The wide band gap semiconductor Cadmium Zinc Telluride (CZT) is of recent interest for medical imaging at room temperature. A number of properties, including superior energy resolution, 3D photon position sensitivity, compact size, direct photon conversion and energy-resolving capability, make CZT a promising candidate for positron emission tomography (PET) and photon-counting X-ray imaging systems. Despite these advantages, drawbacks, such as low mobility of holes, hole trapping, charge sharing effect and characteristic X-ray escape degrade the performance of large volume CZT detectors. In this research, characterization and evaluation of single-crystal CZT photon detector using simulation and experimental studies were done. First, a comprehensive analytical model was developed and implemented by using Monte Carlo simulation and finite element analyses. This model includes the generation and transportation of charge carries within CZT detectors, and it provides useful guidance in optimizing the electrode design and associated readout circuits. Second, the performance of a 20×20×5mm3 CZT crystal with 8×8 pixel anodes and a planar cathode was integrated with readout electronics that can be used to build a PET system was studied. The experiments demonstrate an energy resolution of ~2.26±0.84% full width half maximum (FWHM) at 662 keV and 19±3 ns coincidence time resolution with planar parallel field configuration. A novel algorithm based on charge sharing effect and transient signal analysis targeting the improvement of spatial resolution, was proposed. The sub-pitch spatial resolution is found to be ~30 µm and ~250 µm under signal-to-noise ratio of ~17, for inside and outside the valid range of charge sharing, respectively. Finally, the feasibility of CZT in photon-counting Computed Tomography (CT) was studied by using monoenergetic sources, with a special attention paid to energy degradation due to characteristic X-ray escape and the charge sharing effect. The effects of detector configuration and incident beam location were also investigated. The results show that the pixel size can be reduced to 500 µm without significant count loss (~5%) and charge loss (~15%) for the photo-counting X-ray applications. / Thesis / Doctor of Philosophy (PhD)

The repair of damaged or diseased bone tissue often requires the use of metallic implants which form an interface with the surrounding bone tissue. Understanding this interface is important for improving the outcomes of implant placement and overall health of patients. Bone is a composite material of organic collagen fibrils and inorganic mineral phases that have structural variations across multiple length scales. This heterogeneous and hierarchical nature poses characterization challenges for (i) understanding bone, (ii) creating biomaterial structures that mimic it, and (iii) approaches for evaluating biomaterials. These challenges formed the basis for the three papers presented in this thesis. In Chapter 3, leporine bone was examined using atom probe tomography (APT) to visualize in vivo mineralized collagen fibrils, their chemical composition, and spatial arrangement in 3D with sub-nanometer accuracy. This provided new insight into the location of biomineral with respect to collagen and demonstrated the power of APT for understanding collagen-mineral arrangement. In Chapter 4, commercially pure titanium was laser ablated to generate periodic surface structures inspired by the periodicity of collagen. Three different periodicities were generated with submicron-scale roughness and a high degree of reproducibility. All the surfaces were non-cytotoxic and encouraged cells to adhere perpendicular to the orientation of the surface structures. In Chapter 5, a simple five-minute room temperature ionic liquid treatment was developed to investigate the same laser-ablated titanium periodic structures with osteoblast-like cells adhered. The development of this technique fulfills an important niche in biological imaging by allowing for simultaneous and repeated visualization of submicron surface features and wet cells. Therefore, the combined impact of this thesis is novel imaging and biomaterials evaluation strategies to (i) improve understanding of bone structure; (ii) leading to bioinspired biomaterials design; and (iii) new methods for simultaneous biological and biomaterials evaluation. / Thesis / Doctor of Philosophy (PhD) / Bone implant devices are required to treat, augment, or replace bone tissue in dental and orthopaedic applications. These, often metallic, implanted devices have success when a structural and functional connection with natural bone tissue is created, a phenomenon known as osseointegration. Good osseointegration is required to ensure stability of the implant without compromising the quality of life of the patient. In order to improve osseointegration of biomaterials, both sides of the interface, i.e. the bone and implant surface, must be better understood. This thesis focuses on exploring methods to improve the evaluation and understanding of both bone structure at the nanoscale and structured metallic implant surfaces for the design of bone-interfacing biomaterials.

No description available.

Myxomatous mitral valve disease (MMVD) is the most common heart disease in dogs. However, prospectively acquired data describing the natural history and prognostic factors in a large population of dogs affected by this disease are sparse. Thus, the Longitudinal Outcome of canine (K9) myxomatous mitral valve disease registry (LOOKmitral) was established to prospectively collect clinical and diagnostic data from a large population of dogs affected by MMVD. A total of 6,102 dogs were enrolled in the LOOK-mitral registry from November 1st, 2015, to October 31st, 2018, in thirteen cardiology specialty practices. We first described the baseline characteristics of the dogs enrolled in the registry, which mainly confirmed previous findings. Moreover, we provided new additional results, such as the presence of systolic dysfunction in some small breed dogs and how the intensity of the murmur correlates with the severity of MMVD also in large breed dogs. Second, we described the baseline treatment characteristics at the time of enrollment. These data showed that the results of the "Effect of Pimobendan in Dogs with Preclinical Myxomatous Mitral Valve Disease and Cardiomegaly" (EPIC) trial and left atrial and left ventricular dimensions, assessed by echocardiography, influenced veterinary cardiologist's prescription of cardiovascular drugs in affected dogs. Lastly, we evaluated predictors of reoccurrence of congestive signs within 180 days after successfully treating the first episodes of heart failure in dogs enrolled in the LOOKMitral registry. While this study failed to identify accurate predictors of recurrence, dogs with larger left ventricular internal dimensions at end-diastole were more likely to present with reoccurrence of clinical signs suggesting that closer monitoring of these dogs may be recommended. / Doctor of Philosophy / Despite being the most common heart disease in dogs, data on a large group of dogs affected by myxomatous mitral valve disease (MMVD) are currently sparse in veterinary medicine. The Longitudinal Outcome Of canine (K9) Mitral valve disease (LOOK-Mitral) was established in 2015 to collect data on a large population of dogs affected by MMVD. A total of 6,102 dogs were enrolled in thirteen referral centers over three years. First, the baseline characteristics of dogs enrolled in the registry were described. These data mainly confirmed previous findings. Moreover, they provided some new insight like the possible presence of contractile dysfunction in some small breed dogs and the correlation between the intensity of the heart murmur and the severity of the disease also in large breed dogs. Second, we described the medical treatment prescribed or modified by veterinary cardiologists at the enrollment visit. These data showed that the "Effect of Pimobendan in Dogs with Preclinical Myxomatous Mitral Valve Disease and Cardiomegaly" (EPIC) trial, a clinical trial published during the enrollment period, and the heart ultrasound (echocardiography) data influence cardiologist prescription habits. Lastly, we evaluated if any clinical or echocardiographic variable could predict the reoccurrence of clinical signs of heart failure within 180 days from the first manifestation of those clinical signs in dogs enrolled in the LOOK-Mitral registry. While this study failed to accurately identify predictors of reoccurrence, dogs with larger left ventricular chamber sizes were more likely to present reoccurrence of clinical signs suggesting that closer monitoring of these dogs may be recommended.

INTRODUCTION: Despite the use of modern minimally invasive surgical techniques, post-operative complications following lung cancer resection remain common and challenging to predict. Pulmonary ventilation imaging modalities offer detailed regional assessment of airflow obstruction and are highly sensitive to subclinical airway and/or parenchymal disease. Nevertheless, ventilation imaging is seldom integrated into pre-operative lung function assessment and risk stratification procedures. Therefore, the objective of this thesis was to quantify the burden of ventilation defects observed by Technegas SPECT and 129Xe MRI before lung cancer resection and establish their association with the occurrence and clinical impact of post-operative complications. METHODS: Patients undergoing lung cancer resection at St. Joseph’s Healthcare Hamilton were recruited into a prospective, proof-of-concept, six-week observational study. Participants were evaluated prior to resection surgery to document baseline demographics and clinical characteristics, performed standard pulmonary function tests and sputum induction, and underwent Technegas SPECT and 129Xe MRI to assess ventilation. Abnormal ventilation was quantified as the ventilation defect percent (VDP) and was considered abnormal if VDP was ≥mean+2 standard deviations of a healthy population. Following surgery, participants were followed for 4 weeks to document the incidence of post-operative complications, as specified by the Ottawa TM&M categorization system, and the length of hospital stay. RESULTS: One hundred and twenty-three participants were enrolled, of whom 103 were evaluated pre-operatively and followed for post-operative outcomes. Of the 103 participants (69±8 years, 58% female), 89% (92/103) underwent minimally invasive surgery, and 74% (76/103) underwent lobectomy. Abnormal ventilation was observed pre-operatively by Technegas SPECT and 129Xe MRI for 59% (58/99) and 84% (82/98) of participants, respectively. In a subset of 69 participants in whom sputum was collected, 51% (35/69) had intraluminal inflammation. A total of 64 post-operative complications occurred; 16 (25%) were pulmonary, and 48 (75%) were pleural complications. A post-operative complication occurred in 42% (41/103) of participants. Pre-operative Technegas SPECT and 129Xe MRI VDP were higher for participants with post-operative complications compared to those without (Technegas SPECT: 26±17% vs 19±7%, p=0.02; 129Xe MRI: 13±12% vs 7±6% p=0.003) and were positively correlated with post-operative length of hospital stay (Technegas SPECT: r=0.43, p<0.0001; 129Xe MRI: r=0.49, p<0.0001). Multivariable regression models revealed that preoperative Technegas SPECT and 129Xe MRI VDP were predictors of post-operative complications (Technegas SPECT: Odds ratio=1.08, p=0.005; 129Xe MRI: Odds ratio=1.16, p=0.002) and post-operative length of hospital stay (Technegas SPECT: unstandardized β=0.13, p<0.001; 129Xe MRI: unstandardized β=0.24, p<0.001). CONCLUSIONS: Abnormal ventilation, quantified by Technegas SPECT and 129Xe MRI VDP, is prevalent prior to lung cancer resection and a predictor of post-operative complications and length of hospital stay. / Thesis / Master of Science (MSc) / Post-operative complications are frequent adverse events following lung cancer resection, resulting in substantial patient morbidity and mortality that have a significant clinical and economic impact. Despite this, post-operative complications remain inadequately predicted, and limited research has been dedicated to reducing the risk of pulmonary complications after lung cancer resection. Standard clinical screening tools, such as pulmonary function tests, are used for patient selection in lung cancer resection surgery; however, they provide a global estimate of a complex multicompartment organ and may lack the sensitivity to detect subclinical lung pathology that influences post-operative outcomes. Thus, using high-resolution medical imaging modalities such as single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI), we investigated the prevalence and clinical relevance of abnormal ventilation, a functional consequence of airway and/or parenchymal disease. One hundred and three participants were enrolled in a six-week prospective, proof-of-concept observational study. Participants performed pre-operative imaging and were followed for four weeks post-operatively to document post-operative complications and relevant clinical outcomes. Pre-operative SPECT and MRI revealed a high prevalence of abnormal ventilation. The pre-operative ventilation defect burden was greater in participants who developed one or more complications during the four-week post-operative period and was an independent predictor of both the incidence of post-operative complications and the length of hospital stay. These observations provide proof-of-concept evidence that abnormal ventilation, assessed by two ventilation imaging modalities, is prevalent and clinically relevant prior to lung cancer resection. Taken together, this thesis establishes that ventilation imaging may have implications for risk stratification and risk modification in patients scheduled to undergo lung cancer resection.

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Yes / The structural features required for mitochondrial uptake of BODIPY-based optical imaging agents have been explored. The first derivatives of this class of dyes shown to have mitochondrial membrane potential-dependent uptake in both cancer and heart cells have been developed. / Daisy Appeal Charity (Grant: DAhul0211), the University of Hull scholarship, Newcastle University, EPSRC and High Force Research Ltd, EPSRC Fellowship (EP/G005206/1)

Myxomatous mitral valve degeneration (MMVD) is the most common canine cardiac disease. In the studies presented in this dissertation, we used advanced echocardiographic techniques to elucidate several aspects of MMVD in dogs. Our hypothesis was that the mitral valve (MV) morphology could have a role in the development of MMVD. First, we tested whether we could use real time three-dimensional transthoracic echocardiography (RT-3DTTE), and an offline software for MV analysis to evaluate canine MV. We described that the technique was feasible and repeatable, we evaluated the morphology of the MV in healthy dogs, and we provided reference values for MV morphologic variables in this species. Then, we used the same technique to compare healthy dogs to dogs affected by MMVD. We found that dogs affected by MMVD have more circular and flatter valve. We then analyzed the MV of healthy Cavalier King Charles Spaniels (CKCSs), given the high predisposition of this breed for MMVD. Our findings indicate that compared to healthy dogs of other breeds, the MV of healthy CKCSs is flatter and has less leaflet tenting, corroborating our hypothesis that an altered MV morphology could represent a predisposing factor for disease development. We also used RT–3DTTE to characterize the area of the regurgitant MV orifice of dogs affected with MMVD, finding that the technique requires further standardization in order to become clinically useful. The elevation of pulmonary venous pressure caused by MMVD can, in some dogs, cause pulmonary arterial hypertension (PH), which is a risk factor associated with worse outcome in dogs with MMVD. Diagnosis of PH in dogs with MMVD is usually made by estimating pulmonary pressure using Doppler echocardiography. We are currently evaluating the accuracy of this technique, compared to invasive measurement of pulmonary pressure. Only preliminary data are presented regarding this study, as the disclosure of the blinding would have infringed the power of the study. Our preliminary results demonstrate that there is only moderate agreement between the two techniques, indicating that caution should be used when deriving the non-invasive estimation of systolic pulmonary pressure in order to make clinical decisions. / Ph. D. / The studies collected in this dissertation focus on myxomatous mitral valve disease (MMVD), which is the most common heart disease in dogs, and the most common cause of cardiac-related death in this species. This disease mainly affects one of the heart valves, i.e. the mitral valve (MV), impeding its normal functionality. In the studies presented in this dissertation, we used advanced non-invasive ultrasonographic techniques to investigate the mechanisms involved in this disease. We hypothesized that a different shape of the MV in some dogs could contribute to the development of the disease. We used 3D ultrasounds to build models of the MV and analyze the shape of it. We first demonstrated that using this technique in dogs was feasible and repeatable, and that the MV of normal dogs was elliptical and saddle-shaped. We then compared the shape of the MV of normal dogs, to the shape of the MV of dogs affected with MMVD. We found that dogs with the disease have a MV that is flatter and more circular. In our next study, we examined the shape of the MV of a breed of dogs that is predisposed to develop MMVD: Cavalier King Charles Spaniels (CKCSs). Our study found that healthy CKCSs have an overall flatter MV when compared with the other breeds, and that the normal MV of CKCSs is similar to the MV of affected dogs of other breeds. This finding support our hypothesis that an abnormal shape of the MV could contribute to the development of the disease. In another study, we saw to evaluate whether we could use 3D ultrasounds for investigating the shape of the hole that creates on affected MV. We concluded that this technique still requires more standardization before being used for evaluation of dogs. In another study, of which some preliminary results are presented in this dissertation, we are testing how accurate it is to evaluate the pressure of the pulmonary artery using ultrasonography. We are doing this by comparing this technique to a direct measurement of the pressures with a catheter in the pulmonary artery. We found that measurements obtained with the two techniques do not agree very well, which most likely indicates the evaluation of the pulmonary artery pressure using ultrasonography requires caution.

In this dissertation, I present novel optical tools for studying the uptake and release of serotonin in living brain tissue. These optical tools include small molecules that act as either substrates or antagonists of the serotonin transporter (SERT) and genetically encoded biosensors that work orthogonally to these small molecules to detect the release of endogenous serotonin in living brain tissue. Together, these optical methods comprise an imaging platform to study the uptake and release of serotonin in living brain tissue. One small molecule, SERTlight, has been employed to characterize the synaptic reuptake inhibitor (SynRI) properties of 12-methoxyibogamine (ibogaine) and its metabolites. Both in isolation and in complex with one another, these tools constitute new techniques for studying the uptake and release of serotonin in living brain tissue with improved spatial resolution, temporal resolution, and ease of use compared to previously established methods. It is the sincere hope of the Sames and Sulzer Laboratories that these tools will enable and inspire future generations of neuroscientists to study the serotonin system at synaptic resolution with the goal to better understand serotonin action in both normal and diseased states.

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