Browsing by Subject "Medicine"

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    Open Access
    A cross-sectional study of ECG patterns and outcomes of patients thrombolysed for ST-elevation myocardial infarction at a district, public Cape Town hospital
    (2018) Kibamba, Crispin Ngoy; Malan, Jacques; Bruijns, Stevan
    Introduction There is insufficient data to describe ST-elevation myocardial infarction (STEMI) in sub-Saharan African settings using common diagnostic criteria. This study describes the outcomes at discharge (survival, death or transferred) of patients thrombolysed for STEMI at a public hospital without primary percutaneous coronary intervention capability as well as associated ECG changes. Materials and methods A retrospective, cross- sectional study was conducted at an urban, public emergency centre in Cape Town, South Africa that did not have direct access to percutaneous coronary intervention for STEMI. Descriptive statistics for age, length of stay and the various timings surrounding thrombolysis were presented using proportions, mean and standard deviation. Assumptions were tested using the X2 - test or Fishers Exact test. A p-value less than 0.05 was considered significant. Results The study enrolled 104 patients of which 25 were excluded for insufficient data and two for thrombolysis of an incorrect STEMI diagnosis. Of the remaining patients, 56 (64%) survived to discharge, 26 (30%) required transfer and five (6%) died. There was no difference between regions affected and patient outcome (p=0.31). Resolution of ST-segments was seen in 48 (86%) survivors. It was not seen in 21 (81%) who were transferred and in none that died. The difference between resolution of ST-segments between survivors versus those transferred or dead was highly significant (p< 0.001). Conclusion This study described a higher than expected thrombolysis failure rate as well as a higher than expected association of poor outcome with inferior STEMI. It highlights the need for improved health care records to improve health research in low-resourced settings. The creation of a STEMI registry could contribute to research but will need funding. The use of clinical messaging apps to gain senior ECG interpretation may provide an additional layer toward quality care.
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    A descriptive study of the type 2 diabetic population with hypertriglyceridemia of more than 2.5 mmol/l at presentation with subsequent analysis of their baseline and follow up variables
    (2023) Vermooten, Barbara; Blom, Dirk
    Background Type 2 diabetes mellitus and the dyslipidaemia that often accompanies it are major risk factors for atherosclerotic cardiovascular disease. Elevated triglycerides mark the accumulation of atherogenic remnant lipoproteins. Because there is little South African data on hypertriglyceridaemia in diabetes we retrospectively reviewed baseline and follow-up data of patients attending a specialized lipid clinic. Aim of the study The primary aim of this study is to describe biochemical and demographic variations of a diabetic population with hypertriglyceridemia and to further investigate whether there are correlations between glycemic control, lipid modifying therapy and hypoglycemic therapy with lipid outcomes, specifically LDL cholesterol, remnant cholesterol, triglycerides, and HDL-C. Methods We reviewed the medical records of 100 diabetic patients with hypertriglyceridemia of >2.5mmol/L who attended the Groote Schuur Hospital Lipid clinic for at least two years. The patients were randomly selected from the Lipidology database, and selection was made based on inclusion criteria for this study. We documented four six-monthly follow-up visits and documented the visit with the lowest recorded triglyceride levels if it was outside the two-year follow-up. Results The study population was predominantly (63%) female with a mean (SD) age at presentation of 50.87 (10.44) years. Obesity (BMI >30 kg/m²) was highly prevalent (66.3%) and diabetes was generally poorly controlled (76.16% patients had a HbA1C >7%). Baseline triglycerides ranged from 2.6mmol/L to 63.3mmol/L with a median and mean (SD) of 4.64 mmol/L and 10.47 (12.57) mmol/L, respectively. Baseline agarose electrophoresis patterns were: 0% type I, 0% type IIA, 51.4% type IIB, 10.3% type III, 18.7% type IV and 19.6% type V. LDL particle size determined by acrylamide gradient gel electrophoresis was intermediate or small in 61 of 64 (95%%) of patients with visible LDL. At baseline calculated mean (SD) remnant cholesterol (48 patients) was 1.55 (0.24) mmol/L, ranging from 1.1mmol/L to 2mmol/L. Triglycerides and calculated remnant cholesterol were strongly correlated (r2=0.9395, p=0.000). There was no correlation between baseline TG and HDL-C, baseline BMI and baseline waist circumference (waist/hip ratio could have possibly corrected for different anthropometry), but there was a positive correlation between triglycerides and alcohol intake, (r2=0.224, P=0.012). There was no correlation between baseline triglycerides and HbA1C (p=0.8423) or fasting glucose (p=0.0857). The change in total triglycerides from initial presentation to the follow-up visit with the lowest documented value was a mean (SD) decrease of 2.91 (4.98) mmol/L, ranging from either no change to a decrease of 32.68mmol/L. The mean (SD) reduction in HbA1C was 0.94 (1.64) % ranging from an increase of 1.7% to a decrease of 7.8%. Fibrates were initiated in 43% of patients. Patients prescribed fibrates had higher mean (SD) baseline TG levels of 18.56(15.48) mmol/L, compared to levels of 4.11(1.85) mmol/L in patients who were not prescribed a fibrate. At baseline mean (SD) TC values were 8.33 (3.18). The mean (SD) LDLC at baseline was 4.26 (1.45) mmol/L ranging from 0.5 to 7.6 mmol/L. Only 4.1% of all patients with a calculable LDL-C achieved values below 1.8mmol/L during follow-up. Conclusions In this study diabetic patients with elevated triglycerides who attended a specialist lipid clinic were frequently obese and often had poorly controlled diabetes. Although dyslipidaemia and glycaemia improved following intensification of therapy most patients did not reach their treatment goals. Our study highlights the heterogeneity of hypertriglyceridaemia, the difficulties of achieving good metabolic control, and the need for ongoing follow-up as severe hypertriglyceridaemia relapses readily.
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    A descriptive study of the use of cardiac point of care ultrasound (PoCUS) in public emergency centres in Cape Town
    (2021) Ganas, Ushira; Malan, Jacques J; Bruijns, Stevan R
    Background Cardiac point of care ultrasound (PoCUS) has evolved into an important diagnostic tool in the daily practice of emergency medicine. Its use has been advocated internationally, but its limitations have also been emphasised. The indications for cardiac PoCUS vary somewhat in different parts of the world, and training programs may also differ. We set out to describe the self-reported indications and imaging windows used at a selection of secondary-level, public hospital emergency centres in Cape Town. Methods A descriptive study with prospective data collection from the emergency centres of Mitchells Plain District, Victoria and New Somerset Hospitals was used. Data were collected over a three-month period, by all formally consented providers who have completed a basic emergency ultrasound course, using a purpose-designed data collection tool for all cardiac PoCUS scans. The study was approved the University of Cape Town's Human Research Ethics Committee (581/2017). Results We recruited 15 PoCUS providers who recorded 267 data entries over the 3-month study period. Seventeen surveys were excluded leaving 250 for analysis. The most common indication for cardiac PoCUS was electrocardiogram abnormalities,27% (n= 112); dyspnoea,25% (n= 102); chest pain,16%(n=65); cardiomegaly on chest xray,12%(n=51); new murmur,6%(n=23); and chest trauma,5%(n=22). Other indications made up the remaining 10%(n=40). Parasternal long and short axis were the predominantly used views. Conclusion The results of the study suggest that cardiac PoCUS is used for a wide range of indications which are recommended in training guidelines. However, some indications are outliers but may be useful in low-middle income settings. Further research needs to be done to ascertain the extent of the use of cardiac PoCUS, and possibly the need for a more comprehensive training program with adequate training in these clinical conditions, to ensure safe practice.
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    A histopathological and genomics study of the mutated human FAM111B gene related POIKTMP disease
    (2023) Tambwe, Nadine; Arowolo, Afolake
    Fibrosis is a pathological feature of many chronic inflammatory diseases, eventually leading to organ failure and death. POIKTMP is a rare, multi-organ fibrosing disease which is associated with mutations of the human FAM111B gene. FAM111B gene codes for a protein whose function is not well characterized. Therefore, elucidating the mechanism of FAM111B or its mutations in POIKTMP is beneficial to understanding the complexities surrounding this multisystemic fibrosing disease. The study sought to understand the pathogenesis of fibrosis, its role in POIKTMP and its causative gene mutation: FAM111B Y621D. First, Sanger sequencing was used to confirm the presence of the FAM111B Y621D mutation using DNA isolated and amplified from post-mortem FFPE tissues of a POIKTMP patient first described with the disease in South African Following that, qRT-PCR was employed to assess gene expression changes between the patient and the familial control. The RT2 Profiler Human fibrosis PCR Array was then used to associate POIKTMP and 84 known fibrotic markers to propose a possible fibrotic pathway associated with POIKTMP disease using mRNA from the lung and skin POIKTMP patient tissues. Gene-set enrichment analysis (GSEA) using Enrichr, a computational GSEA tool, was used to predict enrichment analysis between the identified upregulated fibrosis markers and the FAM111B gene. Finally, Immunohistochemistry was used to identify cellular and sub-cellular protein distribution of FAM111B and other fibroproliferative markers of interest to annotate pathological changes. The results from this study validated the FAM111B Y621D mutation in the affected tissues. Next, FAM111B mRNA was shown to be downregulated in the lungs and skeletal muscle tissues of the POIKTMP patient. The human fibrosis PCR array experiments identified eight upregulated fibrotic markers: MMP3, MMP13, PDGFA, ITGB-1, THBS-2, COL3A1, TGFβ3, and CCN2 in the patient lungs and skin tissues, which were validated by qRT-PCR. Furthermore, these genes with FAM111B form a gene-list that was used in interrogating various gene-set libraries in the gene-set enrichment analysis. FAM111B was enriched in some gene-set libraries within the Diseases/Drugs and Cell type categories. The GSEA terms enriched within these libraries are the pathways associated with SARS-COVID-19 perturbations and cell/tissue types related to the small intestine, breast, oesophagus, thyroid, smooth muscle and stromal cells of some of these organs. Lastly, immunohistochemistry results corroborated this study's mRNA expression analysis by showing that FAM111B was more highly expressed in the skin than in the lung patient. TGF-β1 and Ki-67 markers were 12 assessed from protein expression, which resulted in higher expression in the POIKTMP patient skin tissue than in the lungs. Altogether, our data suggest that FAM111B and mutations in this gene play a pivotal role in POIKTMP and other fibrosing organ diseases, representing a potential disease biomarker and possible therapeutic target in POIKTMP and other fibrotic disorders.
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    Open Access
    A histopathological and genomics study of the mutated human FAM111B gene related POIKTMP disease
    (2023) Tambwe, Nadine; Arowolo, Afolake
    Fibrosis is a pathological feature of many chronic inflammatory diseases, eventually leading to organ failure and death. POIKTMP is a rare, multi-organ fibrosing disease which is associated with mutations of the human FAM111B gene. FAM111B gene codes for a protein whose function is not well characterized. Therefore, elucidating the mechanism of FAM111B or its mutations in POIKTMP is beneficial to understanding the complexities surrounding this multisystemic fibrosing disease. The study sought to understand the pathogenesis of fibrosis, its role in POIKTMP and its causative gene mutation: FAM111B Y621D. First, Sanger sequencing was used to confirm the presence of the FAM111B Y621D mutation using DNA isolated and amplified from post-mortem FFPE tissues of a POIKTMP patient first described with the disease in South African Following that, qRT-PCR was employed to assess gene expression changes between the patient and the familial control. The RT2 Profiler Human fibrosis PCR Array was then used to associate POIKTMP and 84 known fibrotic markers to propose a possible fibrotic pathway associated with POIKTMP disease using mRNA from the lung and skin POIKTMP patient tissues. Gene-set enrichment analysis (GSEA) using Enrichr, a computational GSEA tool, was used to predict enrichment analysis between the identified upregulated fibrosis markers and the FAM111B gene. Finally, Immunohistochemistry was used to identify cellular and sub-cellular protein distribution of FAM111B and other fibroproliferative markers of interest to annotate pathological changes. The results from this study validated the FAM111B Y621D mutation in the affected tissues. Next, FAM111B mRNA was shown to be downregulated in the lungs and skeletal muscle tissues of the POIKTMP patient. The human fibrosis PCR array experiments identified eight upregulated fibrotic markers: MMP3, MMP13, PDGFA, ITGB-1, THBS-2, COL3A1, TGFβ3, and CCN2 in the patient lungs and skin tissues, which were validated by qRT-PCR. Furthermore, these genes with FAM111B form a gene-list that was used in interrogating various gene-set libraries in the gene-set enrichment analysis. FAM111B was enriched in some gene-set libraries within the Diseases/Drugs and Cell type categories. The GSEA terms enriched within these libraries are the pathways associated with SARS-COVID-19 perturbations and cell/tissue types related to the small intestine, breast, oesophagus, thyroid, smooth muscle and stromal cells of some of these organs. Lastly, immunohistochemistry results corroborated this study's mRNA expression analysis by showing that FAM111B was more highly expressed in the skin than in the lung patient. TGF-β1 and Ki-67 markers were assessed from protein expression, which resulted in higher expression in the POIKTMP patient skin tissue than in the lungs. Altogether, our data suggest that FAM111B and mutations in this gene play a pivotal role in POIKTMP and other fibrosing organ diseases, representing a potential disease biomarker and possible therapeutic target in POIKTMP and other fibrotic disorders.
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    A molecular approach to precision medicine in South African children with Epilepsy: towards a genetics-based diagnostic service for Epilepsy
    (2024) McIntosh, Caitlin; Esterhuizen, Alina; Fieggen Karen
    Background: Epilepsy is a neurological disorder characterised by unprovoked, recurring seizures. SubSaharan Africa carries the highest burden of epilepsy in the world, owing mainly to the increased risk factors such as infectious and parasitic disease, and traumatic brain injury. A proportion of this burden is genetic, however, genetic testing for epilepsy in South Africa is limited, currently only accessible in the private healthcare sector via international referral. Genetic testing in epilepsy is an internationally recognised diagnostic tool which can inform the diagnosis and patient management, with options for precision treatment, frequently resulting in improved outcomes. The main aim of this research project, therefore, was to design and validate a next-generation sequencing (NGS) gene panel for South African paediatric patients with drug-resistant epilepsy. The panel design was aimed primarily at the developmental and epileptic encephalopathies, where the yield of informative findings is highest, and the results often carry implications for treatment. The secondary aim of the project was to perform preliminary pharmacogenetic testing, to determine if variants previously associated with antiseizure drug metabolism in other populations are present in this study group. Materials and Methods: Forty probands with clinically complex, drug-resistant epilepsy with no identified, acquired cause were recruited from the neurology epilepsy service at the Red Cross War Memorial Children's Hospital in Cape Town. All 40 probands were tested with a panel of 78 genes selected on the basis of association with disease and clinical actionability. NGS data files were subject to variant prioritisation, followed by variant confirmation by cycle sequencing, segregation analysis, and final classification according to ACMG criteria. All 40 probands were tested with two pharmacogenomic arrays, one generalised array, the Veridose® Core Panel produced by Agena Bioscience (San Diego, USA), and one custom-designed anti-seizure medication-specific SNV array targeting eight SNVs across six different genes. Results: Three pathogenic variants were identified; two in SCN1A and one in GRIN2A, with a pickup rate of 7.5% (3/40). Two variants of uncertain significance were identified in GABRG2 and GRIN2B. The findings were aligned with the electroclinical features in each patient. The pharmacogenomic analysis revealed one variant, EPHX1 rs1051740, which appeared to be statistically significantly differently distributed in the study group to the general African population (P = 0.02). Three other variants, EPHX1 rs2234922, SCN1A rs3812718, and CYP2d6 s59421388 appear to be trending towards significance, with P-values of 0.08, 0.05, and 0.05, respectively. Conclusion: The main outcome of this project was the successful development of an NGS-based diagnostic protocol for paediatric epilepsy using the gene panel approach, now ready for implementation in the local diagnostic testing laboratory. Moreover, the genetic cause of epilepsy was identified in three study participants, with treatment implications in two (variants in SCN1A). The pharmacogenomic analysis in this project did not reveal specific insights owing to the small study group, but provided exposure to pharmacogenomic analysis, and may be used as a basis for further research into the pharmacogenomics of epilepsy in larger African cohorts.
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    A Molecular Epidemiological Study of Human Parainfluenza 4 in the Western Cape, South Africa
    (2021) Parsons, Jane; Hardie, Diana; Smuts, Heidi
    Background Human parainfluenza 4 (HPIV 4) is a recognised cause of acute respiratory infection (ARI). However, there is no published data on the epidemiology of this virus in South Africa. This thesis describes the molecular epidemiology of HPIV 4 over a 4-year period (2014-2017). Respiratory samples from infants, children and adults presenting with respiratory illness in the Western Cape, South Africa were studied. Method A retrospective 4-year study using routine diagnostic samples from patients with ARI was conducted in Western Cape, South Africa. A database search of positive HPIV 4 samples detected by the Seegene Anyplex RV 16 diagnostic assay was extracted. Epidemiological information was recorded to determine age, gender, hospital ward (used as a proxy for disease severity), specimen type (upper or lower respiratory tract) and collection date (to indicate seasonality). To determine genetic evolution, novel primers targeting the haemagglutinin-neuraminidase (HN) in both HPIV 4 subtypes were designed to amplify a 733 bp and 738 bp sequence for HPIV 4A and HPIV 4B respectively. This product was then sequenced and aligned with known reference sequences from GenBank, using BioEdit. These aligned sequences were analysed using the phylogenetic analysis tool, MEGA 6, and Highlighter plots to determine sequence divergence events and evolution. A real-time PCR assay, targeting the phosphoprotein, was developed to rapidly distinguish subtype A and B viruses. Results HPIVs were the 6th most common respiratory viruses detected in diagnostic samples. In all, there were 312/7456 (4.2 %) HPIV 4 positive samples in patients with a median age of 12 months. Males had a higher infection rate. HPIV 4 was the most prevalent of the HPIVs accounting for 47% of all HPIVs. Respiratory infections due to HPIV 4 were seasonal, peaking in autumn and mid-winter (March to August). The overall prevalence of HPIV 4 increased over the study period. Of the HPIV 4-positive samples that were subtyped, 59 were subtype A and 26 subtype B. Both subtypes co-circulated during each season. 71 % of patients who were positive for HPIV 4 were co-infected with one or more additional respiratory virus with Adenovirus (27 %), Human Rhinovirus (23 %) and Bocavirus (19 %) as the most common. HPIV 1 and HPIV 3 were both able to co-infect patients with HPIV 4, but no co-infections with HPIV 2 were detected. Phylogenetic trees constructed using neighbour joining (NJ) method showed that most of the South African HPIV 4 subtypes did not group with the closest significant reference sequences from GenBank. The phylogenetic tree for HPIV 4A revealed 4 genetic groupings. There were many nucleotide changes increasing with time as well as a non-synonymous change in HPIV 4A, at location N161D. HPIV 4B had an amino acid change in location G198R in the HN protein sequenced. Conclusion HPIV 4 with an overall prevalence of 4 % over the study period was identified as a significant cause of ARI in the Western Cape, South Africa. Mono-infection with HPIV4 was associated with severe disease. In hospitalized infants who were HPIV 4 positive, between ¼ to 1/3 were from patients in ICU. Of these almost half (46 %) had HPIV 4 as a single infection. Further studies are needed to fully understand the molecular epidemiology of this infection.
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    A phantom based evaluation on the effects of patient breathing motion on Stereotactic Body Radiotherapy treatment volumes
    (2020) Coetzee, Nicolene; Burger, Hester; Joubert Nanette
    Aim: The aim of the study was to design an upper body phantom to mimic the movement of the lesion inside the lungs during a breathing cycle. Phantom design included an assessment of the motion observed for lung lesions, identification of suitable phantom materials as well as design of a motorized arm to mimic the movements observed inside the lung area of the phantom. Introduction: Expansion margins are added to clinical target volumes contoured by Oncologists in order to safeguard against under- or over-treatment of the target volume. They are designed to account for errors during setup, inaccuracies on the linear accelerator, and movement of targets inside the patient. If the margins are too small, there is a risk that the lesion/target may not receive the necessary dose, due to being partially missed. On the other hand, if the margins are too wide, the lesion will be covered, but normal tissue may receive unnecessary dose, resulting in additional side effects to the patient. Assessment of the impact of these margins is not possible in a static phantom and the availability of a low-cost motorized phantom would assist in the validation of these margins. Method: Previously treated patients' 4D CT scanning data were used to quantify the amount of movement seen for lesions within the lung. A phantom was then designed and built in an attempt to mimic both patient anatomy and movement. Materials were identified to replicate anatomical shape and densities of various organs in the thorax, as seen on CT scan data. Two treatment planning systems (Monaco, (Elekta) and Eclipse (Varian)) were used to determine the dosimetric characteristics of the materials. This was compared to actual dose as delivered by a linear accelerator (Elekta Synergy). Results: Paths were calculated from the breathing cycles during the 4D-CT scan sets and templates designed to mimic these movements. A thorax phantom was built with the appropriate materials suitable and matched densities to replicate a human thorax. Comparing transmission for these materials on a linear accelerator for 6MV and 10MV energy, the deviation from planned versus measured dose varied between 1.67% to 3.32% and 0.45% to 2.30%, respectively for the silicon material and between 0.77% to 3.22% and 0.17% to 2.57% for the 3D printed bone for 6MV and 10MV. iv Conclusion: The measurements done on the linear accelerator matched closely with the calculated values on the treatment planning system for transmission through the materials in the customised phantom. Various proposals were put forward to mimic the movement of the targets within the lung regions. However, it was not possible to manufacture a mechanically based working model due to the small movements observed (<5mm). It is recommended that a robotic solution be investigated as alternative to mimic these small movements.
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    A prospective cohort study on ambient air pollution, airborne pollen (and fungal spores) and respiratory morbidities including childhood asthma in adolescents from the Western Cape Province
    (2018) Olaniyan, Toyib Adedamola; Dalvie, Mohamed Aqiel; Jeebhay, Mohamed Fareed; Röösli, Martin
    Background: The epidemiological studies investigating environmental risk factors associated with asthma among children living in informal settlements are scant as are studies on the independent and co-pollutant effect of short- and long-term exposures to ambient air pollutants as well as fungal spores on asthma-associated outcomes. This study systematically investigated these factors among schoolchildren residing in informal settlements in the Western Cape province of South Africa. Methods: A cohort study of grade-4 schoolchildren (n=590) recruited from six primary schools in four informal settlements was conducted over 12 months. In addition, a panel study, investigated the children for 2 consecutive school weeks in both summer and winter. Spirometry and fractional-exhaled nitric oxide (FeNO) measurements were conducted during the school day, while the International Study on Asthma and Allergy in Children (ISAAC) standardised questionnaire was administered to the parent or guardian at the child’s home at baseline and follow-up. The presence of atopy was determined based on a positive Phadiatop test on sera. In the cohort study, annual NO2 and PM2.5 levels were computed for each child’s address using a land-use regression model. Daily PM10 levels obtained from a stationary monitor near two of the study areas were used for the panel study. Airborne pollen and fungal spore measurements were obtained directly from a stationary monitor placed in each study area. Results: The prevalence of doctor-diagnosed asthma was 3.4% and only half of them were on asthma treatment. The prevalence of wheezing in the past 12 months (12.9%), airway obstruction (17.6%) and airway inflammation (10.2%) was much higher. The presence of damp conditions, visible mould growth, passive smoking as well as paraffin-use for cooking and heating were significant indoor risk factors for asthma. The estimated annual average NO2 level of 16.6 µg/m3 was below the WHO annual exposure standards, however more than a third of children were exposed to annual PM2.5 levels above the 10 µg/m3 WHO standard and the allergic symptom threshold level of 100 spores/m3 for Alternaria spores. In the panel study, daily exposure of schoolchildren to Alternaria and Cladosporium spores independently decreased FEV1 (-27.56 ml, 95% CI: -50.60 to -4.51 ml per 10 spores/m3 increase in Alternaria; and -86.19ml, 95% CI: -131.69 to -40.70 ml per 50 spores/m3 increase in Cladosporium respectively) from lag day-0 to lag day-5, especially in the winter monitoring period. In the cohort study, an interquartile range increase of 14.2 µg/m3 in annual NO2 was associated with an risk of new onset ocular-nasal symptoms (adjusted odds ratio – aOR: 1.63, 95% CI: 1.01 – 2.60), wheezing (aOR: 3.57, 95% CI: 1.18 – 10.92), more than two or more asthma symptom score (aOR: 1.71, 95% CI: 1.02 – 2.86), and airway inflammation defined as FeNO > 35ppb (aOR: 3.10, 95% CI: 1.10 – 8.71), independent of PM2.5 exposures. In addition, an interquartile increase of 83.1 spores/m3 in 24-hour annual Alternaria spore levels was associated with an increased risk of airway inflammation incidence and having a ≥ 10% increase in FeNO at follow-up both in the single-pollutant model and two-pollutant model. Conclusion: This study demonstrated a large proportion of undiagnosed and untreated asthma in schoolchildren living in informal settlements, with both indoor and outdoor mould exposures playing an important role in addition to ambient chemical pollutants. The incidence of new onset asthma symptoms and airway inflammation associated with NO2 at levels below the WHO Air Quality Standards raises the issue of the adequacy of these standards in protecting respiratory health. Raised long-term levels of airborne Alternaria spores contributing to increased airway inflammation is likely to form the basis for the increased risk of acute symptoms and airway effects observed in association with exposure peaks.
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    A qualitative exploration of the perceived factors that influence alcohol consumption among South African girls and young women (AFYW) and the relationship with sexual risk behaviour
    (2023) Grant, Jamie; Knight, Lucia
    South Africa (SA) has one of the highest rates of problematic alcohol consumption, with rates particularly concerning among young people. SA adolescent girls and young women (AGYW), from low-resourced settings, exhibit increasingly problematic alcohol consumption behaviours. As alcohol is a key determinant of sexual risk behaviours, it increases AGYW's already disproportionate burden of potentially negative sexual and reproductive health outcomes. This paper reports on analysis of qualitative data from interviews with AGYW and stakeholders, conducted in six SA provinces. Data were thematically analysed to explore respondent's perceptions of factors influencing AGYW's alcohol consumption and experiences of alcohol-induced sexual risk behaviour. Reasons for alcohol consumption included AGYW's desires for pleasure and enhanced sociability, but also to suppress negative emotions. Access to alcohol and social modelling were also perceived as influential factors. Alcohol consumption increased sexual risk through condomless sex and risk of sexual and physical violence against AGYW. Findings indicate that AGYW face negative social reactions to their consumption habits because they contradict social norms of youth and femininity. An understanding of motivations for alcohol use among AGYW, and the influence of the social environments, are useful for formulating alcohol risk-reduction strategies for AGYW and the communities in which they live.
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    A retrospective description of a 12 month caseload at four private emergency centres in South Africa
    (2023) King, Jonathan; Hodkinson, Peter
    Introduction In South Africa, private emergency departments (ED) are often the first port of call for a substantial proportion of the population served by the private healthcare sector. This study aims to describe the number, acuity and chief complaint of patients that presented to a sample of urban private EDs within South Africa. Methods A retrospective review of patient data from January 2018 to December 2018 was performed for four private facilities from a large private healthcare group. Data collected include demographics, time of arrival, disposal, triage score and presenting complaint. Results A total of 71079 patients presented to the four facilities. The South African Triage Scale (SATS) scores were as follows: red (5%), orange (11%), yellow (65%) and green (19%). Patients arrived mostly during the day (08:00-17:00 (54%)), evening (17:00-22:00 (27%)) and night (22:00-08:00 (19%)). Disposal of patients included admission (14%), discharge (77%), transfer to another facility (2%) and those who left without being seen (3%). The most frequent presenting complaints included gastrointestinal complaints, falls, respiratory issues, fever, traffic accidents and chest pain. Conclusion This study is the first description of the caseload and case mix in private EDs in South Africa. The most common presenting complaints were gastrointestinal and respiratory, with chest pain being the commonest red triaged complaint. Such complaints are similar to international data. In contrast, trauma related to assault is ranked 20th in private as opposed to 1st in the public sector. Admission rates are in keeping with US data, but lower than SA public, UK and Australia. Lastly, many green patients are follow ups which likely relates to the fee-for-service nature of the private sector and continuum of care fulfilled by ED doctors.
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    A study of the expression and cellular function of the human FAM111B gene
    (2021) Rhoda, Cenza; Arowolo, Afolake
    POIKTMP, a multi-systemic fibrosing disease, results from mutations in the human FAM111B gene. Studies have also suggested high expression of this gene in cancers. Despite rising interest in the pathological effects of FAM111B mutations and overexpression of FAM111B, knowledge of the physiological role of this gene remains limited. Therefore, this study sought out to provide insights into the cellular function of FAM111B and to investigate the pathological effect of the FAM111B Y621D mutation. First, bioinformatics studies coupled with quantitative PCR and Western blots analysis were employed to assess FAM111B gene and protein expression in cancerous and non-cancerous cell lines. Subsequently, FAM111B gene expression was downregulated and upregulated in the human fibrosarcoma (HT1080) cell line by RNA-interference mediated gene silencing and recombinant gene expression technologies. The effect of these FAM111B dysregulations was studied using cellbased functional assays: proliferation, apoptosis, migration, and invasion assays. Furthermore, the functional pathways and interacting proteins of the FAM111B protein was determined using mass spectroscopy proteomics. Finally, preliminary studies in a POIKTMP patient-derived fibroblasts were attempted to recapitulate the results obtained using the HT1080 cell line. The results from this study indicated that FAM111B gene and protein overexpression occurs in cancer cells. Second, the depletion of FAM111B suggests a decelerated rate of cell proliferation and migration (14%), and increased apoptosis (1.4-fold). Conversely, overexpression of FAM111B resulted in a marked reduction in apoptosis (3-fold) and increased cell migration by 27 %, howbeit, no evidence of increased proliferation. Furthermore, Y621D FAM111B mutant cells showed reduced expression of FAM111B, decreased apoptosis (1.1-fold), cellular invasion (24%), and indicates an increase in cell proliferation and migration (18 %). The proteomics data suggested wild-type FAM111B interacts with HSP7C, a molecular chaperone, which alongside BAG3 and BCL2 to minimise apoptosis. Similarly, Y621D's interaction with G3V3W4, a component of the 20S proteasome complex involved in the proteolytic degradation of damaged proteins, may suggest the rapid clearance of this mutant protein.
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    A study of the genital microbiotas of black South African women and men: associations with human papillomavirus and HIV infections
    (2018) Onywera, David Harris; Meiring, Tracy L; Williamson, Anna-Lise
    Persistent genital infection with oncogenic or high-risk human papillomavirus (HPV) is causally associated with cervical cancer in women and some penile cancers in men. The role of the complex genital microbiota in HPV infection has not been extensively addressed. This study characterised the genital microbiotas of heterosexually-active Black South African women and men, predominantly of the Xhosa ethnicity, recruited from a community in Cape Town, South Africa. The association of the genital microbiotas with prevalent HPV, HIV, demographic, behavioural, and clinical characteristics of the participants was examined. In Chapter 2 the bacterial communities in cervicovaginal samples from 62 HIVseronegative South African women were profiled by Ion Torrent PGM sequencing of the V4 hypervariable region of the bacterial 16S rRNA gene (IT-V4 method). The cervicovaginal microbiotas (CVMs) were found to cluster into three distinct community state types (CSTs): Lactobacillus iners-dominated CVMs (CST I (38.7%, 24/62)), unclassified Lactobacillusdominated CVMs (CST II (4.8%, 3/62)), and diverse CVMs (CST III (56.5%, 35/62)) with an array of heterogeneous bacteria, predominantly the bacterial vaginosis (BV)-associated Gardnerella, Prevotella, Sneathia, and Shuttleworthia. The majority of the women had nonLactobacillus-dominated CVMs. Lactobacilli are recognised as protective against sexually transmitted infections. Among the Lactobacillus species detected in the women, L. iners was the most prevalent and abundant. This species is recognised as the least protective amongst the vaginal lactobacilli. Women in CST I were more likely to be on hormonal contraception compared to women in CST III (relative risk (RR): 2.6 [95% CI 1.3-5.3]; p=0.005). Further research is required to confirm this association and to determine the biological mechanism. Microbiome research methodologies are constantly improving and in Chapter 3 the performance of two bacterial 16S rRNA gene amplicon-based methodologies were compared. The CVMs of 19 women were characterised using the IT-V4 method (Chapter 2) and using the Illumina 16S rRNA metagenomics method (IM-V3/V4 method). The latter method involves sequencing the V3 and V4 hypervariable regions of the 16S rRNA gene on the Illumina MiSeq platform. The two methods showed a high degree of correlation (r=0.89, p< 0.0001) in the average relative abundance of shared bacterial taxa. Procrustes analyses of the weighted UniFrac distances further showed a statistically consistent clustering between the two methods (M 2 =0.3, p< 0.0001). The IM-V3/V4 method proved to have a greater throughput, longer read-length, and lower error rates than the IT-V4 method and was therefore used in the subsequent chapters (4 and 5). In Chapter 4, the CVMs of 87 HIV-seronegative women from the same cohort were examined using the IM-V3/V4 method. The CVMs clustered into eight CSTs. Only 23 women (26.4%) had CVMs dominated by a single Lactobacillus species, this included two women (2.3%) with L. crispatus (CST-1), two (2.3%) with L. jensenii (CST-2), and 19 (21.8%) with L. iners (CST-3). The majority of the women (64.4% (56/87)), however, had diverse and heterogeneous CVMs (CST-8) that were associated with BV (p2, p<0.05). In the final experimental chapter, the penile microbiotas of 238 Black South African men were characterised. This is the first large-scale study of the penile microbiota of South African men. Corynebacteriaceae (47.2%) and Prevotellaceae (6.6%) were found to be the most abundant bacterial families. The penile bacterial communities clustered into six CSTs (designated 1-6). A majority of the men (53.4% (127/238)) had Corynebacterium-dominated microbiotas (CST-1). The remaining CSTs (2-6) had lower relative abundances of Corynebacterium than CST-1 and were colonised with several vaginal bacteria. The prevalences of these CSTs (2-6) in men together with their respective most abundant genera (besides Corynebacterium) were as follows: CST-2 (9.2%; unclassified Clostridiales and Porphyromonas), CST-3 (8.8%; Gardnerella), CST-4 (7.6%; Chryseobacterium and Acinetobacter), CST-5 (18.5%; unclassified Clostridiales and Porphyromonas), and CST-6 (2.5%; Lactobacillus). One hundred and thirty (54.6%) and 102 (42.9%) of the men were positive for HPV and high-risk HPV, respectively, as detected by the Roche Linear Array HPV Genotyping assay. Of the 130 HPV-positive men, 37 (28.5%) and 93 (71.5%) had single and multiple HPV types, respectively. Men in CST-1 were less likely to have high-risk HPV and multiple HPV infections relative to men in CSTs 2-6 (RR: high-risk HPV: 0.8 [95% CI 0.6-1.0]; p=0.027 and multiple HPV: 0.8 [95% CI 0.6-1.0]; p=0.042). LefSe revealed that prevalent HPV infection was strongly associated with higher relative abundances of Sneathia, Porphyromonas, Prevotella, Dialister, and Campylobacter (LDA score >3, p3, p< 0.05). The relative abundances of the latter three bacteria together with Peptoniphilus were strongly associated with high-risk HPV infection (LDA score >3, p <0.05). In our cohort, 88 men (37.0%) were positive for HIV. Of these, 71.6% and 60.2% were positive for HPV and highrisk HPV infection, respectively. Among the HIV-negative men (n=150), 44.7% and 32.7% were positive for HPV and high-risk HPV infection, respectively. Although HIV status did not impact the overall composition of the penile microbiotas, HIV-infected men had higher relative abundances of Staphylococcus, Faecalibacterium, Strenotrophominas, Jonquetella, Ruminococcus, Roseburia, and Lamia (LDA score >2, p<0.05) Men with BV-negative female sexual partners (66.5% (157/236)) had higher relative abundances of Lactobacillus in their penile microbiotas than men with BV-positive female partners (p=0.007). Atopobium, Sneathia, and Saccharofermentans were significantly more prevalent in men with BV-positive female partners than men with BV-negative partners (p<0.020). The main limitations of our study include relatively small sample size of women, insufficient participant information such as host genetics, other STIs (e.g., herpes simplex virus) and abnormal vaginal flora (e.g., aerobic vaginitis), using a less sensitive method to diagnose BV in women, and inherent biases evident in any retrospective study. Moreover, we did not adjust for confounding factors in our analysis due to the small sample size. Despite the underscored limitations, our findings provide insight into the baseline genital microbiotas of the Black South African women and men. The associations identified in this cross-sectional study between specific microbiota members and HPV infection, particularly the association between Sneathia and HPV/high-risk HPV infection, identified in both women and men, are hypothesis-generating and warrant further investigation. The study forms a critical starting point for future longitudinal confirmatory association studies and studies examining these bacteria as potential biomarkers or risk factors for HPV infection.
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    A study on the role of oxidative stress and protein kinase signalling in hyperglycaemia induced cardiac remodelling
    (2023) Amtha, Nikhil; Gwanyanya, Asfree
    Background Almost one-third of all deaths in patients with uncontrolled diabetes mellitus and hyperglycaemia are due to cardiovascular diseases. Chronic exposure of the heart to hyperglycaemia leads to a maladaptation called pathological cardiac remodelling and occurs via oxidative stress due to excess production of reactive oxygen species (ROS). In the heart, ROS modulates cardiac differentiation, cardiomyocyte proliferation, and myocardial tissue growth via ROS-sensitive protein kinases such as the mitogen-activated protein kinase (MAPK). Although there are several different MAPKs, the p38 MAPKs are involved in cardiogenesis and implicated in stimulating myocyte apoptosis, hypertrophy, or even antiapoptotic effects. As such, the role of p38 MAPKs in diabetic cardiac remodelling, especially during cardiac development, remains unclear. This study aims to elucidate the effect of hyperglycaemia on the p38 MAPK signalling pathway in a cardiac developmental model. Methods Pluripotent mouse embryonic stem cells (mESCs) were differentiated in vitro into cardiaclike pulsatile embryoid bodies (EBs) using the hanging drop method. Once pulsatile, EBs were further cultured for 72 hours in either baseline (25mM) or high glucose (50mM) media or with the pro-oxidant hydrogen peroxide (100μM). Changes in EB morphology and beating characteristics were observed using transmitted light microscopy. Immunocytochemistry and fluorescence microscopy imaging was used to detect changes in biomarkers. The nuclear uptake of propidium iodide (PI) was used to evaluate cell viability, whereas the 5-ethynyl-1- deoxyuridine (EdU) assay was used to determine cell proliferation. Western blot was used to analyse protein expression. Results Treatment with hydrogen peroxide stunted EB growth and decreased EB diameter, consistent with the presence of oxidative stress. High glucose increased the number of pyknotic-like nuclei and reduced the number of EdU-positive nuclei. Furthermore, hyperglycaemia elevated the expression of phosphorylated p38 MAPK, without altering total p38 MAPK expression levels. Inhibition of p38 MAPK by SB203580 in high glucose attenuated the increased number of pyknotic-like nuclei in high glucose and enhanced the number of EdUpositive nuclei compared to high glucose alone. High glucose also reduced the expression of the mitochondrial fusion regulatory protein, optic atrophy-1 (OPA1), with the inhibition of p38MAPK in high glucose attenuating this effect. Conclusion Hyperglycaemia induced pyknotic-like phenomenon, suppressed the proliferation, and reduced mitochondrial fusion protein machinery of mESC-derived cardiac-like cells. These effects were likely triggered by a mild form of oxidative stress and involved the activation of p38 MAPK. The findings provide insights into the mechanisms underlying diabetic developmental cardiac remodelling and identify p38MAPKs as a potential therapeutic target.
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    A study to characterise the “arsenic rash” observed at a copper smelter in Tsumeb, Namibia
    (2022) Kew, Gregory Paul; Myers, Jonny; Todd, Gail
    This study is located at a copper smelter. Arsenic is a component of copper bearing ore and arsenic trioxide is a by-product of copper smelting. The vapours (“off-gases”) that are released from the molten copper-bearing ore cool and condense in evaporative coolers to form arsenic-containing dust in the smelter's flues and stacks. The dust is filtered in “bag houses” and the captured powder is transported to Godfrey Roasters where the arsenic trioxide is driven off by heat. From there, the hot roaster gases are collected in what are known as “arsenic kitchens”, where fume is allowed to cool. The arsenic trioxide settles to the floor of the rooms as coarse dust and also forms crystalline deposits on the walls and ceilings. It is removed from the kitchens and prepared for shipment as a dust containing approximately 98% arsenic trioxide. Workers are exposed to arsenic containing dust during maintenance work on the copper smelter's flues and the bag houses, or whilst performing various tasks in the arsenic plant roasters and kitchens. The smelter has approximately 500 permanent employees and variable numbers of contractors, which can increase the total employee compliment by 1000. Skin rashes are the most common occupational disease reported at the copper smelter. The underlying cause of these acute transient rashes have historically been attributed by smelter employees to arsenic exposure, as encapsulated in the widely-used term, “arsenic rash”. Previous smelter reports have shown that the highest rates of skin rashes occurred at the arsenic plant and ausmelt baghouse. The appearance and anatomical distribution of the rash was described in these reports. Notwithstanding the use of the term, “arsenic rash”, the role of arsenic trioxide (As2O3) in the development of these rashes has been uncertain. In particular, a question has been raised as to whether the rash represents an allergy to either the arsenic trioxide or some other constituent of baghouse dust. Other uncertainties have related to the roles of skin hygiene practices and Personal Protective Equipment (PPE). This study included three levels of enquiry: a detailed questionnaire (exploring personal risk factors, skin hygiene practices, PPE use and descriptions of the rashes experienced); a clinical examination by a dermatologist; and skin patch testing (using both standard allergens as well as selected chemical agents from 4 selected workplaces, namely “pure” As2O3 powder from the arsenic plant, baghouse dust from the ausmelt & convertor plants, and “cake” from the Effluent Treatment Plant (“ETP”)). Analysis of the chemical compounds present in the four samples was performed by an external certified laboratory in Pretoria, South Africa. For the purposes of skin patch testing, all four samples were “standardised” to 2g/dL As2O3 in water by the Smelter's quality assurance lab. The epidemiological techniques varied according to the different objectives. For objectives 1 and 2: retrospective case control. For objective 3: exposure characterisation for use in exposure-response analysis. For objectives 4 & 5: retrospective case-control study, with controls matched for area of work in the smelter. Cases (N=27) comprised all employees who had one or more work-related rash incident within the preceding 12-24 months. These are relatively rare events, limiting the number of cases available for the study. Controls (N=24) comprised purposively selected co-workers, one control for each case, who performed the same type of work in the same workplace but who had never developed a rash. The principal variables included potential determinants of skin reactions to workplace materials (pure arsenic dust from the arsenic plant, baghouse dust from the ausmelt and converter and filter cake from the effluent treatment plant), reactions to patch testing, a history of allergy, prior experience of a similar rash, duration of service in the smelter and age. Ethical approval to conduct the study was obtained from the University of Cape Town's Health Research Ethics Committee (UCT HREC) (reference number 261/2016), and from the Office of the Permanent Secretary for Health, Namibia (letter dated 17 January 2018). Five study objectives were formulated, the outcomes of which are summarised as follows: Study objective 1: To interrogate if skin hygiene and hand cleansing practices used in the smelter, notably the use of barrier creams and soaps, are risk factors for developing a skin rash, and if so, at which anatomical location. The study data showed that hand washing practices of cases and controls were very similar, suggesting that handwashing practices are not a risk factor for developing a skin rash at any anatomical location, notably the hands. Furthermore, the data showed that the hand cream being issued as a barrier to chemical contact is not protective. However, both findings could be due to a non-differential bias whereby responses to the questionnaires in both groups of participants were influenced by a desire to appear compliant with company policy and conscientious with regard to cleanliness. Study objective 2: To interrogate the use of PPE by employees in the smelter, and whether or not this is a contributory factor to the development of the rash Whilst responses for the individual PPE related questions were generally similar in cases & controls, the combined prevalence of rashes in the area of the face (41%), respirator contact points (12.5%) and the neck area (19.6%) is high (73%). The rest of the body combined only accounts for 27%. Also, more specific questioning of the cases suggests that the respirators are a substantial contributor to the rashes in the face & neck areas. The lack of statistical significance between cases and controls for the individual PPE related questions could be due to the same non-differential bias operative in objective 1. Study objective 3(a & b): To characterise the nature of the chemical constituents in the production byproducts obtained from the various workplaces of the smelter operations (“workplace materials”). These “workplace materials” are the substances (usually in dust form) to which employees are exposed and which may trigger the skin reactions. The analysis addressed this in two ways; objective 3a looked at the chemical constituents of the workplace materials “as-is” (taken from the samples collected directly from the various workplaces as part of the smelter's Quality Assurance (QA) programme, and therefore as they are experienced by workers), and objective 3b looked at the chemical solutions used in the study skin tests, after standardisation for arsenic trioxide at 2g of arsenic trioxide per 100mL of water. Objective 3a: The proportionate concentrations of As2O3 varied from 5% to 98% across the 4 samples from the 4 workplace locations, namely the arsenic plant (98%), ausmelt baghouse (83%), convertor baghouse (21%) and ETP (5%). Lead and sulphur were identified as additional potential irritants in the convertor baghouse dust and the ETP cake. Both baghouse dusts (ausmelt & converter) had alkaline pH, the As2O3 sample from the arsenic plant had an acid pH and the pH of the ETP sample was close to neutral. Objective 3b: The samples were standardised to 2g/dL As2O3 in water, to better ascertain the skin responses to arsenic trioxide specifically at varying dilutions. This concentration was chosen because it is the point of solubility of arsenic trioxide in water. Consequently, the two samples with relatively lower As2O3 in the source material (converter Baghouse dust & ETP cake) had proportionately increased concentrations of their non-arsenic constituents after standardisation. These proportionate increases were 19% (ausmelt baghouse), 373% (converter baghouse) and 1799% (ETP). Should any of the non-arsenic constituents be irritants, their irritancies would be equivalently affected. Following standardisation for arsenic, the pH for the ausmelt sample went up from pH 7.8 to pH 8.8, the converter sample went from pH 8.7 to pH 9.6 and the ETP sample went from pH 6.7 to 7.8. The arsenic plant sample had a pH of 4.5 after standardisation. Unfortunately, the smelter lab did not provide a pH of the pre-standardised arsenic plant sample. The high pH levels (8.8 & 9.6) or low pH level (4.5) are independently capable of causing irritation. Study objective 4: To characterise the nature of the dermatological response to these exposures, notably whether the reactions are allergic or irritant in nature. The main finding of this study is that arsenic trioxide is an irritant not an allergen, because of its low pH as well as an inherent dermal toxicity. The grounds for this conclusion are (1) the clinical appearance of the skin reactions where arsenic trioxide was in contact with the skin and (2) the dose-response relationship with increased concentrations of arsenic trioxide with the skin. The presence of arsenic trioxide in the baghouse dust and ETP cake confers irritant properties to these operational materials. The baghouse dusts are additionally irritant because of their high pH. The ETP cake produced a dosedependent irritant reaction even though it was pH neutral. Irritancy has implications on exposure prevention, in that all employees are potentially affected, not only a subset of vulnerable people. Study objective 5: To try to ascertain any causal relationship between baghouse dust (and notably the As2O3 in the dust) and the pathological outcomes The irritancy of arsenic trioxide in the arsenic plant sample was clearly demonstrable even though it was significantly diluted during the standardisation process (to 2g/dL). Arsenic plant workers in the realworld setting are exposed to undiluted concentrations of arsenic trioxide dust, which explains the high prevalence of irritant skin reactions amongst workers in this area. This study has demonstrated that the alkaline pH of baghouse dust confers additional irritancy to that already conferred by the arsenic trioxide present in the dust. This explains the high prevalence of irritant skin reactions amongst workers exposed to baghouse dust. This report ends with some recommendations, based on the findings of the study, as well as knowledge gaps identified.
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    A two-year review of necrotising enterocolitis in very low birth weight infants (<1500g) in a South African tertiary hospital
    (2019) Gumede, Mbalenhle Purity; Tooke, Lloyd
    Background: There is paucity of local data on the profile of preterm very low birth weight (VLBW) infants who develop moderate to severe necrotising enterocolitis (NEC) and their outcomes. Methods: A retrospective folder review of VLBWs who developed Modified Bell’s stage II NEC or higher at Groote Schuur Hospital (GSH) nursery between January 2012 and December 2013 was performed. Outcomes were defined as requirement for surgery and mortality. Results: Forty seven infants were included (5% incidence). Gestational ages ranged from 25 to 36 weeks, 53% were 10 mg/L (60%) and subserosal gas radiologically (84%). Half the patients received mechanical ventilation, 38% required inotropes. The mortality rate was 64%. Three of the five infants that received surgery survived. Conclusion: Despite a similar incidence to global counterparts, our VLBW infants have severe NEC disease often requiring advanced life support, with a high mortality rate. HIV exposure may increase the risk of NEC development.
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    Absenteeism and musculoskeletal pain : an interactive network of variables
    (2000) Boshoff, Susan; Bridger Robert S,; Ehrlich, Rodney I
    Bibliography: leaves 79-84.
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    Achievement of secondary prevention goals 6 to 9 months after Acute Coronary Syndrome : a retrospective, cross-sectional analysis
    (2014) Griffiths, Bradley Paul; Ntsekhe, Mpiko
    Study Rationale: Good evidence exists to support the use of secondary prevention medications (aspirin, HMG-CoA reductase inhibitors [statins], beta-blockers and angiotensin-converting enzyme inhibitors [ACEIs] or angiotensin receptor blockers [ARBs]) and smoking cessation in patients after acute coronary syndromes. At present, little is known about adherence to medication and smoking behaviour after discharge in South Africa. This information is essential to optimising both in-patient care and post-discharge planning of these patients. Methods: We conducted a cross sectional analysis of all patients discharged from the Groote Schuur Hospital Coronary Care Unit with a diagnosis of acute coronary syndrome between 15 November 2011 and 15 April 2012. A follow up telephone call was performed 6 to 9 months after discharge, and a standardized questionnaire completed detailing current medication use, reasons for non-adherence, and smoking status at time of the interview. Results: Prescribing of secondary prevention medications at discharge was found to be high (aspirin 94.5%, statins 95.7%, beta blockers 85.4%, ACEIs/ARBs 85.9%), and 70.7% of patients were discharged on a combination of all 4 drugs. At 6 to 9 month follow-up, the proportion of patients using these medications had reduced by 8.9% for aspirin, 10.1% for statins, 6.2% for beta-blockers and 17.9% for ACEIs/ARBs. Only 47.2% remained on all 4 drugs, a reduction of 23.5%. Of the 56% of patients who were smokers on admission to hospital, 31% had stopped smoking at the time of interview. Conclusions: Despite high rates of pre-discharge prescription of recommended therapy following admissions for acute coronary syndromes, we observed a significant decline in adherence rates 6 to 9 months post discharge and a poor rate of smoking cessation. An exploration of possible reasons for these findings suggests that efforts to educate patients about the importance of long-term adherence need to be improved. Furthermore, more effective interventions are needed to improve smoking cessation than in-hospital reminders about the hazards of smoking
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    Activation of MAIT cells by antigen presenting cells: a comprehensive analysis and assessment of HIV and TB disease on these interactions
    (2019) Balfour, Avuyonke; Shey, Muki; Meintjies, Graeme
    MAIT cells are non-classical, innate-like T lymphocyte subsets, which recognize microbial vitamin B metabolites and rapidly respond by producing pro-inflammatory cytokines such as IFN-γ, TNF-α and cytotoxic molecules, which may result in the killing of bacteria-infected cells. Unlike conventional T cells, MAIT cells can be activated by either antigen presentation on MR1 or directly by cytokines. MAIT cells play a protective role against bacterial infections in mice but so far, no human studies have confirmed a direct role of MAIT cells in the control of bacterial infections or prevention of disease progression. Circulating MAIT cell numbers decrease in patients with active TB, but findings regarding functional changes have been conflicting. The aims of this study were to assess the cellular interactions between antigen presenting cells and MAIT cells, and determine the effect of TB, HIV and HIV-associated TB on MAIT cell numbers, activation, inhibitory and functional profile. We recruited 26 healthy controls (HC) without HIV or TB disease, 30 people with HIV only, 30 with active TB only, and 26 with HIV-associated TB. All TB patient samples were obtained before treatment. Blood was collected from all participants and peripheral blood mononuclear cells (PBMC) isolated from the blood and cryopreserved. Later, PBMC were thawed, rested and stimulated with BCG expressing GFP (BCG-GFP) and heat-killed (HK) M.tb. Media only, LPS and PHA were used as stimulation controls. The numbers, functional profile, inhibitory and activation status of MAIT cells were determined by flow cytometry. Soluble cytokines were measured by ELISA and multiplex Luminex assays. For HIV-infected participants with no TB and patients with HIV-associated TB, the median CD4 counts were 501 cells/µL and 228 cells/µL, and HIV viral loads were 1673 copies/mL and 66509 copies/mL, respectively. 63% and 69% of HIV infected patients were on ART in the HIV alone and HIV/TB groups, respectively. We observed lower frequencies of circulating MAIT cells in individuals with active TB only or HIV only compared to HC. HIV/TB resulted in lower but nonsignificant MAIT cell frequencies and numbers compared to HC. In response to stimulation with whole mycobacteria, MAIT cells were more highly activated (expressing high HLA-DR) in people with TB and HIV-associated TB compared to HC. Furthermore, MAIT cells from people with active TB only had significantly upregulated PD-1 expression compared to HC. MAIT cells from individuals with active TB and HIV-associated TB had a lower capacity to degranulate (express CD107a) and produce IFN-γ compared to HC. HIV-infection alone did not affect these functions. The levels of soluble IFN-α2 were reduced in the groups with HIV only and active TB only while IFN-γ was reduced in all patient groups. Blocking experiments revealed that MAIT cell activation in response to BCG was primarily through MR1 antigen presentation pathway. The level of monocyte and dendritic cell infection (expression of GFP) was similar in all groups. We observed a positive correlation between monocyte infection and the frequencies of MAIT cells producing IFN-γ in people with active TB only. We also observed a positive correlation between the amount of soluble IL-12 and the proportion of MAIT cells producing IFN-γ and CD107a in HC and in people with HIV infection, respectively. Our data show that HIV, TB and or HIV/TB result in a decrease in circulating MAIT cells, impaired functional profile, and a significant alteration in activation status and inhibitory potential. The MR1 antigen presentation was the predominant pathway for MAIT cell activation. There was also a relationship observed between MAIT cell activation and magnitude of innate response to mycobacterial antigens. These results provide further evidence of the potential role of MAIT cells in infectious disease pathogenesis and demonstrate how HIV and TB alter their function.
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    Acute cognitive dysfunction, short and long-term outcomes and the impact of medical follow-up following hospitalisation for general medical illness in Cape Town, South Africa
    (2023) Abdullah, Mohamed; Peter, Jonathan; Raubenheimer Peter
    Background. Delirium is an important and common general medical condition with a high morbidity and mortality rate independently associated with increases in the length of hospital stay, the requirement for institutional care, persistent cognitive deficits, and functional decline. The Gold standard for testing delirium continues to evolve but requires lengthy bedside cognitive testing by trained specialists. In a busy acute general medical setting, the use of these tools is impractical. Many alternatives and shorter tools have been developed for screening, diagnosis, and assessing the severity of delirium, but the majority have only been validated for use in geriatric populations or intensive care settings in developed countries. Objective. In this study, we validate the simple ‘RACY' 4-question delirium screening tool for use in general medical tertiary hospital admissions. Methods. This was a prospective observational cohort study conducted amongst acute general medical admissions at Groote Schuur Hospital, in Cape Town, South Africa, admitted between 30 September 2013 and 30 January 2014. ROC characteristics and diagnostic accuracy of the ‘RACY' 4-question delirium screening tool, sensitivity analysis of factors influencing RACY performance, and interrater agreement were obtained. Reference delirium testing was performed by neuropsychologists, using the Confusion Assessment Method. Results. A total of 609 medical in-patients were included. The prevalence of delirium was 16.9% (95% CI: 13.7-20.6, 82/485), and the median (IQR) age of admissions was 50 (36-65) years. The AUROC for RACY was 0.859. A cut-point of RACY ≤ 2 offered the best overall diagnostic utility classifying 8 out of 10 patients correctly with sensitivity, specificity, positive and negative likelihood ratios (+LR, -LR) of 74.4% (95% CI: 63.6-83.4, n/N: 61/82); 83.6% (95% CI: 79.6-87.5, n/N: 337/403); 4.5 (95% CI: 3.5-5.9); and 0.3 (95% CI: 0.2-0.4) respectively. Alternatively, a cut-point of RACY ≤ 3 optimised rule-out utility with a sensitivity and NPV of 94.0% (95% CI: 86.3-98.0, n/N: 77/82) and 97.6% (95% CI: 94.4-99.2, n/N: 201/206). RACY testing could be performed in less than a minute. Overall interrater agreement was 70% with a kappa of 0.55. Conclusions. The rapid RACY tool is a simple valid and reliable method to screen for delirium amongst new general medical admissions in a developing country setting.