Warfarin is one of the most widely used anticoagulants. Therapy is complicated by warfarin’s narrow therapeutic range and pronounced variability in individual dose requirements. Although warfarin therapy is uncommon in children, it is crucial for children with certain congenital or acquired heart diseases. Treatment in children is especially difficult due to the lack of i) a decision support tool for efficient and consistent dose adjustments, and ii) a flexible warfarin formulation for accurate and reproducible dosing. The overall aim of this thesis was to develop a PKPD-based pharmacometric model for warfarin that describes the dose-response relationship over time, and to identify important predictors that influence individual dose requirements both in adults and children. Special emphasis was placed on investigating the contribution of genetic factors to the observed variability. A clinically useful pharmacometric model for warfarin has been developed using NONMEM. The model has been successfully reformulated into a KPD-model that describes the relationship between warfarin dose and INR response, and that is applicable to both adults and children. From a clinical perspective, this is a very important change since it allows the use of information on dose and INR that is available routinely. The model incorporates both patient and clinical characteristics, such as age, weight, CYP2C9 and VKORC1 genotype, and baseline and target INR, for the prediction of an individualised starting dose. It also enables the use of information from previous doses and INR observations to further individualise the dose a posteriori using a Bayesian forecasting method. The NONMEM model has been transferred to a user-friendly, platform independent tool to aid use in clinical practice. The tool can be used for a priori and a posteriori individualisation of warfarin therapy in both adults and children. The tool should ensure consistent dose adjustment practices, and provide more efficient individualisation of warfarin dosing in all patients, irrespective of age, body weight, CYP2C9 or VKORC1 genotype, baseline or target INR. The expected outcome is improved warfarin therapy compared with empirical dosing, with patients achieving a therapeutic and stable INR faster and avoiding high INRs that increase the risk of bleeding.

No description available.

The county hospital of Dalarna has for the last couple of years carried through a process of digitalization. The result is that within the county it exists image plate systems from two different manufacturers. In an attempt to create a tool for dose optimization and dose surveillance the county of Dalarna would like to investigate if the exposure index from Agfa and Fuji is suitable as a dose indicator. An investigation of the exposure index, S, from Fuji has already been done. This thesis has been continuing the investigation by evaluating the stability of the exposure index, lgM, from Agfa. Simultaneously an observation if there is a simple relation between the exposure indicators from Agfa and Fuji has been performed. The result showed that the average of lgM, for a set of images from the same type of examination, is appropriate as a dose indicator to the image plate for that specific examination type and X-ray equipment. The usefulness is linked to the same tube voltage and Speed Class for a specific examination, and is to a certain degree restricted by the collimating. There is a relation between the exposure index from Agfa and Fuji, and there is in a simple way possible to transform S-values to lgM-values for comparison. The relation turned out to be examination specific.

<p>The purpose of this research was to verify experimentally the buildup region dose calculation for Pinnacle³ (version 9.0), a commercial treatment planning system, commissioned and in use at the Saskatoon Cancer Center. To achieve this, buildup dose measurements using Attix parallel-plate ionization chamber and calculations by Pinnacle³, for a variety of clinical setups, were compared. The clinical setups involved 6 MV and 15 MV photon beams, open fields, enhanced dynamic wedges, physical wedges, block tray, 85, 100 and 120 cm source-to-surface distances (SSDs), and field sizes 3 x 3, 4 x 4, 5 x 5, 8 x 8, 10 x 10, 12 x 12, 15 x 15, 20 x 20, 30 x 30 cm². The dose difference (DD) and distance-to-agreement (DTA) were used to evaluate the discrepancy between measured and calculated dose values. Significant discrepancies between measured and calculated buildup dose values were observed because the modeling in Pinnacle³ is based on measurements made using a cylindrical ionization chamber. Based on the criteria of DD less than 2% or DTA less than 2 mm, 93.7% of 1,710 dose points for the 6 MV photon beam passed while for the 15 MV photon beam, 96.1% of the 2,244 dose points passed. The dose points that did not pass these criteria were mostly for open fields, block tray fields, fields with physical wedges of 15 degrees and 30 degrees and for fields with shorter source-to-surface distances. This is attributed to the high electron contamination associated with these fields. The low levels of discrepancies between measured and calculated dose values for the 15 MV beam as compared to those of the 6 MV beam need further investigations. The good agreement between measured and calculated dose values after remodeling the Electron Contamination in Pinnacle³ based on Attix chamber measurements is an indication that the Electron Contamination equation in Pinnacle³ may be adequate for modeling of electron contamination in the buildup dose region. The disagreement between Attix chamber and EBT 2 film measured buildup dose values was less than 3% for 89.9% of the buildup dose measurements compared. It is recommended to use a good parallel plate ionization chamber, such as the Attix chamber, for measurements in the buildup region.</p>

<p>Since its inception in the 1970's, computed tomography (CT) has revolutionized the practice of medicine and evolved into an essential tool for diagnosing numerous diseases not only in adults but also in children. The clinical utility of CT examinations has led to a rapid expansion in CT use and a corresponding increase in the radiation burden to patients. CT radiation is of particular concern to children, whose rapidly growing tissues are more susceptible to radiation-induced cancer and who have longer life spans during which cancerous changes might occur. In recent years, the increasing awareness of CT radiation risk to children has brought about growing efforts to reduce CT dose to the pediatric population. The key element of all dose reduction efforts is to reduce radiation dose while maintaining diagnostic accuracy. Substantiating the tradeoff between the two is the motivation behind this dissertation work.</p> <p>The first part of this dissertation involved the development of an accurate method for estimating patient-specific radiation dose and potential cancer risk from CT examinations. A Monte Carlo program was developed and validated for dose simulation in a state-of-the-art CT system. Combined with realistic computer models of patients created from clinical CT data, the program was applied to estimate patient-specific dose from pediatric chest and abdomen-pelvic CT examinations and to investigate the dose variation across patients due to the variability of patient anatomy and body habitus. The Monte Carlo method was further employed to investigate the effects of patient size and scan parameters on dose and risk for the entire pediatric population. </p> <p>The second part of this dissertation involved the development of tools needed to study the diagnostic accuracy of small lung nodules on pediatric CT images. A prior method for modeling two-dimensional symmetric liver/lung lesions was extended to create three-dimensional nodules with asymmetric shapes and diffused margins. A method was also developed to estimate quantum noise in the lung region of a CT image based on patient size.</p> <p>The last part of this dissertation involved assessment of diagnostic accuracy using receiver operating characteristic (ROC) observer experiments. A pilot study of 13 pediatric patients (1-7 years old) was first conducted to evaluate the effect of tube current on diagnostic accuracy, as measured by the area under the ROC curve (Az). A study of 30 pediatric patients (0-15 years old) was then conducted to assess protocol- and scanner-independent relationships between image quality (nodule detectability and noise) and diagnostic accuracy. The relationships between diagnostic accuracy and nodule detectability, between noise and scan parameters, and between dose/risk and scan parameters were lastly combined to yield the relationship between diagnostic accuracy and dose/risk.</p> <p></p> <p>For pediatric patients in the same weight/protocol group, organ dose variation across patients was found to be generally small for large organs in the scan coverage (< 10%), larger for small organs in the scan coverage (1-18%), and the largest for organs partially or completely outside the scan coverage (6-77%). Across the entire pediatric population, dose and risk associated with a chest scan protocol decreased exponentially with increasing patient size. The average chest diameter was found to be a stronger predictor of dose and risk than weight and total scan length.</p> <p></p> <p>The effects of bowtie filter and beam collimation on dose and risk were small compared to the effects of helical pitch and tube potential. The effects of any scan parameter were patient size-dependent, which could not be reflected by the difference in volume-weighted CT dose index (CTDIvol).</p> <p>Over a nodule detectability (product of nodule peak contrast and display diameter to noise ratio) range of approximately 52-374 mm with an average of 143 mm, tube current or dose had a weak effect on the diagnostic accuracy of lung nodules. The effect of 75% dose reduction was comparable to inter-observer variability, suggesting a potential for dose reduction.</p> <p>Diagnostic accuracy increased with increasing nodule detectability over the range of 25-374 mm, but reached a plateau beyond a threshold of ~ 99 mm. The trend was analogous to the relationship between Az and signal-to-noise ratio and suggested that the performance of the radiologists saturates (or increases slowly) beyond a threshold nodule detectability level; further reducing noise or increasing contrast to improve nodule detectability beyond the threshold yields little gain in diagnostic accuracy.</p> <p>For a typical product of nodule contrast and physical diameter (1400 HU&middotmm) and a set of most commonly used scan parameters (tube potential of 120 kVp, helical pitch of 1.375, slice thickness of 5 mm, gantry rotation period of 0.4 second, image pixel size of 0.48 mm), diagnostic accuracy increased with effective dose and effective risk for a given patient size, but reached a plateau beyond a threshold dose/risk level. At a given effective dose, Az increased with decreasing patient size, i.e., the dose needed to achieve the same noise and hence diagnostic accuracy increased with patient size. To achieve an Az of 0.90, the dose needed for a 22-cm diameter (male) patient was about quadruple of that for a 10-cm diameter patient. While the effective risk associated with achieving the same diagnostic accuracy also increased with patient size, the risk associated with an Az of 0.90 was only twice as high for a 22-cm diameter (male) patient than for a 10-cm diameter patient due to the older age of the larger patient.</p> <p>The research in this dissertation has two important clinical implications. First, the quantitative relationships between patient dose/risk and patient size, between patient dose/risk and scan parameters, between diagnostic accuracy and image quality, and between diagnostic accuracy and radiation dose can guide the design of pediatric CT protocols to achieve the desired diagnostic accuracy at the minimum radiation dose. Second, patient-specific dose and risk information, when included in a patient's dosimetry and medical records, can inform healthcare providers of prior radiation exposure and aid in decisions for image utilization, including the situation where multiple examinations are being considered.</p> / Dissertation

The feasibility of using a thyroid uptake counter, normally used to measure the uptake of radioactive iodine in thyroid treatments, to assay radioactivity deposited in a persons lungs has been investigated. Variations in radioactive material distributions in the lungs, the response of the detector system to radionuclides of interest to homeland security, and the change in detection efficiency due to the varying thicknesses of intervening tissue of the victims have been simulated using the Monte Carlo N-Particle transport code (MCNP5) developed by Los Alamos National Laboratory. Point source and homogenously distributed models were created for Co-60, I-131, Cs-137, Ir-192, and Am-241 sources to simulate radiation transport between the lungs of multiple phantom models representing children and adults and the radiation detection system. To validate the simulations undertaken, the response of the counter to radiation sources in air and behind layers of Lucite have been modeled and compared to measured results.

Monte Carlo (MC) methods are widely accepted as the most accurate technique for calculating dose distributions in radiation therapy physics. Simulating the particle transport through the treatment head of a linear accelerator utilizing a MC based code is both a widespread and practical approach to determining detailed clinical beam characteristics such as the energy, angular and spatial distribution of particles which are needed to properly quantify dose. One particular and versatile MC code, the Monte Carlo N-Particle (MCNP) radiation transport code, developed by Los Alamos National Laboratory, has been commonly used to model ionizing radiations for medical physics applications. In this thesis, a Varian 2100C linear accelerator (linac) is modeled and the electron and photon transport through the primary components of the treatment head are simulated using MCNP Version 5_1.3. The 6 MV photon spectra was characterized in a standard 10 x 10 cm2 field and subsequent dose calculations were made in a Virtual Water (VW) phantom. Energy fluence, percent depth dose and beam profile measurements were taken in a modeled VW phantom and the calculated data was compared to measured reference data. In addition, a human phantom was modeled for future dose calculations using the modeled linac. The linac model created can incorporate different beam energies for determining the dose distribution of multiple beam treatments in phantoms for standard 6 MV plans. The adaptability of this MCNP model allows for any number of geometries and sources encountered in medical physics to be computed and applied with relative ease. Future studies can involve adding complex multi-leaf collimator beam shaping and calculating the dose in human phantom models, which would serve as a basis for studies involving MCNP modeling for dose optimization in medical physics applications.

No description available.

High-dose morphine has been extensively used in the control of postoperative and cancer pain. Patients receiving prolonged administration of high-dose morphine are known to be associated with certain cardiovascular complications and tissue regeneration defects. This research thesis aims to investigate the biological effects and molecular mechanisms of high-dose morphine on the vascular endothelial function, angiogenesis and wound regeneration using murine models of morphine-dependence and cultured endothelial cell assays. Mice were subjected to placebo or morphine (20 mg/kg, i.p.) injection for consecutive 14 days. Aortas were harvested for assessment of vasomotor function by isometric force recordings. Protein expression p47phox (a major subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase) was determined by Western blotting. Generation of superoxide anions was detected under confocal microscope. Endothelium-dependent relaxations to acetylcholine were significantly reduced in morphine-treated animals, but were normalized by superoxide scavenging. Fluorescent densities of dihydroethidium and expression of p47phox were increased in the aorta of morphine-treated mice. In the second part of this thesis, the candidate determined the effects of high-dose morphine on angiogenesis and mobilization of endothelial progenitor cells (EPCs) in a mouse model of excisional wound injury. Excisional wound was created on control and morphine-dependent mice. Wound healing was compared by measuring the final-to-initial wound area ratio. Generation of superoxide anions in the wound was determined by luminol-enhanced chemiluminescence. Circulating mononuclear cells were isolated and measured for EPC (defined as CD34+/CD133+ cell) counts. In vivo and in vitro measurements of angiogenesis following morphine treatment were performed using the Matrigel assay. The results showed that wound closure was significantly reduced in mice treated with morphine when compared with controls, and higher levels of superoxide anions were generated in these wounds. High-dose morphine reduced numbers of circulating EPCs following creation of excisional wound. Matrigel assay showed impaired angiogenesis in animals and reduced capillary tube formation in cultured endothelial cells treated with high-concentration of morphine. Collectively, this research thesis demonstrated a number of novel findings. First, high-dose of morphine impairs vascular endothelial function by increased production of vascular superoxide anions. Activation of NADPH oxidase may be the molecular mechanisms responsible for reduced bioavailability of endothelium-derived NO. Second, systemic administration of high-dose morphine delays healing of excisional wounds and impairs angiogenesis. This antiangiogenic effect is associated with increased superoxide anions production and impaired mobilization of EPCs. In line with direct endothelial dysfunction, impaired angiogenesis and EPC mobilization resulted from high-dose morphine treatment may cause increased cardiovascular morbidity in human subjects receiving higher therapeutic dose of morphine.

Thesis (M.S.)--James Madison University, 2009. / Includes bibliographical references.