Congenital heart defects (CHD) are structural anomalies affecting the heart, are found in 1% of the population and arise during early stages of embryo development. Without surgical and medical interventions, most of the severe CHD cases would not survive after the first year of life. The improved health care for CHD patients has increased CHD prevalence significantly, and it has been estimated that the population of adults with CHD is growing ~5% per year. Understanding the causes of CHD would greatly help improve our knowledge of the pathophysiology, family counseling and planning and possibly prevention and treatment in the future. The aim of my thesis was to identify novel or known CHD genes enriched for rare coding genetic variants in isolated CHD cases and learn about the relative performance of different study designs. High-throughput next generation sequencing (NGS) was used to sequence all coding genes (whole exome) coupled with various analytical pipelines and tools to identify candidate genes in different family-based study designs. Since there is no general consensus on the underlying genetic model of isolated CHD, I developed a suite of software tools to enable different family-based exome analyses of de novo and inherited variants (chapter 2) and then piloted these tools in several gene discovery projects where the mode of inheritance was already known to identify previously described and novel pathogenic genes, before applying them to an analysis of families with two or more siblings with CHD. Based on the tools developed in chapter 2, I designed a two-stage study to investigate isolated parent-offspring trios with Tetralogy of Fallot (chapter 3). In the first stage, I used whole exome sequence data from 30 trios to identify genes with de novo coding variants. This analysis identified six de novo loss-of-function and 13 de novo missense variants. Only one gene showed recurrent de novo mutations in NOTCH1, a well known CHD gene that has mostly been associated with left ventricle outflow tract malformations (LVOT). Besides NOTCH1, the de novo analysis identified several possibly pathogenic novel genes such as ZMYM2 and ARHGAP35, that harbor de novo loss-of-function variants (frameshift and stop gain, respectively). In the second stage of the study, I designed custom baits to capture 122 candidate genes for additional sequencing using NGS in a larger sample size of 250 parent-offspring trios with isolated Tetralogy of Fallot and identified six de novo variants in four genes, half of them are loss-of-function variants. Both of NOTCH1 and its ligand JAG1 harbor two additional de novo mutations (two stop gains in NOTCH1 and one missense and a splice donor in JAG1). The analysis showed a strongly significant over-representation of de novo loss-of-function variants in NOTCH1 (P=3.8 ×10-9). To assess alternative family-based study design in CHD, I combined the analysis from 13 isolated parent-offspring trios with 112 unrelated index cases of isolated atrioventricular septal defects (AVSD) in chapter 4. Initially, I started with a case/control analysis to test the burden of rare missense variants in cases compared with 5,194 ethnically matching controls and identified the gene NR2F2 (Fisher exact test P=7.7×10-07, odds ratio=54). The de novo analysis in the AVSD trios identified two de novo missense variants in the same gene. NR2F2 encodes a pleiotropic developmental transcription factor, and decreased dosage of NR2F2 in mice has been shown to result in abnormal development of atrioventricular septa. The results from luciferase assays show that all coding sequence variants observed in patients significantly alter the activity of NR2F2 target promoters. My work has identified both known and novel CHD genes enriched for rare coding variants using next-generation sequencing data. I was able to show how using single or combined family-based study designs is an effective approach to study the genetic causes of isolated CHD subtypes. Despite the extreme heterogeneity of CHD, combining NGS data with the proper study design has proved to be an effective approach to identify novel and known CHD genes. Future studies with considerably larger sample sizes are required to yield deeper insights into the genetic causes of isolated CHD.

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In less than a decade of research, graphene has earned a long list of superlatives to its name and is expected to have applications in various fields such as electronics, photonics, optoelectronics, materials, biology and chemistry. Graphene has also attracted a lot of attention because its properties can be engineered either via intrinsic changes or by modification of its environment. Raman spectroscopy has become an ideal characterization method to obtain qualitative and quantitative information on these changes. This thesis investigates the possibility to change, supplement and monitor the electonic and optical properties as well as the chemical reactivity of graphene. It is achieved by i) substrate effect, ii) introduction of defects in the structure of graphene and iii) the combination of graphene with other two- dimensional crystals such as hexagonal boron nitride (h-BN) and transition metal dichacolgenides. In particular, the experimental work presented here describes: I - The influence of the type of substrate on the Raman intensity of graphene. This work leads to the calculation of the Raman scattering efficiency of graphene after CaF2 is found to be a suitable substrate for this kind of study in contrast to Si/SiOx that strongly modulates the Raman intensities. The G peak scattering efficiency is found to be about 200 x 10-5 m-1 Sr-1 at 2.4 eV while that of the 2D peak is one order of magnitude higher, confirming the resonant nature of the 2D peak Raman scattering process. II - An attractive method to produce large (up to several hundreds of microns across) and high quality graphene by anodic bonding. This cheap, fast and solvent-free method also allows introduction of vacancy like defects in the samples in a relatively controllable way. III - The Raman signatures of several types of defect such as sp3 sites, vacancies and substitutional atoms. For low defect concentration (stage 1) the intensitiy ratio I(D)/I(D') is constant and is 13 for sp3 sites, 9 for substitutional atoms and 7 for vacancies. This signature is explained using the local activation model recently proposed to model the amorphization trajectory of graphene with containing vacancy-like defects. IV - Controlled modification of graphene through mild oxygen plasma. The influence of sp3 sites on monolayer and bilayer graphene's electrical properties are discussed. In the case of bilayer under controlled conditions, it is possible to modify only the top layer. This may lead to decoupling between the two layers, which could explain the good mobility measured for this system. The possiblity to use such system as a sensor is discussed. V - The characteristic Raman signature of aligned graphene/h-BN superlattices. The Raman spectrum shows strong changes in perfectly aligned superlattices, which could be attributed to the reconstruction of the Dirac spectrum. VI - A prototype photovoltaic cell made of a graphene and tungsten disulphide (WS2) heterostructure with an external quantum efficiency of about 30%. The beneficial combination of an excellent absorption in WS2 atomically thin films due to the presence of van Hove singularities and graphene used as a transparent, flexible and conductive electrode is demonstrated.

Defects in semiconductors are crucial to device operation, as they can either be beneficial or detrimental to the device operation depending on the application. For efficient devices it is important to characterize the defects in semiconductors so that those defects that are bad are eliminated and those that are useful can be controllably introduced. In this thesis, deep level transient spectroscopy (DLTS) and high-resolution Laplace-DLTS (LDLTS) have been used to characterize deep level defects introduced by energetic particles (electrons or Ar ions) and during metallization using electron beam deposition on silicon and germanium. Schottky diodes were used to form the space-charge region required in DLTS and LDLTS measurements. From the DLTS and LDLTS measurements the activation enthalpy required to ionize a trap, ET, and defect carrier capture cross-section ó were deduced. LDLTS proved particularly useful since it could separate deep levels with closely spaced energy levels (the limit being defects with emission rates separated by a factor greater than 2), which was not possible by conventional DLTS. The majority carrier traps in gallium-, boron- and phosphorus-doped silicon introduced after MeV electron irradiation and during electron beam deposition have been characterized, and several defects such as the divacancy, A-center and E-center and other complex defects were observed after the two processes. Annealing studies have shown that all deep levels are removed in silicon after annealing between 500°C-600°C. Both electron and hole traps introduced in n-type germanium by electron irradiation, Ar sputtering and after electron beam deposition have been characterized using DLTS and LDLTS. The E-center is the most common defect introduced in germanium after MeV electron irradiation and during electron beam deposition. Annealing shows that defects in germanium were removed by low thermal budget of between 350°C - 400°C and it has been deduced that the E-center (V-Sb) in germanium anneals by diffusion. The identification of some of the defects was achieved by using defect properties such as defect signature, introduction rates, annealing behavior and annealing mechanisms, and then comparing these properties to theoretical defect models and results from other techniques. / Thesis (PhD)--University of Pretoria, 2010. / Physics / unrestricted

INTRODUCTION: Congenital Heart Defects are the most common congenital defects in the United States. They affect a significant proportion of all births, and many babies with CCHDs are not expected to survive their first year. While diagnostic and surgical interventions have drastically improved mortality rates, a growing population of adolescent and adult CHD patients continue to face unique developmental, psychological and QoL issues. METHODS: Medical journal articles were utilized to determine the prevalence, mortality rates, survival rates, adverse psychological outcomes, and follow-up rates for CHD patients as they transitioned through adolescence. Most articles came from Pediatrics, The Journal of Pediatrics, and Circulation. RESULTS: From 1980-2005, the prevalence of CHDs in the United States increased, while CHD mortality decreased by nearly half. Over a similar time period, CHD patients were more likely to have poor psychological, behavioral, and QoL outcomes than their healthy peers. Specifically, CHD patients were likely to have developmental disorders, lower QoL, and loss to follow-up when transitioning to adult care providers. CHD patients also demonstrated a poor understanding of their condition, especially with respect to need for follow-up, identifying symptoms of deteriorating heart condition, and the negative effects of smoking, drugs, and alcohol. DISCUSSION: Diagnostic and surgical interventions for CHD patients have led to increased survival. However, many of these interventions occur in the early stages of life, leaving a gap in medical management of CHD patients as they transition through adolescence. This is represented by high attrition rates for those following-up with adult care providers, adverse psychosocial outcomes, and patients’ lack of knowledge about their condition. CHD patients may benefit from more comprehensive, coordinated and formal transition programs that incorporate good social support systems, self-efficacy, and education about their condition.

In this dissertation work, the study focuses on large areal growth of MoS2 monolayers and a study of the structural, optical and electrical properties of such monolayers before and after transfer using a polymer-lift off technique. This work will discuss the issue of contact resistance and the effect of defects (both intrinsic and extrinsic) on the overall quality of the monolayer films. The significance of this dissertation work is that a reproducible strategy for monolayer MoS2 film growth and quantification of areal coverage as well as the detrimental effects of processing on device performance is presented.

Background: Primary prevention efforts for both gastroschisis and omphalocele are limited by the lack of known risk factors. Our objective was to investigate associations between potential maternal risk factors and gastroschisis and omphalocele within a large population-based sample of participants enrolled in the National Birth Defects Prevention Study (NBDPS). Methods: Demographic, health-related, and environmental exposure data from the NBDPS were collected from women with expected delivery dates between October 1997 and December 2003. Data were collected on 485 cases of gastroschisis, 168 cases of omphalocele, and 4967 controls. Results: Women who had offspring with gastroschisis were younger (adjusted odds ratio [AOR], 0.84; 95% confidence interval [CI], 0.81-0.86) and less likely to be black (AOR, 0.54; 95% CI, 0.34-0.85) than controls. They also were more likely to have smoked (AOR, 1.51; 95% CI, 1.12-2.03), taken ibuprofen (AOR, 1.61; 95% CI, 1.23-2.10), and consumed alcohol (AOR, 1.38; 95% CI, 1.06-1.79) than controls. Women who had offspring with omphaloceles were more likely to have consumed alcohol (AOR, 1.53; 95% CI, 1.04-2.25) and be heavy smokers (AOR, 4.26; 95% CI, 1.58-11.52) than controls. Conclusions: Our results suggest a moderately increased risk of gastroschisis among women who used tobacco, alcohol, and ibuprofen during early pregnancy. A modestly elevated risk was observed for omphaloceles among women who used alcohol during the first trimester and among women who were heavy smokers.

The traditional design of printed circuit board assembly focuses on finding a set of parameter values (that characterizes the process), such that the desired circuit performance specifications are met. It is usually assumed that this set of values can be accurately realized when the circuit or the assembly is built. Unfortunately, this assumption is not realistic for assemblies produced in mass scale. Fluctuations in manufacturing processes cause defects in actual values of the parameters. This variability in design parameters, in turn, causes defects in the functionality of the assemblies. The ratio of the acceptable assemblies to total assemblies produced constitutes the yield of the assembly process. Assembly yields of area array packages are heavily dependent on design of the board as much as package and process parameters. The economics of IC technology is such that the maximization of yield rather than the optimization of performance has become the topic of prime importance. The projected value of yield has always been a factor for consideration in the advancement of Integrated Chip technology. Due to considerable reduction in the package size, minimum allowable tolerance and tight parameter variations, electronic assemblies have to be simulated, characterized and tested before translating them to a production facility. Also, since the defect levels are measured in parts per million, it is impractical to build millions of assemblies for the purpose of identifying the best parameter. A mathematical model that relates design parameters and their variability to assembly yield can help in the effective estimation of the yield. This research work led to the development of a mathematical model that can incorporate variability in the package, board and assembly related parameters and construction of an effective methodology to predict the assembly yield of area array packages. The assembly yield predictions of the model are based on the characteristics of input variables (whether they follow a normal, empirical or experimental distribution). By incorporating the tail portion of the parameter distribution (up to ±6 standard deviation on normal distribution), a higher level of accuracy in assembly yield prediction is achieved. An estimation of the interaction of parameters is obtained in terms of the expected number of defective joints and/or components and a degree of variability around this expected value. As an implementation of the mathematical model, a computer program is developed. The software is user friendly and prompts the user for information on the input variables, it predicts the yield as expected number of defective joints per million and expected number of defective components (assemblies) per million. The software can also be used to predict the number of defects for a user-specified number of components (less or more than one million assemblies). The area array assembly yield model can be used to determine the impact of process parameter variations on assembly yields. The model can also be used to assess the manufacturability of a new design, represent the capability of an assembly line for bench marking purposes, help modify designs for better yield, and to define the minimum acceptable manufacturability standards and tolerances for components, boards and designs. / Master of Science

We examine the problem of the dynamics of a hexagonal close packed crystal with a single substitutional impurity. The effects of the mass and the force constant changes due to the introduction of the impurity atom are taken into account assuming nearest neighbor interactions under the harmonic approximation. Using Green’s function and group theoretical methods, the equations of motion for the perturbed normal modes are obtained in an exact form. The calculations are performed by allowing for very general force constant changes which can have noncentral as well as central contributions. The analytical expressions obtained expressions obtained by Mannheim and Cohen for cubic systems.

Improving the formability and crashworthiness of wrought magnesium alloys are the two biggest challenges in current magnesium technology. Magnesium is the best material candidate for enabling required improvements in fuel economy of combustion engines and increases in ranges of electric vehicles. In hexagonal closed-packed (HCP) structures, effects of grain size/morphology and crystallographic texture are particularly important. Prior research has established a general understanding of the dependences of strength and strain anisotropy on grain morphology and texture. Unfortunately, deformation, recrystallization, and grain growth strategies that control the microstructures and textures of cubic metals and alloys have not generally worked for HCPs. For example, in Magnesium, the deformation texture induced by primary forming operations (rolling, extrusion, etc.) is not randomized by recrystallization and may strengthen during grain growth. A strong texture reduces formability during secondary forming (stamping, bending, hemming etc.) Thus, the inability to randomize texture has impeded the implementation of magnesium alloys in engineering applications. When rare earth solutes are added to magnesium alloys, distinct new textures are derived. However, rare earth texture derivation remains insufficiently explained. Currently, it is hypothesized that unknown mechanisms of alloy processing are at work, arising from the effects of grain boundary intrinsic defect structures on microstructural evolution. This dissertation is a comprehensive attempt to identify formal methodologies of analyzing the behavior of grain boundaries in magnesium. We focus particularly on twin boundaries and asymmetric tilt grain boundaries using molecular dynamics. We begin by exploring twin nucleation in magnesium single crystals, elucidating effects of heterogeneities on twin nucleation and their relationships with concurrent slip. These efforts highlighted the necessity of imperfections to nucleate {10-12} twins. Subsequent studies encountered the importance of deformation faceting on the high mobility of {10- 12} and stabilization of observed twin mode boundaries. Implementation of interfacial defect theory was necessary to decipher the complex mechanisms observed which govern the development of defects in grain boundaries, disconnection pile-up, facet nucleation, interfacial disclination nucleation, disconnection movements, disconnection transformation across interfacial disclinations, crossaceting, and byproducts of interactions between lattice dislocations and grain boundaries.