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Item ABBV744 as a potential inhibitor of SARSCoV2 main protease enzyme against COVID19(Nature Research) Zeynab Fakhar; Shama Khan; Afrah Alkhuriji; Suliman Y. AlOmar; Aijaz AhmadA new pathogen severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) has spread worldwide and become pandemic with thousands new deaths and infected cases globally. To address coronavirus disease (COVID‑19), currently no effective drug or vaccine is available. This necessity motivated us to explore potential lead compounds by considering drug repurposing approach targeting main protease (Mpro) enzyme of SARS‑CoV‑2. This enzyme considered to be an attractive drug target as it contributes significantly in mediating viral replication and transcription. Herein, comprehensive computational investigations were performed to identify potential inhibitors of SARS‑CoV‑2 Mpro enzyme. The structure‑based pharmacophore modeling was developed based on the co‑crystallized structure of the enzyme with its biological active inhibitor. The generated hypotheses were applied for virtual screening based PhaseScore. Docking based virtual screening workflow was used to generate hit compounds using HTVS, SP and XP based Glide GScore. The pharmacological and physicochemical properties of the selected lead compounds were characterized using ADMET. Molecular dynamics simulations were performed to explore the binding affinities of the considered lead compounds. Binding energies revealed that compound ABBV‑744 binds to the Mpro with strong affinity (ΔGbind −45.43 kcal/mol), and the complex is more stable in comparison with other protein–ligand complexes. Our study classified three best compounds which could be considered as promising inhibitors against main protease SARS‑CoV‑2 virusItem Antiplatelet Therapy Combined with Anastrozole Induces Features of Partial EMT in Breast Cancer Cells and Fails to Mitigate Breast-Cancer Induced Hypercoagulation(MDPI, 2021-04-16) Xulu, Kutlwano R.; Augustine, Tanya N.Thromboembolic complications are a leading cause of morbidity and mortality in cancer patients. Cancer patients often present with an increased risk for thrombosis including hypercoagulation, so the application of antiplatelet strategies to oncology warrants further investigation. This study investigated the effects of anastrozole and antiplatelet therapy (aspirin/clopidogrel cocktail or atopaxar) treatment on the tumour responses of luminal phenotype breast cancer cells and induced hypercoagulation. Ethical clearance was obtained (M150263). Blood was co-cultured with breast cancer cell lines (MCF7 and T47D) pre-treated with anastrozole and/or antiplatelet drugs for 24 h. Hypercoagulation was indicated by thrombin production and platelet activation (morphological and molecular). Gene expression associated with the epithelial-to-mesenchymal transition (EMT) was assessed in breast cancer cells, and secreted cytokines associated with tumour progression were evaluated. Data were analysed with the PAST3 software. Our findings showed that antiplatelet therapies (aspirin/clopidogrel cocktail and atopaxar) combined with anastrozole failed to prevent hypercoagulation and induced evidence of a partial EMT. Differences in tumour responses that modulate tumour aggression were noted between breast cancer cell lines, and this may be an important consideration in the clinical management of subphenotypes of luminal phenotype breast cancer. Further investigation is needed before this treatment modality (combined hormone and antiplatelet therapy) can be considered for managing tumour associated-thromboembolic disorder.Item Aqueous extract of moringa (Moringa oleifera) leaf (AEMOL) on the growth, sensory and histology parameters of broiler chickens(ALÖKI Kft, 2020-07) Mbajiorgu, Ejikeme F.; Alabi, O. J.; Ng’Ambi, J. W.A completely randomized design experiment was used to determine the effects of aqueous extract of Moringa oleifera leaf (AEMOL) on growth, sensory and histology parameters of broiler chickens. Treatment 1 served as the control (antibiotics), Treatment two was given ordinary water (AEMOL0). Treatments 3, 4, 5 and 6 contained 30, 60, 90 and 120 ml of AEMOL per litre of water per day, respectively. Data obtained were analyzed using one-way analysis of variance and mean separation was done using Duncan’s test for multiple comparisons. Results showed that the extract influenced (P < 0.05) the feed intake and water intake at the broiler starter phase WHILE birds on the control diet had higher values. Finisher phase results showed that final weight, weight gain, feed intake, FCR and water intake were influenced (P < 0.05) by the extract with birds treated with 60 ml/l of AEMOL doing better for most parameters except the FCR. All the digestibility and sensory parameters measured were also influenced (P < 0.05) by the extract. However, histological parameters measured were not affected (P > 0.05) by the extract. It could be concluded that the extract inclusion levels up to 90 ml/l can be used to replace antibiotic growth promoter without compromising the advantages of antibiotic growth promoter.Item Blood pressure measurements in the ankle are not equivalent to blood pressure measurements in the arm(2014-12) Goldstein, L.N.; Wells, M.; Sliwa, K.Background. Blood pressure (BP) is often measured on the ankle in the emergency department (ED), but this has never been shown to be an acceptable alternative to measurements performed on the arm. Objective. To establish whether the differences between arm and ankle non-invasive BP measurements were clinically relevant (i.e. a difference of ≥10 mmHg). Methods. This was a prospective cross-sectional study in an urban ED making use of a convenience sample of 201 patients (18 - 50 years of age) who were not in need of emergency medical treatment. BP was measured in the supine position on both arms and ankles with the correct size cuff according to the manufacturer’s guidelines. The arm and ankle BP measurements were compared. Results. There was a clinically and statistically significant difference between arm and ankle systolic BP (SBP) and mean arterial pressure (MAP) (–13 mmHg, 95% confidence interval (CI) –28 - 1 mmHg and –5 mmHg, 95% CI –13 - 4 mmHg, respectively), with less difference in diastolic BP (DBP) (2 mmHg, 95% CI –7 - 10 mmHg). Only 37% of SBP measurements and 83% of MAP measurements were within an error range of 10 mmHg, while 95% of DBP measurements agreed within 10 mmHg. While the average differences (or the bias) were generally not large, large variations in individual patients (indicating poor precision) made the prediction of arm BP from ankle measurements unreliable. Conclusion. Ankle BP cannot be used as a substitute for arm BP in the ED.Item Critical value reporting : a survey of 36 clinical laboratories in South Africa(2014-01) Schapkaitz, E.; Mafika, Z.Objective: Critical value policies are used by clinical laboratories to decide when to notify caregivers of life-threatening results. Despite their widespread use, critical value policies have not been published locally. A survey was designed to determine critical value policies for haematology tests in South Africa. Methods: A survey was carried out on 136 identified laboratories across South Africa in January 2013. Of these, 36 responded. Data collected included critical value policies, critical values for haematology parameters, and critical value reporting. Results: Of the 36 laboratories surveyed, 11.1% (n=4) were private, 33.3% (n=12) were affiliated to academic institutions and 55.6% (n=20) were peripheral or regional National Health Laboratory Service laboratories. All the laboratories confirmed that they had a critical value policy, and 83.3% of such policies were derived from local clinical opinion. Mean low and high critical limits for the most frequently listed tests were as follows: haemoglobin <6 and >20 g/dl, platelet count <41 and >1 000 ×109 /l, white cell count <2 and >46×109 /l, activated partial thromboplastin time >101 seconds, and international normalised ratio >6. In almost all cases critical value reporting was performed by the technologist on duty (97.2%). The majority of laboratories required that the person notified of the critical value be the doctor who ordered the test or the caregiver directly involved in the patient’s care (83.3%); 73.3% of laboratories indicated that they followed an algorithm if the doctor/caregiver could not be reached. Conclusion: Each laboratory is responsible for establishing clinically relevant critical limits. Clinicians should be involved in developing the laboratory’s critical value policy. The findings of this survey may be of value to local laboratories that are in the process of establishing or reviewing critical value policiesItem Development of the Wits Face Database: an African database of high-resolution facial photographs and multimodal closedcircuit television (CCTV) recordings [version 1; peer review: 2 approved](2021) Bacci, Nicholas; Davimes, Joshua; Steyn, Maryna; Briers, NanetteForensic facial comparison is a commonly used, yet under-evaluated method employed in medicolegal contexts across the world. Testing the accuracy and reliability of facial comparisons requires large scale controlled and matching facial image databases. Databases that contain images of individuals on closed-circuit television (CCTV), with matching formal and informal photographs are needed for this type of research. Although many databases are available, the majority if not all are developed in order to improve facial recognition and face detection algorithms through machine learning, with very limited if any measure of standardisation. This paper aims to review the available databases and describe the development of a high resolution, standardised facial photograph and CCTV recording database of male Africans. The database is composed of a total of 6220 standardised and uncontrolled suboptimal facial photographs of 622 matching individuals in five different views, as well as corresponding CCTV footage of 334 individuals recorded under different realistic conditions. A detailed description of the composition and acquisition process of the database as well as its subdivisions and possible uses are provided. The challenges and limitations of developing this database are also highlighted, particularly with regard to obtaining CCTV video recordings and ethics for a database of faces. The application process to access the database is also briefly described.Item Forensic facial comparison: current status, limitations, and future directions.(MDPI, 2021-12-03) Bacci, Nicholas; Davimes, Joshua G.; Steyn, Maryna; Briers, NanetteGlobal escalation of crime has necessitated the use of digital imagery to aid the identification of perpetrators. Forensic facial comparison (FFC) is increasingly employed, often relying on poorquality images. In the absence of standardized criteria, especially in terms of video recordings, verification of the methodology is needed. This paper addresses aspects of FFC, discussing relevant terminology, investigating the validity and reliability of the FISWG morphological feature list using a new South African database, and advising on standards for CCTV equipment. Suboptimal conditions, including poor resolution, unfavorable angle of incidence, color, and lighting, affected the accuracy of FFC. Morphological analysis of photographs, standard CCTV, and eye-level CCTV showed improved performance in a strict iteration analysis, but not when using analogue CCTV images. Therefore, both strict and lenient iterations should be conducted, but FFC must be abandoned when a strict iteration performs worse than a lenient one. This threshold ought to be applied to the specific CCTV equipment to determine its utility. Chance-corrected accuracy was the most representative measure of accuracy, as opposed to the commonly used hit rate. While the use of automated systems is increasing, trained human observer-based morphological analysis, using the FISWG feature list and an Analysis, Comparison, Evaluation, and Verification (ACE-V) approach, should be the primary method of facial comparison.Item Harnessing Thor’s Hammer: Experimentally induced lightning trauma to human bone by high impulse current.(Elsevier B.V., 2021) Bacci, Nicholas; Audustine, Tanya N.; Hunt, Hugh G. P.; Nixon, Ken J.; Hoffman, Jakobus; Bam, Lunga; de Beer, Frikkie; Randolph-Quinney, PatrickLightning fatality identification relies primarily on soft tissue traumatic pattern recognition, prohibiting cause of death identification in cases of full skeletonisation. This study explores the effects of high impulse currents on human bone, simulating lightning-level intensities and characterising electrically induced micro-trauma through conventional thin-section histology and micro-focus X-ray computed tomography (μXCT). An experimental system for high impulse current application was applied to bone extracted from donated cadaveric lower limbs (n = 22). μXCT was undertaken prior to and after current application. Histological sections were subsequently undertaken. μXCT poorly resolved micro-trauma compared to conventional histology which allowed for identification and classification of lightning-specific patterns of micro-trauma. Statistical analyses demonstrated correlation between current intensity, extent and damage typology suggesting a multifaceted mechanism of trauma propagation - a combination of electrically, thermally and pressure induced alterations. This study gives an overview of high impulse current trauma to human bone, providing expanded definitions of associated micro-trauma.Item HIV1 resupression on a firstline regimen despite the prescence of phenotypic drug resistance(Public Library of Science) Adriaan Basson; Salome Charalambous; Christopher Hoffmann; Lynn MorrisWe have previously reported on HIV-1 infected patients who fail anti-retroviral therapy but manage to re-suppress without a regimen change despite harbouring major drug resistance mutations. Here we explore phenotypic drug resistance in such patients in order to better understand this phenomenon. Patients (n = 71) failing a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen, but who subsequently re-suppressed on the same regimen, were assessed for HIV-1 genotypic drug resistance through Sanger sequencing. A subset (n =23) of these samples, as well as genotypically matched samples from patients who did not re-suppress (n = 19), were further assessed for phenotypic drug resistance in an in vitro single cycle assay. Half of the patients (n = 36/71, 51%) harboured genotypic drug resistance, with M184V(n=18/36,50%)andK103N(n=16/36,44%)being the most prevalent mutations. No significant difference in the median time to re-suppression (31–39 weeks) were observed for either group (p = 0.41). However, re-suppressors with mutant virus rebounded significantly earlier than those with wild-type virus (16 vs. 33 weeks; p = 0.014). Similar phenotypic drug resistance profiles were observed between patients who re-suppressed and patients who failed to re-suppress. While most remained susceptible to stavudine (d4T) and zidovudine (AZT), both groups showed a reduced susceptibility to 3TC and NNRTIs. HIV- 1 infected patients on an NNRTI-based regimen can achieve viral re-suppression on the same regimen despite harbouring viruses with genotypic and phenotypic drug resistance. However, re-suppression was less durable in those with resistance, reinforcing the importance of appropriate regimen choices, ongoing viral load monitoring and adherence counselling.Item Laboratory information system data demonstrate successful implementation of the prevention of the mother- child transmission programme in South Africa(2014-03) Sherman, G.G.; Lilian, R.R.; Bhardwaj, S.Background: Monitoring the prevention of mother-to-child transmission (PMTCT) programme to identify gaps for early intervention is essential as South Africa progresses from prevention to elimination of HIV infection in children. Early infant diagnosis (EID) by an HIV polymerase chain reaction (PCR) test is recommended at 6 weeks of age for all HIV-exposed infants. The National Health Laboratory Service (NHLS) performs the PCR tests for the public health sector and stores test data in a corporate data warehouse (CDW). Objectives: To demonstrate the utility of laboratory data for monitoring trends in EID coverage and early vertical transmission rates and to describe the scale-up of the EID component of the PMTCT programme. Methods. HIV PCR test data from 2003 to 2012 inclusive were extracted from the NHLS CDW by year, province, age of infant tested and test result and used to calculate EID coverage and early vertical transmission rates to provincial level. Results: Rapid scale-up of EID over the first decade of the PMTCT programme was evident from the 100-fold increase in PCR tests to 350 000 by 2012. In 2012, 73% of the estimated 270 000 HIV-exposed infants requiring an early PCR were tested and the early vertical transmission rate had fallen to 2.4% as a result of successful implementation of the PMTCT programme. Conclusions: Laboratory data can provide real time, affordable monitoring of aspects of the PMTCT programme and assist in achieving virtual elimination of paediatric HIV infection in South Africa.Item National sentinel site surveillance for antimicrobial resistance in Klebsiella pneumoniae isolates in South Africa, 2010-2012(South African Medical Association, 2014-08) Perovic, O.; Singh- Moodley, A.; Duse, A.; Elliott, G.; Bamford, C.; Swe Swe-Han, K.; R Kularatne, R.; Lowman, W.; Whitelaw, A.; Nana, T.; Wadula, J.; Lekalakala, R.; Saif, A.; Marais, E.Background: The increasing rates of antimicrobial resistance observed in the nosocomial pathogen Klebsiella pneumoniae are of major public health concern worldwide. Objectives: To describe the antibiotic susceptibility profiles of K. pneumoniae isolates from bacteraemic patients submitted by sentinel laboratories in five regions of South Africa from mid-2010 to mid-2012. Molecular methods were used to detect the most commonly found extended-spectrum beta lactamase (ESBL) and carbapenemase resistance genes. Methods: Thirteen academic centres serving the public healthcare sector in Gauteng, KwaZulu-Natal, Free State, Limpopo and Western Cape provinces submitted K. pneumoniae isolates from patients with bloodstream infections. Vitek 2 and MicroScan instruments were used for organism identification and susceptibility testing. Multiplex polymerase chain reactions (PCRs) were used to detect blaCTX-M, blaSHV and blaTEM genes in a proportion of the ESBL isolates. All isolates exhibiting reduced susceptibility to carbapenems were PCR tested for blaKPC and blaNDM-1 resistance genes. Results: Overall, 68.3% of the 2 774 isolates were ESBL-positive, showing resistance to cefotaxime, ceftazidime and cefepime. Furthermore, 46.5% of all isolates were resistant to ciprofloxacin and 33.1% to piperacillin-tazobactam. The major ESBL genes were abundantly present in the sample analysed. Most isolates (95.5%) were susceptible to the carbapenems tested, and no isolates were positive for blaKPC or blaNDM-1. There was a trend towards a decrease in susceptibility to most antibiotics. Conclusion: The high proportion of ESBL-producing K. pneumoniae isolates observed, and the prevalence of ESBL genes, are of great concern. Our findings represent a baseline for further surveillance in SA, and can be used for policy and treatment decisions.Item Overview of the Haematological effects of COVID19 infectionWiggill, Tracey M.; Mayne, Elizabeth S.; Vaughan, Jenifer L.; Louw, SusanFrom its early origins, COVID-19 has spread extensively and was declared a global pandemic by the World Health Organization in March of 2020. Although initially thought to be predominantly a respiratory infection, more recent evidence points to a multisystem systemic disease which is associated with numerous haematological and immunological disturbances in addition to its other effects. Here we review the current knowledge on the haematological effects of COVID-19.Item Reagent‑free detection of Plasmodium falciparum malaria infections in feld‑collected mosquitoes using mid‑infrared spectroscopy and machine learning(Nature Research, 2024) Okumu, Fredos O.; Mwanga, Emmanuel P.; Kweyamba, Prisca A.; Siria, Doreen J.; Mshani, Issa H.; Mchola, Idrisa S.; Makala, Faraja E.; Seleman, Godian; Abbasi, Said; Mwinyi, Sophia H.; González‑Jiménez, Mario; Waynne, Klaas; Baldini, Francesco; Babayan, Simon A.Field-derived metrics are critical for efective control of malaria, particularly in sub-Saharan Africa where the disease kills over half a million people yearly. One key metric is entomological inoculation rate, a direct measure of transmission intensities, computed as a product of human biting rates and prevalence of Plasmodium sporozoites in mosquitoes. Unfortunately, current methods for identifying infectious mosquitoes are laborious, time consuming, and may require expensive reagents that are not always readily available. Here, we demonstrate the frst feld-application of mid-infrared spectroscopy and machine learning (MIRS-ML) to swiftly and accurately detect Plasmodium falciparum sporozoites in wild-caught Anopheles funestus, a major Afro-tropical malaria vector, without requiring any laboratory reagents. We collected 7178 female An. funestus from rural Tanzanian households using CDC-light traps, then desiccated and scanned their heads and thoraces using an FT-IR spectrometer. The porozoite infections were confrmed using enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction (PCR), to establish references for training supervised algorithms. The XGBoost model was used to detect sporozoite-infectious specimen, accurately predicting ELISA and PCR outcomes with 92% and 93% accuracies respectively. These fndings suggest that MIRS-ML can rapidly detect P. falciparum in feld-collected mosquitoes, with potential for enhancing surveillance in malaria-endemic regions. The technique is both fast, scanning 60–100 mosquitoes per hour, and cost-efcient, requiring no biochemical reactions and therefore no reagents. Given its previously proven capability in monitoring key entomological indicators like mosquito age, human blood index, and identities of vector species, we conclude that MIRS-ML could constitute a low-cost multi-functional toolkit for monitoring malaria risk and evaluating interventions.Item Tamoxifen induces hypercoagulation and alterations in ERα and ERβ dependent on breast cancer sub‑phenotype ex vivo(Nature, 2020-11-06) Pather, Kyrtania; Augustine, T. N.Tamoxifen shows efficacy in reducing breast cancer-related mortality but clinically, is associated with increased risk for thromboembolic events. We aimed to determine whether breast tumour subphenotype could predict propensity for thrombosis. We present two ex vivo Models of Tamoxifentherapy, Model 1 in which treatment recapitulates accumulation within breast tissue, by treating MCF7 and T47D cells directly prior to exposure to blood constituents; and Model 2 in which we recreate circulating Tamoxifen by treating blood constituents prior to exposure to cancer cells. Blood constituents included whole blood, platelet-rich plasma and platelet-poor plasma. Hypercoagulation was assessed as a function of thrombin activity, expression of CD62P and CD63 activation markers defined as an index of platelet activation, and platelet morphology; while oestrogen receptor expression was assessed using immunocytochemistry with quantitative analysis. We determined, in concert with clinical studies and contrary to selected laboratory investigations, that Tamoxifen induces hypercoagulation, dependent on sub-phenotypes, with the T47D cell line capacity most enhanced. We determined a weak positive correlation between oestrogen receptor expression, and CD62P and CD63; indicating an association between tumour invasion profiles and hypercoagulation, however, other yet unknown factors may play a predictive role in defining hypercoagulation.Item The diagenetic alterations of historic skeletons from the Crown Mines Cemetery, South Africa(2023) Lander, Stacey L.; Brits, Desiré ; Hosie, MargotHuman skeletons associated with early gold mining in Johannesburg, South Africa are investigated. An unmarked cemetery was buried beneath a mine dump which resulted in macroscopically stained and poorly preserved bones. Histological assessments were conducted to understand the postmortem treatment of the remains, determine the extent of bone degradation, and understand how this environment affected the bone’s microstructure. Various diagenetic alterations and the general histological index were assessed using normal and polarized light microscopy of thin anterior midshaft femur sections (n = 50). Degradation was identified in the periosteal and endosteal regions, while the intra-cortical region remained well-preserved. Bacterial bioerosion, microcracks, infiltrations, inclusions, and staining were found throughout the sample. Numerous non-Wedl micro-foci of destruction were observed, filled with exogenous material. The degradation suggested that the remains were buried in neutral soil that was subsequently covered by acidic mine dumps which resulted in a corrosive environment. Although the skeletons were poorly preserved, their histological integrity was more promising, especially the intra-cortical area. This is important for future investigations of archaeological bone, as this area can lead to more accurate descriptions of skeletal assemblages. Targeted sampling of this region could produce promising estimates of age, descriptions of pathology, and biomolecular results, which require further study.Item The Novel Coronavirus and Haemostatic abnormalities pathophysiology clinical manifesttations and treatment recommendationsSusan Louw; Barry Jacobson; Elizabeth Mayne; Tracey WiggillThe COVID-19 pandemic, caused by the SARS-C0V-2 virus, was initially considered and managed in a similar manner to the previous SARS epidemic as they are both caused by coronaviruses. What has now become apparent is that a major cause of morbidity and mortality in COVID-19 is abnormal thrombosis. This thrombosis occurs on a macro- and microvascular level and is unique to this disease. The virus has been demonstrated in the endothelium of the pulmonary alveoli and as such is thought to contribute to the devastating respiratory complications encountered. D-dimer concentrations are frequently raised in COVID to levels not frequently seen previously. The optimal anticoagulation treatment in COVID remains to be determined, and the myriad of pathophysiologic effects caused by this virus in the human host have also yet to be fully elucidated.