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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 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 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 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 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 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 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 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 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 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 Cognitive and motor development in 3 to 6 year old children born to mothers with Hyperglycaemia first detected in pregnancy in an urban African populationSoepnel, Larske ; Nicolaou, Veronique ; Draper, Catherine ; Levitt, N. ; Klipstein-Grobusch, Kerstin ; Norris, ShaneObjectives: Hyperglycaemia first detected in pregnancy (HFDP), on the rise in urban sub-Saharan Africa (SSA), may negatively impact foetal neurodevelopment, with potential long-term cognitive consequences for the child. Data on this association from SSA is lacking, and we aimed to investigate the association in 3- to 6-year-old children in Soweto, South Africa. Methods: In this comparative study, we compared cognitive skills measured with the Herbst Early Childhood Development Criteria test in 95 children born to mothers with HFDP and 99 participants unexposed to maternal HFDP. Fine and gross motor skills were secondary outcomes. Ordinal regression analysis with known confounders was performed for children born at-term. Results Of children exposed to HFDP born at-term, 24.3% scored ‘high’ and 25.7% scored ‘low’ in the cognitive subsection of the test, as opposed to 37.7% and 12.9% in the HFDP-unexposed group, respectively. In ordinal regression, exposed participants had a significantly lower odds of scoring in a higher cognitive category when adjusting for maternal confounders and socio-economic status (OR 0.33, 95% CI 0.15–0.74, p = 0.007). No difference was found in gross motor development between the two groups; differences in fine motor development were attenuated after adjustment for maternal pregnancy factors and household socioeconomic status (OR 0.62, 95% CI 0.28–1.37, p = 0.239). Conclusions: for Practice Exposure to HFDP was negatively associated with cognitive development at preschool age. Optimising maternal (preconception) health and early childhood cognitive stimulation could help more children reach their developmental potential.Item A long walk to freedom: the epidemiology of penetrating trauma in South Africa- analysis of 4 697 patients over a six year period at Chris Hani Baragwanath Academic HospitalBhana, Malini; Fru, Pascaline; Plani, FrancoBackground: Despite the city of Johannesburg having one of the highest rates of crime in the world, no national databank for trauma exists. This study profiles the victims of penetrating trauma and identifies geographical areas in which it occurs, while describing the outcomes and patterns of injury. Methods: A retrospective study including penetrating trauma patients triaged as Priority 1, presenting at the Chris Hani Baragwanath Academic Hospital's (CHBAH) trauma department over a six-year period (2011-2016). Results: A total of 4 697 patients were included. The majority of victims were Black African males (92.1%) between the ages of 29-40 years, and stabbings were the most common mechanism of injury (71.8%), followed by gunshots. The commonest body area affected was the thorax, with a consequent haemothorax the most likely result. Weekends accounted for over 48% of all presentations - the last weekend of the month being the busiest. Region D was the area in Johannesburg with the highest trauma incidence (51.9%), with the oldest townships in Soweto found to be "hot spots". Conclusion: Penetrating trauma is inherently linked to alcohol abuse and interpersonal violence in South Africa,1 primarily affecting its young economic, working-class citizens. The data provided some insight into the burden, structure and challenges of our trauma system. These should be regarded as opportunities to implement change and improve our surveillance and prevention, beginning with a national trauma databankItem Comorbidities in black South Africans with established rheumatoid arthritisLala, Vikash ; Mohammed, Tickly; Musenge, Eustasius ; Govind, NimmishaObjective: Comorbidities contribute both to morbidity and mortality in rheumatoid arthritis (RA). The aim of the current study was to investigate the prevalence and spectrum of comorbidities in South Africans with established RA. Methods: A retrospective, consecutive case record review of 500 Black South African patients with established disease of ≥5 years attending a tertiary rheumatology service was performed. Common comorbidities including those listed in the Charlson Comorbidity Score (CCS) were documented. Results: Most patients, 463 known alive (AG) and 37 known deceased (DG), were female (87%). Mean (SD) age and disease duration were 60 (11.1) and 10.7 (5.0) years respectively, and 98% had ≥1 comorbidities. Median CCS was 2, significantly higher in DG than AG (4 vs 2, P < .0001). Despite hypertension (70%) and hypercholesterolemia (47%) being the commonest comorbidities overall and type 2 diabetes (T2D) occurring in 15.4%, clinical cardiovascular events were rare (0.6%). Peptic ulcer disease (odds ratio [OR] = 8.67), congestive cardiac failure (OR = 7.09), serious infections (OR = 7.02) and tuberculosis (OR = 2.56) were significantly more common in DG than AG. Multivariate analysis showed that American College of Rheumatology functional class 3/4 was associated with increased risk for serious infections (OR = 3.84) and tuberculosis (OR = 2.10). Conclusion: Despite the high burden of cardiometabolic comorbidities in South Africans with established RA, cardiovascular events were rare. Serious infections and tuberculosis, both associated with severe functional disability, are a major cause of morbidity and mortality.Item Locked down impact of covid 19 restrictions on trauma presentations to the emergency departmentVenter, Anica; Lewis, Carolyn; Saffy, Patricia; Chadinha, LouisBackground: COVID-19 was recognised as a global pandemic on 11 March 2020. In South Africa (SA), a nationwide lockdown was implemented at midnight on 26 March to prepare for the predicted surge and slow the spread of the virus. Objectives: To compare the volume and type of presentations of trauma secondary to interpersonal violence and road traffic collisions (RTCs) during two 5-month periods, from February to June 2019 and 2020, in the emergency department (ED) of an academic tertiary hospital in Gauteng Province, SA. In 2020, February - June included the lockdown period. Methods: An observational retrospective audit of the patient register at the Helen Joseph Hospital ED was conducted, comparing the number of trauma presentations secondary to interpersonal violence (assaults with gunshot wounds, general assaults including mob assaults, assaults with stab wounds) and RTC presentations between February and June 2019 and 2020. Results: A total of 4 300 trauma presentations secondary to interpersonal violence and RTCs were noted in the 5-month period February - June 2019, as opposed to 3 239 presentations in February - June 2020 (25% decline). A 40% decline in the number of RTCs, from 1 704 in February - June 2019 to 1 026 in the corresponding period for 2020, was noted and found to be statistically significant (p=0.03). Declines in the volume of trauma cases secondary to interpersonal violence and of overall trauma cases were only directional in favour of 2020, but not statistically significant. Conclusions: The volume of trauma presentations secondary to interpersonal violence and RTCs in the Helen Joseph Hospital ED decreased during the lockdown period. The decline in the volume of RTCs was statistically significant, but declines in the volume of trauma presentations secondary to interpersonal violence and in the volume of overall trauma presentations were not.Item An all-oral 6-month regimen for multidrug resistant Tuberculosis: A multicenter randomized controlled clinical trial (the Next Study)Esmail, Aliasgar ; Oelofse, Suzette ; Lombard, Carl ; Perumal, Rubeshan ; Variava, Ebrahim ; Martinson, NeilRationale: Improving treatment outcomes while reducing drug toxicity and shortening the treatment duration to 6 months remains an aspirational goal for the treatment of multi drug resistant /rifampicin-resistant tuberculosis(MDR/RR-TB). Objectives: To conduct a multicenter randomized controlled trial in adults with MDR/RR-TB(i.e., without resistance to fluoroquinolones or aminoglycosides) . Methods: Participants were randomly assigned(1:1ratio)to a 6 month all-oral regimen that included levofloxacin, bed aquiline, and linezolid or the standard-of-care(SOC)>9-month World Health Organization(WHO)-approved injectable-based regimen. The primary endpoint was a favorable WHO-defined treatment outcome (which mandates that prespecified drugs substitution is counted as an unfavorable outcome)24 months after treatment initiation. The trial was stopped prematurely when bed aquiline-based therapy became the standard of care in South Africa. Measurements and Main Results: In total,93 of 111 randomized participants(44 in the comparator arm and 49 in the intervention alarm) were included in the modified intention-to-treatanalysis;51(55%)were HIV coinfected(medianCD4count,158cells/ml).Participants in the intervention arm were 2.2 times more likely to experience a favorable 24-month outcome than participants in the SOC arm(51%[25of49]vs. 22.7%[10of44];riskratio,2.2[1.2–4.1];P=0.006).Toxicity-related drug substitution occurred more frequently in the SOC arm(65.9%[29of44] vs.34.7%[17of49];P=0.001)],82.8%(24of29)owing to kanamycin (mainly hearing loss; replaced by bed aquiline) in the SOC arm, and 64.7% (11of17) owing to fluoroquinolones or aminoglycosides (mainly anemia) in the intervention alarm. Adverse event–related treatment discontinuation in the safety population was more common in the SOC arm(56.4%[31of55]vs.32.1%[17of 56];P=0.007).However, grade 3 adverse events were more common in the intervention alarm(55.4%[31of56]vs.32.7[18of55];P=0.022). Culture conversion was significantly better in the intervention arm (hazardratio,2.6[1.4–4.9];P=0.003)after censoring those with bed aquiline replacement in the SOC arm(and this pattern remained consistent after censoring for drug replacement in both arms ;P=0.01). Conclusions: Compared with traditional injectable-containing regimens, an all-oral 6-month levofloxacin, bed aquiline, and linezolid–containing MDR/RR-TB regimen was associated with a significantly improved 24-month WHO-defined treatment outcome (predominantly owing to toxicity-related drugs substitution).However, drug toxicity occurred frequently in both arms. These findings form strategies to develop future regimens for MDR/RR-TB. Clinical trial registered with www.clinicaltrials.gov (NCT02454205).Item The dynamics of pathology dataset creation using urine cytology as an exampleMcAlpine, Ewen; Michelow, Pamela; Celik, TurgayIntroduction: Dataset creation is one of the first tasks required for training AI algorithms but is underestimated in pathology. High-quality data are essential for training algorithms and data should be labelled accurately and include sufficient morphological diversity. The dynamics and challenges of labelling a urine cytology dataset using The Paris System (TPS) criteria are presented. Methods: 2,454 images were labelled by pathologist consensus via video conferencing over a 14-day period. During the labelling sessions, the dynamics of the labelling process were recorded. Quality assurance images were randomly selected from images labelled in previous sessions within this study and randomly distributed throughout new labelling sessions. To assess the effect of time on the labelling process, the labelled set of images was split into 2 groups according to the median relative label time and the time taken to label images and intersession agreement were assessed. Results: Labelling sessions ranged from 24 m 11 s to 41 m 06 s in length, with a median of 33 m 47 s. The majority of the 2,454 images were labelled as benign urothelial cells, with atypical and malignant urothelial cells more sparsely represented. The time taken to label individual images ranged from 1 s to 42 s with a median of 2.9 s. Labelling times differed significantly among categories, with the median label time for the atypical urothelial category being 7.2 s, followed by the malignant urothelial category at 3.8 s and the benign urothelial category at 2.9 s. The overall intersession agreement for quality assurance images was substantial. The level of agreement differed among classes of urothelial cells - benign and malignant urothelial cell classes showed almost perfect agreement and the atypical urothelial cell class showed moderate agreement. Image labelling times seemed to speed up, and there was no evidence of worsening of intersession agreement with session time. Discussion/conclusion: Important aspects of pathology dataset creation are presented, illustrating the significant resources required for labelling a large dataset. We present evidence that the time taken to categorise urine cytology images varies by diagnosis/class. The known challenges relating to the reproducibility of the AUC (atypical) category in TPS when compared to the NHGUC (benign) or HGUC (malignant) categories is also confirmed.Item Osteogenic competence and potency of the bone induction principle inductive substrates that initiate bone formation by autoinductionRipamonti, Ugo; Duarte, Raquel ; Ferretti, Carlo ; Reddi, H.The de novo induction of bone has always been a fascinating phenomenon, keeping skeletal reconstructionists and cellular developmental biologists continuously engaged to finally provide a molecular and cellular approach to the induction of bone formation. A significant advancement was made by the purification and cloning of the human recombinant bone morphogenetic proteins, members of the transforming growth factor-b supergene family. Human bone morphogenetic proteins are powerful inducers of bone in animal models including nonhuman primates. Translation in clinical contexts has however, proven to be surprisingly difficult. This review also describes the significant induction of bone formation by the human transforming growth factor-b3 when implanted in heterotopic intramuscular sites of the Chacma baboon Papio ursinus. Large mandibular defects implanted with 250mg human transforming growth factor-b3 in human patients showed significant osteoinduction; however, the induction of bone was comparatively less than the induction of bone in P ursinus once again highlighting the conundrum of human osteoinduction: is the bone induction principle failing clinical translation?Item A biostatistical support system in health sciences is this sustainable in a resourcerestricted environmentLibhaber, Elena ; Chirwa, Tobias ; Kramer, BeverleyBackground: Training in biostatistics is important for strengthening capacity in health research. This is particularly true for Africa, where research output in the health sciences has been low. Training initiatives for the continent are therefore essential. The aim of the present study was to analyse the quality and financial sustainability of the expanded biostatistical support system at a South African health sciences institution between 2013 and 2017. Methods: A cross-sectional investigation of the initiatives created between the years 2013 and 2017 in the University of the Witwatersrand, Faculty of Health Sciences Research Office was undertaken. An assessment of the one-on-one consultations carried out by postgraduate students and staff, financial costs of the support system and the number of postgraduate student graduations were analysed. Results: The number of statistical consultations increased over the period examined. The consultations were highly recommended by the postgraduate students and staff (consulters). A clear rise in the number of Masters and PhD student graduates and an increase in research units were observed from 2013 to 2017, although these cannot be solely associated with the biostatistical support system. The finances for maintaining the support system are cost effective as the number of graduates increases. The total cost to the Research Office is US$ 225 per graduate per annum. Conclusions: The expansion of the biostatistical support system has indirectly contributed to an increased number of graduates and research publication units in the institution. While the current finances support the system, any increases in enrolments or growth in diversification of biostatistical requirements may place a strain on the financial sustainability. This service is of value to developed and developing countries.Item Cultureconfirmed neonatal bloodstream infections and meningitis in South Africa 201419 a crosssectional studyMashau, Rudzani C.; Meiring, Susan ; Dramowski, Angela; Magobo, Rindidzani E.; Quan, Vanessa C. ; Von Gottberg, Anne ; Cohen, Cheryl ; Velaphi, Sithembiso ; Govender, Nelesh; Perovic, OlgaBackground: Few population-level estimates of invasive neonatal infections have been reported from sub-Saharan Africa. We estimated the national incidence risk, aetiology, and pathogen antimicrobial susceptibility for cultureconfirmed neonatal bloodstream infections and meningitis in South Africa. Methods: We conducted a cross-sectional study of neonates (<28 days of life) admitted to neonatal or paediatric wards of 256 public sector health facilities in South Africa during 2014–19. Diagnostic pathology records from Jan 1, 2014, to Dec 31, 2019, were extracted from a national pathology data warehouse. A case was defined as a neonate with at least one positive blood or cerebrospinal fluid culture during a 14-day period. Incidence risk was calculated using annual numbers of registered livebirths. Among the causative pathogens identified, we calculated the proportion of cases attributed to each of them, as well as the rates of antibiotic susceptibility of Gram-positive and Gram-negative bacteria. Findings: Among 43 438 records of positive cultures, there were 37 631 incident cases of neonatal infection with at least one pathogen isolated. The overall incidence risk of culture-confirmed infections was 6·0 per 1000 livebirths (95% CI 6·0–6·1). The incidence risk of late-onset sepsis (days 3–27 of life) was 4·9 per 1000 livebirths (4·9–5·0) and that of early-onset sepsis (days 0–2 of life) was 1·1 per 1000 livebirths (1·1–1·1); risk ratio 4·4 (95% CI 4·3–4·5). The cause of infection differed by syndrome, timing of infection onset, facility, and province, although Klebsiella pneumoniae (26%), Acinetobacter baumannii (13%), and Staphylococcus aureus (12%) were the dominant pathogens overall. Gram-negative bacteria had declining susceptibility to most antibiotics over the study period. Interpretation We found a high incidence risk of late-onset sepsis with provincial variations, predominance of K pneumoniae, and declining antibiotic susceptibility among Gram-negative bacteria. This national surveillance in an upper-middle-income country provides a baseline burden of neonatal infections against which the impact of future clinical and public health interventions can be measured.