This thesis examines the overarching theme of inhaled corticosteroid (ICS) dose response effects on a variety of asthma outcome measures; with further importance placed on the application of these findings to personalising ICS dosing for the individual asthmatic. The introduction provides a detailed summary of the current recommendations for the treatment of adult asthma, with particular reference to the mechanism of action and clinical utility of ICS for the treatment of asthma. Current methods of assessing ICS dose response are presented, as well as the common influences that affect these responses. Novel therapeutic theories and the identification of specific asthmatic phenotypes are also introduced, in order to demonstrate the shift towards personalising treatment for asthma. The first two studies examine the dose response of ICS on two specific factors that influence asthma. The third study presents an examination of pharmacological manipulation of the ICS dose response using an additional agent. The following two studies address: how asthma outcomes relate to each other in patients receiving ICS; in addition to an overall assessment of the ICS dose response across a broad range of both ICS moieties and outcome measures. The final study examines for any detrimental effect of an ICS dose ramp on bone metabolism, an important potential long-term adverse effect of higher ICS dosing. The discussion draws together all the results obtained in relation to ICS dose response in asthma, and how these apply to current clinical practice for the individual patient. Furthermore, hypotheses are generated for areas of future study based on the findings from this work.

Este trabalho objetivou adaptar um método de controle de larvas do mexilhão dourado (Limnoperna fortunei) com a utilização de radiação ultravioleta e verificar seu efeito sobre cianobactérias e cianotoxinas presentes na água. Limnoperna fortunei (Dunker, 1857), conhecido vulgarmente como mexilhão dourado é proveniente do sudeste asiático. Foi, provavelmente, introduzido nos nossos mananciais, não intencionalmente, através da água de lastro, com os primeiros registros na América do Sul, em 1991, no Rio da Prata, nas proximidades de Buenos Aires, Argentina. No Brasil foi visto pela primeira vez na área do Delta do Jacuí, em frente ao porto de Porto Alegre, RS, no ano de 1998. Além de ameaçar à biodiversidade de ecossistemas, vem provocando a obstrução das tubulações e trocadores de calor junto às estações de tratamento de água e indústrias que utilizam água bruta para resfriamento. As estações de tratamento, além de enfrentarem problemas com o entupimento pelo mexilhão, defrontam-se também com as florações de cianobactérias. As florações, conhecidas também como blooms, são eventos de multiplicação e acumulação de microalgas ou cianobactérias nos corpos hídricos, que podem durar de algumas horas ao longo do dia a meses. As cianobactérias podem liberar cianotoxinas que estão presentes principalmente no interior das células, e são liberadas na lise celular, que ocorre principalmente por senescência natural. Os experimentos foram realizados em uma unidade piloto, onde concentrações conhecidas de larvas do mexilhão dourado foram submetidas a doses de radiação ultravioleta, na faixa de 200 a 800 mWs/cm2. As amostras de água bruta utilizadas nos testes foram avaliadas por meio de métodos analíticos adequados (APHA, 2005). Foram determinados os parâmetros de temperatura (°C), pH, turbidez (NTU), dureza (mgCaCO3/L) e sólidos suspensos (mg/L), os quais poderiam influenciar nas condições dos testes. As mesmas condições testadas para o mexilhão foram utilizadas nos experimentos com cianobactérias. As larvas de mexilhão dourado e a água bruta utilizada no experimento foram obtidos no delta do Jacui, Porto Alegre, Rio Grande do Sul, Brasil. A cianobactéria Microcystis aeruginosa, produtora de microcistina, foi cultivada em laboratório. A mortalidade instantânea das larvas aproximou-se dos 100% nas condições do teste com a dosagem de 781mWs/cm2 , com DL50 de 324 mWs/cm2. Na água residual dos experimentos de exposição à radiação UV, foram realizados ensaios ecotoxicológicos crônicos com Pimephales promelas, Ceriodaphnia dubia e Selenastrum capricornutum, a fim de detectar a presença de subprodutos que poderiam gerar toxicidade aos organismos de diferentes níveis tróficos. Os resultados desta avaliação ecotoxicológica não demonstraram toxicidade residual. Os dados obtidos demonstraram-se satisfatórios no controle daslarvas de mexilhão, entretanto não promoveram a lise das células de M. aeruginosa e a conseqüente liberação de microcistinas nas condições testadas. / L. fortunei (Dunker, 1857), commonly known as golden mussel comes from Southeast Asia. It might have been unintentionally introduced in our water sources through ballast water, with the first records in 1991, in Rio de la Plata, near Buenos Aires, Argentina, South America. In Brazil it was first seen in 1998, in Jacuí Delta, opposite Porto Alegre’s harbor. Besides threatening the biodiversity of ecosystems, this mussel has caused the obstruction of pipes and heat exchangers along the water treatment plants and industries that use raw water for cooling. Treatment plants facing problems with the clogging of mussels also have to contend with the cyanobacterial blooms. The blooms are events of multiplication and accumulation of algae or cyanobacteria in water bodies that can last from a few hours to days or months. The cyanobacteria may release cyanotoxins present mainly in cells and are released upon cell lysis, which occurs primarily by natural senescence. Thus, the aim of study is to adapt a control method of golden mussel larvae (L. fortunei) using ultraviolet radiation and verify its effect on cyanobacteria and cyanotoxins in the water. The experiments were performed in a pilot unit, where known concentrations of mussel larvae were subjected to doses of ultraviolet radiation ranging from 200 to 800 mWs/cm2, and the quality of water used, evaluated. The same conditions tested for the mussels were used in experiments with cyanobacteria. Mussel larvae and raw water used in the experiments were obtained from the Jacuí Delta, Porto Alegre, Rio Grande do Sul, Brazil. The cyanobacteria Microcystis aeruginosa, witch produces microcystin, was grown in culture in our laboratory. The instantaneous mortality of larvae was approximately 100% with 781mWs/cm2 in test conditions, with LD50 of 324 mWs/cm2. Ecotoxicological tests were performed with Pimephales promelas, Ceriodaphnia dubia, and Selenastrum capricornutum, to detect the presence of byproducts that could cause toxicity to organisms of different trophic levels in the residual water. The results of ecotoxicological evaluation showed no residual toxicity. The data showed to be satisfactory in larvae control, but did not cause lysis in cells of M. aeruginosa and the consequent release of microcystins in the water.

Contamination of methylmercury (MeHg) in aquatic products has been a wide spread health concern. The objective of this study is to determine total mercury (THg) and MeHg concentrations in different species of aquatic products from major offshore farms in China, and to assess health impacts from consumption. Results showed that the concentrations of THg and MeHg ranged 5.6–328.4 ng/g (wet weight) and 4.3–303.6 ng/g (wet weight) in aquatic products, respectively, and were very variable among species and origin sources. Target hazard quotient (THQ) suggested that MeHg exposure via consumption posed high health risks to children aged 2–7 and higher income families. Residents above the age of 13 and with low income have relatively lower health risk of MeHg exposure. Health impacts on heart attacks and newborns’ IQ from MeHg exposure were evaluated using dose-response relationships. Results showed that mother’s consumption of aquatic products (at 6 ounce per day) may cause a loss of 0.38 IQ points for newborns. For non-pregnant, consumption of aquatic products may cause an increase rate of mortality and morbidity of heart attacks at 10.59 and 78.45 per 100,000 persons, respectively. The negative health impact of consuming seawater fish was higher than freshwater fish.

Lung disease affects tens of millions of Americans, making it one of the most common medical conditions in the United States. Many of these lung diseases are classified as chronic airway disease. Because of this, it is important to be able to catch the development early so as to begin treatment as soon as possible to delay the progression and subsequently monitor that progression. One method of doing so is the use of quantitative computed tomography (CT). Study of the airway anatomy can be quantified using such measures as minor inner diameter (MinD), major inner diameter (MajD), wall thickness (WT), inner area (IA), and outer area (OA). Changes in these measures can then be tracked over time to determine how the airways are being affected by disease. The challenge with the desired longitudinal imaging is that prolonged radiation exposure can be dangerous to the patient. In order to make longitudinal imaging more feasible, it is important to determine what quantitative measures can reliably be made at different radiations doses so as to optimize radiation dose and quantitative assessment. Working to make this determination, three different radiation doses were tested to evaluate their quantitative outputs. A high dose (14.98 mGy), medium dose (6.00), and low dose (0.74 mGy) were used to image six different porcine subjects. Images were collected at these doses both while the lungs were in-vivo and once the lungs had been fixed and excised ex-vivo. All of the scans were then processed using APOLLO (VIDA Diagnostics). From the complete airway trees, quantitative measures were collected from thirty-five airways. For the whole lung analysis, the medium and low dose in-vivo scans and the high dose ex-vivo scans were compared to the high dose in-vivo scans to compare assess MinD, MajD, WT, IA, and OA. Then, in order to determine how well the CT measures represent the actual anatomy, a total of thirteen cube samples containing airways were segmented from one of the lungs (based on volume analysis of the lung pre- and post-fixation and visual inspection). The cubes were imaged in CT, for the purpose of aiding in the establishment of original location and studying the effect of a narrowed imaging window, and microscopic CT (μCT). Since μCT can have a resolution on the scale of microns, the values measured in these images were considered ground-truth. The CT and μCT cubes were then registered to the high dose ex-vivo scan so as to compare the cube values with the ex-vivo values from each of the three doses. The same five measures were collected and analyzed. The MinD, MajD, WT, IA, OA were statistically analyzed between the three in-vivo radiation dose scan sets, the high dose in- and ex-vivo scans, and the µCT cube, CT cube, and the three ex-vivo radiation dose sets. Preliminary results for the in-vivo scans show that the low dose and medium dose scans can reliably (< 5% error) be used to evaluate airways with minor diameters between 3.42 mm and 10.34 mm and major diameters between 3.98 mm and 12.06 mm. Comparison of the high-dose in-vivo and ex-vivo scans showed that the fixation and excision of the lungs did not significantly affect the ex-vivo lungs' ability to be used as a model for the in-vivo lungs. Finally, analysis of the various forms of the ex-vivo airways showed that there were few statistically significant differences between the datasets. These results support the use of using the low (0.74 mGy) radiation dose when studying airway disease affecting airways with minor diameters between 3.42 mm and 10.34 mm and major diameters between 3.98 mm and 12.06 mm. They also show that the quantitative measures from CT are representative of the true measures of the airways.

No conclusive evidence exists to determine that epidural steroid injections (ESIs) provide lasting improvements in chronic pain due to herniated discs, in the Workers' Compensation population. Recently, an article by Armon et.al was published by the American Academy of Neurology, which stated that the routine use of ESIs is not recommended and that further studies are needed to elucidate this controversy (Armon, Argoff, Samuels, & Backonja, 2007). In 1998, back pain in the United States was estimated to have incurred total health-care expenditures of $90.7 billion. Medicare part B. claims in 1999 for 40.4 million individuals amounted to $49.9 million for lumbar epidural steroid injections alone. The practice of evidence based medicine will reduce health care costs and discomforts of the procedure. The objective of this study was to determine if ESIs will result in reduction of pain levels and pain medications used, and to determine the cost of treatment. In this retrospective cohort chart review study, where claimants served as their own controls, pain levels and medications used, were retrospectively assessed using documented pain scores based on the numerical pain scale, and medications prescribed, respectively. Further correlations were made with clinical and MRI findings. Costs were derived based on the amount billed by the provider to the insurance company. A randomized list of 600 charts from the insurance company's database was obtained and 120 were selected for study based on criteria. Data abstracted included gender, weight, date of injury, clinical symptoms, MRI findings, pain scores before and after ESIs, medications used before and after ESIs , date of ESIs, total amount billed for the ESIs, surgery, and total cost of the injury to date of data abstraction. The mean pain score before was 6.97 and 7.51 after ESIs The mean number of pain medication groups before was 2.41 and 3.10 after ESIs. The mean morphine equivalent dose before was 10.50mg and 22.07mg after ESIs. There was no significant correlation between amount billed for ESI and pain level. It was concluded that use of ESIs in the treatment chronic radicular pain does not reduce workers' pain levels, amount of pain medications, or narcotic consumed. These measures of discomfort remained the same, or were increased regardless of money spent.

Phase I clinical trials in oncology aim to evaluate the toxicity risk of new therapies and identify a safe but also effective dose for future studies. Traditional Phase I trials of chemotherapies focus on estimating the maximum tolerated dose (MTD). The rationale for finding the MTD is that better therapeutic effects are expected at higher dose levels as long as the risk of severe toxicity is acceptable. With the advent of a new generation of cancer treatments such as the molecularly targeted agents (MTAs) and immunotherapies, higher dose levels no longer guarantee increased therapeutic effects, and the focus has shifted to estimating the optimal biological dose (OBD). The OBD is a dose level with the highest biologic activity with acceptable toxicity. The search for OBD requires joint evaluation of toxicity and efficacy. Although several seamleass phase I/II designs have been published in recent years, there is not a consensus regarding an optimal design and further improvement is needed for some designs to be widely used in practice. In this dissertation, we propose a modification to an existing seamless phase I/II design by Wages and Tait (2015) for locating the OBD based on binary outcomes, and extend it to time to event (TITE) endpoints. While the original design showed promising results, we hypothesized that performance could be improved by replacing the original adaptive randomization stage with a different randomization strategy. We proposed to calculate dose assigning probabilities by averaging all candidate models that fit the observed data reasonably well, as opposed to the original design that based all calculations on one best-fit model. We proposed three different strategies to select and average among candidate models, and simulations are used to compare the proposed strategies to the original design. Under most scenarios, one of the proposed strategies allocates more patients to the optimal dose while improving accuracy in selecting the final optimal dose without increasing the overall risk of toxicity. We further extend this design to TITE endpoints to address a potential issue of delayed outcomes. The original design is most appropriate when both toxicity and efficacy outcomes can be observed shortly after the treatment, but delayed outcomes are common, especially for efficacy endpoints. The motivating example for this TITE extension is a Phase I/II study evaluating optimal dosing of all-trans retinoic acid (ATRA) in combination with a fixed dose of daratumumab in the treatment of relapsed or refractory multiple myeloma. The toxicity endpoint is observed in one cycle of therapy (i.e., 4 weeks) while the efficacy endpoint is assessed after 8 weeks of treatment. The difference in endpoint observation windows causes logistical challenges in conducting the trial, since it is not acceptable in practice to wait until both outcomes for each participant have been observed before sequentially assigning the dose of a newly eligible participant. The result would be a delay in treatment for patients and undesirably long trial duration. To address this issue, we generalize the time-to-event continual reassessment method (TITE-CRM) to bivariate outcomes with potentially non-monotonic dose-efficacy relationship. Simulation studies show that the proposed TITE design maintains similar probability in selecting the correct OBD comparing to the binary original design, but the number of patients treated at the OBD decreases as the rate of enrollment increases. We also develop an R package for the proposed methods and document the R functions used in this research. The functions in this R package assist implementation of the proposed randomization strategy and design. The input and output format of these functions follow similar formatting of existing R packages such as "dfcrm" or "pocrm" to allow direct comparison of results. Input parameters include efficacy skeletons, prior distribution of any model parameters, escalation restrictions, design method, and observed data. Output includes recommended dose level for the next patient, MTD, estimated model parameters, and estimated probabilities of each set of skeletons. Simulation functions are included in this R package so that the proposed methods can be used to design a trial based on certain parameters and assess performance. Parameters of these scenarios include total sample size, true dose-toxicity relationship, true dose-efficacy relationship, patient recruit rate, delay in toxicity and efficacy responses.

Ultrafine particles (UFPs) are present in the ambient atmosphere and are generated from atmospheric gases, pollution sources, and combustion. Candles emit carbonaceous soot particles similar to UFPs present in the ambient atmosphere. With the exception of lead, airborne concentrations of candle emissions have not been shown capable of causing cancer or cardiopulmonary disease during normal use. The purpose of this research is to determine the occupational risk associated with candle emissions. Candle studies employ chambers to measure candle emission exposures and assess public health risk. Chambers used in previous studies did not match normal room conditions. They were affected by turbulence and high temperature, which affected particle distribution and constituent concentrations, while making it difficult to extrapolate the results. The chamber designed for this study sought to avoid the problems noted above. This study also employed a room constructed to closely simulate a normal work environment. Candle suppliers and users were surveyed to determine occupational candle use and settings. Scented, unscented, and church candles were measured in both ventilated and unventilated environments. A condensation nuclei counter was used to measure UFPs from candle emissions. Relative to previous chamber designs, results indicated a reduction in candle soot generation, no significant airborne concentrations of metals, and airborne concentrations of polycyclic aromatic hydrocarbons (PAHs), below occupational limits. Scented candles generated more soot than unscented candles. UFP studies have demonstrated only weak associations between ambient UFP exposures and cardiopulmonary disease. However, ambient UFP exposures were used as a benchmark for candle soot exposures. The lifetime average daily dose (LADD) was calculated from the candle soot measurement data and ambient UFP data. Candle soot generated inside the test room ranged from 5.73 x 109 to 1.86 x 1011 number of candle soot particles inhaled daily compared to the 3.25 x1011 to 2.45 x 1012 soot particles inhaled in the ambient environment. The calculated candle soot dose was nearly an order of magnitude less than the calculated ambient dose. The conclusion is that candle emissions do not pose a health risk under normal occupational use.

Computer designed missing tissue and dose compensators have been produced and dosimetrically tested under a linear accelerator 6MV X-ray beam. Missing tissues compensators were developed to correct for patient external contour change only. Target dose compensators were developed to achieve a uniform dose throughout the target volume. With compensators present in the beam, data acquisition was repeated in a water phantom and an Anthropomorphic phantom. Clinically acceptable dose uniformity was achieved within these phantoms. For external contour compensation flat isodose curves were obtained giving an even dose in the region of interest. The dose difference found was within plus/minus 3% only. For the phantoms containing inhomogeneities dose uniformity to target volume was achieved within plus/minus 7%. Prediction of radiation dose was made using a GE Target Series 2 Treatment Planning Computer for each of the phantoms. Validation of the computer predicted dose was carried out using diode and TLD measurements. The measured data in the water tank was consistent with the computer data within plus/minus 2% for external contour changes and for inhomogeneities. The TLD measured results in the anthropomorphic phantom agreed with the planning computer results within 6%. Up to 4% of the difference is explainable due to supra-linearity and scatter effects / Master of Science (Hons) (Physics)

The radiation dose in radiation therapy is mainly measured by ion chamber. The ion chamber measurement will not be accurate if there is not enough phantom material surrounding the ion chamber to provide the electron equilibrium condition. The lack of electron equilibrium will cause a reduction of dose. This may introduce problems in treatment planning. Because some planning algorithms cannot predict the reduction, they over estimate the dose in the region. Electron disequilibrium will happen when the radiation field size is too small or the density of irradiated material is too low to provide sufficient electrons going into the dose volume. The amount of tissue required to provide electron equilibrium in a 6MV photon beam by three methods: direct calculation from Klein-Nisina equation, measurement in low density material phantom and a Monte Carlo simulation is done to compare with the measurement, an indirect method from a planning algorithm which does not provide an accurate result under lateral electron disequilibrium. When the error starts to happen in such planning algorithm, we know that the electron equilibrium conditions does not exist. Only the 6MV photon beam is investigated. This is because in most cases, a 6MV small fields are used for head and neck (larynx cavity) and 6MV fields are commonly used for lung to minimise uncertainity due to lateral electron at higher energies. / Master of Science (Hons)

Master of Science in Medicine / Rationale: Asthma management aims to achieve optimal control on the minimal effective dose of medication. We assessed the effectiveness of two algorithms to guide ICS dose in well-controlled patients on ICS+LABA in a double-blind study, comparing dose adjustment guided by exhaled nitric oxide (eNO) to clinical care algorithm(CCA) based on symptoms and lung function. Methods: We randomised non-smoking adult asthmatics on minimum FP dose 100μgs daily +LABA to ICS adjustment using eNO or CCA, assessed over 5 visits during 8 months treatment. Primary endpoints were asthma-free days and asthma related quality of life (QOL). Analysis was by mixed model regression and generalised estimating equations with log link. Results: 69 subjects were randomised (eNO:34, CCA:35) and 58 completed the study. At baseline mean FEV1 was 94% pred., mean eNO (200ml/sec) 7.1 ppb, median ACQ6 score 0.33. Median ICS dose was 500 μg (IQR 100-500) at baseline and 100 μg on both eNO (IQR 100-200) and CCA arms (IQR 100–100) at end of study. There were no significant differences between eNO and CCA groups in asthma-free days (RR=0.92, 95% CI 0.8–1.01), AQL (RRAQL<median = 0.95, 95% CI 0.8–1.1) or exacerbation-free days (HR = 1.03, 95%CI 0.6–1.7). Neither clinic FEV1 (overall mean difference FEV1 % pred. -0.24%, 95% CI -2.2–1.7) nor a.m. PEF (mean difference 1.94 L/min (95% CI -2.9–6.8) were significantly different. Similar proportions of subjects were treated for ≥1 exacerbation (eNO: 50%, 95% CI 32.1–67.9; CCA: 60%, 95% CI 43.9–76.2). Conclusion: Substantial reductions in ICS doses were achieved in well controlled asthmatics on ICS+LABA, with no significant differences in outcomes between eNO or clinically based algorithms.