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A research report submitted in fulfilment of the requirement for the degree Masters in Medicine in Surgery to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 2019 / Background: Phyllodes tumours are rare fibroepithelial neoplasms of the breast. The dilemma with phyllodes tumours is their tendency to local recurrence. This retrospective review of phyllodes tumours in a South African population aims to describe the most common histological and clinical features, and describe the clinical and histological risk factors for local recurrence. Methods: All histological reports of patients diagnosed with a phyllodes tumour after surgery at the University of the Witwatersrand Anatomical Pathology Laboratories in Johannesburg were assessed from 1 January 2005 to 30 June 2016. Clinical and histological parameters were analysed. Results: Over the study period, 185 patients were identified. The median age of the patients was 42 years. There were 89 (48.1%) patients with a benign tumour, 34 (18.4%) with a borderline tumour and 62 (33.5%) with a malignant tumour. The size of the tumours ranged from 11 to 460mm, with a median of 85.0mm  79.6 SD. Breast conserving surgery (BCS) was performed on 64.3% of patients and 35.7% of patients had a mastectomy. There was an overall local recurrence rate of 3.78% (2.2% for benign and 8.1% for malignant tumours). No clinical or histological factors, including margin status, were found to significantly predict local recurrence. Most recurrences (71.4%, n=5) occurred within the first two years. Conclusion: Our study did not find any predictors of local recurrence, but we provide further support to the recent suggestion of revising the common practice of wide local excision with a 1cm margin, to an excision with negative margins combined with close follow-up for two years. / TL (2020)

Magnetic fields pervade the universe, spanning a multitude of scales from the dipolar field on Earth, to the largest gravitationally bound structures such as galaxy clusters [1]. The magnetic fields play a vital role in the evolution of these astronomical systems. In addition to the multitude of scales, magnetic fields are present in different astronomical systems of varying strengths. The strongest observed astronomical magnetic fields are in neutron stars with a field strength of ≈ 1015 G [2], far higher than any man-made fields till date. In stark contrast magnetic fields in the interstellar medium while ubiquitous are only a few µG in field strength. Many fundamental processes in astrophysics have magnetism at their heart, be it cosmic ray particle acceleration, star formation, or the launch of radio galaxy jets, pulsars, etc. One key fundamental process that allows us to detect and characterize cosmic magnetic fields with radio astronomy is the polarization of synchrotron radiation. Synchrotron radiation is intrinsically polarized broadband continuum radiation emitted by relativistic charged particles accelerated by the presence of magnetic fields. The emissivity of the synchrotron radiation is tied to the magnetic field strength B and the spectral index α (defined such that the flux density S ∝ ν −α ) such that ε ∝ B 1+α .

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Digital holography is a method for recording holograms through the use of an optoelectronic sensor, which serves as a replacement for the use of film [1]. Through the use of coherent light, the microparticles’s characterization can be observed with this method. Yet even using partially coherent light, images of particles can be formed revealing particle shape and size at scales larger than 10 micrometers. For example, ragweed pollen sporeclusters and glass microspheres are investigated here. The holographic images results are compared with conventional optical microscope images for validation.

Introduction: Substance use disorders are often associated with widespread structural and functional abnormalities in the brain. The primary aim of this thesis was to reduce existing ambiguity and explore novel topics in the field of addictions neuroscience by conducting three human neuroimaging studies. Results: In the first study, individuals who used alcohol were found to have significant inverse associations between drinks in past week, frequency of heavy drinking, and cortical thickness in a majority of regions examined via MRI. These regions included the dorsolateral prefrontal cortex, the inferior frontal gyrus, and the precentral gyrus. In the second study, when we employed a novel MRI pulse sequence to examine intracortical myelin (ICM) in people with alcohol use disorder, we found that the alcohol use disorder group in fact had greater ICM signal than the control participants, leading us to hypothesize a potential inflammation response in the brain from the prolonged use of alcohol. Finally, in the third study, when we explored large-scale brain activity in a sample of people who use alcohol alone or in combination with other substances, we found that those who used three or more substances displayed the least amount of activation in the salience and temporal networks of the brain. A peculiar finding, however, was that dual users of alcohol and cannabis were found to have the most activation in these networks. Conclusions: Results demonstrate that, indeed, alcohol use is associated with structural and functional abnormalities in the brain. These studies have demonstrated cortical thinning and increased ICM signal in relation to alcohol use broadly. As well, this work has shown that polysubstance use is associated with alterations in various large-scale resting state brain networks. Future research should seek to conduct longitudinal work in order to clarify whether structural and functional brain abnormalities are a cause or a consequence of substance use. / Thesis / Doctor of Philosophy (PhD) / The aim of this thesis was to add to the existing literature surrounding neuroimaging in alcohol use disorder. First, we sought to expand the structural neuroimaging literature by conducting a study with a large sample size and examining the cortical thickness of a variety of brain regions in relation to characteristics of alcohol use. Second, we aimed to add to the structural neuroimaging literature again by examining a particular brain tissue in chronic alcohol users via a novel MRI pulse sequence. Finally, we sought to add to the functional neuroimaging literature by examining large-scale resting state brain networks in a sample of people who use alcohol alone or in combination with tobacco or other drugs (i.e., polysubstance users). Together, these studies have contributed new findings to the addictions neuroscience literature by revealing anatomical and functional brain correlates of alcohol and other substance misuse.

Infectious diseases represent one of the leading causes of death globally. Prompt diagnosis is essential for the onset of clinical treatment but certain cases of underlying bacterial infection deep in the body can remain undiagnosed for weeks. Hidden bacterial infection is the leading cause of fever of unknown origin (FUO), which is observed in 2 % of all hospital admissions around the world. Molecular imaging of bacterial infections is the ideal non-invasive diagnostic tool, but all available probes also detect inflammation. Two targets were selected for development of bacteria-specific molecular imaging probes, namely iron-uptake pathways and peptidoglycans involved in the synthesis of the cell wall. Both, Gram-positive and Gram-negative bacteria use iron-binding molecules called siderophores to scavenge iron from their surroundings. The structural similarities between Fe3+ and Ga3+ allow siderophores to be radiolabelled with 67/68Ga and visualized by nuclear medicine techniques. The clinically proven siderophore Deferoxamine (Dfo) has a plasma half-life of only 5.5 min that does not favor its direct use as a probe. Dfo derivatives with improved pharmacokinetics properties were designed and tested on Staphylococcus aureus cultures. The ciprofloxacin and the ethyloxycarbonyl derivatives of DFO at the primary amino position were among the most successful conjugates targeting the siderophore active-transport mechanism and reaching high relative uptake rates. Furthermore, the peptidoglycan pathway of Gram-positive bacteria was in vitro targeted with vancomycin conjugated to 67Ga-Dfo which showed even higher labelling capacity than 67Ga-Dfo within a few minutes of exposure. In vitro siderophore studies remain challenging due to the lack of methods for the preparation of rigorously iron-depleted media. We developed an iron chelating method with the goal of creating iron-free growth media. / Thesis / Master of Science (MSc)

I DEVELOPED A NEW HIGH THROUGHPUT DUAL CHANNEL HYPERSPECTRAL IMAGING CONFIGURATION BASED ON ACOUSTO-OPTIC TUNABLE FILTER. THE DEVELOPED IMAGING SYSTEM WAS CHARACTERIZED AND EVALUATED IN COMPARISON WITH OTHER CONVENTIONAL CONFIGURATIONS. THE NEW IMAGING SYSTEM PROVED HIGHER THROUGHPUT WITH RESPECT TO THE CURRENTLY USED CONFIGURATIONS.THE IMAGING SYSTEM WAS THEN USED TO QUANTITATIVELY ASSESS AND PRECISELY CLASSIFY SKIN ERYTHEMA INDUCED ARTIFICIALLY ON VOLUNTEERS AND NATURALLY ON SKIN CANCER PATIENTS DUE TO RADIOTHERAPY TREATMENT. / Recent cancer statistics show that 40% of Canadians might contract cancer during their life and 25% of Canadians might die due to cancer. In skin, head and neck cancers, surgery and radiation therapies are the most prevalent treatment options, while radiation therapy is the most commonly used approach. A common problem in radiation therapy is tumors behave differently against ionizing radiation. For instance, with the same dose, some tumors are fully damaged or shrunk, while others are less affected. The difference in individual tumor response to therapy is transformed into a research question: how to quantitatively assess tumor response to radiation and how to tune radiation therapy to achieve full destruction for tumor cells? Few past studies addressed the question, although no definite answer was realized. This work is a part of a project that investigates the hypothesis that radiation response of skin is correlated to individual tumor response. In the case of high correlation, the skin’s faster response to ionizing radiation can be used to modify the irradiation dose to achieve the maximum destruction of individual’s tumor. To examine the project hypothesis, radiation-induced skin redness or erythema was selected as an acute skin reaction to being objectively quantified. Hence, the overall goal of the research thesis work is to objectively assess and precisely quantify radiation-induced erythema or radiation dermatitis. Skin erythema was assessed formerly by multiple optical and non-optical modalities. The current gold standard is the visual assessment (VA). Unfortunately, VA lacks objectiveness, precise communication, and quantification. To push the limitations of VA and past techniques, hyperspectral imaging (HSI) was proposed to be used for erythema assessment. The work detailed in this thesis aims to create more confidence in HSI to be utilized toward objectively quantify skin erythema. To reach this goal, initially, a new high-throughput dual channel acousto-optic tunable filter (AOTF)-based-HSI instrument was developed for monitoring radiation dermatitis. AOTF-HSI instrument design, implementation, and full characterization are presented. Second, the developed AOTF-HSI instrument is evaluated against a liquid crystal tunable filter (LCTF) instrument. Third, to be prepared for clinical operation, the AOTF-HSI equipment was used to classify an artificially-induced erythema on healthy volunteers in an exploratory study. A robust linear discriminant analysis (LDA)-based classification method was developed for the purpose of image classification. Finally, HSI instrument and LDA classification method were utilized in a preliminary clinical study to properly monitor and precisely quantify radiation dermatitis for skin cancer patients. In the clinical study, erythema indices were computed using Dawson’s method. Least square fitting was used to fit the acquired absorbance data, and thus quantify the hemoglobin concentration change along the study duration. Moreover, LDA was used to contrast spectral and digital imaging for erythema classification. In sum, the work documented in this thesis was willfully directed to achieve an efficient, portable, user-friendly hyperspectral imaging system which has the opportunity to be a benchtop in the clinical daily procedure in the near future. / Thesis / Doctor of Philosophy (PhD)

Development of pulmonary hypertension is an independent predictor of poor outcome in dogs affected by myxomatous valvular degeneration (MMVD). Systolic pulmonary arterial pressure is routinely estimated by Doppler echocardiography applying the simplified Bernoulli equation to the velocity of tricuspid regurgitation (sPAP_D). The accuracy of this estimation is unknown in dogs with MMVD, but experimental studies suggest that the method is imperfect. In order to fill this knowledge gap we prospectively enrolled dogs affected by MMVD and cardiac remodeling - American College of Veterinary Internal Medicine (ACVIM) stages B2 and C MMVD for which treatment had been unchanged for at least one month. A flow-directed thermodilution monitoring catheter was percutaneously placed in the right jugular vein and advanced to the main pulmonary artery. Pulmonary arterial systolic pressure was recorded through this catheter connected to a pressure-transducer and data acquisition-analysis system (sPAP_C). A second operator simultaneously acquired tricuspid regurgitant velocity spectra to calculate sPAP_D. Each operator was blinded to the result of the other technique. Twenty dogs were enrolled. Technical difficulties prevented catheterization in 2 dogs. Eighteen measurement pairs were therefore used for comparison of sPAP_C and sPAP_D through Bland-Altman analysis and linear regression. A statistically significant bias between sPAP_C and sPAP_D (mean difference=0.5mmHg; Confidence interval: -6.5mmHg, +7.5mmHg) was not detected. The limits of agreement between the techniques were wide (-27.3mmHg, +28.2mmHg). Regression analysis failed to identify a significant linear association between the two techniques (r=0.11, p=0.17). In conclusion, sPAP_D poorly agrees with sPAP_C measurement in dogs affected by MMVD in ACVIM stages B2 and C. In these dogs, sPAP_D could under- or over-estimate sPAP_C by more than 20mmHg, and therefore caution should be used when interpreting PASP_D. / Master of Science / The most common heart disease of dogs is myxomatous mitral valve disease (MMVD). In many affected dogs, this disease can be complicated by the development of high pressure in the vessels of the lungs, a condition called pulmonary hypertension (PH). On average, dogs with MMVD and PH have shorter survival compared to dogs affected solely by MMVD. The pulmonary pressure in dogs is usually estimated using cardiac ultrasound (echocardiography). This technique has the advantage of being "non-invasive" but it is not a direct measurement of pressure, therefore it may not be accurate. In order to evaluate the accuracy of echocardiography in measuring pulmonary pressure, in this study we compared direct measurements of pulmonary pressure obtained through cardiac catheterization to the measurements estimated using echocardiography, in dogs affected by MMVD. We performed this on 18 dogs affected by MMVD, with one person performing the direct measurements and another performing the echocardiographic ones; the two people were not aware of the measurements obtained with the other technique. We found that the echocardiographic estimated pressures can be very different from the real pressures measured with cardiac catheterization. Particularly, echocardiography resulted both in relevant over- and under-estimation of the real pressure, in an unpredictable way. This study therefore suggests that pulmonary pressures estimated by echocardiography should be interpreted cautiously in dogs affected by MMVD.

Quantitative magnetic resonance imaging (MRI) measurements of the pediatric spinal cord is important for both diagnostic and treatment planning. In recent years several quantitative MRI (qMRI) techniques that have been developed and tested to measure functional and structural information of the spinal cord tissue and microstructure. Several of the existing structural and functional imaging biomarkers (i.e., diffusion tensor imaging (DTI)) have demonstrated potential for providing microstructural information about the spinal cord. However, due to the lack of a standard anatomical template of the pediatric spinal cord, quantification of the spinal cord tissue has been challenging. Therefore, one of the goals of this work is to develop and test tools for quantification as well as the creation of a standard structural template of the typically developing (TD) pediatric spinal cord. This will allow automated measurement of normative values of the spinal cord cross-sectional area (SCCSA) at various levels of the spinal cord. Furthermore, to examine the white matter (WM) microstructure of the pediatric cord we developed a processing pipeline for the atlas-based generation of TD pediatric spinal cord WM tracts. This will facilitate the measurements of normative diffusion values for various WM tracts.A group of 30 TD subjects (age range of 6-17 years old (12.38 ±2.81)), who had no evidence of spinal cord injury or pathology were recruited. We utilized a multiparametric MRI protocol, including high-resolution T2-w structural and diffusion-weighted MRI images to scan the subjects on a 3T MRI scanner. The diffusion data were acquired using a novel iFOV DTI sequence. For quantification, a post-processing pipeline was utilized to generate the structural pediatric template. Next, WM tracts were generated using an atlas-based approach, and diffusion metrics (FA, MD, RD and AD) were quantified in 34 tracts identified in the processing pipeline. Normative SCCSA and DTI diffusion indices were generated for the TD population. Lastly, we demonstrated that DTI indices (i.e. FA) can be a predictive measure of components of the clinical test for spinal cord injury, as well as an indicator of the white matter tracts integrity. Therefore, in the final step of this work, we expanded our quantitative analysis to look at the microstructural and macrostructural changes in 15 children with chronic spinal cord injury (SCI) (AIS A-D, mean age of 12.8 ± 3.1 years). This included measurements of SCCSA, diffusion metrics and T2* WM/GM ratio of various white matter tracts in the patient population. We also examined the relationships between all the metrics and the ISNCSCI clinical scores in SCI subjects. We then compared these measurements between the TD and SCI patients to evaluate the diagnostic utility of these techniques and biomarkers. Statistically significant difference was observed between the two populations in the studied metrics. The results show that the proposed techniques may have the potential to be used as surrogate biomarkers for the quantification of the injured spinal cord. Keywords: diffusion tensor imaging, typically developing, spinal cord injury, spinal cord cross-sectional area, fractional anisotropy, mean diffusivity, axial diffusivity, radial diffusivity / Bioengineering