Background. The diagnosis of fibrotic scar tissue in arrhythmogenic right ventricular cardiomyopathy (ARVC) and other cardiomyopathies is crucial as it forms the substrate for ventricular tachycardia (VT) and fibrillation (VT). Signal-averaged electrocardiography (SAECG) abnormalities are frequent in ARVC and in other cardiomyopathy-related ventricular arrhythmias. The correlation between cardiovascular magnetic resonance (CMR) late gadolinium enhancement (LGE) and parameters of SAECG in ARVC is not known. Method. Thirty-five patients [median age 32 years (IQR 25 – 46)] referred to the ARVC Registry at Groote Schuur Hospital were included in this retrospective study. SAECG was performed with high-amplification and filtered using bidirectional Butterworth filters between 40 and 250 Hz. A filtered averaged QRS (fQRS) was obtained and analysed for fQRS duration, low amplitude signal duration <40 mV (LAS40), and root-mean-square voltage in the last 40ms of the QRS (RMS40). LGE acquired at 5 to 20 minutes after intravenous administration of gadolinium (0.1mmol/kg to 0.2mmol/kg of body mass) was assessed. We evaluated the correlation between SAECG parameters and the presence of LGE. Results. Sixteen patients had definite ARVC, 5 had possible ARVC, 4 had idiopathic VT/VF, 2 had Athlete's heart, 1 had dilated cardiomyopathy (DCM), 1 had hypertrophic cardiomyopathy (HCM), 1 had SVT and 1 had pericardial constriction. LGE was present in 13 (81%) ARVC patients, 2 (40%) with possible ARVC, 1 (50%) with athlete's heart and in all patients with DCM and HCM. Patients with idiopathic VT/VF, pericardial constriction and supraventricular tachycardias had no myocardial LGE on CMR. Comparing patients with LGE and those without LGE on CMR, there were no differences in fQRS, (114ms [102.3 – 119] versus 111ms [99.5 -130], p = 0.608); LAS40 (34.5ms [16.8 - 40.8] versus 31ms [27.5 – 45], p = 0.566) and a RMS40 (23.5 µV [14.3 – 47.5] versus 33 µV [18.5 – 43.5], p= 0.621), respectively. LGE was present in 6 (60%) patients who had VT at presentation, in 9 (56%) with VT at baseline or follow-up and in all (2) patients who survived cardiac arrest. Three oneway analyses of variance (fQRS vs LGE, LAS40 vs LGE and RMS40 vs. LGE) confirmed that there was no correlation between LGE technique on CMR and SAECG for the detection of myocardial fibrosis in ARVC and other myocardial disorders: for fQRS F(1 , 33) = 1.47, p = 0.23,  2 = 0.02; for LAS40 F(1 , 33) =0.95, p = 0.34,  2 = 0.02 and for RMS40 F(1 , 33) = 0.36, p= 0.85,  2 = 0.02. Conclusion. In this study comparing assessment of myocardial fibrosis by LGE CMR and SAECG, there was no correlation between CMR and SAECG in detection of myocardial fibrosis in ARVC and other cardiovascular diseases.

Bibliography: leaves [98]-109.

The effects on seawater quality from Cape Town's marine outfalls and their use for sewage disposal has been a concern for local residents for over a century. This dissertation explores the production of scientific evidence that contrasts public experience and independent science. Beginning with the 2015 application by the City of Cape Town (CoCT) for a permit renewal to continue discharging 38 million cubic meters of sewage daily off the city's Atlantic coast, the study considers the arguments of concerned citizens, photographers and independent scientists who warned that the outfalls are responsible for poor seawater quality. This dissertation begins by tracing the contemporary experiences of concerned citizens as they discovered that the outfall was polluting the ocean and then considers the evidence utilised by the CoCT in their responses to these concerns and in their permit application. The study finds that the CoCT's commissioned CSIR report and the use of tourism-orientated Blue Flag criteria are not compatible with the public interest and independent findings, and further finds that a managerialist approach to scientific data has confused the fulfilment of departmental mandates with the public interest, though they are not the same thing. Through the signing of international treaties, its constitution and various legislations, South Africa prescribes to the precautionary principle, but the author argues that this principle has not been applied in this scenario and that retrospective attitudes towards beach management and seawater quality concerns have been applied instead. Consequently, the implementation of a proactive and forward-looking procedure is recommended, and transparency, ocean modelling and the precautionary principle should be applied to the management of Cape Town's marine outfalls and to concerns over its water quality and attendant data.

Background - Erythema induratum (EI) is a reactive disorder to mycobacterium tuberculosis infection, a diagnosis not to be missed. Erythema nodosum (EN) is the main clinical differential of EI, but a distinctly different pathological condition that can be difficult to distinguish from EI. Methods – In this retrospective review we assess clinical and histological features of 40 EI cases and 16 EN cases. Six experienced dermatologists blindly diagnosed these cases based on clinical images, thereafter the histology was revealed, and they adjusted their diagnoses accordingly. Fleiss Kappa statistics were applied to determine inter-rater variability. A multi-variate logistic regression model determined the clinical and histological features that contribute most to an accurate diagnosis. Results - After assessing the clinical picture 48.8% of the EI cases and 74% of the EN cases were correctly diagnosed. With added histology results 67.1% EI and 81.2% EN cases were correct. EI cases showed inter-rater variability of 0.478 (pvalue < 0.01) before and 0.469 (p-value < 0.01) after histology was revealed. These features combined in a logistic regression model had a higher diagnostic accuracy than the assessors with regard to EI cases. The model was accurate in 100% and 80% of EI and EN cases respectively. Conclusions - While the study was limited by its retrospective nature and small sample size, valuable features (ulceration, vasculitis and lobular or septal panniculitis) were identified. A biopsy of the lower leg markedly increased the diagnostic accuracy, but there was less concordance between assessors, more research is needed to confirm these results.

Introduction: Cardiomyopathies are disorders of the myocardium that can lead to heart failure, arrhythmias and sudden death. Heritable forms include dilated, hypertrophic and arrhythmogenic cardiomyopathy (DCM, HCM and ACM respectively). As heterogeneous disorders, over 50 genes have been implicated in these cardiomyopathies to date. However, the yield of genetic testing ranges from less than 40% in idiopathic DCM to over 50% in ACM and HCM, indicating that many causal genes are yet to be identified. This is particularly true in African populations, where the genetics of cardiomyopathy is underexplored. In a review of the role of next-generation sequencing in gene discovery, over 20 new cardiomyopathy genes were found to have been identified through exome sequencing of cardiomyopathy patients. The literature review also highlighted the need for functional validation of newly identified disease genes. Therefore, the aims of this investigation were to utilise exome sequencing to identify disease-causing mutations in South African families with heritable cardiomyopathy, and to establish methods of variant validation through functional modelling in zebrafish. Methods: Five probands and 34 relatives were included in this investigation. The probands and their relatives were clinically examined and diagnosed with DCM, HCM or ACM at Groote Schuur Hospital, Cape Town. Exome sequencing was performed on each of the five probands as well as at least one other family member. Variants of interest were identified by filtering the exome sequencing data by allele frequency, variant quality, variant consequence, predicted deleteriousness, and the potential inheritance patterns as determined by family history analysis. Variants occurring in known cardiomyopathy genes were prioritised, but genes outside the cardiac panel were considered based on literature mining, expression in the heart, and results of prior animal models. Candidate variants were validated by Sanger sequencing and assessed using international criteria for pathogenicity. The candidate ACM gene POLG was investigated in zebrafish larvae using two genetic manipulations. Firstly, zebrafish polg was disrupted using CRISPR/Cas9 in single-cell embryos and, at three days post-fertilisation, the phenotypic effects were compared to uninjected control larvae, as well as larvae in which other known cardiomyopathy genes were disrupted. Secondly, human POLG cDNA was cloned, and the c.2942A>G variant introduced using site-directed mutagenesis; this construct was used to generate variant POLG mRNA that was injected into zebrafish embryos. Larvae were phenotypically examined at four days post-fertilisation and compared to three control groups (unmutated POLG-injected, water-injected, and uninjected embryos). Results: In three families, genotype-phenotype correlations were identified that have not yet been reported in South Africa, although this genetic overlap between cardiomyopathies has been described elsewhere. Family 1: the mutation MYH7 c.4394C>T (p.S1465L) was identified in three siblings with DCM. Although MHY7 is typically associated with HCM, mutations in this region have been reported in DCM patients in other populations. Family 2: the mutation GLA c.774_775del (p.R259Rfs*5) was found in a mother and her son, both of whom had been diagnosed with HCM. The finding of a pathogenic truncating GLA mutation in this family resulted in the genetic rediagnosis of those individuals with Fabry disease, an HCM phenocopy. Family 3: in this large DCM family consisting of three affected brothers and their nephew, no pathogenic variants were identified, but two variants of uncertain significance (VUSs) were found in the genes DSC2 and PKP2. Both variants fulfilled some criteria for pathogenicity, but have not been associated with DCM in South African patients before. In Families 4 and 5, no mutations in known cardiomyopathy-causing genes were identified. Family 4: exome sequencing revealed the variant POLG c.2492A>G (p.Y831C) in this ACM family, with a clinical phenotype consisting of arrhythmia and left ventricular fibrosis. This was a VUS, but in vivo modelling using CRISPR/Cas9 in zebrafish larvae demonstrated that disruption of the gene may impair cardiac development, while expression of the c.2492A>G variant in zebrafish larvae resulted in a significant reduction in heart rate, ventricle size and cardiac output. These results indicate that POLG variation may underly the arrythmia observed in the family, while prior mouse models reported that POLG mutations can induce cardiac fibrosis. Family 5: rare, compound heterozygous missense mutations in ITGB5 were identified as the candidate causative variants in this small family with severe paediatric DCM, possibly affecting adhesion of cardiomyocytes to the extracellular membrane. Conclusion: In total, pathogenic or likely pathogenic mutations were identified in two out of five families studied, while three VUSs with moderate or strong pathogenic potential were identified in two other families. The potential role of POLG in human cardiomyopathy and arrhythmic phenotypes is a finding that should be explored further, as should the putative role of ITGB5 in paediatric cardiomyopathy. This study indicates how exome sequencing, combined with in vivo functional analysis, can identify variants that are likely to contribute to disease in human patients. These techniques may prove useful in bridging the gap in cardiomyopathy knowledge in Africa.

Introduction: The challenges and holistic care needs of adolescents and young adults (AYAs) with cancer in low- and middle-income countries are under-researched. This limits evidencebased information regarding their experiences related to palliative care and quality healthcare services, resulting in a neglect in planning services for this population. Aim: The aim of the research study was to explore and identify the challenges experienced by AYAs with cancer in a Northern Cape public health setting. Objectives: The objectives were to describe the key concerns and priorities experienced by AYAs with cancer, to determine their holistic care needs and to identify the current limitations of healthcare resources that influence the provision of appropriate palliative care for AYAs with cancer in the Northern Cape. Methodology: In this qualitative study, purposive sampling was utilized to select AYAs with cancer and between the ages of 18 and 39 years. The participants recruited were patients from the Northern Cape public health setting who received curative or non-curative cancer treatment at either Robert Mangaliso Sobukwe Hospital or Harry Surtie Hospital oncology centres. Their experiences were explored using individual, open-ended semi-structured interviews. Data were analysed using thematic analysis. Results: A total of twelve participants between the ages of 22 and 39 were identified. Male and female participants were equally representative of the sample and their cancer diagnosis included many diverse tumour types that ranged from Hodgkin's lymphoma, breast cancer, testicular cancer, larynx cancer, melanoma, and colon cancer, to Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome-related malignancies such as Kaposi's sarcoma, cervical cancer, and non-Hodgkin's lymphoma. Six key themes emerged that provided insight into the challenges experienced by AYAs with cancer. These challenges were interrelated on a physical, psychosocial, spiritual and healthcare level, and they included the physical impact of cancer, additional illness burdens such as Human Immunodeficiency Virus and Tuberculosis, health system issues such as poor communication, delayed diagnosis, negative nursing attitudes, poor health services, inadequate resources, and transport problems. Apart from similar challenges experienced by AYAs with cancer in developed countries, such as overwhelming emotional responses, threatened dreams and hopes, a need for emotional counselling and better support systems, participants from this study also reported the impact of socio-cultural influences such as stigmatization, cultural beliefs, socio-demographics, poverty, unemployment, and a lack of cancer awareness and education within communities. Conclusion: AYAs with cancer experience complex, multidimensional, interrelated challenges that include many health system issues. In a middle-income country, these challenges are amplified by additional factors such as communicable diseases, sociocultural influences, and poverty. Consequently, their holistic care needs are largely unmet. Even though the findings may only be generalizable to limited settings, they can be transferred to form specific recommendations on how to improve the quality of life of AYAs with cancer and that of their families in the Northern Cape public health setting. As reflected by these findings, higher interventions on a National Health level in order to implement the current national palliative care policy, are required. Advancements in AYA oncology care that acknowledge their unique developmental age, emotional capacity, distinct life stage, and social background are also pivotal. Notwithstanding the significant challenges that plague quality healthcare delivery in the Northern Cape, further research to elucidate the meaning of age-appropriate care and the development of comprehensive, integrated oncology and palliative care guidelines for AYAs with cancer in South Africa, is necessary in order to acknowledge and address their total pain.

BACKGROUND: Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder (FGID) characterized by recurrent abdominal pain and change in bowel habits and is highly associated with depression and anxiety. IBS is estimated to affect about 5-20% of the global population2,29. However, little data exist regarding the association of IBS in patients with Post Traumatic Stress Disorder (PTSD). Therefore, we investigated the Veterans’ After-discharge Longitudinal Registry (VALOR) cohort of combat-exposed veterans with and without PTSD for comorbid IBS, functional dyspepsia (FD), and Gastroesophageal Reflux Disease (GERD). METHODS: Medical records of veterans enrolled in the VALOR project (N=1649) with (N=1028) and without PTSD (N=619) were examined for the presence of IBS, FD, and GERD based on ICD coding at time points T1 (baseline) and T4 (average follow up 4.7 years). Male and female veterans were recruited into the study at a ratio of 1:1. IBS diagnosis was made using ICD 9/10 coding and PTSD diagnosis was made using the PTSD module of the Structured Clinical Interview for DSM-IV. Statistical analyses of data were performed using Chi-square test, T-test, and logistic regression analyses. RESULTS: Baseline demographics of veterans with PTSD and control subjects were similar. IBS and FD were present in VALOR subjects with (3.9%, 1.2%, respectively) and without PTSD (3.4%, 0.8%) in similar frequencies (p=0.6 and p=0.48, respectively) at baseline whereas GERD without esophagitis is significantly more frequent in the PTSD group relative to the No PTSD group (14.8%, 10.3%, respectively; p=0.01). Over the course of the study the diagnosis of IBS, and other related FGID, decreased from T1 to T4. The only diagnosis that did change significantly was an increase in GERD with esophagitis. At T1, the only diagnosis that was more common in veterans with PTSD compared to veterans without PTSD was GERD without esophagitis. At both T1 and T4 the severity of PTSD did not predict a diagnosis of most FGID including IBS, GERD with esophagitis, or functional dyspepsia. However, rates of GERD without esophagitis were positively correlated with severity of PTSD symptoms. At T1 veterans with re-experiencing symptoms of PTSD were more likely to have IBS. However, at T4 veterans with avoidance symptoms of PTSD were more likely to have IBS, while veterans with re-experiencing symptoms, negative changes in mood of cognition, and those experiencing hyperarousal were more likely to have GERD without esophagitis. CONCLUSIONS: Prior studies have shown that combat-exposed veterans were at risk for IBS, however we report PTSD in combat-exposed veterans did not incur a risk for the association with IBS or FD but did so for GERD, specifically PTSD in combat exposed veterans did incur a risk for the association GERD without esophagitis and was positively correlated to the severity of PTSD symptoms. Specific subgroups of PTSD symptoms were also found to correlate with specific diagnoses. Specifically, the re-experiencing symptom subtype of PTSD was associated with a higher rate of IBS.

Tuberculosis (TB) is a major global health problem. About 15-20% of the global population who are HIV negative have extra-pulmonary TB (EPTB) such as pleural TB. This increases to 50-70% in HIV positive people. The diagnosis of EPTB is challenging because of the low bacillary burden. Interferon gamma (IFN-γ) has been identified as a promising biomarker for the diagnosis of EPTB. The development of rapid and accurate point-of-care (POC) diagnostic technologies becomes crucial in controlling EPTB. Aptamers referred to as "synthetic antibodies" have been recently explored as a replacement for antibodies in diagnostic platforms. These single-stranded nucleic acid molecules have high affinity and specificity comparable, and in some instances even superior, to those of antibodies; in addition to their relatively low cost and simple method of production they have the potential to reduce assay turnaround time. The aim of this thesis was to develop aptamers to IFN-γ, a biomarker specific for EPTB, thus facilitating the development of aptamer-based POC tests for the diagnosis of EPTB.

Includes bibliographical references (leaves 83-99).

Includes bibliographical references.