A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand , in fulfillment of the requirements for the degree of Master of Science in Medicine, 2013 / Sequence analysis from HIV-1 (human immunodeficiency virus type 1) subtype B and more recently subtype C infected patients has revealed that mutations in the HIV-1 protease region that confer drug resistance to boosted protease inhibitor (PIs) are rarely detected at the time of virological failure. Mutations in the HIV-1 subtype B gag-pol cleavage sites are thought to be compensatory mutations which arise as a result of PI use. This study investigated the presence of compensatory mutations in the HIV-1 subtype C gag-pol cleavage sites and matched pol genotypes from South African patients failing a boosted PI-based regimen, as compared to antiretroviral drug naïve patients. A new amplification protocol encompassing the near full-length gag, PR and partial RT was established and used to sequence the HIV-1 gag-pol cleavage sites from 23 proviral DNA samples (p24 antigen cultured peripheral blood mononuclear cells; PBMCs), and 51 patient samples (23 antiretroviral drug-naïve, 26 failing second-line lopinavir/ritonavir containing regimens), all attending the Charlotte Maxeke Johannesburg Hospital. Nucleotide sequences were aligned and codon positions S373Q, A431V, I437T/V, L449P or P453L associated with known gag-pol cleavage site mutations were analysed and compared. The pol genotypes were established using an in house assay. Antiretroviral drug resistant primary virus isolates were grown from samples from patients enrolled on the CIPRA-SA study, and propagated in coculture with PHA-activated, IL-2 stimulated PBMCs. HIV-1 gag-pol cleavage sites and pol genotypes for all primary virus isolates were established as described above. Fifty one of 74 patient samples, used to establish the in-house gag-pol cleavage site assay, were successfully amplified and sequenced. Detailed analysis of the five known gag-pol cleavage sites revealed that 5 patient samples (4 PI-exposed, 1 unknown regimen) encoded for the previously described mutations that impact on gag-pol cleavage in the absence of any major PR mutations. A further five samples from patients on the failing PI-based regimen had major PR mutations. No known mutations in the gag-pol region were identified in patients failing a first line regimen. The pol mutations described in this study were similar to the findings reported for treatment failures in South African HIV-1 subtype C infected patients. Primary virus was grown from only 25 of the 91 PBMC CIPRA samples. None of the 25 CIPRA-SA primary virus isolates had gag-pol cleavage site mutations, and only 9 harboured known RT antiretroviral drug resistant mutations. Overall, the presence of HIV-1 gag-pol cleavage site mutations may account for virological treatment failure in 5 of the South African patient samples analysed. Although the gag-pol cleavage site mutations detected in the current study are only present in a small proportion of treatment-experienced South African patients, this may increase due to more patients accessing second line PI-containing regimens. Thus, future genotyping work incorporating the analysis of the gag-pol cleavage sites in addition to the PR and RT regions is warranted. The antiretroviral drug resistant primary viruses obtained provide valuable reagents for future phenotyping studies.

University of Macau / Faculty of Health Sciences

No description available.

The objective of this research was to develop and verify a mathematical model that enables the prediction of the effects of heat treatment on cast aluminum alloy components. The model, which uses the commercially available software (ABAQUS), predicts dimensional changes, distortion, and residual stresses in heat treated components. An extensive database is developed for an example aluminum alloy (A356) and includes the mechanical, physical, and thermal properties of the alloy all as functions of temperature. The database is obtained through calculations and measurements made on A356 alloy specimens. In addition, boundary conditions ¨C in the form of heat transfer coefficients for each of the heat treatment steps - are obtained from measurements performed with a special quenching system developed at the Center for Heat Treating Excellence at WPI. The database and boundary conditions were used in the software to predict the dimensional changes, distortions, and residual stresses that develop in a commercial A356 cast component that is subjected to a standard commercial heat treating cycle. In order to verify the accuracy of the software predictions, the predictions were compared to their measured counterparts, where dimensional changes and distortion were measured with a coordinate measuring machine, and residual stresses were measured with x-ray diffraction.

Thesis (M.Sc.Eng.) PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / Status asthmaticus (SA) is a severe, acute exacerbation of asthma that is refractory to traditional therapies using standard bronchodilators such as β-agonists and corticosteroids. Inhaled volatile anesthetics are currently used as a rescue therapy for SA due to their potent bronchodilator effects. However, it is unclear whether these agents act in vivo via 1) direct action on airway smooth muscle (ASM); 2) systemic re-circulation; or 3) autonomic reflexes from the central nervous system. Treatment with these agents can also lead to negative side effects, notably hypotension and arrhythmias, especially during prolonged pediatric use. The goals of this thesis were to compare direct versus systemic effects of these inhaled anesthetic agents, and to determine whether sufficient bronchodilation can be achieved via direct diffusion from the airway lumen to the ASM. We designed and developed a computer-actuated, ventilator-valve system to control the serial composition of the inspired gas. Using this system, we delivered inhaled anesthetic agents either a) to the anatomic dead space selectively (direct), or b) continuously throughout inspiration (systemic) in three mongrel canines (20-25 kg) with methacholine-induced bronchoconstriction. Measurements of lung resistance (RL), elastance (EL), and anatomic dead space (VD) demonstrated that isoflurane and sevoflurane result in bronchodilation for both delivery regimes. This suggests that the mechanism of action for these agents is at least partly via direct effects. Fluctuations in VD were not directly coupled with those for RL or EL. Furthermore, there may exist a limit to maximal bronchodilation using inhaled anesthetics, with isoflurane being more potent. In summary, this study illustrates the feasibility of using a targeted anesthetic delivery to treat severe, acute bronchoconstriction. Such a delivery system has the potential to define a rapidly translatable treatment paradigm for SA while increasing patient safety. / 2031-01-01

Previous work on two-treatment comparisons has shown that the use of optimal response-adaptive randomisation with group sequential analysis can allocate more patients to the better-performing treatment while preserving the overall type I error rate. The sequence of test statistics for this adaptive design asymptotically satisfi es the canonical joint distribution. The overall type I error rate can be controlled by utilising the error-spending approach. However, previous work focused on immediate responses. The application of the adaptive design to censored survival responses is investigated and different optimal response-adaptive randomised procedures compared. For a maximum duration trial, the information level at the fi nal look is usually unpredictable. An approximate information time is defi ned. Several treatments are often compared in a clinical trial nowadays. The adaptive design generalised to multi-arm clinical trials is studied. First, a global test is considered. The joint distribution of the sequence of test statistics no longer has the canonical distribution. However, the joint distribution can be derived, since the test statistic is a quadratic form of independent normal variables. Existing critical boundaries are based on normal responses and known variances with equal allocation and equal increments in information. Our results show that these boundaries can be used approximately for designs with other types of responses, unequal variances or unbalanced allocation. If the global null hypothesis is rejected, then pairwise comparisons are conducted at the current and subsequent looks to investigate which treatment effects differ. This is an analogue of Fisher's least signi cant difference method that can control the family-wise error rate. The adaptive design can target any optimal allocation to achieve some optimality criterion, and allows dropping of inferior treatments at interim looks, which can be unequally spaced in information time. Optimal allocation proportions after dropping arms are described. The power is not adversely affected by unbalanced allocation.

Dissolved organic matter (DOM) is found in all freshwaters globally, by dissolving in rainwaterduring its path through soil and on to oceans via. rivers and streams. To provide potable water fit for human consumption, selected streams and rivers are used by either direct abstraction, or by diversion into reservoirs prior to treatment. For ca.100 years, chlorine and its compounds have been used by water treatment companies to disinfect water. However, research has shown that reactions between chlorine and DOM can produce compounds (disinfection by-products, or DBPs) which may be hazardous to human health. This thesis explores the relationship between catchment character, organic matter concentration, and the potential formation of DBPs. In particular, trihalomethanes (THMs) were measured as these are currently the only regulated DBPs in the UK. To achieve this, water samples were collected quarterly over one year from two contrasting catchments, to study seasonal variations in DOM concentration and character. A third catchment was also sampled, with similar catchment characters to the first two catchments, to determine whether geographical location and land use types affected the data. Each catchment was studied to see if catchment characteristics (e.g. class of vegetation, soil type or bedrock) could be mapped using a Geographical Information Systems (GIS) approach), to observe any effects on DOM and/or the DBPs found in treated water, with the aim of producing a risk assessment map to aid the choice of future abstraction locations for drinking water. Hence, samples were chlorinated and chloraminatedin the laboratory before being analysed for DBP formation and residual chlorine concentrations were measured. Catchment specific GIS derived data were statistically analysed with water chemistry data, and detected relationships were explored statistically. Major findings include medium to strong positive correlations between the standardised THM4 (STHM4 - the concentration of THM4 formed from 1 mg L-1 dissolved organic carbon (DOC)) concentration and geology, where an increase of the area of inland rock in a catchment increases STHM4 concentration. Medium strength positive correlations were found between STHM4 and vegetation classes, where, as the area of acid grassland, and heather increase, so does the concentration of STHM4. Negative relationships were discovered showing the obverse, where, as loamy and clayey floodplain soils with naturally high groundwater increased in area, STHM4 concentration dropped (at the Hampshire Avon ii and Conwy catchments combined). The occurrence of coniferous woodland in a catchment was found to correlate with the CHCl3 formation potential of waters (Pearsons, f=0.530, p= < 0.05, n=20), supporting findings in published literature. Laboratory based chlorination and chloramination of sample waters, followed by gas chromatography provided DBP data, specifically THM4. These data show that more chloroform was formed after chlorination than chloramination, and that chloramination formed 3 times more CHBr3 (another THM4 compound) than chlorination, under laboratory formation potential conditions. Results showed that the chlorination of water prior to DOM removal could result in a THM4 concentrations 5 times greater than the current UK regulatory limit, per mg L-1 dissolved organic carbon (DOC), whereas chloramination forms ca.5 times less than the current UK regulation per 1 mg L-1 DOC. However, chlorination of water prior to DOM removal is never done in practice, so this data provides information on the composition of the organic matter and whether DOM from a specific catchment contains specific components that are responsible for an increase in a specific DBP. Data also show that increasing organic nitrogen or organic carbon does not necessarily increase nitrogenous or carbonaceousDBPs (N-DBPs or C-DBPs). However, importantly, data shows that an increase in the area of land use classed as 'urban', results in an increase in DON (likely due to human influences) in the water draining from them, posing potential issues for eutrophication in downstream water bodies and the formation of N-DBPs at water treatment works. Whilst N-DBP detection was explored from several different angles, the development of a definitive method was not possible due to very low N-DBP concentrations, time and financial constraints. However, various methods were adapted to aid in the detection of them, showing promising initial results, providing the background for future projects into the discovery of a suite of N-DBPs such as haloacetonitriles and halonitromethanes. Finally, the data in this thesis have been inputted into maps for each major catchment to present data with a high visual impact, but also to illustrate land use types that have been found to correlate with increases in DBPs and specific nutrients in the water draining from them. However, the high variation in DOM concentration and character from site to site make extrapolation of these risk assessment data, to other catchments, unsafe. Nevertheless, collection of data from a catchment (similar to the work presented here) where a new water abstraction location is desired can prove advantageous in providing information to utility companies of what difficulties they may encounter when treating the water. Though this can be done by grab sampling at each site of interest, this can prove costly and timely and involves both field and laboratory based work aspects, wheras the method presented here requires less cost and time, once the method is initialised, to derive data of similar value. Despite the fact that disinfection performance would always trump DBP minimalisation, this is likely to be a vital tool in ensuring the provision of safe and healthy water fit for the consumption of an ever increasing human population.

No description available.

Magister Scientiae Dentium - MSc(Dent) / The aim of this research project was to assess the accuracy of four different types of VTO [Steyn (1979), Jacobson and Sadowsky (1980), Ricketts (1982) and Holdaway (1984)], in predicting the final result of the incisor and soft tissue response to orthodontic treatment in bimaxillary protrusive patients. / South Africa

No description available.