Each year in the United States, approximately 1.35 million people are a ected by mTBI (aka concussion) and subsequent cognitive impairment. Approximately 33% of mTBI cases results in persistent long-term cognitive de cits despite no abnormalities appearing on conventional neuroimaging scans. Therefore, an accurate and reliable imaging method is needed to determine injury location and extent of healing. The goal of this study was to characterize and quantify mTBI through DTI, an advanced MRI technique that encodes voxel-wise tissue water microstructural di usivity as a tensor, as well as QSM, which measures iron deposition within tissues. We hypothesized that personalizing the analysis of DTI and QSM will provide a better understanding of trauma-induced microstructural damage leading to improved diagnosis and prognosis accuracy. Through regression analysis, a preliminary comparison between DTI data to QSM measurements was performed to determine potential correlations between the two MRI techniques. Further, a large database of healthy pediatric brain DTI data was downloaded and each was warped into a standardized brain template to ultimately use for voxel-wise z-score analysis of individual mTBI patients (n=26). This allowed localization and quantitation of abnormal regions on a per-patient basis. Signi cant abnormalities were commonly observed in a number of regions including the longitudinal fasciculus, fronto-occipital fasciculus, and corticospinal tract, while unique abnormalities were localized in a host of other areas (due to the individuality of each childs injury). Further, through group-based Bonferroni corrected T-test analysis, the mTBI group was signi cantly di erent from controls in approximately 65% of regions analyzed. These results show that DTI is sensitive to the detection of microstructural changes caused by mTBI and has potential to be a useful tool for improving mTBI diagnosis accuracy / Thesis / Master of Applied Science (MASc) / Concussions affect over one million people in the United States each year. In a number of cases, these individuals must cope with persistent long-term cognitive impairment resulting from the injury. A current, significant problem is that concussion cannot be reliably diagnosed using conventional CT and MR imaging methods. Therefore, an accurate and reliable imaging method is needed to determine both injury location and severity, as well as to monitor healing. The goal of this study was to quantify concussion through MR imaging techniques known as Di ffusion Tensor Imaging and Quantitative Susceptibility Mapping, which accurately model the brain's mi- crostructure. Analysis utilizing these MRI methods found signifi cant abnormalities in a number of brain regions of concussed subjects relative to healthy individuals. These results suggest that DTI, in particular, is sensitive to microstructural changes caused by concussions and has the potential to be a useful tool for improving diagnosis accuracy.

OBJECTIVE: Everyday tasks, such as meal preparation and bill paying, require the coordination of multiple cognitive processes and are essential for independent living. In dementia, cognitive impairment disrupts the ability to perform everyday tasks, though subtle difficulties occur prior to the onset of a frank dementia and predict risk of further decline. Current clinical methods of assessing everyday functioning fail to elucidate the reasons people experience mild functional difficulties, but new sensitive and objective measures of mild functional difficulties may advance our understanding of the cognitive mechanisms associated with very early functional decline. In separate paradigms, prior work has identified two markers of mild functional difficulties that distinguish healthy older adults from younger adults: (1) micro errors, inefficient reaching movements (e.g., reaching for but not using a distractor object) and (2) inefficient eye movements during verbal description of common everyday activities (e.g., making coffee). The present study used a novel single, streamlined paradigm that integrates analysis of inefficient eye movements with inefficient reaching to increase sensitivity for early detection and advance our understanding of mild functional difficulties. METHODS: Thirty-four older adults with healthy cognition (n = 28) or mild cognitive impairment (n = 6) completed a novel, non-immersive virtual reality (VR) test involving two everyday tasks (Breakfast and Lunch) during which both eye movements and reaching movements were measured. Participants also completed clinical questionnaires and a performance-based test (with real objects) of everyday functioning as well as cognitive testing. Analyses examined whether eye movements are (1) associated with precision of reaching movements during the VR task (Aim 1); (2) associated with clinical measures of everyday function (Aim 2); and (3) show meaningful patterns across the VR tasks (beginning vs. end; between vs. within subtask) that are differentially associated with cognitive measures (Aim 3). RESULTS: Within the VR task, participants spent the highest proportion of time viewing objects necessary for completion of the current task step (target objects) compared to distractor objects or objects not needed at the current task step. Relations between efficiency of eye movements and reaching movements during the VR task were not statistically significant (Aim1). Time spent viewing non-target objects in the VR task was moderately correlated with errors on the performance-based test, but not with clinical questionnaires of everyday functioning (Aim 2). Participants spent a greater proportion of time viewing non-target objects at the beginning of the task sequence compared to later in the task sequence, as well as between sub-tasks compared to within sub-tasks, but correlation coefficients between these viewing patterns and cognitive tests failed to reach statistical significance (Aim 3). CONCLUSIONS: Results provide preliminary evidence that eye movements during execution of a VR task of everyday functioning involving reaching movements may be a reliable and sensitive measure of subtle, real-world functional difficulties. Eye movement patterns suggest premature decay of task goals and interference from competing task goals are mechanisms that may contribute to early functional decline in older adults. Further study is required to demonstrate the utility of eye movements in predicting cognitive and functional decline in older adults. / Psychology

This thesis reports on the research outcome of corrosion mechanism and corrosion rate of mild steel in different environments (saline, alkaline solutions and concrete media) using potentiodynamic polarization technique. The study also included the effect of corrosion on bond strength between reinforcing steel and concrete using pull-out test. Corrosion of mild steel and 316L stainless steel with different surface conditions in 1, 3 and 5% saline (NaCl + Distilled water) was investigated. Specimens ground with 200 and 600 grit silicon carbide grinding paper as well as 1¿m surface finish (polished with 1¿m diamond paste) were tested. In case of mild steel specimens, reduction in surface roughness caused increase in corrosion rate, while in 316L stainless steel corrosion rate decreased as the surface roughness improved. Metallographic examination of corroded specimens confirmed breakdown of passive region due to pitting corrosion. Corrosion of mild steel was also investigated in alkaline solution (saturated calcium hydroxide, pH =12.5) contaminated with 1, 3 and 5% saline. A series of corrosion experiments were also conducted to examine the efficiency of various concentrations of calcium nitrite (CN) on corrosion behaviour of both as-received and polished mild steel in alkaline solution containing 3% saline after 1 hour and 28 days of exposure. Corrosion rate was higher for the as-received than polished mild steel surface under the same testing conditions in NaCl alkaline solution with and without nitrites due to the effect of surface roughness. Morphology investigation of mild steel specimens in alkaline solution ii containing chlorides and nitrites showed localized pits even at nitrite concentration equal to chloride concentration. Corrosion of steel bars embedded in concrete having compressive strengths of 20, 30 and 46MPa was also investigated. The effect of 2 and 4% CN by weight of cement on corrosion behaviour of steel bar in low and high concrete strengths specimens were also studied. All reinforced concrete specimens were immersed in 3% saline solution for three different periods of 1, 7 and 15 days. In order to accelerate the chemical reactions, an external current of 0.4A was applied. Corrosion rate was measured by retrieving electrochemical information from polarization tests. Pull-out tests of reinforced concrete specimens were then conducted to assess the corroded steel/concrete bond characteristics. Experimental results showed that corrosion rate of steel bars and bond strength were dependent on concrete strength, amount of CN and acceleration corrosion period. As concrete strength increased from 20 to 46MPa, corrosion rate of embedded steel decreased. First day of corrosion acceleration showed a slight increase in steel/concrete bond strength, whereas severe corrosion due to 7 and 15 days corrosion acceleration significantly reduced steel/concrete bond strength. Addition of only 2% CN did not give corrosion protection for steel reinforcement in concrete with 20MPa strength at long time of exposure. However, the combination of good quality concrete and addition of CN appear to be a desirable approach to reduce the effect of chloride induced corrosion of steel reinforcement. At less time of exposure, specimens without CN showed higher bond strength in both concrete mixes than those with CN. After 7 days of corrosion acceleration, the higher concentration of CN gave higher bond strength in both concrete mixes. The same trend was observed at 15 days of corrosion acceleration except for the specimen with 20MPa compressive strength and 2% CN which recorded the highest deterioration in bond strength.

Asthma is an inflammatory airways disease affecting over 339 million people of all ages worldwide. More than 10% of asthmatics have uncontrolled severe disease which is insensitive to high doses of oral corticosteroid treatment. Type 2 innate lymphoid cells (ILC2) are pro-inflammatory lymphomononuclear cells proposed as critical drivers of eosinophilic inflammatory disease of the upper and lower airways. Controlling this activity may provide novel therapies for asthma. This thesis aimed to investigate factors that affect the local activation and expansion of ILC2 in the airways including anti-inflammatory medications such as (i) corticosteroids, (ii) neuro-immune regulation of ILC2, and (iii) effect of locally generated cytokines on ILC phenotypes and the relationship to the ongoing airway inflammatory profile. We firstly investigated the effect of intranasal corticosteroids on activation levels of ILC2 in the upper airway of allergic rhinitics with mild asthma following controlled nasal allergen challenge (Chapter 2). Following pre-treatment with intranasal corticosteroid there was an attenuation in the allergen-induced increase in total ILC2 and IL-5/13+ ILC2 in the nasal mucosa. In addition, HLA-DR expression on ILC2 in the nasal mucosa was down-regulated. Overnight culture with IL-2, TSLP or IFN-γ up-regulated HLA-DR expression on ILC2, in vitro; an effect that is inhibited in the presence of corticosteroids. Attenuation of HLA-DR expression by ILC2 may be an additional mechanism by which corticosteroids modulate adaptive immune responses in the airways. We have previously reported that lung ILC2 are activated within 7h following allergen-inhalation challenge. Since airway mucosal tissue is highly innervated, we investigated whether neuroimmune interactions may trigger early and rapid host immune responses (Chapter 3). In a diluent-controlled allergen-inhalation challenge cross-over study, where mild asthmatics developed early and late bronchoconstrictor responses with sputum eosinophilia (>3%), NMUR1, a receptor for the neuropeptide, neuromedin-U, was up-regulated on sputum ILC2 in 7h post allergen challenge. This was associated with increased expression of IL-5/IL-13 by sputum ILC2 post-allergen and following in vitro culture. ILC2 activation was mediated through a MAPK/PI3 kinase dependent-signaling pathway that was attenuated in the presence of dexamethasone. Co-culture with IL-33 and TSLP, in vitro up-regulated NMUR1 expression on ILC2 at the protein and transcriptomic level which was attenuated by dexamethasone. The close interplay between neuropeptide signalling and tissue-derived alarmin cytokines may be important interactions for rapid ILC2 activation in airway inflammatory responses in asthma. We have reported increased ILC2 with the highest level of IL-5/13+ ILC2 in the airways of severe asthma with uncontrolled eosinophilia (>3%). The prevalence and phenotypic analyses of innate lymphoid cells subsets in severe asthma with neutrophilic or mixed granulocytic airway inflammatory endotypes remains unclear and was investigated in Chapter 4. Sputum ILC3 were most abundant in severe asthma with neutrophilic airway inflammation where IL-17A+ ILC3 correlated with airway neutrophilia. ILC2 were predominant in severe asthma with airway eosinophilia. Importantly, we identified an intermediate ILC2 phenotype displaying ILC3-like markers (c-kit and IL-17A) in severe asthma with neutrophilic and mixed granulocytic airway inflammation. Inflammasome related cytokines, IL-1β and IL-18 were significantly increased in the airways of these patients. At both proteomic and transcriptomic levels, flow sort-purified ILC2 trans-differentiated to the intermediate phenotype when co-cultured with IL-1β+IL-18. Blocking inflammasome-related cytokines may control T2-low severe asthma exacerbations. Collectively, the findings of this thesis highlight the role of corticosteroids, neuropeptides and airway inflammasome related cytokines as modulators of ILC fate and activity in asthma. / Thesis / Doctor of Philosophy (PhD) / Asthma is a disease of the airways that makes breathing difficult. About 10% of asthma patients have uncontrolled severe symptoms despite treatment with high doses of corticosteroids which imposes many unwanted side effects. Investigating processes that worsen the disease will help to discover new treatments for asthma. Type 2 innate lymphoid cells (ILC2) are novel cells that produce large quantities of factors which attract and activate effector cells to the lungs which in turn make breathing difficult. This thesis investigated whether controlling ILC2 activity reduces asthma symptoms by studying i) responsiveness of ILC2 to corticosteroids using a controlled allergen exposure through the nose in people with allergic rhinitis and mild asthma, ii) the role of airway nerves and mediators on ILC2 activation, and iii) the ability of signals produced by the lungs to impact factors released by ILC2 and the relationship to effector cells found in the airways of severe asthma. Overall, ILC2 activation can be modulated by corticosteroids, nerve derived factors and lung tissue derived cytokines, and this is associated with changes in the number and type of effector cells in the lungs.

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