New Framework and Metrics for Economic Evaluation of Medical Technology in the Presence of Heterogeneity and Its Application to the Evaluation of Bariatric Surgery

Thesis (Ph.D.)--University of Washington, 2016-07

In vitro studies of drug transformations: application to forensic toxicology

The forensic toxicologist faces challenges in the detection of drugs and poisons in biological samples due to transformations which occur both during life and after death. For example, changes can result from drug metabolism during life or from the use of formalin solution for post mortem embalming purposes. The former requires the identification of drug metabolites and the latter the identification of chemical reaction products in order to know which substances had been administered. The work described in this thesis was aimed at providing ways of tackling these challenges and was divided into two parts. Part 1 investigated the use of in vitro drug metabolism by human liver microsomes (HLM) to obtain information on drug metabolites and Part 2 investigated the chemical reactions of drugs and a carbamate pesticide with formalin solution and formalin-blood. The initial aim of part I was to develop an in vitro metabolism method using HLM, based on a literature review of previous studies of this type. MDMA was chosen as a model compound to develop the HLM method because its metabolism was known and standards of its metabolites were commercially available. In addition, a sensitive and selective method was developed for the identification and quantitation of hydrophilic phase I drug metabolites using LC/MS/MS with a conventional reverse-phase (C18) column. In order to obtain suitable retention factors for polar drug metabolites on this column, acetyl derivatives were evaluated for converting the metabolites to more lipophilic compounds and an optimal separation system was developed. Acetate derivatives were found to be stable in the HPLC mobile phase and to provide good chromatographic separation of the target analytes. In vitro metabolism of MDMA and, subsequently, of other drugs involved incubation of 4 µg drug substance in pH 7.4 buffer with an NADPH generating system (NGS) at 37oC for 90 min with addition of more NGS after 30 min. The reaction was stopped at 90 min by the addition of acetonitrile before extraction of the metabolites. Acetate derivatives of MDMA metabolites were identified by LC/MS/MS using multiple reaction monitoring (MRM). Three phase I metabolites (both major and minor metabolites) of MDMA were detected in HLM samples. 3,4-dihydroxy-methamphetamine and 4-hydroxy-3-methoxymethamphetamine were found to be major metabolites of MDMA whereas 3,4-methylenedioxyamphetamine was found to be a minor metabolite. Subsequently, ten MDMA positive urines were analysed to compare the metabolite patterns with those produced by HLM. An LC/MS method for MDMA and its metabolites in urine samples was developed and validated. The method demonstrated good linearity, accuracy and precision and insignificant matrix effects, with limits of quantitation of 0.025 µg/ml. Moreover, derivatives of MDMA and its metabolites were quantified in all 10 positive human urine samples. The urine metabolite pattern was found to be similar to that from HLM. The second aim of Part 1 was to use the HLM system to study the metabolism of some new psychoactive substances, whose misuse worldwide has necessitated the development of analytical methods for these drugs in biological specimens. Methylone and butylone were selected as representative cathinones and para-methoxyamphetamine (PMA) was chosen as a representative ring-substituted amphetamine, because of the involvement of these drugs in recent drug-related deaths, because of a relative lack of information on their metabolism, and because reference standards of their metabolites were not commercially available. An LC/MS/MS method for the analysis of methylone, butylone, PMA and their metabolites was developed. Three phase I metabolites of methylone and butylone were detected in HLM samples. Ketone reduction to β-OH metabolites and demethylenation to dihydroxy-metabolites were found to be major phase I metabolic pathways of butylone and methylone whereas N-demethylation to nor-methylone and nor-butylone were found to be minor pathways. Also, demethylation to para-hydroxyamphetamine was found to be a major phase I metabolic pathway of PMA whereas β-hydroxylation to β-OH-PMA was found to be a minor pathway. Formaldehyde is used for embalming, to reduce decomposition and preserve cadavers, especially in tropical countries such as Thailand. Drugs present in the body can be exposed to formaldehyde resulting in decreasing concentrations of the original compounds and production of new substances. The aim of part II of the study was to evaluate the in vitro reactions of formaldehyde with selected drug groups including amphetamines (amphetamine, methamphetamine and MDMA), benzodiazepines (alprazolam and diazepam), opiates (morphine, hydromorphone, codeine and hydrocodone) and with a carbamate insecticide (carbosulfan). The study would identify degradation products to serve as markers for the parent compounds when these were no longer detectable. Drugs standards were spiked in 10% formalin solution and 10% formalin blood. Water and whole blood without formalin were used for controls. Samples were analysed by LC/MS/MS at different times from the start, over periods of up to 30 days. Amphetamine, methamphetamine and MDMA were found to rapidly convert to methamphetamine, DMA and MDDMA respectively, in both formalin solution and formalin blood, confirming the Eschweiler-Clarke reaction between amine-containing compounds and formaldehyde. Alprazolam was found to be unstable whereas diazepam was found to be stable in both formalin solution and water. Both were found to hydrolyse in formalin solution and to give open-ring alprazolam and open-ring diazepam. Other alprazolam conversion products attached to paraformaldehyde were detected in both formalin solution and formalin blood. Morphine and codeine were found to be more stable than hydromorphone and hydrocodone in formalin solution. Conversion products of hydromorphone and hydrocodone attached to paraformaldehyde were tentatively identified in formalin solution. Moreover, hydrocodone and hydromorphone rapidly decreased within 24 h in formalin blood and could not be detected after 7 days. Carbosulfan was found to be unstable in formalin solution and was rapidly hydrolysed within 24 h, whereas in water it was stable up to 48 h. Carbofuran was the major degradation product, plus smaller amounts of other products, 3-ketocarbofuran and 3-hydrocarbofuran. By contrast, carbosulfan slowly hydrolysed in formalin-blood and was still detected after 15 days. It was concluded that HLM provide a useful tool for human drug metabolism studies when ethical considerations preclude their controlled administration to humans. The use of chemical derivatisation for hydrophilic compounds such as polar drug metabolites for analysis by LC/MS/MS with a conventional C18 column is effective and inexpensive, and suitable for routine use in the identification and quantitation of drugs and their metabolites. The detection of parent drugs and their metabolites or conversion and decomposition products is potentially very useful for the interpretation of cases in forensic toxicology, especially when the original compounds cannot be observed.

Beyond Blame: cultural barriers to medical reporting

The paper explores the attitudes of medical physicians towards adverse incident reporting in health care, with particular focus on the inhibiting factors or barriers to participation. It is recognised that there are major barriers to medical reporting, such as the ‘culture of blame’. There are, however, few detailed qualitative accounts of medical culture as it relates to incident reporting. Drawing on a 2-year qualitative case study in the UK, this paper presents data gathered from 28 semi-structured interviews with specialist physicians. The findings suggest that blame certainly inhibits medical reporting, but other cultural issues were also significant. It was commonly accepted by doctors that errors are an ‘inevitable’ and potentially unmanageable feature of medical work and incident reporting was therefore ‘pointless’. It was also found that reporting was discouraged by an anti-bureaucratic sentiment and rejection of excessive administrative duties. Doctors were also apprehensive about the increased potential for managers and non-physicians to engage in the regulation of medical quality through the use of incident data. The paper argues that the promotion of incident reporting must engage with more than the ubiquitous ‘culture of blame’ and instead address the ‘culture of medicine’, especially as it relates to the collegial and professional control of quality.

Using serious games for improving medical education: an application to cytopathology

El objetivo principal del proyecto es desarrollar una plataforma compuesta por aplicaciones educativas gamificadas para el entrenamiento de personal médico en países de recursos limitados en citopatología mediante dispositivos Android de bajo presupuesto. Antes de desplegar la plataforma en países con recursos limitados, va a ser probada en un curso de Introducción a Citopatología de la Escuela Médica de Harvard. El proyecto final debe funcionar tanto en PCs como en dispositivos Android de bajo coste (p.e. 50 dólares americanos, Amazon Kindle Fire 7 pulgadas) y no puede depender de una conexión a internet continua. Se han analizado algunas aplicaciones con propósito de juego y simulaciones gamificadas para tener una base de conocimiento común entre expertos médicos y desarrolladores. También se han estudiado juegos y aplicaciones cuyo objetivo es hacer uso de imágenes médicas para entrenamiento de personal médico o están enfocadas al diagnóstico mediante colaboración por parte de personal no-médico. Esto nos ha permitido identificar las mejores mecánicas de juego para nuestro caso de uso. A continuación, se han comparado diferentes herramientas de edición y motores de juegos desde el punto de vista del rendimiento ofrecido, las plataformas soportadas, su documentación y licencia. Todo ello nos ha permitido elegir la tecnología de desarrollo (libGDX). Finalmente, diseñamos e implementamos un sistema integrado de aplicaciones (editor de contenido y generador de juegos). El sistema está enfocado a reducir la dependencia entre el personal experto y los desarrolladores para crear y mantener contenido educativo. Se trata de una arquitectura formada por un servicio RESTful, y un editor asociado, orientado a la gestión de contenido educativo orientado para citopatología y dos clientes para diferentes plataformas (PC y Android) que consumen dicho servicio. Finalmente, se presentan las conclusiones y el trabajo futuro del proyecto.

Classification of Airborne LIDAR Intensity Data Using Statistical Analysis and Hough Transform with Application to Power Line Corridors

Light Detection and Ranging (LIDAR) has great potential to assist vegetation management in power line corridors by providing more accurate geometric information of the power line assets and vegetation along the corridors. However, the development of algorithms for the automatic processing of LIDAR point cloud data, in particular for feature extraction and classification of raw point cloud data, is in still in its infancy. In this paper, we take advantage of LIDAR intensity and try to classify ground and non-ground points by statistically analyzing the skewness and kurtosis of the intensity data. Moreover, the Hough transform is employed to detected power lines from the filtered object points. The experimental results show the effectiveness of our methods and indicate that better results were obtained by using LIDAR intensity data than elevation data.

Vibrational spectroscopic studies of laboratory scale polymer melt processing : application to a thermoplastic polyurethane nanocomposite

A laboratory scale twin screw extruder has been interfaced with a near infrared (NIR) spectrometer via a fibre optic link so that NIR spectra can be collected continuously during the small scale experimental melt state processing of polymeric materials. This system can be used to investigate melt state processes such as reactive extrusion, in real time, in order to explore the kinetics and mechanism of the reaction. A further advantage of the system is that it has the capability to measure apparent viscosity simultaneously which gives important additional information about molecular weight changes and polymer degradation during processing. The system was used to study the melt processing of a nanocomposite consisting of a thermoplastic polyurethane and an organically modified layered silicate.

From cultural studies to cultural science

This paper, first presented at a symposium on the 'past, present and future of cultural studies,' traces disciplinary changes in the study of culture from the perspective of 'cultural science', a term that was used by some of the earliest practitioners of cultural studies, including Raymond Williams. The paper goes on to describe some of the present moment, including work on the creative industries, show that a new version of cultural science is needed, based on evolutionary principles, in dialogue with the evolutionary approach in economics that was called for a century ago by Thorstein Veblen. This evolutionary turn, or 'cultural science 2.0,' it is argued, offers a radical and challenging future for cultural studies.

Identification of alcohol involvement in injury-related hospitalisations using routine data compared to medical record review

Objective: To quantify the extent to which alcohol related injuries are adequately identified in hospitalisation data using ICD-10-AM codes indicative of alcohol involvement. Method: A random sample of 4373 injury-related hospital separations from 1 July 2002 to 30 June 2004 were obtained from a stratified random sample of 50 hospitals across 4 states in Australia. From this sample, cases were identified as involving alcohol if they contained an ICD-10-AM diagnosis or external cause code referring to alcohol, or if the text description extracted from the medical records mentioned alcohol involvement. Results: Overall, identification of alcohol involvement using ICD codes detected 38% of the alcohol-related sample, whilst almost 94% of alcohol-related cases were identified through a search of the text extracted from the medical records. The resultant estimate of alcohol involvement in injury-related hospitalisations in this sample was 10%. Emergency department records were the most likely to identify whether the injury was alcohol-related with almost three-quarters of alcohol-related cases mentioning alcohol in the text abstracted from these records. Conclusions and Implications: The current best estimates of the frequency of hospital admissions where alcohol is involved prior to the injury underestimate the burden by around 62%. This is a substantial underestimate that has major implications for public policy, and highlights the need for further work on improving the quality and completeness of routine administrative data sources for identification of alcohol-related injuries.