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A dissertation submitted to the Faculty of Dentist University of the Witwatersrand, Johannesburg, in part fulfilment of the requirements for the degree of Master Dentistry in the Branch of Maxillo-Facial and Oral Surgery. / Pain, swelling and trismus are common features after oral surgery, particularly after the surgical removal of impacted third molar teeth. The Maxillo-Facial and Oral Surgeon has a vast array of drugs at his disposal to combat post-operative pain, but none of these are perfect in terms of efficacy and side effects. Recently, the non-steroidal anti-inflammatory drugs have been receiving much attention as post-operative analgesics. / IT2018

Submitted in partial fulfilment of the academic requirements for the degree: Master of Education - Research Methodology in the Department of Educational Psychology of the Faculty of Education at the University of Zululand, 2010. / There is ongoing debate regarding the public health message of introducing a microbicide that is less efficacious than condoms into the HIV prevention field. One key issue is whether the availability of microbicides would undermine women's bargaining power to negotiate condom use. Most microbicide trials report increased condom use among participants. This analysis attempts to separate the influence of increased safer sex counselling from the direct impact of gel use as a facilitator to condom acceptability. In-depth interviews were conducted with a random sample of women participating in the MDP 301 Phase III microbicide trial, and a sub-sample of their male partners. Data from 63 female and 5 male interviews were analysed to assess the impact that participating in a clinical trial and using a vaginal microbicide/placebo gel had on condom usage. Two thirds of women reported not using condoms prior to study participation due to male opposition. Most of the women interviewed were unable to explain their partners' resistance to condoms. Some of the underlying factors were related to men's resistance to using condoms with a main or long term partner (as opposed to casual partners); preference for skin-to-skin contact; or rumours about negative health implications such as condoms containing maggots. A third of women started using condoms, although inconsistently, after joining the trial. Women used participation in the trial as the rationale for discussing the risks of HfV infection and condom use with their partners. Men appeared to be more willing to use condoms in the presence of gel, and this was partially due to the gel counteracting the negative effects of condom use on sexual pleasure. Joining the trial appeared to create an opportunity for women to discuss sex with their partners, and the introduction of gel into the relationship serves as a bargaining tool for condom use with their partners.

To assess non-inferiority of an experimental product to an active control in a clinical trial, an ideal design is to include a placebo arm to ensure both the experimental product and the active control is superior to placebo. We aim to identify methodology to control Type I error rate and maintain adequate power in a superiority/non-inferiority seamless clinical trial defined as: 1. selecting the best experimental treatment dose vs. placebo out of multiple treatment doses in Stage I; and 2. assessing non-inferiority of the chosen experimental dose to an active control, after adding subjects to yield adequate power for non-inferiority, in Stage II. The trial design here is an antihypertensive trial with change in systolic blood pressure as the outcome. The trial has three experimental treatment doses arms of experimental, a placebo control arm, and an active control arm. A simulation study of 20,000 such trials was conducted. We apply multiple comparison methodologies in Stage I to detect the most beneficial experimental treatment dose versus placebo, and test non-inferiority of the selected experimental dose to the active control in Stage II. Simulated Type I error rate and power for claiming non-inferiority are calculated for various dose-response trends. The need to adjust alpha to control Type I error either stage is assessed, seeking the optimal approach for doing so. Next, type I error and power for various fixed and variable non-inferiority margins are evaluated, exploring a range of margins informed by the first stage results of the study. A variable non-inferiority margin informed completely by the first stage of the trial approach results in inflated error rate which cannot be controlled by suggested multiplicity adjustments. We assess a synthesis approach between the fixed and variable margins, to both control the family-wise error rates and reach adequate power, depending on a tuning parameter defined in our work. We conclude that well-designed and adequately controlled seamless superiority/non-inferiority trials are possible with appropriate multiple comparisons adjustments and could result in less development time and fewer subjects needed to assess efficacy than separate trials.

Circulating concentrations of vitamin D metabolites are associated with risk for a variety of diseases, including colorectal cancer. It is not known what level of circulating 25(OH)D is optimal for health; however, over-the-counter (OTC) vitamin D supplements are commonly used to improve status, though their effectiveness is unknown. It is also not known if polymorphic variation in genes associated with the vitamin D endocrine system is associated with differences in vitamin D metabolite levels or colorectal neoplasia.METHODS: A double-blind, randomized, placebo-controlled trial examined the effect of 400 IU OTC cholecalciferol on circulating concentrations of 25(OH)D. Associations between polymorphic variation in VDR, RXRA, GC, and CASR and circulating vitamin D metabolites or colorectal neoplasia were examined through analysis of the Ursodeoxycholic Acid (UDCA) and Wheat Bran Fiber (WBF) clinical trial data. A single nucleotide polymorphism (SNP) tagging approach was employed and a total of 42 VDR, 32 RXRA, 35 CASR and 25 GC tagSNPs were analyzed.RESULTS: The net change in serum 25(OH)D in the supplement versus placebo group was 2.3 ng/ml (8.5% change, P = 0.06). Principal components analyses revealed gene-level associations between RXRA and serum 1,25(OH)2D concentrations (p = 0.01) as well as GC and 25(OH)D concentrations (p < 0.01). Seven individual GC polymorphisms were significantly associated with circulating measures of 25(OH)D in addition to CASR polymorphism rs1042636 and proximal colorectal neoplasia (p-value =0.02), following a multiple comparisons adjustment. The CART analysis identified rs17467825 as predictive of continuous measures of 25(OH)D. GC polymorphisms rs1555563, rs7041, and rs222029 were identified as significantly predictive of the 25 ng/ml threshold for insufficiency.CONCLUSION: The results demonstrate that daily 400 IU OTC cholecalciferol is sufficient to maintain baseline concentrations of 25(OH)D in healthy adults, but not to significantly increase levels in all individuals. The results also identified polymorphisms in RXRA, GC, and CASR associated with or that predict vitamin D metabolite levels or colorectal neoplasia risk. The results justify further investigation on the optimal vitamin D supplementation dose for the general population and genetic variation that may be related to circulating concentrations of vitamin D metabolites or colorectal neoplasia.

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Research report: Faculty of Health Sciences / ABSTRACT Labour induction in an underresourced environment poses a tremendous challenge. While labour induction is a common obstetric procedure, it poses potential hazards for mother and fetus. This is largely dependent on method and agent used and can be expensive on limited resources because of high purchase prices, refrigerated storage, monitoring equipment and manpower. Misoprostol is a unique anti-ulcer agent that has good properties as an induction agent, but as yet not fully evaluated. It is relatively cheap, easily available, simple to store and has a long shelf life, and would amount to considerable cost saving in an underresourced setting if it were proven to be effective and safe for induction of labour. A simple reliable method of administration and appropriate dosage regimen of misoprostol for the purposes of induction of labour is needed. This study was undertaken in two phases; Part A. The clinical trial where an oral misoprostol suspension was given in a stepwise manner for the induction of labour alone or in combination with an inexpensive mechanical method (Foley catheter bulb) is compared with the “standard” method of induction i.e. dinoprostone 2 mg gel in a randomized controlled trial. Altogether 750 patients (250 in each arm) were recruited. Part B. (a) In vitro study to verify if misoprostol has a direct stimulatory effect on gut smooth muscle similar to sihlambezo.1 There is an increase in the incidence of meconium stained liquor in women who have taken sihlambezo or castor oil and misoprostol.2 It is postulated that misoprostol crosses the placenta and stimulates foetal bowel activity directly rather than as a result of asphyxia caused by excessive uterine contractions due to misoprostol. Strips of rat uterine and intestinal smooth muscle were mounted on a strain gauge with a chart recorder in a physiological bath as was done in the Pharmacology department for the original sihlambezo studies. The model was perfused with doubling concentrations of each test substance, and the concentration noted at which the first uterine muscle and the first bowel muscle activity was detected. The test substances were: #1; prostaglandin E2 (Dinoprostone) #1; oxytocin (Syntocinon) #1; misoprostol freshly dissolved in water #1; misoprostol freshly dissolved in a weak hydrochloric acid solution to approximate stomach content pH #1; misoprostol dissolved in water and stored for 2 hours, 6 hours, 24 hours and 1 year. For each substance, the ratio between the minimum stimulatory concentration for uterine to bowel smooth muscle was calculated, and these ratios compared between substances. The absolute minimum stimulatory concentrations were compared between the different misoprostol preparations to determine the effects of storage and acidification. (b) In vitro study to find out if misoprostol dissolved in water is stable and over what duration of time. This has practical importance, because if it is unstable, it may imply that a fresh sample has to be prepared each time the induction agent is given, and this may be several times per patient per induction. This would escalate the cost of the drug, especially in an underresourced setting such as ours, and would mean more manpower i.e. nursing staff, would be required for each case of induction. We also wanted to establish if acidification of the preparation would affect misoprostol stability as was implied to happen when misoprostol is given vaginally3. References 1 Mitri F, Hofmeyr GJ, van Gelderen CJ. Meconium during labor, self medication and other associations. S Afr Med J 1987: 71: 431-433. 2 Hofmeyr GJ, Gulmezoglu AM. Vaginal misoprostol for cervical ripening and labor induction in late pregnancy (Cochrane Review). In: The Cochrane Library, Issue 3, 1999. Oxford: Update Software. 3 Gunalp S, Bildirici I. The effect of vaginal pH on the efficacy of vaginal misoprostol for induction of labour. Acta Obstet Gynaecol Scand 2000; 79(4): 283-5.

Increased interest has focused on associations between dietary fatty acids and cardiovascular disease (CVD). Current findings delineating effects of consuming saturated fatty acids (SFA) from dairy on CVD risk remain controversial. The objective of this thesis was to investigate the effects of consuming two types of dairy fat, namely those from cheese and butter on, human plasma and RBC fatty acid profiles, compared with monounsaturated fatty acids (MUFA), polyunsaturated fatty acids (PUFA) and carbohydrate (CHO). A secondary objective was to investigate the association between consuming these dietary fatty acids and endogenous de novo fatty acid synthesis. A randomized, full-feeding, crossover, single-blinded clinical trial was conducted at the Institute of Nutrition and Functional Foods (INAF), Laval University and Richardson Centre for Functional Foods and Nutraceuticals (RCFFN), the University of Manitoba. A total of 92 women and men with abdominal obesity and relative low high density lipoprotein cholesterol (HDL-C) levels were randomized into a series of 5 treatments. The duration of each treatment was 4 weeks and separated by at least 4 weeks washout period. For plasma fatty acid profile, total plasma SFA after cheese treatment was found to be higher (P<0.05) than after MUFA, PUFA and CHO treatments, whereas total plasma SFA after butter treatment was only found to be higher (P<0.05) than after MUFA and PUFA treatments. Total plasma MUFA after MUFA treatment was higher (P<0.05) than after all other treatments, and total plasma PUFA after PUFA treatment was higher (P<0.05) than after all other treatments. Unlike plasma fatty acid profile, RBC total SFA after two dairy treatments were not higher than after CHO and PUFA treatments. Consistent with the plasma fatty acid profile, RBC total MUFA after MUFA treatment were found to be higher (P<0.05) than after all other treatments. Similarly, RBC total PUFA after PUFA treatment were higher (P<0.05) than after all other treatments. We did not detect any differences in de novo palmitic acid synthesis across all treatments in the present study. However, we did see a positive correlation between de novo palmitic acid synthesis and body fat mass. In summary, present results suggest that consuming dairy fats, from cheese or butter, can significantly modulate plasma fatty acids in a manner that increases plasma total SFA, including myristic acid (C14:0), pentadecanoic acid (C15:0), palmitic acid (C16:0) and heptadecanoic acid (C17:0). However, the effect of consuming dairy fats on RBC fatty acid profile is relatively minor. Additionally, the de novo fatty acid synthesis data suggests that the quality of dietary fatty acids does not associate with human endogenous fatty acid synthesis; unlike body fat mass. / May 2017

M.Med. Faculty of Health Sciences, University of the Witwatersrand, 2009 / Purpose To compare the outcomes of primary viscocanalostomy with trabeculectomy augmented with mitomycin C (MMC) in black South African patients with primary open-angle glaucoma (POAG). Method A prospective, randomized study was conducted over a four year period. Fifteen black South African patients with bilateral open-angle glaucoma requiring surgery that met the inclusion criteria and gave informed consent to participate in the trial were randomized to receive either a viscocanalostomy or a trabeculectomy with MMC in the first eye requiring surgery. The fellow eye then received the alternate procedure. Patients were followed up for two years postoperatively. Results There were no significant differences between the two surgical groups preoperatively. Twelve eyes in each group were followed for twenty-four months. In both groups the intraocular pressure (IOP) was significantly reduced post-operatively (p < 0.01) and the average number of medications used per eye was significantly reduced (p < 0.02). At twenty-four months, complete success (IOP less than or equal to 18mmHg without glaucoma medication and with no evidence of glaucoma progression) was seen in 75% of eyes undergoing trabeculectomy with MMC that completed the follow up, but in only 33% of eyes undergoing viscocanalostomy (p = 0.0498). Survival curves for both success and qualified success (IOP less than or equal to 18mmHg with glaucoma medications) in the two surgical procedures confirmed the superiority of trabeculectomy with MMC over viscocanalostomy. Conclusion Viscocanalostomy may offer some advantages because it is less invasive, but intraocular pressure control appears to be superior with trabeculectomy with MMC and this continues to be the filtering procedure of choice for the management of glaucoma in black South African patients.