1,031 research outputs found

    Simultaneous Multiparametric and Multidimensional Cardiovascular Magnetic Resonance Imaging

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    The 2023 wearable photoplethysmography roadmap

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    Photoplethysmography is a key sensing technology which is used in wearable devices such as smartwatches and fitness trackers. Currently, photoplethysmography sensors are used to monitor physiological parameters including heart rate and heart rhythm, and to track activities like sleep and exercise. Yet, wearable photoplethysmography has potential to provide much more information on health and wellbeing, which could inform clinical decision making. This Roadmap outlines directions for research and development to realise the full potential of wearable photoplethysmography. Experts discuss key topics within the areas of sensor design, signal processing, clinical applications, and research directions. Their perspectives provide valuable guidance to researchers developing wearable photoplethysmography technology

    Novel 129Xe Magnetic Resonance Imaging and Spectroscopy Measurements of Pulmonary Gas-Exchange

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    Gas-exchange is the primary function of the lungs and involves removing carbon dioxide from the body and exchanging it within the alveoli for inhaled oxygen. Several different pulmonary, cardiac and cardiovascular abnormalities have negative effects on pulmonary gas-exchange. Unfortunately, clinical tests do not always pinpoint the problem; sensitive and specific measurements are needed to probe the individual components participating in gas-exchange for a better understanding of pathophysiology, disease progression and response to therapy. In vivo Xenon-129 gas-exchange magnetic resonance imaging (129Xe gas-exchange MRI) has the potential to overcome these challenges. When participants inhale hyperpolarized 129Xe gas, it has different MR spectral properties as a gas, as it diffuses through the alveolar membrane and as it binds to red-blood-cells. 129Xe MR spectroscopy and imaging provides a way to tease out the different anatomic components of gas-exchange simultaneously and provides spatial information about where abnormalities may occur. In this thesis, I developed and applied 129Xe MR spectroscopy and imaging to measure gas-exchange in the lungs alongside other clinical and imaging measurements. I measured 129Xe gas-exchange in asymptomatic congenital heart disease and in prospective, controlled studies of long-COVID. I also developed mathematical tools to model 129Xe MR signals during acquisition and reconstruction. The insights gained from my work underscore the potential for 129Xe gas-exchange MRI biomarkers towards a better understanding of cardiopulmonary disease. My work also provides a way to generate a deeper imaging and physiologic understanding of gas-exchange in vivo in healthy participants and patients with chronic lung and heart disease

    Cerebrovascular dysfunction in cerebral small vessel disease

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    INTRODUCTION: Cerebral small vessel disease (SVD) is the cause of a quarter of all ischaemic strokes and is postulated to have a role in up to half of all dementias. SVD pathophysiology remains unclear but cerebrovascular dysfunction may be important. If confirmed many licensed medications have mechanisms of action targeting vascular function, potentially enabling new treatments via drug repurposing. Knowledge is limited however, as most studies assessing cerebrovascular dysfunction are small, single centre, single imaging modality studies due to the complexities in measuring cerebrovascular dysfunctions in humans. This thesis describes the development and application of imaging techniques measuring several cerebrovascular dysfunctions to investigate SVD pathophysiology and trial medications that may improve small blood vessel function in SVD. METHODS: Participants with minor ischaemic strokes were recruited to a series of studies utilising advanced MRI techniques to measure cerebrovascular dysfunction. Specifically MRI scans measured the ability of different tissues in the brain to change blood flow in response to breathing carbon dioxide (cerebrovascular reactivity; CVR) and the flow and pulsatility through the cerebral arteries, venous sinuses and CSF spaces. A single centre observational study optimised and established feasibility of the techniques and tested associations of cerebrovascular dysfunctions with clinical and imaging phenotypes. Then a randomised pilot clinical trial tested two medications’ (cilostazol and isosorbide mononitrate) ability to improve CVR and pulsatility over a period of eight weeks. The techniques were then expanded to include imaging of blood brain barrier permeability and utilised in multi-centre studies investigating cerebrovascular dysfunction in both sporadic and monogenetic SVDs. RESULTS: Imaging protocols were feasible, consistently being completed with usable data in over 85% of participants. After correcting for the effects of age, sex and systolic blood pressure, lower CVR was associated with higher white matter hyperintensity volume, Fazekas score and perivascular space counts. Lower CVR was associated with higher pulsatility of blood flow in the superior sagittal sinus and lower CSF flow stroke volume at the foramen magnum. Cilostazol and isosorbide mononitrate increased CVR in white matter. The CVR, intra-cranial flow and pulsatility techniques, alongside blood brain barrier permeability and microstructural integrity imaging were successfully employed in a multi-centre observational study. A clinical trial assessing the effects of drugs targeting blood pressure variability is nearing completion. DISCUSSION: Cerebrovascular dysfunction in SVD has been confirmed and may play a more direct role in disease pathogenesis than previously established risk factors. Advanced imaging measures assessing cerebrovascular dysfunction are feasible in multi-centre studies and trials. Identifying drugs that improve cerebrovascular dysfunction using these techniques may be useful in selecting candidates for definitive clinical trials which require large sample sizes and long follow up periods to show improvement against outcomes of stroke and dementia incidence and cognitive function

    Engineering of Second-Generation Acoustic Reporter Genes

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    A major outstanding challenge in the fields of biological research, synthetic biology, and cell-based medicine is visualizing the functions of natural and engineered cells noninvasively inside opaque organisms. Ultrasound imaging has the potential to address this challenge as a widely available technique with a tissue penetration of several centimeters and spatial resolution below 100 µm. Recently, the first genetically encoded acoustic reporters were developed based on bacterial gas vesicles (GVs) to link ultrasound signals to molecular and cellular function. However, the properties of these first-generation acoustic reporter genes (ARGs) resulted in limited sensitivity and specificity for imaging gene expression in vivo. The goal of my thesis work has been to engineer second-generation ARGs with improved acoustic and expression phenotypes compared to the existing first-generation constructs. I took two complementary engineering approaches to developing these constructs: homolog screening and directed evolution, sometimes referred to as the “nature and nurture” of protein engineering. The resulting constructs offer major qualitative and quantitative improvements, including much stronger ultrasound contrast, the ability to produce nonlinear signals distinguishable from background tissue in vivo, stable long-term expression, and compatibility with in vitro multiplexed imaging. In collaboration with others in the lab, we demonstrate the capabilities of these next-generation ARGs by imaging in situ gene expression in mouse models of breast cancer and tumor-homing therapeutic bacteria, noninvasively revealing the unique spatial distributions of tumor growth and colonization by therapeutic cells in living subjects and providing real-time guidance for interventions such as needle biopsies. This thesis is organized as follows: in the first two chapters, I introduce the key background needed to understand both the importance and properties of ARGS, and how they have been and could be engineered. In the next two chapters, I detail specific efforts to engineer them—one involving the construction of a high-throughput, semi-automated setup for acoustic phenotyping of cells and its application to ARG directed evolution, and another involving the screening of several GV cluster homologs to identify ones suitable for use as improved ARGs. Finally, I conclude with insights gleaned from these two ARG engineering projects and suggestions for future ones. The approaches, results, and ideas presented in this thesis represent the current state-of-the-art in ARG engineering and application. While recent technology development in this field has unlocked exciting new use cases for ARGs in noninvasive biological imaging, most of their potential for basic science and disease diagnosis and treatment has yet to be realized.</p

    The Role of Maternal Obesity and Consumption of a Western-style Diet on Offspring Brain Development and Behavior via an Inflammatory Mechanism

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    Currently almost 1 in every 3 women of childbearing age in the US are classified as obese. Consumption of a diet high in fats and sugars, such as the average American diet, is one of the largest predictors of increased levels of adiposity in an individual. Further, obesity is characterized in part by a low-grade chronic inflammatory state in peripheral circulation. Maternal obesity is a known risk factor for lasting impacts on neurobehavioral development in offspring. We therefore hypothesized that maternal consumption of a Western-Style diet and obesity-induced inflammation disrupts neurodevelopment of the serotonin system in the amygdala, increasing anxiety behaviors in non-human primate offspring. Indeed, our analyses suggest that maternal adiposity levels were associated with decreased offspring serotonin innervation in the amygdala which were associated with increased anxiety behaviors. Further, the number TPH2+ cells in the raphe nuclei, the site of serotonergic neuron cell bodies, were reduced in maternal WSD offspring. These finding suggested that maternal WSD and adiposity were associated with increased anxiety behavior in offspring through disrupting the development of the central serotonergic system during perinatal development.Further examinations of the mechanisms by which maternal WSD and obesity influence offspring neurobehavioral development suggest that obesity-induced inflammation is driving the observed perturbations in the serotonergic system. As the primary immune cell of the central nervous system, microglia play an integral role throughout perinatal neurodevelopment. Quantifying microglial number and morphology in the offspring amygdala suggested that maternal WSD and adiposity levels influenced microglia function throughout both pre and postnatal development. Specifically, maternal WSD appeared to elicit persistent effects on offspring microglia number while levels of adiposity appeared to have a more transient effect in prenatal development. These findings suggest that maternal WSD and obesity may elicit their effects on offspring neurobehavioral development through modulation of microglia during perinatal development. This dissertation includes previously published and co-authored material

    Numerical approach for the evaluation of hemodynamic behaviour in peripheral arterial disease : A systematic review

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    Reduced blood flow to the lower extremities causes peripheral arterial disease (PAD), which is caused by atherosclerotic plaque in the arterial wall. If this impairment is not treated, it will result in severe vascular diseases like ulceration and gangrene. Previous research has shown that while evaluating the pathology of the peripheral artery, the assumption of the model geometry significantly impacts the uncertainty of the stenosis area. However, more work needs to be done to understand the interaction between mechanical better and flow conditions in the peripheral artery using a separate computer model of the cardiovascular system. This paper reviews the numerical approach on pre and post-treatment of hemodynamic behavior in peripheral arterial disease (PAD). The goal of this study was to thoroughly examine the most recent developments with the application of computational studies in PAD from 2017 to 2022. While FSI investigation highlights the behavior of both the fluid and structure domains (blood and artery) during the numerical analysis of blood flow, CFD simulations primarily focus on the fluid domain (blood) behavior. Out of 92 research publications, 19 were appropriate for this assignment. This thorough study divides the publications into the categories of CFD, and FSI approaches. The results were then reviewed in accordance with the wall characteristic, analytical method, geometry, viscosity models, and validation. This paper summarizes the parameters of geometrical construction, viscosity models, analysis methods, and wall characteristics taken into consideration by the researchers to identify and simulate the blood flood flow in the stenosis area. These parameters are summarised in this study. Additionally, it could offer systematic data to help future studies produce better computational analyse
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