Attention has begun to focus on the pulmonary delivery of antifungal agents for invasive fungal infections as inhalation of the fungal spores is often the initial step in the pathogenesis of many of these infections. Invasive fungal infection in the lungs in immunocompromised patients has high mortality rates despite current systemic (oral or intravenous) therapies. However, drug delivery of antifungal agents directly to the lungs could potentially result in high concentrations of drug in the lungs, a quicker onset of action, and reduction of systemic side effects. Voriconazole (VRC) is a second, generation triazole antifungal agent with increased potency, a broad spectrum of antifungal activity, and a fairly poor aqueous solubility. It is the recommended therapeutic agent for the treatment of Invasive Pulmonary Aspergillosis (IPA), and its use has improved therapeutic outcomes in immunocompromised patients with IPA. Still, systemic administration by oral or intravenous delivery is limited by high inter- and intra-patient pharmacokinetic variability, many potential drug interactions, and a narrow therapeutic index with many adverse effects, leading to clinical failures. Therefore, development of novel particulate formulations containing VRC for targeted drug delivery to the lungs is critical to improving therapeutic outcomes in patients with invasive fungal infections in the lungs. Within the framework of this dissertation, two particle engineering processes, thin film freezing (TFF) and advanced evaporative precipitation into aqueous solution (AEPAS), were investigated. The goal was to investigate microcrystalline VRC, nanocrystalline VRC, and nanostructured amorphous VRC formulations suitable for pulmonary delivery and to determine the effect of morphology on the in vivo deposition and distribution of inhaled particulate VRC formulations. TFF process parameters significantly affected the solid state properties and aerodynamic performance of the dry powder formulations containing VRC. Following dry powder insufflation into the lungs of mice, microstructured crystalline TFF-VRC achieved higher and more prolonged concentrations of VRC in the lungs with slightly lower systemic bioavailability than nanostructured amorphous TFF-VRC-PVP K25. AEPAS and TFF of template nanoemulsions did not lead to production of crystalline nanoparticles, as predicted. In particular, VRC proved to be a difficult molecule to stabilize in the nanocrystalline and nanostructured amorphous states. Ultimately, this body of work demonstrated that the particle engineering process, TFF, could be used to develop voriconazole formulations suitable for dry powder inhalation with more favorable pharmacokinetic parameters compared to inhaled voriconazole solution. / text

The use of hydraulic fracturing has increased rapidly and is now a necessary technique for the development of shale oil and gas resources. However, production rates from these plays typically exhibit high levels of decline. After one year, rates often decrease by over fifty percent. Refracturing – the process of hydraulically fracturing a well that has previously been fractured – is a proposed technique designed to offset these high decline rates and provide a sustainable increase in production. Benefits from refracturing can occur due to a variety of reasons, including the extension of fracture length, the increase in fracture conductivity or the reorientation of the fracture into new areas of the reservoir. In this thesis, the simulation of refracturing treatments on horizontal wells with the use of a diverting agent is described. Diverting agents are used to distribute flow more evenly along the wellbore and to replace the use of costly downhole equipment employed to isolate sections of the wellbore. When diverting agent is deposited, a cake forms with an associated permeability. Flow is diverted from the fractures with high amounts of diverting agent because the larger cake results in a greater resistance to flow. The diverting agent cake breaks down with time at reservoir temperature so that production is uninhibited. Two different models are used to account for the application of diverting agent. One assumes the diverting agent cake forms in the perforation tunnel and the other assumes it forms in the fracture. The propagation of competing fractures is calculated using a computer code developed at the University of Texas called UTWID. In both models, the simulations showed successful diversion of flow. Previously understimulated fractures – that is, shorter fractures or fractures that would grow less preferentially under normal fracturing treatments – grew at a faster pace after pumping of the diverting agent. A sensitivity analysis was conducted on several of the key refracturing design parameters, and the interdependence of the parameters was demonstrated. The simulations support the concept that diverting agents can be used to more evenly stimulate the entire length of the lateral. / text

In online shopping buyers do not have enough information about sellers and cannot inspect the products before purchasing them. To help buyers find reliable sellers, online marketplaces deploy Trust and Reputation Management (TRM) systems. These systems aggregate buyers’ feedback about the sellers they have interacted with and about the products they have purchased, to inform users within the marketplace about the sellers and products before making purchases. Thus positive customer feedback has become a valuable asset for each seller in order to attract more business. This naturally creates incentives for cheating, in terms of introducing fake positive feedback. Therefore, an important responsibility of TRM systems is to aid buyers find genuine feedback (reviews) about different sellers. Recent TRM systems achieve this goal by selecting and assigning credible advisers to any new customer/buyer. These advisers are selected among the buyers who have had experience with a number of sellers and have provided feedback for their services and goods. As people differ in their tastes, the buyer feedback that would be most useful should come from advisers with similar tastes and values. In addition, the advisers should be honest, i.e. provide truthful reviews and ratings, and not malicious, i.e. not collude with sellers to favour them or with other buyers to badmouth some sellers. Defining the boundary between dishonest and honest advisers is very important. However, currently, there is no systematic approach for setting the honesty threshold which divides benevolent advisers from the malicious ones. The thesis addresses this problem and proposes a market-adaptive honesty threshold management mechanism. In this mechanism the TRM system forms a feedback system which monitors the current status of the e-marketplace. According to the status of the e-marketplace the feedback system improves the performance utilizing PID controller from the field of control systems. The responsibility of this controller is to set the the suitable value of honesty threshold. The results of experiments, using simulation and real-world dataset show that the market-adaptive honesty threshold allows to optimize the performance of the marketplace with respect to throughput and buyer satisfaction.

My PhD research involves multi-disciplinary areas of study such as measuring perfusion of blood vessels in hamster dorsal skin using laser speckle imaging technique. In this study the changes were measured in blood flow velocity and diameters of micro vasculatures after the influence of glycerol application. The second study identifies the changes in morphology and optical properties of eye tissue after applying hyper-osmotic agent such as 100% anhydrous glycerol. Further investigation on the reversal process was performed without any application of 0.9% saline. The third study identified the variation in fluorescence in hamster dorsal skin tissue and enucleated porcine eyes with temperature. This study investigated the variation in fluorescence intensity with temperatures starting at 14°C and compared in vivo and in vitro results for consistency. The fourth study investigated an implantable drug delivery package that was fabricated using PMMA and implanted between the sub-conjunctival and super-scleral space and release the content of the device by either mechanical pressure or light-activated ophthalmic Nd:YAG laser after optically clearing the eye tissue by topical application of a hyper-osmotic agent, 100% anhydrous glycerol. A hyper-osmotic agent creates a transport region in the conjunctiva and sclera to get visual access of the compartments in the drug delivery package. This new technology would provide the option to the patient of one time implantation of the carrier system containing the drug. Each time the patient requires medication a ND-YAG or other laser beam will propagate through the cleared eye tissue to release the drug in measurable doses at the discretion of the doctor from the package directly in to the vitreous humor. In this study we have measured half-life of the dye in the vitreous humor or posterior chamber and biocompatibility. The last study had drawn distinction between the fluorescence signals based on the location (anterior or posterior chamber) of the 10% Na fluorescence dye in the in vivo rabbit and ex vivo pig eyes. / text

MRI can benefit from an increase in the sensitivity of contrast agents. The CEST MRI technique in particular suffers from very poor sensitivity when using diamagnetic contrast agents. Polymerized CEST MRI contrast agents could increase the sensitivity per macromolecule over monomer contrast agents. The increase in sensitivity is related to the increase in number of contrast agents per polymer. A contrast agent with increased sensitivity can be used to image on the molecular level in vivo, where the concentration of targets is very low. A polymerized diaCEST contrast agent was synthesized by coupling a salicylic acid analogue to a poly (acrylic acid) backbone. The CEST effect of the coupled analogue was compared to its uncoupled form for different concentrations and pH values. A RL-QUEST method was used to calculate the exchange rate of the analogue for different pH values before and after coupling. The polymerized diaCEST agent was attempted to be loaded into DOPC and bis-SorbPC liposomes, and was also attempted to be targeted to folate receptors in a KB cell culture. These studies establish the foundation for translation of polymerized diaCEST contrast agents to additional in vitro and in vivo investigations.

Sammanfattning Problemformulering: Vilka upplevda effekter har belöningssystem på agent- och principalproblem i en ledningsgrupp i svenska medelstora familjeföretag och hur är de uppbyggda? Syfte: Syftet är att undersöka hur uppbyggandet av belöningssystem till ledningsgruppen egentligen ser ut i svenska medelstora familjeföretag och vilka upplevda effekter det har på agent- och principalproblemen. Metod: Uppsatsen är en kvalitativ studie med en deduktiv ansats. Vi ger en överblick på hur vi har diskuterat oss fram till valen av metoderna samt det värde de tillför uppsatsen. Teoretisk referensram: I kapitlet presenterar vi tillämpning av teorier, begrepp och modeller som används i studien. Vi ger en förklaring på begreppen som rör studier om familjeföretag, agent- och principalteorin, belöningssystem och deras samverkan med varandra. Dessa mynnar senare ut i en övergripande modell som förklarar vår problemformulering. Den teoretiska referensramen ligger senare till grund för analysen av det empiriska materialet. Empirisk metod: I kapitlet förklarar vi hur undersökningen och insamlandet av material har gått till på ett metodiskt empiriskt sätt. I kapitlet presenteras de delaktiga företagen, tillvägagångssätt och urvalsramen. Datamaterialet består av en primär karaktär som skapats via intervjuerna. Empirisk referensram: Här presenteras insamlad fakta utifrån våra djupintervjuer med respondenterna. Slutsats: Studien visar att belöningssystemets uppbyggnad och upplevda effekter i en ledningsgrupp är starkt beroende på graden av upplevda agent- och principalproblem. De altruistiska motiven i familjeföretag är för utbredda för att helt och hållet elimineras.

A new class of polymer stabilized gadolinium trifluoride nanoparticles (NPs) have been developed as contrast agents for magnetic resonance imaging (MRI) and computed tomography (CT), with potential long term goals in targeted imaging and anti-cancer therapy. The NPs are comprised of a 90/10 mixture of GdF3/EuF3 and are coated with linear polyacrylic acid (PAA) chains consisting of 25 repeating units. The resulting aggregates are stable in serum and possess unprecedented mass relaxivities [i.e. ~100-200 s-1(mg/mL)-1]. Electron microscopy images reveal various NP morphologies which depend on the exact synthesis protocol. These include highly cross-linked oblong clusters with 30-70 nm cross sections, extensively cross-linked aggregates with 100-300 nm cross sections, and distinct polymer stabilized nanocrystals with 50 nm diameters. Their application as contrast agents in T1-weighted MRI studies, CT imaging at various X-ray energies, and preliminary rat brain perfusion studies was also tested. NP contrast enhancement was compared to Gd-DPTA (Magnevist®) and iopramide (Ultravist 300®) to demonstrate their high contrasting properties and potential as multimodal contrast agents.

Freight transport is the output of an economic market, which converts commodity flows into vehicle flows. Interactions in this market influence vehicle flows and since freight market characteristics (product differentiation and economies of scale/scope) violate perfect competition conditions, the output of this market cannot be predicted directly, unless these interactions are represented in the forecasting models. Traditional freight modelling frameworks do not consider these interactions and consequently they may provide inaccurate freight flow forecasts. In this dissertation, a freight modelling framework is proposed using simulation of freight agent interactions in the economic market to forecast freight flows. The framework is named FREMIS (FREight Market Interactions Simulation). The FREMIS framework consists of two demand models to represent shipper decisions (bundling of shipments and carrier selection) in the market and functions based on profit maximizing behaviour to simulate carrier proposals for contracts. Besides that, learning models are proposed to simulate agent learning processes based on their interactions. The framework was developed aiming to create a realistic representation of freight markets using feasible data collection methods. To illustrate the feasibility of the data collection, a customized web survey was implemented with shippers and carriers in a freight market. Two probabilistic models were developed using the data. The first model, a shipment bundling model was proposed combining a probabilistic model and a vehicle routing algorithm. The results of the probabilistic model are presented in this dissertation, where the locations of shipments (origin and destination) influence the probability of bundling them. Second, three carrier selection models were developed aiming to analyse the nonresponse bias and non-attendance problem in the survey. All of these models assumed heteroskedasticity (different scale or variance) in shipper behaviour. In all models, the hypothesis of agents’ heteroskedasticity cannot be rejected. Besides that, nonresponse bias and non-attendance problem were identified in the survey. In conclusion, the models obtained from the survey were consistent with their behavioural assumptions and therefore they can be adopted during FREMIS implementation.

L'interoperabilite semantique est une question importante, largement identifiee dans les technologies d'organisation et de l'information et dans la communaute de recherche en systemes d'information. L'adoption large du Web afin d'acceder a des informations distribuees necessite l'interoperabilite des systemes qui gerent ces informations. Des solutions et reflexions comme le Web Semantique facilitent la localisation et l'integration des donnees d'une maniere plus intelligente par l'intermediaire des ontologies. Il offre une vision plus semantique et comprehensible du web. Pourtant, il souleve un certain nombre de defis de recherche. Un des principaux defis est de comparer et aligner les differentes ontologies qui apparaissent dans des taches d'integration. Le principal objectif de cette these est de proposer une approche d'alignement pour identifier les liens de correspondance entre des ontologies. Notre approche combine les techniques et les methodes d'appariement linguistiques, syntaxiques, structurelles ou encore semantiques (basees sur les instances). Elle se compose de deux phases principales : la phase d'enrichissement semantique des ontologies a comparer et la phase d'alignement ou de mapping. La phase d'enrichissement est basee sur l'analyse des informations que les ontologies developpent (des ressources web, des donnees, des documents, etc.) et qui sont associes aux concepts de l'ontologie. Notre intuition est que ces informations ainsi que les relations qui peuvent exister entre elles participent a l'enrichissement semantique entre les concepts. A l'issue de la phase d'enrichissement, une ontologie contient plus de relations semantiques entre les concepts qui seront exploitees dans la deuxieme phase. La phase de mapping prend deux ontologies enrichies et calcule la similarite entre les couples de concepts. Un processus de filtrage nous permet de reduire automatiquement le nombre de fausses relations. La validation des correspondances est un processus interactif direct (avec un expert) ou indirect (en mesurant le degre de satisfaction de l'utilisateur). Notre approche a donne lieu a un systeme de mapping appele ROMIE (Resource based Ontology Mapping within an Interactive and Extensible environment). Il a ete experimente et evalue dans deux differentes applications : une application biomedicale et une application dans le domaine de l'apprentissage enrichi par les technologies (ou e-learning).

The ill-effects of stress due to fatigue significantly impact the welfare of individuals and consequently impact overall corporate productivity. This study introduces a simplified model of stress in the workplace using agent-based simulation. This study represents a novel contribution to the field of evolutionary computation. Agents are encoded initially using a String Representation and later expanded to multi-state Binary Decision Automata to choose between work on a base task, special project or rest. Training occurs by agents inaccurately mimicking behaviour of highly productive mentors. Stress is accumulated through working long hours thereby decreasing productivity performance of an agent. Lowest productivity agents are fired or retrained. The String representation for agents demonstrated near average performance attributed to the normally distributed tasks assigned to the string. The BDA representation was found to be highly adaptive, responding robustly to parameter changes. By reducing the number of simplifications for the model, a more accurate representation of the real world can be achieved.