School of Pathology (Journal Articles)
Permanent URI for this collectionhttps://hdl.handle.net/10539/37877
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Item A histopathological snapshot of bladder cancer: a Johannesburg experience of 1480 histopathology reports(Springer, 2025-03) Jonosky, Jaclyn; Adam, AhmedPurpose To evaluate the histopathological characteristics of bladder cancer in patients presenting to Johannesburg hospitals over a 13-year period (2010–2023). Methods Following ethical clearance, a retrospective observational, descriptive review of histopathological reports over 13 years was conducted in Johannesburg. Inclusion criteria was bladder biopsies, TURBT specimens, and radical cystectomy (RC) specimens positive for bladder cancer. Exclusion criteria was non-primary bladder cancers (prostate, cervical, colon) and urothelial carcinoma of upper tract origin (N=970). Of the initial specimens (N=2450), 1480 met the inclusion criteria, representing 858 patients, owing to multiple transurethral resections of bladder tumours (TURBT). Categorical variables were summarised as counts and percentages, while numerical variables were reported as means with standard deviations or medians with interquartile ranges, depending on data distribution and tested via the Shapiro‒Wilk test. Statistical compari sons were performed using Fisher’s exact test (sex), one-way ANOVA, or the Kruskal‒Wallis test (age). Statistical signifi cance was set at p<0.05. Results Urothelial carcinoma accounted for 88.8% of bladder cancer, squamous cell carcinoma (7.7%), adenocarcinoma (1.5%), and other malignancies (2%). High-grade urothelial carcinoma was predominant at 75%. Non-muscle invasive disease accounted for 72% of these cases, while 28% were muscle invasive. Data from radical cystectomies showed a high proportion of aggressive and advanced disease. Conclusions The study highlights the predominance of high-grade non-muscle invasive bladder cancer in Johannesburg, consistent with global trends. The findings suggest a shift in bladder cancer trends in Johannesburg away from assumed squamous cell carcinoma towards urothelial carcinoma.Item Resistance mutations that distinguish HIV-1 envelopes with discordant VRC01 phenotypes from multi-lineage infections in the HVTN703/HPTN081 trial: implications for cross-resistance(Elsevier, 2025-02) Cohen, Paula; Lambson, Bronwen E.; Mkhize, Nonhlanhla N.; Morris, Lynn; Moore, Penny L.; Moodley, Chivonne; Yssel, Anna E. J.; Moyo-Gwete, Thandeka; York, Talita; Gwashu-Nyangiwe, Asanda; Ndabambi, Nonkululeko; Thebus, Ruwayhida; Williamson, CarolynThe Antibody Mediated Prevention (AMP) trials showed that passively infused VRC01, a broadly neutralizing antibody (bNAb) targeting the CD4 binding site (CD4bs) on the HIV-1 envelope protein (Env), protected against neutralization-sensitive viruses. We identified six individuals from the VRC01 treatment arm with multi-lineage breakthrough HIV-1 infections from HVTN703, where one variant was sensitive to VRC01 (IC50 < 25 ug/mL) but another was resistant. By comparing Env sequences of resistant and sensitive clones from each participant, we identified sites predicted to affect VRC01 neutralization and assessed the effect of their reversion in the VRC01-resistant clone on neutralization sensitivity. In four pairs, a single mutation restored partial or full sensitiv ity to VRC01, whereas in the fifth participant, transfer of the entire β23-V5 loop was required. No VRC01 resistance mutations could be identified in the sixth participant, with the discordant clones differing by >100 amino acids. Mutations responsible for the differential neutralization phenotypes occurred at distinct sites across Env, including residues in loop D, the CD4-binding loop, and between the β23 and V5 loops. Analysis of deep sequencing env data showed that VRC01 resistance was likely the property of the acquired virus, rather than occurring through post-acquisition evolution. Although VRC01-resistant parental clones generally retained sensitivity to other CD4-binding site bNAbs, they were less potently neutralized than the VRC01-sensitive clones. In conclu sion, VRC01 resistance mutations occurred through multiple mutational pathways, but sensitivity to second-generation CD4bs bNAbs was retained even in VRC01-resistant transmitted viruses, confirming the potential of these bNAbs for HIV-1 prevention studies.Item The importance of morphological identification of African anopheline mosquitoes (Diptera: Culicidae) for malaria control programmes(BMC, 2018-01) Erlank, Erica; Koekemoer, Lizette L.; Coetzee, MaureenBackground: The correct identification of disease vectors is the first step towards implementing an effective control programme. Traditionally, for malaria control, this was based on the morphological differences observed in the adults and larvae between different mosquito species. However, the discovery of species complexes meant that genetic tools were needed to separate the sibling species and today there are standard molecular techniques that are used to identify the two major malaria vector groups of mosquitoes. On the assumption that species-diagnostic DNA polymerase chain reaction (PCR) assays are highly species-specific, experiments were conducted to investigate what would happen if non-vector species were randomly included in the molecular assays. Methods: Morphological keys for the Afrotropical Anophelinae were used to provide the a priori identifications. All mosquito specimens were then subjected to the standard PCR assays for members of the Anopheles gambiae complex and Anopheles funestus group. Results: One hundred and fifty mosquitoes belonging to 11 morphological species were processed. Three species (Anopheles pretoriensis, Anopheles rufipes and Anopheles rhodesiensis) amplified members of the An. funestus group and four species (An. pretoriensis, An. rufipes, Anopheles listeri and Anopheles squamosus) amplified members of the An. gambiae complex. Conclusions: Morphological identification of mosquitoes prior to PCR assays not only saves time and money in the laboratory, but also ensures that data received by malaria vector control programmes are useful for targeting the major vectors.Item Molecular and physiological analysis of Anopheles funestus swarms in Nchelenge, Zambia(BMC, 2018-01) Zawada, Jacek W.; Dahan‑Moss, Yael L.; Muleba, Mbanga; Dabire, Roch K.; Maïga, Hamid; Venter, Nelius; Davies, Craig; Hunt, Richard H.; Coetzee, Maureen; Koekemoer, Lizette L.Background: Anopheles funestus has been recognized as a major malaria vector in Africa for over 100 years, but knowledge on many aspects of the biology of this species is still lacking. Anopheles funestus, as with most other anophelines, mate through swarming. A key event that is crucial for the An. funestus male to mate is genitalia rotation. This involves the 135° to 180° rotation of claspers, which are tipped with claws. This physical change then enables the male to grasp the female during copulation. The aim of this investigation was to molecularly characterize wild An. funestus swarms from Zambia and examine the degree of genitalia rotation within the swarm. Methods: Anopheles funestus swarms were collected from Nchelenge, northern Zambia, during dusk periods in May 2016. All the adults from the swarm were analysed morphologically and identified to species level using a multiplex PCR assay. Anopheles funestus s.s. specimens were molecularly characterized by restriction fragment length polymorphism type and Clade type assays. The different stages of genitalia rotation were examined in the adult males. Results: A total of six swarms were observed during the study period and between 6 and 26 mosquitoes were caught from each swarm. Species analysis revealed that 90% of the males from the swarms were An. funestus s.s. MWtype, with 84% belonging to clade I compared to 14% clade II and 2% failed to amplify. Very few specimens (3.4%) were identified as Anopheles gambiae s.s. Eighty percent of the males from the swarm had complete genitalia rotation. Conclusions: This is the first time that An. funestus swarms have been molecularly identified to species level. Anopheles funestus swarms appear to be species-specific with no evidence of clade-type differentiation within these swarms. The An. funestus swarms consist mainly of males with fully rotated genitalia, which strongly suggests that swarming behaviour is triggered primarily when males have matured.Item The importance of morphological identification of African anopheline mosquitoes (Diptera: Culicidae) for malaria control programmes(BioMed Central (BMC), 2018-01) Erlank, Erica; Koekemoer, Lizette L.; Coetzee, MaureenBackground: The correct identification of disease vectors is the first step towards implementing an effective control programme. Traditionally, for malaria control, this was based on the morphological differences observed in the adults and larvae between different mosquito species. However, the discovery of species complexes meant that genetic tools were needed to separate the sibling species and today there are standard molecular techniques that are used to identify the two major malaria vector groups of mosquitoes. On the assumption that species-diagnostic DNA polymerase chain reaction (PCR) assays are highly species-specific, experiments were conducted to investigate what would happen if non-vector species were randomly included in the molecular assays. Methods: Morphological keys for the Afrotropical Anophelinae were used to provide the a priori identifications. All mosquito specimens were then subjected to the standard PCR assays for members of the Anopheles gambiae complex and Anopheles funestus group. Results: One hundred and fifty mosquitoes belonging to 11 morphological species were processed. Three species (Anopheles pretoriensis, Anopheles rufipes and Anopheles rhodesiensis) amplified members of the An. funestus group and four species (An. pretoriensis, An. rufipes, Anopheles listeri and Anopheles squamosus) amplified members of the An. gambiae complex. Conclusions: Morphological identification of mosquitoes prior to PCR assays not only saves time and money in the laboratory, but also ensures that data received by malaria vector control programmes are useful for targeting the major vectors.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 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 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.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 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.