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京都大学 / 新制・課程博士 / 博士(医学) / 甲第24090号 / 医博第4866号 / 新制||医||1059(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 岩田 想, 教授 林 康紀, 教授 松田 道行 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Concomitant with antibiotic use is the development of bacterial strains that are resistant to such compounds. Presently, the rate at which antibiotic-resistant pathogenic bacteria are emerging is outpacing our resupply of new antibacterials; therefore, renewed efforts to identify novel therapies are urgently needed. Transition metals are required by all life forms and, for bacteria, an adequate supply of nutrient metal is necessary to establish infection in a host. Indeed, as an antibacterial defense mechanism, eukaryotes have developed various means by which to restrict the availability of metal to the invading pathogen, thereby limiting its chances for successful colonization. As such, bacterial metal acquisition and homeostasis have been suggested as potential antibiotic targets to explore for the identification of new antibacterial small molecules. In this thesis I discuss my development of a high-throughput screening assay that specifically selects for compounds that perturb bacterial iron homeostasis. The results of this work led to the identification of a series of spiro-indoline-thiadiazole compounds that are toxic to bacteria via iron chelation. In addition to molecules that perturb the availability of bacterial intracellular iron, we present a series of spiro-indoline-thiadiazole analogs that inhibit bacterial growth by limiting zinc availability. Furthermore, we show that the respective zinc-perturbing analogs re-sensitize an otherwise drug-resistant strain of NDM-1-harbouring Klebsiella pneumoniae to carbapenem antibiotics. We discuss the potential for this class of compounds to serve as carbapenem adjuvants for treating infections caused by metallo-β-lactamase-containing pathogens. / Thesis / Doctor of Philosophy (PhD)

The thesis begins by examining the history of the newborn screening (NBS) process in the United States and why it is the way it is today. The next section explores why certain genetic conditions, such as Long QT Syndrome (LQTS), do not fulfill requirements for the recommended uniform screening panel (RUSP). Lastly, ethical considerations of expanded NBS in the age of genomic technology are examined by highlighting the principles of autonomy, beneficence, equity, cost-effectiveness, privacy and trust. Overall, the NBS process benefits children by identifying serious rare diseases and intervening early to prevent harm; however, a deeper ethical analysis highlights some of the concerns with expanding mandatory, universal NBS in the age of precision medicine. The focus must be on educating the public and healthcare professionals about the NBS process and using evidence-based protocols for adding new conditions to the panel. / Urban Bioethics

Background and Objectives: Community pharmacy screening for chronic disease risk factors can promote early detection. Little is known about how pharmacy services are used post-screening. The PIAAF Pharmacy study screened elderly participants for hypertension, diabetes, and atrial fibrillation (AF) in 26 pharmacies in Ontario and Alberta. The primary objective was to determine whether patients screening at risk for AF, hypertension and diabetes had increased odds and rates of pharmacy service receipt than those at lower risk. Methods: Participants’ pharmacy data were extracted. A conceptual framework of potentially influential factors was constructed. Measurable factors were used as variables in regression analyses. Generalized estimating equations (GEE) were created to model 1) receipt of all pharmacy services, 2) receipt of medication review, and 3) receipt of influenza vaccination. Results: 165 of 535 patients received 229 pharmacy services. 64% were medication reviews and 25% were influenza vaccinations. Screening at high risk for diabetes, hypertension, and AF was not associated with increased receipt of pharmacy services, except for influenza vaccine, which was associated with screening as high risk for diabetes (OR = 1.69 [95% CI 1.09, 2.64]). Screening in October (IRR = 2.85 [95% CI 1.67, 4.84]), eligibility for annual-only medication reviews (IRR = 2.15 [95% CI 1.53, 3.01]), number of medications (IRR = 1.92 [95% CI 1.07, 3.46]), new medications (IRR = 2.00 [95% CI 1.37, 2.93]), and living in Alberta (IRR = 1.46 [95% CI 1.07, 2.01]) were associated with increased rates of receiving pharmacy services. Discussion and Conclusions: Screening results were not associated with increased receipt of pharmacy services, with the exception of influenza vaccine and high risk of diabetes. A gap exists between screening and pharmacy service receipt. Pharmacists can use screening interventions and individual screening results as an opportunity to provide pharmacy services to those with chronic disease risk factors. / Thesis / Master of Health Sciences (MSc) / Community pharmacies may be ideal locations for screening of chronic diseases such as diabetes, high blood pressure, and abnormal heart rhythms. It is not well understood how pharmacy services are used in people after screening for these risk factors. This project aims to see if people screening at higher risk levels were more likely to receive pharmacy services than those at lower risk. We used patients’ pharmacy data to see what services they had received after screening, and then created statistical models to determine which patient-, pharmacy-, community-, and screening-related factors were associated with a greater chance of receiving pharmacy services. Being at risk of diabetes, high blood pressure, and irregular heart rhythms were not associated with a greater likelihood of receiving pharmacy services, except in those at high risk for diabetes—these patients were found be associated with a higher chance of receiving flu shots.

In Canada, nearly 25% of school-aged children have vision problems. Common childhood vision disorders include amblyopia, refractive errors, and strabismus. Early identification and treatment of these disorders can prevent long-term vision loss and improve academic achievement. In 2018, the Ontario Ministry of Health and Long-Term Care legislated universal childhood vision screening of all senior kindergarten students. Although studies have explored the effectiveness of these interventions, few have explored the barriers and facilitators to program implementation. This study used a qualitative descriptive approach to examine the perceptions of key informants regarding the factors influencing the implementation of school-based vision screening in Ontario, and the role of nurses in supporting implementation. Semi-structured interviews were conducted with parents (n = 3), optometrists (n = 3), clinical research personnel (n = 2), public health staff (n = 5), school staff (n =2), and community vision program personnel (n = 2) from across Ontario. The Consolidated Framework for Implementation Research (CFIR) was used to frame the analysis. The following factors were found to influence vision screening implementation: (1) student and parent needs; (2) presence of external partnerships; (3) dedication of tangible resources; (4) presence of internal networks and communications; and (5) the cost, complexity, and perceived quality of the vision screening program. Participants reported that public health nurses’ knowledge and skills, and their position within schools, communities, and the health system, facilitated vision screening implementation. This study suggests that a comprehensive and coordinated approach is necessary when implementing school-based vision screening programs. Future research examining vision screening implementation should consider the use of the CFIR to guide all phases of the implementation process, and explore the experience and perspectives of vision screening implementation of students, non-English speaking families, and those who had experienced failed vision screening. / Thesis / Master of Science (MSc) / In Canada, nearly 25% of school-aged children have vision problems. In 2018, the Ontario Ministry of Health and Long-Term Care passed a law requiring that all senior kindergarten students have their vision screened. This study used a qualitative descriptive approach to explore the perceptions of key informants regarding factors influencing implementation of school-based vision screening in Ontario, and the role of nurses in supporting implementation of this practice. The Consolidated Framework for Implementation Research was used to frame the analysis. The results of this study suggest that a comprehensive and coordinated approach is necessary when implementing school-based vision screening programs. Furthermore, participants reported that public health nurses’ knowledge and skills, and their position within schools, communities, and the health system, facilitated vision screening implementation. Therefore, public health units are encouraged to strategically utilize public health nurses when implementing vision screening. Practice, policy, education, and future research implications are discussed.