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Thesis (M.Fam.Med.)--University of the Witwatersrand, Faculty of Health Sciences, 2014. / Background The combined influence of processes of care, lifestyle advice and drug treatment on glycaemic control in Type 2 diabetes in primary care settings is not well documented. Aim To describe the provision of lifestyle advice, selected processes of care and drug treatment to, and assess the influence of these factors on glycaemic control in, a sample of adults with type 2 diabetes mellitus attending the Johan Heyns Community Health Centre in Sedibeng District, Gauteng. Methods A cross-sectional design was used. Participants consisted of 200, consecutively chosen, adult volunteers with type 2 diabetes. Information on demographics, reported receipt of lifestyle advice and anthropomorphic measurements was collected through questionnaire-based interviews. This was followed by a record review of all participants’ clinic files for information on current drug management, co-morbid medical conditions and documentation of processes of care, in the preceding 12 months, in respect of HbA1c, blood pressure (BP), weight, waist circumference (WC) and body mass index (BMI) monitoring. HbA1c values were used to ascertain glycaemic control. Performance of processes of care was assessed in accordance with Society for Endocrinology, Metabolism and Diabetes of South Africa (SEMDSA) guidelines. Parsimonious models for glycaemic control were constructed through multivariate logistic regression. Results Mean age of the sample was 58 years with 58% in the 50-64 year age group. Blacks (88%) and females (63%) were in the majority. Over two-thirds had diabetes for under 10 years and 98% had at least one co-morbid condition, mainly hypertension (92%). Obesity was noted in 65%, while 95% of females and 83% of males had a WC that conferred substantial cardio-metabolic risk. Receipt of advice on any of diet, exercise or weight control from a health professional in the preceding 12 months was reported by 79%, with 67% reporting receipt of advice on all three. Under 2% of patient records met the SEMDSA standard for processes of care for HbA1c, weight, WC and BMI monitoring, while 93% achieved the standard for BP monitoring. Exclusive oral treatment was prescribed in 62%, and the majority of these were on combined metformin and sulphonylurea; 5% were on insulin monotherapy. Optimal glycaemic control (HbA1c < 7%) was noted in only 25% of the sample. On multivariate analyses, the presence of CCF conferred higher odds of controlled glycaemia (OR = 3.17, P = 0.035). Compared with insulin monotherapy, treatment with either combined metformin and insulin (OR = 0.216, P = 0.02), or with the combination of all 3 drug classes ( metformin, sulphonylurea and insulin) (OR = 0.185, P = 0.027), conferred lower odds of glycaemic control. Conclusions This study highlights substantial shortcomings in the compliance with key processes of care and the achievement of optimal glycaemic control for type 2 diabetes mellitus in the current research setting. An inverse association was noted between glycaemic control and the use of combined oral and insulin drug therapy. Measured processes of care and reported receipt of lifestyle advice showed no association with glycaemic control. CCF co-morbidity conferred improved odds of controlled glycaemia.

Background: Type 2 diabetes mellitus (T2DM) is defined by an increase in serum glucose, however, this leads to the belief that only the serum glucose levels need be monitored and treated. Hence many other risk factors such as obesity, lipids and blood pressure which increase the risk of coronary heart disease, myocardial infarction, stroke and peripheral vascular disease are neglected. Consequently, T2DM patients that are at greater risk of developing cardiovascular disease (CVD), are often not receiving optimal comprehensive care. Aims: To identify the treatment gaps of cardiovascular risk factors in patients with T2DM using both national and international current treatment guidelines. Methods: Using a public sector database, data was obtained on the treatment of 666 T2DM patients. Records of patients were selected on the basis of established T2DM diagnoses, receiving oral hypoglycaemic and/or insulin therapy. The following patient data was recorded: demographics (age, gender, ethnicity), systolic blood pressure (SBP), diastolic blood pressure (DBP), glycated haemoglobin (HbA1c), total cholesterol (TC), triglycerides (TG), HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C) , family history, cardiovascular history and all chronic medications. The following parameters were applied to the cohort: SBP <130 mmHg, DBP <80 mmHg. In the event of proteinuria: SBP ≤120 mmHg, DBP ≤70 mmHg. HbA1c <7.0%, TC <4.5 mmol/L, LDL-C <2.5 mmol/L, HDL-C >1.0 mmol/L (males), HDL-C >1.2 mmol/L (females) and TG <1.7 mmol/L. In patients with established CVD, LDL-C target: ≤1.8 mmol/L. Results: The study cohort consisted of 666 T2DM-patients. 55% females. Mean age was 63 years (SD: 11.8), mean HbA1c was 8.7% (SD: 2.4). The mean SBP and DBP readings for the cohort were 133.66 (SD: 19.9) and 78.07 mmHg (SD: 11.6), respectively. Mean LDL-cholesterol was 2.6 mmol/L (SD: 0.9). 26.2% reached HbA1c of ≤7%, 45.8% reached ≤130/80 mm Hg blood pressure targets, 53.8% reached LDL-C of ≤2.5mmol/L and all 3 were reached by 7.5% of the cohort. TC ≤4.5 mmol/L was reached by 53.8%, 60.2% reached TG ≤1.7mmol/L, 58.6% males and 52.8% females reached HDL-C targets of ≥1.0 mmol/L and ≥1.2 mmol/L, respectively. There were 17.9% of patients with CVD reaching targets of LDL-C ≤1.8 mmol/L whilst 16.4% of patients with nephropathy reaching targets of ≤120/70 mm Hg. Almost half (48.2%) were not receiving lipid-lowering therapy, yet would be deemed eligible for therapy. Blood pressure targets may have been better reached with appropriate dosage reductions in addition to the introduction of further antihypertensive combination therapy. CVD was present in 15.5%. Conclusions: T2DM patients are at high-risk for CVD. Many trials have demonstrated the benefits of targeting CVD risk factors (HbA1c, blood pressure, serum lipids) in T2DM. Less than 10% of CVD risk factor targets were reached by the study cohort despite treatment guideline recommendations. The data from the study suggests poor control of modifiable cardiovascular risk factors and significant under treatment of T2DM in clinical practice. Whether improvement lies in the form of therapeutic titration adjustment or an increase in patient education, there needs to be a more aggressive multi-factorial therapeutic approach to treating this high risk group of patients in order to reduce overall morbidity, mortality and improve patient outcomes.

<div>New approaches in topology optimization and manufacturing techniques are generating multi-scale, physically realized mechanical components from advanced materials. Current optimization formulations do not consider the dependence of strength on feature size. By failing to account for the mechanical models of this behavior, sub-optimal structures are generated.</div><div><br></div><div>A currently available academic density-based topology optimization code is extended to incorporate strength constraints. A continuum theory of failure novel to the optimization field is implemented to account for both general yielding and fracture dominated failure. The fracture limit is then formulated in terms of well-established models of brittle and quasi-brittle size dependence. Additional models of size dependence based on assumed flaw sizes are considered using the theory of linear elastic fracture mechanics. To unify the optimized topology and the empirical geometric-scaling models used, a novel geometric measure of local size is proposed. This measure interprets the evolving density field using a consistent domain of support and maintains consistency with gradient-based methods of optimization. The geometric measure is evaluated using test-problems which consider a minimum compliance objective under geometric constraints.</div><div><br></div><div>The resulting optimized structures are presented for the geometric and size-dependent strength constrained formulations. The geometrically constrained results illustrate the flexibility and robustness of the proposed local size measure. The various models of size-dependent strength illustrate the impact and necessity of considering physical models of material within the topology optimization formulation. Results which exhibit clear "micro-structural" features and scale transitioning architectures are presented for limited multi-scale optimization studies.</div><div><br></div><div>An attempt at physical validation considering a single model of quasi-brittle material failure is made. Existing approaches for generating 3D volumetric meshes from image data are leveraged to yield CAD interpretations of optimized structures. Structures are then printed using a 3D printing PolyJet process with a previously established size-dependent material. Structures are destructively evaluated under displacement controlled load testing. The resulting tests indicate that the stress states in the structure fail to induce the expected size-dependent material characteristics. Furthermore, the testing results indicate the difficulty in properly accounting for boundary conditions in the topology optimization approach.</div>

This thesis studies loss aversion and reference-dependent preferences. The second chapter and the fourth chapter analyze the price strategy for the monopolist with a loss-averse consumer following the reference-dependent model of Kőszegi and Rabin (2006). The second chapter takes into account the happiness of not paying at the highest price and the disappointment of not paying at the lowest price and finds that this happiness has a positive effect on the monopolist's revenue and this disappointment has a negative effect on the monopolist's revenue. The fourth chapter proposes a two-period pricing model and shows that the monopolist could make use of two-price strategy to earn a revenue that is greater than the product value. The revenue of the two-period model is higher than one-period model when the weight of gain-loss utility is big enough. The third chapter studies the winner's regret with bidders when they have reference-dependent preferences in the sealed-bid first-price auction, second-price auction and all-pay auction and shows that the optimal bid is smaller with regret than without regret for loss-averse bidders, is greater for gain-seeking bidders and is the same for risk-neutral bidders.

Cyclin-Dependent Kinase 11 (CDK11) is a serine/threonine kinase encoded at human locus 1p36.3 by two paralogous genes CDK11A and CDK11B. CDK11 has diverse roles in the regulation of transcription, splicing, apoptosis and mitosis. In proliferating cells, two predominant isoforms are expressed: CDK11p58 and CDK11p110. CDK11p110 is expressed throughout the cell cycle and regulates transcription and splicing. CDK11p58 is expressed at mitosis via IRES-dependent translation; it mediates mitotic progression and faithful chromosome segregation. Loss of Cdk11 in murine models causes early embryonic lethality, demonstrating that CDK11 is essential for normal development. Furthermore, dysregulated CDK11 expression is associated with numerous late-onset disease states, indicating its importance in adult life. In cancer, abnormal expression of CDK11 correlates with poor prognosis in a variety of tumours. Moreover, deletion of the chromosomal region 1p36.3, containing the CDK11 locus, is frequently observed in cancer and has recently been identified in a case of the development disorder, Cornelia de Lange Syndrome (CdLS). This thesis aimed to examine the functions of CDK11 and the impact of their dysregulation in cancer and developmental phenotypes. The initial aim was to investigate the novel role for CDK11 in regulating autophagy in cancer cells; CDK11 depletion causes a marked autophagy phenotype, with accumulation of autophagy protein LC3. I demonstrate that this CDK11-mediated autophagy occurs as a consequence of mitotic dysregulation. Subsequently, I examined the role of autophagy following aberrant mitosis and chromosome missegregation. I show that autophagy is important in the maintenance of aneuploid karyotypes, with loss of autophagy impairing the survival of aneuploid cell populations. I then investigated the effects of CDK11 in regulating cancer cell motility and determined that CDK11 depletion retards cancer cell migration. However, I was unable to identify any failure in cell adhesion or cell polarization to explain this migration phenotype. Subsequently, I interrogated the CDK11 interactome to further characterize the mechanisms through which CDK11 regulates both novel and established functions. This work indicated the involvement of the distinct CDK11 isoforms in pathways that have not previously been reported. This included the interaction of CDK11p110 with ribosomal and spliceosomal proteins during mitosis and the interaction of CDK11p58 with spliceosomal and proteosomal constituents also during mitosis. These findings may provide the foundation for further study. Finally I describe work undertaken to sequence the CDK11 locus in a cohort of CdLS patients, with no known causative genetic mutation, to investigate CDK11A/CDK11B as candidate disease-associated genes. Although no causative mutation in CDK11A or CDK11B was identifying, sequencing of this region indicated NCBI and UCSC genome assemblies of this locus were inaccurate due to the genomic duplication. This has been confirmed by others and corrected in the most recent genome assemblies.

Abstract There are a remarkable variety of sex determination systems among different animal taxa. In most animals, sex is determined chromosomally. Although in an increasing number of animals sex determination has been found to be influenced primarily by the environment. Species with genotypic sex determination (GSD) have their sex determined at the time of fertilization, by genetic factors alone and those with environmental sex determination (ESD) have their sex determined by environmental factors that act after fertilization. Temperature-dependent Sex Determination (TSD), whereby the sex of the developing embryos depends on the temperature at which they develop is widespread in oviparous reptiles and occurs in all crocodilians, marine turtles and tuatara examined to date and is common in many freshwater turtles and lizards. SECTION ONE Temperature-dependent sex determination (TSD) was never expected to occur in viviparous reptiles, as thermoregulation by pregnant females would result in relatively stable gestation temperatures. Temperature-dependent sex determination and viviparity goes against all the basic assumptions that TSD occurs in oviparous reptiles where temperatures within a nest vary widely. However, skewed sex ratios as a result of incubation temperature indicated the possibility of TSD in the viviparous lizard Eulamprus tympanum. In my first experiments I show the first recorded case of a viviparous reptile with TSD. The developing embryos of the viviparous skink E. tympanum are subject to TSD, with gestation temperature having a highly significant effect on sex and warmer temperatures giving rise to male offspring (Chapter 1). Sex is fully determined at the time of birth and can be differentiated histologically into testes or ovaries (Chapter 2). The morphology and histological characteristics of the gonads of neonatal E. tympanum resulting from the treatment temperatures described in chapter 1 illustrate that sex in E. tympanum is easily distinguished at the time of birth and corresponds with the presence or absence of hemipenes. Males are histologically characterised by an elongated gonad consisting of seminiferous tubules with either no cortical epithelium or, if present at all, in a very thin band. If they are present, M�llerian ducts, showing signs of degeneration, are attached to the kidney by a shortened mesosalpinx. Females are histologically characterised by an irregularly shaped gonad consisting of a thick cortical epithelium that occasionally contains oocytes. The M�llerian ducts are obvious structures attached to the kidney by a fibrous mesosalpinx. The presence or absence of hemipenes is a reliable technique for determining sex in newborn E. tympanum. Sex determination is easiest to perform on neonates within the first few days of birth as hemipenes become increasingly difficult to evert as neonates age, however, with practice they are easily identified without full eversion. SECTION TWO The thermal biology of E. tympanum in the field is restricted by both the thermal properties of their habitat (Chapter 3) and behavioural modifications when faced with a predation threat (Chapter 4). The available temperatures in the field suggest that TSD is biologically relevant in the species and not just a laboratory artefact; E. tympanum can attain mean selected temperatures achieved in the laboratory but the proportion of time at the temperature is restricted. Females actively thermoregulate in the field, although they are restricted in their efficiency of thermoregulation by environmental constraints, for example, microhabitat structure, weather conditions, predator avoidance and social ranking. The highly territorial nature and high densities of E. tympanum present in Kanangra Boyd National Park potentially force less dominant individuals into less favourable habitats that are significantly cooler. An important point is that gravid females in more favourable habitats in the period encompassing the middle third of development (the assumed sex determining period) are selecting higher temperatures, with lower variance and have greater thermoregulatory efficiency than during the rest of pregnancy, therefore, thermoregulating more precisely during this thermosensitive period (Chapter 3). Chemosensory cues provide important information on the risk of predation. Hence, chemoreception is a common mechanism used by many species to detect the presence of, and subsequently respond to, a potential predator. The perceived risk of predation may force retreat to sub-optimal conditions, forcing a trade-off between the risk of predation and the ability to acquire resources. The basking regime maintained by gravid female E. tympanum, can directly alter sex ratios of offspring produced through temperature-dependent sex determination (Chapter 1). The avoidance of predator scents may restrict basking ability and in turn alter the sex of offspring produced. I measured responsiveness to chemical cues using tongue flicks as an indicator of chemical discrimination in females of different reproductive condition. I then measured activity and basking behaviour of gravid and non-gravid females in experimental enclosures in the presence of various chemical stimuli to determine if basking opportunity is compromised by the presence of a predator scent. Females respond differently depending upon reproductive condition, with gravid females responding most significantly to a predator scent. Activity, basking frequency, and time spent in the open (basking duration) are significantly reduced in gravid females in the presence of a predator stimulus. Under laboratory conditions, gravid females modify their behaviour and forego the opportunity to bask when there is a perceived predation risk (Chapter 4). SECTION THREE As female viviparous reptiles can regulate the temperature of the embryo by maternal temperature selection (Chapter 1), the occurrence of TSD in E. tympanum opens the possibility for females to select the sex of offspring. Reproducing females may benefit by facultatively adjusting their investment into sons over daughters or vice versa, in response to population wide shifts in adult sex ratios. Female E. tympanum, can manipulate the sex of their offspring in response to sex imbalances in the population using temperature-dependent sex determination (Chapter 5). When adult males are scarce, females produce male-biased litters and when adult males are common, females produce female-biased litters. The cues used by a female to assess the adult population are not known, but presumably depends upon the female�s experience throughout the breeding season and is the subject of further investigation (Chapter 6). The maternal manipulation of offspring sex ratio in E. tympanum suggests a selective advantage of temperature-dependent sex determination. Any facultative sex ratio response needs to recognise the scarcity of one sex in order to overproduce that sex in the next generation; offspring sex ratio will vary inversely with adult sex ratio. Maternal sex allocation in E. tympanum is linked with population (or adult) sex ratio (Chapter 5), and one of the mechanisms by which females recognise an imbalance may be linked to visual recognition of males (Chapter 6). Females maintained throughout pregnancy without any male stimulus produce entirely male offspring (Chapter 5). In contrast females exposed to male stimulus produce both sexes (Chapter 5). Females respond differently to varying degrees of male stimulus and visual recognition of males in a population may be more important than chemoreception. In the absence of visual cues, females produce more male offspring, even when chemosensory cues are present (Chapter 6). The study system presented here offers many advantages over oviparous species with TSD, due to E. tympanum being relatively short lived and fast maturing. Thus, the fitness consequences over multiple generations as a result of gestation can be investigated. Viviparity allows maternal control of embryonic temperature during gestation and a means of maternal sex allocation. Until now the maternal side of TSD and sex allocation has been where the mother deposits her eggs and the allocation of sex steroid hormones at oviposition, both of which have been difficult to study. The work presented and the study system itself should inspire great interest in TSD and viviparous reptiles.

Tight gas reservoirs are those reservoirs where the matrix has a low permeability range (k < 0.1 md). The literature documents laboratory experiments under restressed conditions that show stress dependent rock properties are more significant in tighter rocks. For gas reservoirs, real gas properties are also sensitive to variations of pressure, and the correct description of gas flow must include pressure-dependent gas properties. Under these circumstances the resulting equation for real gas flow is a second order, non-linear, partial differential equation. Non-linearities include pressure-dependence of gas viscosity, gas compressibility, reservoir permeability and reservoir porosity. This paper investigates dynamic permeability change as a function of net overburden stress in tight gas reservoirs. The gas reservoir simulator used for this work included pressure-dependent reservoir permeability. Radial flow cases are analyzed using this simulator. During this study we found that from analysis of production data alone, it is impossible to determine the correct permeability value for tight gas reservoirs with pressure-dependent permeability. For the cases studied, the transient performance was similar for both constant permeability and pressure-dependent permeability. This similarity causes constant permeability and pressure-dependent permeability to be indistinguishable, based on analysis of transient performance data. It was found that the productivity index decreases when pressure-dependent permeability is more significant. Finally, this study verified that the method of Ibrahim et al.28 under estimates original gas in place (OGIP) for tight gas reservoirs with pressure-dependent permeability.

The current state of shale gas reservoir dynamics demands understanding long-term production, and existing models that address important parameters like fracture half-length, permeability, and stimulated shale volume assume constant permeability. Petroleum geologists suggest that observed steep declining rates may involve pressure-dependent permeability (PDP). This study accounts for PDP in three potential shale media: the shale matrix, the existing natural fractures, and the created hydraulic fractures. Sensitivity studies comparing expected long-term rate and pressure production behavior with and without PDP show that these two are distinct when presented as a sequence of coupled build-up rate-normalized pressure (BU-RNP) and its logarithmic derivative, making PDP a recognizable trend. Pressure and rate field data demonstrate evidence of PDP only in Horn River and Haynesville but not in Fayetteville shale. While the presence of PDP did not seem to impact the long term recovery forecast, it is possible to determine whether the observed behavior relates to change in hydraulic fracture conductivity or to change in fracture network permeability. As well, it provides insight on whether apparent fracture networks relate to an existing natural fracture network in the shale or to a fracture network induced during hydraulic fracturing.

Aim; The aim of this study is to increase our knowledge of stress resilience children coming from backgrounds of substance abuse and to look at what consequences they may encounter, for not being able to express their emotions and deal with happenings experienced in their upbringing. Method; A qualitative approach has been used with e-mail interviews to collect our material, with young adults whom see themselves as having a history of alcoholism in the nearest family when growing up and despite this managed well in life. Result: We have concluded that resiliency is a way of coping with stressful situations. It is a way of repressing emotions when the emotions become too unbearable. When repressing the emotions you are denying the self the right to development, the right to exist as a person. And this leads to co-dependency.