Magister Pharmaceuticae - MPharm / Antimicrobial resistance is a global concern associated with increased morbidity and mortality. It has been estimated that, by 2050, the continuous escalation of antimicrobial resistance, globally, will result in more deaths per year, compared to cancer and diabetes. The direct and indirect impact of ineffective antibiotics, and therefore, antimicrobial resistance, will be hardest felt by low and middle-income countries, as the financial burden will be too great to manage. Carbapenems are considered the last line of antimicrobials to treat multidrug-resistant bacterial infections. They are the preferred choice to treat infections, presenting with extended-spectrum beta-lactamases (ESBL) producing Enterobacteriacea. Various strains of bacteria that have become resistant, due to the selective pressure, as a result of carbapenem over use, are referred to as Carbapenem-resistant Enterobacteriaceae (CRE). / 2022

South Africa has the largest HIV-infected population in the world, with 2015 estimates of 7 million people living with HIV and 180,000 AIDS-related deaths. The South African government began scale-up of a public-sector HIV care and treatment program in 2004, and by the end of 2015, 3.4 million HIV-infected individuals were on antiretroviral therapy (ART). When scale-up began in South Africa, ART was only available to HIV-infected individuals with CD4 counts ≤200 cells/µL or WHO clinical stage 4 disease. In 2010, treatment was extended to patients who were pregnant or who had tuberculosis and a CD4 ≤350 cells/µL, and in 2011, eligibility was extended to all patients with CD4 ≤350 cells/µL. In 2013 patients with WHO clinical stage 3 disease became eligible. In 2015, the eligibility threshold was increased to CD4 ≤500 cells/µL, and in 2016, the South African National Department of Health announced that the country would implement a “test and treat” strategy, offering free ART to all HIV-infected individuals, regardless of CD4 count. This dissertation examines the effectiveness of several expansions and modifications to South Africa’s treatment program. In study 1, we investigated whether the 2011 extension of HIV treatment to patients with CD4 counts ≤350 cells/µL successfully increased the number of newly-eligible patients on treatment (those with CD4 counts between 201–350 cells/µL) without crowding out previously-eligible patients with more severe disease (CD4 counts ≤200 cells/µL), focusing on a network of rural clinics in KwaZulu-Natal. We found encouraging results, with newly-eligible patients (CD4 201–350) initiating treatment at a greater frequency (73.0 additional patients per month; 95% CI: 42.1; 103.9) and 47% faster than before (95% CI: 19%; 82%), while previously eligible patients (CD4 ≤200) experienced no decline in the number of patients initiating treatment or the speed of treatment uptake. In study 2, we evaluated whether the introduction of a single-pill fixed-dose combination (FDC) treatment for ART initiators in South Africa had an impact on attrition from care compared to the previously-recommended multiple-pill regimen. We focused on an urban clinic in Johannesburg, using four different clinic attendance measures to define attrition (generally a combined measure of loss to follow-up and mortality). An intention-to-treat analysis revealed an estimated 11.3 percentage point decrease in attrition (95% CI: -22.0; -0.6) associated with the policy change, while a regression discontinuity analysis estimated an 18.0 percentage point drop in attrition (95% CI: -33.6; -2.4) associated with single-pill FDC treatment relative to multiple pills, controlling for unmeasured confounding. In study 3, we used stratified instrumental variable analysis to examine whether the effect of FDCs on attrition varied across subsets of the patient population in the same Johannesburg clinic we evaluated in study 2. We saw larger effects among women (RD -0.25; 95% CI: -0.42; -0.09), non-anemic patients (RD -0.24; 95% CI: -0.41; -0.08), patients with early-stage (as opposed to advanced) clinical disease (RD -0.20; 95% CI: -0.32; -0.07), and those with high CD4 counts (for CD4 ≥350 cells/µL, RD -0.58; 95% CI: -1.58; 0.42). These results suggest that healthier patients saw the greatest improvement in retention in care following the switch from multiple-pill to single-pill regimens. In an era where the healthiest HIV-infected patients are now being targeted for ART treatment, FDCs can play a large role in preventing attrition from care. These three studies depict an HIV program that has successfully grown to treat increasing numbers of patients using up-to-date strategies of care. Given the immense scale and cost of South Africa’s HIV treatment program, it is important to continue to monitor its effectiveness, especially as it introduces new treatments and strategies and adapts to the changing epidemic.

The evaluation of ammoniation of mature grass (1/3 Festuca sp, 1/3 Bromus and 1/3 Dactylis sp) as a basal diet for pregnant ewes and its effects on ruminal fermentation were studied. Ammoniation increased the forage dry matter intake (DMI), crude protein (CP), and gross energy digestibility. Ruminal pH and total volatile fatty acid were not affected by ammoniation (P>.05). Individual VFA concentrations were affected significantly. In a third experiment, ammoniated wheat straw was evaluated as a basal diet for wintering pregnant ewes. Ammoniated straw replaced grass hay in the diet. Dry matter intake was not different (P>.05). Final body weight total gain, and fleece weight were higher for controls (P.05). A fourth experiment evaluated how rehydrating wheat straws prior to ammoniation affected utilization by pregnant western white-face ewes. These treatments increased dry matter and crude protein intakes significantly (P.05). Lamb birth weight was not affected by treatment (P=.874) and fleece weight increased (P<.05). Nutritive value of 5 barley and 10 wheat straw varieties was evaluated for ruminants with the in situ technique. Fiesta and Kombar barley varieties exhibited the highest dry matter disappearance (P In a final study, nitrogen and energy balance was measured on lactating western white-face ewes during early and late lactation. Milk production was .683 and .711 L/d during early and late lactation. Efficiency of milk production was .429 and .338 milk L/kg DM consumed for early and late lactation, respectively. Nitrogen balance was positive during both stages of lactation. Milk gross energy and metabolizable energy were 15.13 and 14.16% for early and late lactation, respectively.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20975号 / 医博第4321号 / 新制||医||1026(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 川上 浩司, 教授 鈴木 茂彦, 教授 開 祐司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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I investigated percent coverage, plant height, species richness, and woody stem density in plant communities in ten study plots during spring and fall (2010-2012) within 3 different treatments (continual mowings, one fall mowing, and one fall mowing with native wildflower seeds) on highway 25 right-of-way in Oktibbeha and Winston counties, Mississippi. I recorded 277 plant species including native and non-native forbs, legumes, grasses, rushes/sedges, and woody plants. Non-native agronomic grasses exhibited greatest coverage greater than 90 percent occurring in all treatments. Percent coverage of plants less than 0.46m height category exceeded 100 while, greater than 0.46m plant height categories averaged 55 percent. Woody stem density ranged from 7,772 year 1 to 10,025 stems/hectare year 2. I detected no significant differences in plant height or woody stems among treatments. One mowing per year retained agronomic plant cover for erosion control and annual cost savings up to 75 percent for roadside maintenance.

The United States Supreme Court has not yet examined several aspects of the death penalty. One aspect is the ability for the state to forcefully medicate an incompetent inmate, which may result in the inmate appearing competent for execution. While the Supreme Court' ruled that it is unconstitutional to execute an inmate who is incompetent, inmates who would have had their executions vacated due to mental illness are executed because the state can put them on an involuntary medication regimen. According to many experts, involuntary medication regimens mask the affects of their illness instead of providing a cure. Experts often refer to this practice as the "chemical straitjacket." Because the effects of antipsychotic medication, inmates may be sedated to a point where they appear competent, but in reality, they are sedated to a point where their mental illness is still present yet undetectable. As a result, placing condemned inmates on involuntary medication regimens has the possibility to violate the inmate's Fifth, Sixth, Eighth and Fourteenth Amendment rights. The intent of this thesis is to examine whether the Supreme Court has successfully upheld its duty to promote a fair judicial system by allowing the medicate to execute scheme to continue. Through the analysis of case law, law review articles, and the American Constitution, this thesis will evaluate the treatment of condemned inmates who show signs of incompetence. Through analysis, this thesis aims to raise awareness to an issue that, in the opinion of this writer, deserves the attention of American courts and other governing bodies.

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Yes / We investigated whether companion drug resistance was associated with adverse outcome of the shorter MDR-TB regimen in Bangladesh, after adjusting for fluoroquinolone resistance. MDR/RR-TB patients registered for treatment with a standardized gatifloxacin-based shorter MDR-TB regimen were selected for the study. Drug resistance was determined using the proportion method, gatifloxacin and isoniazid minimum inhibitory concentration testing for selected isolates, and whole genome sequencing. Low-level and high-level fluoroquinolone resistance were the most important predictors of adverse outcomes, with pyrazinamide resistance having a significant yet lower impact. In patients with fluoroquinolone-/second-line injectable-susceptible TB, non-eligibility to the shorter MDR-TB regimen (initial resistance to either pyrazinamide, ethionamide, or ethambutol) was not associated with adverse outcome (aOR 1.01; 95%CI 0.4-2.8). Kanamycin resistance was uncommon (1.3%). Increasing levels of resistance to isoniazid predicted treatment failure, also in a subgroup of patients with high-level fluoroquinolone-resistant TB. Our results suggest that resistance to companion drugs of the shorter MDR-TB regimen, except kanamycin resistance, is of no clinical importance as long as fluoroquinolone susceptibility is preserved. Hence, contrary to current WHO guidelines, exclusions to the standard regimen are justified only in the case of fluoroquinolone, and possibly kanamycin resistance. / Damien Foundation Belgium for its financial and logistic support to run the project including its research activities. European Research Council (Starting Grant INTERRUPTB 311725).