemalis change across a broad urbanization gradient and due to local vegetation characteristics. While urbanization excludes host-specific parasites, cities are still faced with the consistent presence of generalist parasites. Considering the persistence of these parasites, we are then tasked with the goal of understanding whether these generalists represent a concern, and therefore, will require a solution. The gut microbiome is one aspect that may be affected by parasitic infections. By characterizing and quantifying changes in the microbiome of birds infected with the malaria parasite (Plasmodium relictum GRW04), we can determine whether the host microbiome is subject to infections or contribute to host immunity. My research, supported by independent studies, suggests that select bacteria are depleted by malaria, potentially harming the host. At an even smaller scale, epigenetic changes, that can define gene expression and host plasticity, may also be impacted in infected hosts. By measuring changes in DNA methylation, we can see whether this epigenetic marker is altered by infections. DNA methylation is highly variable, but we again find specific markers associated with infections. Though still preliminary, these markers, much like the bacteria impacted by infections, represent targets for future experimental studies to develop mitigation strategies. Avian diseases, like many other challenges in the world, are complex, highly variable and lack a simple solution. The research conducted in my dissertation highlights some of this complexity and presents two unique aspects of host biology that may contribute to future disease mitigation efforts
Assessing Feasibility of an Implanted Knee Brace for ACL Injury Prevention Using Robotic Cadaveric Motion Replay
No full textAnterior cruciate ligament (ACL) injury has become a public epidemic in sports medicine, with disproportionately high rates among women and limited effective prevention strategies. This dissertation presents a novel surgically implanted knee brace intended to prevent ACL rupture by engaging only in high-risk scenarios while remaining slack during normal activity. The ultimate objective of this work was to demonstrate the feasibility of such a device, identifying optimal anatomical insertion points.To achieve this, a subject-specific, kinematically clamped robotic system was developed as an testing platform. The system has the ability to reproduce high-fidelity bone kinematics — including injury scenarios — on cadaveric specimens with precise control and repeatability. Motion trajectories were derived from motion capture data and applied using subject-specific anatomical coordinate systems built around each specimens’ natural knee flexion axis to ensure physiologically accurate loading.The first phase of this work validated the robotic platform by reproducing both non-injurious and a clinically relevant ACL rupture from sex-specific kinematic data, confirming its utility for injury mechanism research. The second phase employed motion capture to understand sub-injurious bone kinematics during high load on the contralateral limb. Extrapolated kinematics were then used and enabled a systematic evaluation of candidate implant insertion points, with the optimal location identified as the pair that maximized separation between injury and non-injury motions — providing protective engagement before ligament failure.By combining a high-precision robotic testing platform with targeted implant design, this work establishes a reproducible, ethically viable pathway for developing and refining preventative knee devices. Beyond advancing ACL injury mechanism research, these findings highlight the potential for engineered, sex-specific interventions to reduce injury incidence in at-risk populations
Supporting Children with Communication Disabilities through Family-Centered Practices
No full textChildren with communication disabilities experience significant disparities in health and access to services (Morris, 2023). Health outcomes are also linked to individual, community, and sociocultural characteristics through complex interactions (Bronfenbrenner, 1994; Stransky et al., 2018). Studies included in this dissertation demonstrate the application of systems theories and practical integrative health frameworks, such as family-centered practice, across three distinct studies: a high-quality, rigorous intervention context for non-autistic children with speech sound disorder; a comprehensive assessment for a complex case study of a minimally speaking autistic adolescent; and a larger single-case study of assessment procedures for autistic children with and without language concerns. Leveraging the characteristics of a systems-based model in support of individuals with unique language and communication profiles, this research examines the application of specific family-centered practices, such as adapting treatment within an evidence based practice framework, integrating of client and family perspectives and caregiver-reported measures in assessment, and evaluating the ecological validity of assessment findings. The three studies included in this dissertation effectively demonstrate how family-centered clinical practices promote holistic care and effective clinical decision-making, thus improving services and overall outcomes for children and youth with communication disabilities
An Exploration of Tau in the Absence of Amyloid and its Relevance to the Alzheimer's Disease Continuum
Get PDFRationale: Biomarker frameworks for Alzheimer’s disease (AD) purport that amyloid is the primary pathologic driver of disease progression, with tau regarded as a secondary process. Indeed, the presence of tau in the absence of amyloid (A-/T+) has been labeled as non-AD pathologic change. These four studies examine the role of tau independent of amyloid on cognitive outcomes in preclinical AD. Design: All studies used positron emission tomography (PET) and neuropsychological data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) among older adults across the clinical continuum. Aim 1 involved a systematic literature review and empirical investigation of tau PET positivity cut-points using receiver operating characteristics and t-tests. Aim 2 examined cognitive profiles of the A-/T+ biomarker group relative to other biomarker groups (e.g., A-/T-, A+/T-, A+/T+) using ANCOVAs. Aim 3 assessed longitudinal cognitive trajectories of the A-/T+ group using linear mixed effects models. Aim 4 explored the moderating effect of apolipoprotein E (APOE) genetic risk on associations of amyloid and tau PET with cognition using multiple linear regression. Results: The systematic literature review revealed heterogeneity in methods used to derive tau PET cut-points, and our empirical follow-up identified the method that best differentiated tau PET positive and negative individuals (Aim 1). The A-/T+ group demonstrated cognitive performance cross-sectionally (Aim 2) and longitudinally (Aim 3) that fell between the biomarker normal (A-/T-) and AD biomarker (A+/T+) groups. Examining the PET variables continuously (Aim 4), only tau was associated with cognition and moderated by APOE 4 genetic risk for memory outcomes. Conclusions: Tau influences cognitive outcomes independent of amyloid, and the A-/T+ biomarker profile may be considered part of the Alzheimer’s continuum rather than a non-AD pathologic process given poorer cognitive performance relative to the biomarker normal group. The derivation of tau PET cut-points may influence the identification of A- /T+ individuals, and methods used should reflect the research question of interest. Importantly, despite the exclusion of A-/T+ individuals from many research studies and clinical trials, our studies highlight the need for further characterization of this group and suggests that tau may offer a promising treatment target even in the context of amyloid negativity
Mesozooplankton trophic structure in the Argo Basin, Northwest Australia
Get PDFWe used stable isotope analysis (SIA) and compound-specific isotope analysis of amino acids (CSIA-AA) to assess trophic positions (TP) of five zooplankton size fractions (0.1–5 mm) in the Southern Bluefin Tuna spawning region off northwest Australia. SIA was also used to assess relative trophic structure of nine zooplankton taxa. Size-fractioned SIA gave unrealistic TP ranges and large site variability. In contrast, SIA of taxonomic groups and size-fractioned CSIA-AA showed broadly similar TP ranges and relatively low site variability. Both indicated a TP range of less than one full trophic step. An additional size-variable component of 0 to 0.7 trophic steps was estimated for protistan consumers based on δ15N enrichment differences between trophic amino acids alanine and glutamic acid. Appendicularians had low TP, indicating direct feeding on primary producers. A similar low TP of Oncaea spp. as well as lower-than-expected δ15N enrichment of taxa with carnivorous tendencies (Corycaeus and Lucifer spp.) suggest that discarded appendicularian houses with remnant filter-concentrated phytoplankton are broadly used as a dietary supplement within the zooplankton assemblage. Overall, our results indicate a compressed and efficient food web in which appendicularians play a central role in linking picophytoplankton-dominated productivity to tuna larvae, and where trophic steps for protistan grazers are mainly intermediate to >0.5 mm zooplankton size classes
Time Constant Estimation on a Low-Cost, Low-Power Microcontroller Using the Matrix Pencil Method
Get PDFAn algorithm to accurately determine the time constant of a circuit simplifies reading out resistive and capacitive sensors. However, implementing such an algorithm on low-cost, low-power microcontrollers requires overcoming hardware limitations, such as analog-to-digital converter (ADC) noise, limited memory, and the lack of a floating-point unit. This work utilizes the matrix pencil method to estimate the time constant of a decaying exponential signal and outlines the nontrivial firmware implementation of the algorithm on a low-cost, low-power microcontroller. Experimental results show that time constants over more than two orders of magnitude can be accurately estimated to be within around 2% of the nominal value with a standard error of about 0.2% of the nominal value, despite the hardware limitations. This is a significant improvement over previous methods for accurately determining the time constant of a circuit using subpar hardware
Real-world clinical utility of a multi-protein, blood-based biomarker assay for disease activity assessments in multiple sclerosis
Get PDFBackgroundBlood-based biomarkers have emerged as promising tools to optimize treatment decisions in multiple sclerosis (MS) including initiation, switch, or cessation of disease modifying therapies.ObjectivesThe clinically validated MS disease activity (MSDA) test measures 18 proteins to derive a disease activity score. This study tests the clinical utility of MSDA in real-world practice.MethodsTwenty clinicians from 14 clinics conducted a chart review utilizing a retrospective, longitudinal design, with a pre-post component. Chart reviews captured clinician decision-making before and after receipt of each MSDA result, while separate clinician assessments also captured the perceived impact of MSDA on MS management.ResultsA total of 352 charts were reviewed. The overall rate of clinical decision changes after MSDA testing (19.4%) exceeded predefined benchmarks. The proportion of patient time points where clinicians "strongly agreed" or "agreed" that MSDA results influenced their decision-making was greater when multiple longitudinal MSDA results were available compared to a single result: 69.2% (95%CI: [60.2%, 78.3%) vs. 59.8% (95%CI: [43.7%, 76.0%]), respectively.ConclusionWhen used in addition to standard of care, MSDA demonstrates clinical utility for real-world decision-making in MS management, based on objective changes in treatment plan and clinician-reported impact, which increases with longitudinal use