Research Articles (Immunology)

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Predicting cerebral palsy and 18-month neurodevelopmental outcome in infants with presumed hypoxic ischaemic encephalopathy : role of general movements assessment and early neurological examination
(Frontiers Media, 2025-10-03) Kali, Gugulabatembunamahlubi T.J.; Du Preez, Jacomina C.F.; Van Zyl, Jeanetta I.; Burger, Marlette; Katsabola, Hillary; Pepper, Michael Sean
INTRODUCTION : General movements assessment (GMA), including the Motor Optimality Score—Revised (MOS-R) and the Hammersmith Infant Neurological Examination (HINE), has been shown in different settings to predict cerebral palsy (CP) and delayed neurodevelopment with high accuracy. However, their combined predictive ability has not been fully evaluated in infants with presumed hypoxic–ischaemic encephalopathy (HIE). OBJECTIVE : This study aimed to assess the predictive ability of combined GMA, MOS-R, and HINE at 3 months in term or near-term infants diagnosed with presumed HIE, for neurodevelopmental outcome at 18 months. METHODS : A cohort of presumed HIE infants treated with therapeutic hypothermia (TH) underwent GMA, MOS-R, and HINE at 12–15 weeks, and neurodevelopmental assessments using the Bayley Scales of Infant and Toddler Development Third Edition (BSID-III) at 9–12 and at 18–24 months of age. Combined early assessments were analysed for their predictive ability across different domains on the BSID-III. RESULTS : Twenty-four infants were included; 7 (29%) had both 12-month and 18-month BSID-III assessments, 12 (50%) were seen only at 12 months, and 5 (21%) only at 18 months. Two infants with absent fidgety movements (FMs) and poor motor repertoire were later diagnosed with CP or showed delays in two domains on the BSID-III assessment at 18 months. While most infants had some abnormality in the MOS-R categories, only absent FMs and abnormal finger variability showed some association with the 18-month BSID-III assessment on univariate analysis. Of the four infants classified as at risk for CP on the HINE at 3 months, two had some motor abnormalities at 18 months. Combining the GMA, MOS-R, and HINE had high sensitivity and negative predictive value (100%), but low specificity (0–17.6%) and positive predictive value (6.2%–25%) for the BSID-III outcome. CONCLUSION : Combining GMA, MOS-R, and HINE was highly sensitive in this cohort, but had low specificity. This may lead to overdiagnosis, but it may be a useful screening tool for identifying typically developing infants who do not need intensive follow-up.
Minimal impact of feed intolerance during therapeutic hypothermia for hypoxic ischaemic encephalopathy in a South African cohort with a standardised feeding regimen
(Frontiers Media, 2025-07-30) Samaai, Ilhaam; Pepper, Michael Sean; Pillay, Shakti; Horn, Alan R.
INTRODUCTION : Enteral feeding during therapeutic hypothermia (TH) for neonatal hypoxic ischaemic encephalopathy (HIE), is beneficial, but there is insufficient evidence to guide timing and feed advancement strategies. The aim of this study was to describe feed tolerance and outcomes after TH with a standardized progressive early enteral feeding regimen. METHODS : Data were retrospectively reviewed from neonates with HIE who were treated with TH for HIE in the Groote Schuur Hospital (GSH) Neonatal intensive care unit (NICU), between 1 July 2019 and 31 October 2022. Enteral feeds were commenced at age 12–24 h and incremented daily if tolerated, at 12 ml/kg/day for the first 3 days and 24 ml/kg thereafter. Nutritional, morbidity and mortality outcomes were compared between neonates with and without early feed intolerance (EFI) by the fourth day of life. RESULTS : Thirty three percent (16/48) developed EFI. However, by day six the median (IQR) enteral volumes were, 120 (110–120) and 90 (90–99), in neonates without and with feed intolerance respectively. There were no differences in resuscitation characteristics. Neonates with EFI, had higher HIE grades, more amplitude integrated electro-encephalograph (aEEG) suppression at 48 h (p = 0.002), later attainment of full nutritive sucking or cup feeds (p < 0.001) and longer hospital stays (p = 0.038). There were no differences in other morbidities. Mortality was 6% and necrotising enterocolitis did not occur in either group. CONCLUSIONS : Early feeding was generally well tolerated. Feed intolerance was more frequent in neonates with severe HIE, but most neonates achieved independence from IV fluids by day six.
Management of HER2-low metastatic breast cancer : a comprehensive statement by an expert group from the Middle East and Africa region
(Shiraz University of Medical Sciences, 2025-10) Dawood, Shaheenah S.; Mokhtar, Mohsen; Alwbari, Ahmed M.; Rapoport, Bernardo Leon; Esin, Ece; Jaafar, Hassan N.; Zekri, Jamal M.; Berrada, Narjiss; Özyılkan, Özgür; El-Saghir, Nagi S.
Approximately 50 to 67% of breast cancers (BCs), traditionally categorized as human epidermal growth factor receptor 2 (HER2)-negative, but demonstrating low HER2 expression, are now being defined as a new HER2-low subset or HER2-low category of BC. For metastatic BC (mBC), standard therapy options include targeted approaches, such as cyclin-dependent kinase 4/6 inhibitors, phosphoinositide 3-kinase inhibitors, poly (adenosine diphosphate-ribose) polymerase inhibitors, and anti-programmed death-ligand 1 agents, depending on tumor type and its molecular profile. Recent clinical trials reported significant clinical benefits from novel anti‑HER2 antibody‑drug conjugates, such as trastuzumab deruxtecan in HER2‑low mBC. Novel treatment options have increased the complexity of the clinical decision‑making process, particularly for treatment sequencing for each clinical setting. A regional expert committee meeting was held to discuss the challenges, overcome limitations, and present recommendations to enhance HER2 reporting as well as treatment of patients with HER2‑low mBC in the Middle East and Africa region.
Genetic variants associated with suspected neonatal hypoxic ischaemic Encephalopathy : a study in a South African context
(MDPI, 2025-03) Foden, Caroline J.; Durant, Kevin; Mellet, Juanita; Joubert, Fourie; Van Rensburg, Jeanne; Masemola, Mogomane Yvonne Khomotso; Velaphi, Sithembiso C.; Nakwa, Firdose L.; Horn, Alan R.; Pillay, Shakti; Kali, Gugu; Coetzee, Melantha; Ballot, Daynia E.; Kalua, Thumbiko; Babbo, Carina; Pepper, Michael Sean; NESHIE Working Group; michael.pepper@up.ac.za
Neonatal encephalopathy suspected to be due to hypoxic ischaemic encephalopathy (NESHIE) carries the risk of death or severe disability (cognitive defects and cerebral palsy). Previous genetic studies on NESHIE have predominantly focused on exomes or targeted genes. The objective of this study was to identify genetic variants associated with moderate–severe NESHIE through whole-genome, unbiased analysis. Variant filtering and prioritization were performed, followed by association testing both on a case–control basis and to compare the grades of severity and/or progression. Association testing on neonates with NESHIE (N = 172) and ancestry-matched controls (N = 288) produced 71 significant genetic variants (false discovery rate corrected p-value < 6.2 × 10−4), all located in non-coding regions and not previously implicated in NESHIE. Disease-associated variants in non-coding regions are considered to affect regulatory functions, possibly by modifying gene expression, promoters, enhancers, or DNA structure. The most significant variant was at position 6:162010973 in the Parkin RBR E3 ubiquitin protein ligase (PRKN) intron. Intronic variants were also identified in genes involved in inflammatory processes (SLCO3A1), DNA repair (ZGRF1), synaptogenesis (CNTN5), haematopoiesis (ASXL2), and the transcriptional response to hypoxia (PADI4). Ten variants were associated with a higher severity or lack of improvement in NESHIE, including one in ADAMTS3, which encodes a procollagen amino protease with a role in angiogenesis and lymphangiogenesis. This analysis represents one of the first efforts to analyze whole-genome data to investigate the genetic complexity of NESHIE in diverse ethnolinguistic groups of African origin and provides direction for further study.
Antiretroviral-induced toxicity in umbilical cord blood-derived haematopoietic stem/progenitor cells
(Wiley, 2025-04) Hendricks, Candice Laverne; Ellero, Andrea Antonio; Mellet, Juanita; Stivaktas, Voula; Pepper, Michael Sean; michael.pepper@up.ac.za
Improvements in administration and efficacy of antiretroviral therapy (ART) have reduced rates of mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) to < 2%. However, in utero exposure to antiretrovirals (ARVs) leads to abnormalities in HIV-exposed uninfected (HEU) infants. We determined the effect of five ARVs on human umbilical cord blood (UCB)-derived haematopoietic stem/progenitor cells (HSPC) with the aim of exploring a potential causal relationship with haematological abnormalities. Efavirenz (EFV) was cytotoxic to HSPCs alone and in combination with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC). Dolutegravir (DTG) had a biphasic effect on HSPC expansion. Immunophenotypic analysis showed increased erythroid and granulocyte precursors after 7-day culture with these drugs. Finally, using colony forming unit (CFU) assays, we observed impairment in the formation of CFU-GEMM and CFU/Burst forming unit (BFU) erythroid (E) in the presence of DTG, lamivudine (3TC) and TDF, both visually and immunophenotypically. We conclude that multiple potential HSPC toxicities exist with ARVs commonly used in pregnancy, prompting the need for further research to confirm the safety of these drugs in this vulnerable group.
Comparative effects of efavirenz and dolutegravir on metabolomic and inflammatory profiles, and platelet activation of people living with HIV
(MDPI, 2024-09-14) Roux, Crystal Gayle; Mason, Shayne; Du Toit, Louise; Nel, Jan-Gert; Rossouw, Theresa M.; Steel, Helen Carolyn; u04672365@tuks.co.za
Antiretroviral therapy (ART) has reduced the mortality and morbidity associated with HIV. However, irrespective of treatment, people living with HIV remain at a higher risk of developing non-AIDS-associated diseases. In 2019, the World Health Organization recommended the transition from efavirenz (EFV)- to dolutegravir (DTG)-based ART. Data on the impact of this transition are still limited. The current study therefore investigated the metabolic profiles, cytokine inflammatory responses, and platelet activation before and after the treatment transition. Plasma samples from nine virally suppressed adults living with HIV and sixteen healthy, HIV-uninfected individuals residing in Gauteng, South Africa were compared. Metabolite and cytokine profiles, and markers associated with platelet activation, were investigated with untargeted proton magnetic resonance metabolomics, multiplex suspension bead array immunoassays, and sandwich enzyme-linked immunosorbent assays, respectively. In those individuals with normal C-reactive protein levels, the transition to a DTG-based ART regimen resulted in decreased concentrations of acetoacetic acid, creatinine, adenosine monophosphate, 1,7-dimethylxanthine, glycolic acid, 3-hydroxybutyric acid, urea, and lysine. Moreover, increased levels of formic acid, glucose, lactic acid, myo-inositol, valine, glycolic acid, and 3-hydroxybutyric acid were observed. Notably, levels of interleukin-6, platelet-derived growth factor-BB, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-alpha, soluble cluster of differentiation 40 ligand, as well as regulated on activation, normal T-cell expressed and secreted (RANTES) reached levels close to those observed in the healthy control participants. The elevated concentration of macrophage inflammatory protein-1 alpha was the only marker indicative of elevated levels of inflammation associated with DTG-based treatment. The transition from EFV- to DTG-based regimens therefore appears to be of potential benefit with metabolic and inflammatory markers, as well as those associated with cardiovascular disease and other chronic non-AIDS-related diseases, reaching levels similar to those observed in individuals not living with HIV.
Neonatal encephalopathy due to suspected hypoxic-ischaemic encephalopathy
(Springer, 2025-09) Horn, Alan Richard; Pillay, Shakti; Velaphi, Sithembiso Christopher; Ballot, Daynia Elizabeth; Mellet, Juanita; Foden, Caroline J.; Van Rensburg, Jeanne; Babbo, Carina Corte-Real; Kali, Gugulabatembunahlubi Tenjiwe Jabulile; Coetzee, Melantha; Masemola, Mogomane Yvonne Khomotso; Nakwa, Firdose Lambey; Pepper, Michael Sean; michael.pepper@up.ac.za
No abstract available.
Comparison of SARS-CoV-2 molecular results from the first two COVID-19 waves in Gauteng
(AOSIS, 2024-11-24) Govender, Kreshalen; Mafuyeka, Rendani T.; Lukhwareni, Azwidowi; Meyer, Pieter Willem Adriaan; k.govender@up.ac.za
BACKGROUND : Laboratory-based molecular assays return cycle threshold (Ct) values for each gene target. There is limited hyperlocal information describing the Ct, age and sex trends during the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) waves in South Africa. OBJECTIVES : To analyse the demographic and Ct value trends of SARS-CoV-2 molecular assays from two South African hospitals. METHOD : The Seegene Allplex 2019-nCoV™ results from the first two waves (June–July 2020 and November 2020–January 2021) from two major hospitals in Gauteng, South Africa, were extracted from the laboratory information system. Demographic variables and Ct values were analysed. RESULTS : Overall, 2391 samples were analysed over two waves. In both waves, more women were tested than men; 68.4% versus 31.2% in the first wave and 59.8% versus 39.7% in the second wave. Differences in Ct values among the age groups were non-significant overall; however, most median Ct values in all age groups were < 30. Men had lower median Ct values in the first wave, but this trend reversed in the second wave (p < 0.001). The first wave had significantly lower mean and median Ct values per gene target (p < 0.001). CONCLUSION : Patients tested in the first wave had lower Ct values. All age groups in both waves demonstrated infectivity potential; the demographic analysis agreed with South Africa’s coronavirus disease 2019 (COVID-19) epidemiological trends in both waves. CONTRIBUTION : Granular insight into the basic demographic variables and Ct trends of SARS-CoV-2 real-time polymerase chain reaction (RT-PCR) results within and between SARS-CoV-2 waves in South Africa.
HIV-exposed uninfected umbilical cord blood haematopoietic stem/progenitor cells differ immunophenotypically from those from HIV unexposed umbilical cord blood but have similar expansion and colony-forming properties in vitro
(Springer, 2025-06) Hendricks, Candice Laverne; Mellet, Juanita; Stivaktas, Voula; Ambele, Melvin Anyasi; Pepper, Michael Sean; michael.pepper@up.ac.za
No abstract available.
A new dawn : vitalising translational oncology research in Africa with the help of advanced cell culture models
(Elsevier, 2025-06) Klima, Stefanie; Hurrell, Tracey; Goolam, Mubeen; Gouws, Chrisna; Engelbrecht, Anna-Mart; Kaur, Mandeep; Van den Bout, Iman; iman.vandenbout@up.ac.za
The advent of in vitro models such as induced pluripotent stem cells (iPSC) and patient derived (disease) organoids is supporting the development of population and patient specific model systems reflecting human physiology and disease. However, there remains a significant underrepresentation of non-European, especially African model systems. The development of such models should be enthusiastically embraced by Sub-Saharan African countries (SSAC) and middle-income countries (LIMC) to direct their own research focused on the improvement of health of their own populations at a sustainable cost within their respective funding environments. Great care needs to be taken to develop national frameworks to direct, sustainably fund and support such efforts in a way that maximises the output of such models for the investment required. Here, we highlight how advanced culture models can play a role in vitalising local healthcare research by focusing on locally relevant health care questions using appropriate cell culture models. We also provide a potential national platform example that could maximise such output at the lowest cost. This framework presents an opportunity for SSAC and LMIC to base their healthcare research on locally relevant models to ensure that developed health care initiatives and interventions are best suited for the populations they serve and thus represent a reset in global health care research at large. HIGHLIGHTS • Advanced cell culture models herald a unique opportunity for African oncology research. • Rationalizing model development at a national level will achieve amplified advances. • A national framework to optimize African models is proposed.
Kisspeptin fiber and receptor distribution analysis suggests its potential role in central sensorial processing and behavioral state control
(Wiley, 2025-05) Zhang, Limei; Hernandez, Vito Salvador; Zetter, Mario Alberto; Hernandez-Perez, Oscar Rene; Hernandez-Gonzalez, Rafael; Camacho-Arroyo, Ignacio; Eiden, Lee E.; Millar, Robert P.
Kisspeptin (KP) signaling in the brain is defined by the anatomical distribution of KP-producing neurons, their fibers, receptors, and connectivity. Technological advances have prompted a re-evaluation of these chemoanatomical aspects, originally studied in the early years after the discovery of KP and its receptor Kiss1r. Previously, we characterized (Hernández et al. bioRxiv 2024) seven KP neuronal populations in the mouse brain at the mRNA level, including two novel populations, and examined their response to gonadectomy. In this study, we mapped KP fiber distribution in rats and mice using immunohistochemistry under intact as well as short- and long-term post-gonadectomy conditions. Kiss1r mRNA expression was examined via RNAscope, in relation to vesicular GABA transporter (Slc32a1) in whole mouse brain, and to KP and vesicular glutamate transporter 2 (Slc17a6), Kiss1, and Slc32a1 in hypothalamic RP3V and arcuate regions. We identified KP fibers in 118 brain regions, primarily in extra-hypothalamic areas associated with sensorial processing and behavioral state control. KP-immunoreactive fiber density and distribution were largely unchanged by gonadectomy. Kiss1r was expressed prominently in sensorial and state control regions such as the septal nuclei, the suprachiasmatic nucleus, locus coeruleus, hippocampal layers, thalamic nuclei, and cerebellar structures. Co-expression of Kiss1r and Kiss1 was observed in hypothalamic neurons, suggesting both autocrine and paracrine KP signaling mechanisms. These findings enhance our understanding of KP signaling beyond reproductive functions, particularly in sensorial processing and behavioral state regulation. This study opens new avenues for investigating KP's role in controlling complex physiological processes, including those unrelated to reproduction.
Genome sequencing projects reveal new insights into the mammalian Gonadotropin-releasing Hormone II system
(Wiley, 2024-10) Morgan, Kevin; Millar, Robert P.
The type II gonadotropin-releasing hormone (GnRH-II) was first discovered in chicken (Gallus gallus) brain and then shown to be present in many vertebrates. Indeed, its structure is conserved unchanged throughout vertebrate evolution from teleost fish through to mammals suggesting a crucial function. Yet the functional significance has been largely unexplored. Studies in comparative endocrinology show that the GnRH-II system is differentially functional in mammalian species. Intact GnRH-II neuropeptide and receptor genes (GnRH2 and GnRH receptor 2 GnRHR2) occur in marmoset monkeys (Callithrix jacchus), musk shrews (Suncus murinus) and pigs (Sus scrofa). However, one or other or both of these genes are inactivated in other species, where mutations or remnants affecting GnRH2 neuropeptide and/or type II GnRHR exons are retained in conserved genomic loci. New data from DNA sequencing projects facilitate extensive analysis of species-specific variation in these genes. Here, we describe GnRH2 and GnRHR2 genes spanning a collection of 21 taxonomic orders, encompassing around 140 species from Primates, Scandentia, Eulipotyphla, Rodentia, Lagomorpha, Artiodactyla, Carnivora, Perissodactyls, Pholidota, Chiroptera, Afrotheria, Xenarthra and Marsupialia. Intact coding exons for both GnRH2 and GnRHR2 occur in monkeys, tree shrews, shrews, moles, hedgehogs, several rodents (degu, kangaroo-rat, pocket mouse), pig, pecarry and warthog, camels and alpaca, bears, Weddell seal, hyena, elephant, aardvark and marsupials. Inactivating mutations affecting GnRH2 and GnRHR2, some located at conserved sites within exons, occur in species of primates, most rodents, lagomorphs, bovidae, cetaceans, felidae, canidae and other carnivora, pangolins, most bats, armadillo, brushtail and echidna. A functional GnRH-II system appears retained within several taxonomic families of mammals, but intact retention does not extend to whole taxonomic orders. Defining how endogenous GnRH-II neuropeptide operates in different mammals may afford functional insight into its actions in the brain, especially as, unlike the type I GnRH system, it is expressed in the mid brain and not the hypothalamus.
Outcomes of lumen apposing metal stent placement in patients with surgically altered anatomy : multicenter international experience
(Thieme Gruppe, 2024-10) Mangiavillano, Benedetto; Ramai, Daryl; Kahaleh, Michel; Tyberg, Amy; Shahid, Haroon; Sarkar, Avik; Samanta, Jayanta; Dhar, Jahnvi; Bronswijk, Michiel; Van der Merwe, Schalk; Kouanda, Abdul; Ji, Hyun; Dai, Sun-Chuan; Deprez, Pierre; Vargas-Madrigal, Jorge; Vanella, Giuseppe; Leone, Roberto; Arcidiacono, Paolo Giorgio; Robles-Medranda, Carlos; Vasquez, Juan Alcivar; Arevalo-Mora, Martha; Fugazza, Alessandro; Ko, Christopher; Morris, John; Lisotti, Andrea; Fusaroli, Pietro; Dhaliwal, Amaninder; Mutignani, Massimiliano; Forti, Edoardo; Cottone, Irene; Larghi, Alberto; Rizzatti, Gianenrico; Galasso, Domenico; Barbera, Carmelo; Di Matteo, Francesco Maria; Stigliano, Serena; Binda, Cecilia; Fabbri, Carlo; Pham, Khanh Do-Cong; Di Mitri, Roberto; Amata, Michele; Crino, Stefano Francesco; Ofosu, Andrew; De Luca, Luca; Al- Lehibi, Abed; Auriemma, Francesco; Paduano, Danilo; Calabrese, Federica; Gentile, Carmine; Hassan, Cesare; Repici, Alessandro; Facciorusso, Antonio
BACKGROUND AND STUDY AIMS : Although outcomes of lumen-apposing metal stents (LAMS) placement in native anatomy have been reported, data on LAMS placement in surgically altered anatomy (SAA) are sparse. We aimed to assess outcomes of LAMS placement in patients with SAA for different indications. PATIENTS AND METHODS : This was an international, multicenter, retrospective, observational study at 25 tertiary care centers through November 2023. Consecutive patients with SAA who underwent LAMS placement were included. The primary outcome was technical success defined as correct placement of LAMS. Secondary outcomes were clinical success and safety. RESULTS : Two hundred and seventy patients (125 males; average age 61 ± 15 years) underwent LAMS placement with SAA. Procedures included EUS-directed transgastric ERCP (EDGE) and EUS-directed transenteric ERCP (EDEE) (n = 82), EUS-guided entero-enterostomy (n = 81), EUS-guided biliary drainage (n = 57), EUS-guided drainage of peri-pancreatic fluid collections (n = 48), and EUS-guided pancreaticogastrostomy (n = 2). Most cases utilized AXIOS stents (n = 255) compared with SPAXUS stents (n = 15). Overall, technical success was 98%, clinical success was 97%, and the adverse event (AE) rate was 12%. Using AGREE classification, five events were rated as Grade II, 21 events as Grade IIIa, and six events as IIIb. No difference in AEs were noted among stent types ( P = 0.52). CONLUSIONS : This study shows that placement of LAMS is associated with high technical and clinical success rates in patients with SAA. However, the rate of AEs is noteworthy, and thus, these procedures should be performed by expert endoscopists at tertiary centers.
Characterization of portable ultra-low field MRI scanners for multi-center structural neuroimaging
(Wiley, 2025-06) Ljungberg, Emil; Padormo, Francesco; Poorman, Megan; Clemensson, Petter; Bourke, Niall; Evans, John C.; Gholam, James; Vavasour, Irene; Kollind, Shannon H.; Lafayette, Samson L.; Bennallick, Carly; Donald, Kirsten A.; Bradford, Layla E.; Lena, Beatrice; Vokhiwa, Maclean; Shama, Talat; Siew, Jasmine; Sekoli, Lydia; Van Rensburg, Jeanne; Pepper, Michael Sean; Khan, Amna; Madhwani, Akber; Banda, Frank A.; Mwila, Mwila L.; Cassidy, Adam R.; Moabi, Kebaiphe; Sephi, Dolly; Boakye, Richard A.; Ae-Ngibise, Kenneth A.; Asante, Kwaku P.; Hollander, William J.; Karaulanov, Todor; Williams, Steven C.R.; Deoni, Sean
The lower infrastructure requirements of portable ultra-low field MRI (ULF-MRI) systems have enabled their use in diverse settings such as intensive care units and remote medical facilities. The UNITY Project is an international neuroimaging network harnessing this technology, deploying portable ULF-MRI systems globally to expand access to MRI for studies into brain development. Given the wide range of environments where ULF-MRI systems may operate, there are external factors that might influence image quality. This work aims to introduce the quality control (QC) framework used by the UNITY Project to investigate how robust the systems are and how QC metrics compare between sites and over time. We present a QC framework using a commercially available phantom, scanned with 64 mT portable MRI systems at 17 sites across 12 countries on four continents. Using automated, open-source analysis tools, we quantify signal-to-noise, image contrast, and geometric distortions. Our results demonstrated that the image quality is robust to the varying operational environment, for example, electromagnetic noise interference and temperature. The Larmor frequency was significantly correlated to room temperature, as was image noise and contrast. Image distortions were less than 2.5 mm, with high robustness over time. Similar to studies at higher field, we found that changes in pulse sequence parameters from software updates had an impact on QC metrics. This study demonstrates that portable ULF-MRI systems can be deployed in a variety of environments for multi-center neuroimaging studies and produce robust results.
Nitric oxide mediated kisspeptin regulation of steroidogenesis and gametogenesis in the catfish, Clarias batrachus
(Springer, 2024-08) Singh, Ankur; Lal, Bechan; Kumar, Pankaj; Parhar, Ishwar S.; Millar, Robert P.
Nitric oxide (NO) is a gaseous molecule that regulates various reproductive functions. It is a well-recognized regulator of GnRH-FSH/LH-sex steroid secretion in vertebrates including fish. Kisspeptin is a recently discovered neuropeptide which also regulates GnRH secretion. Nitrergic and kisspeptin neurons are reported in close physical contact in the mammalian brain suggesting their interactive role in the release of GnRH. The existence of kisspeptin and NOS is also demonstrated in vertebrate gonads, but information on their reciprocal relation in gonads, if any, is obscure. Therefore, attempts were made to evaluate the functional reciprocal relation between nitric oxide and kisspeptin in the catfish gonads, if any, by administering the nitric oxide synthase (NOS) inhibitor, L-NAME {N(G)-nitro-l-arginine methyl ester}, which reduces NO production, and kisspeptin agonist (KP-10) and assessing their impacts on the expressions of kisspeptin1, different NOS isoforms, NO and steroid production in the gonadal tissue. The results revealed that L-NAME suppressed the expression of kiss1 in gonads of the catfish establishing the role of NO in kisspeptin expression. However, KP-10 increased the expression of all the isoforms of NOSs (iNOS, eNOS, nNOS) and concurrently NO and steroids in the ovary and testis. In vitro studies also indicate that kisspeptin stimulates the production of NO and estradiol and testosterone levels in the gonadal explants and medium. Thus, in vivo results clearly suggest a reciprocal interaction between kisspeptin and NO to regulate the gonadal activity of the catfish. The in vitro findings further substantiate our contention regarding the interactive role of kisspeptin and NO in gonadal steroidogenesis.
Perceptions of prevalence and management of post-acute sequelae of SARS-CoV-2 (PASC) infection among healthcare workers in Kweneng District, Botswana : report of a district-wide survey
(Public Library of Science, 2024-11-27) Mamalelala, Tebogo T.; Karmen-Tuohy, Savannah; Chimbwete, Lettie; Mokone, Ditebogo J.; Shapiro, Roger; Young, Claire; Khilji, Sara Schwanke
Over 9.5 million confirmed cases of COVID-19 infection have been recorded in Africa. The syndrome of post-acute sequelae of SARS-CoV-2 infection (PASC) affects an estimated 32% to 87% of COVID patients globally. Data regarding prevalence and impact of PASC in Botswana are limited. This study used a cross-sectional survey design to query healthcare workers in Kweneng District, Botswana about perceived PASC prevalence, duration, symptoms, impact, and management strategies. The survey was disseminated to participants via pre-existing WhatsApp groups and paper copy. Descriptive statistics were used to analyse quantitative data, including demographic data. 72 respondents consented and completed the survey, from an estimated 650 staff meeting eligibility criteria; 63% were female and 36% were male. The majority (90%) were nurses, with doctors and "other" accounting for 6% and 4% of respondents, respectively; no administrators responded. Over half (72%) worked at primary care facilities and 28% worked in hospitals. Nearly all (93%) indicated seeing patients with PASC on a weekly basis, though the majority (61%) identified these patients as comprising <10% of total patients. The most frequently reported PASC symptom was persistent cough (64%), followed by shortness of breath (54%) and fatigue (49%). A substantial minority of respondents were unsure how to manage common PASC symptoms, with 29% and 36% indicating uncertainty regarding management of persistent cough and fatigue, respectively. Findings indicate that PASC symptoms are frequently encountered in clinical practice in Botswana with significant overlap with acute COVID-19, influenza-like illnesses, and tuberculosis, likely placing increased burden on existing health system processes. Providers reported uncertainty in managing presumed PASC, and current practice patterns may contribute to unintended adverse effects. Clear clinical algorithms for PASC screening, diagnosis, and management should be developed and disseminated in Botswana to mitigate the effects of PASC symptoms and improve the quality of life of COVID-19 survivors.
Current and emerging insights into the causes, immunopathogenesis, and treatment of cutaneous squamous cell carcinoma
(MDPI, 2025-05) Anderson, Ronald; Mkhize, Nomzamo M.; Kgokolo, Mahlatse C.M.; Steel, Helen Carolyn; Rossouw, Theresa M.; Anderson, Lindsay; Rapoport, Bernardo Leon
The increasing incidence of cutaneous squamous cell carcinoma (cSCC), together with the ominous risks of metastasis and recurrence, underscores the importance of identifying novel therapies and validated biomarkers to augment patient management, particularly in the context of well-established and advanced disease. Following a brief overview of the well-recognized epidemiology, clinical features, and diagnosis of cSCC, the current review is focused on risk factors, most prominently excessive exposure to ultraviolet radiation (UVR) as a cause of persistent, pro-tumorigenic mutagenesis, and immune suppression. The next phase of the review encompasses an evaluation of the search for key driver mutations in the pathogenesis of cSCC, including the role of these and other mutations in the formation of immunologically reactive neoepitopes. With respect to additional mechanisms of tumorigenesis, immune evasion is prioritized, specifically the involvement of cell-free and infiltrating cellular mediators of immune suppression. Prominent amongst the former are the cytokine, transforming growth factor-β1 (TGF-β1), the prostanoid, prostaglandin E2, and the emerging immune suppressive nucleoside adenosine. In the case of the latter, tumor-infiltrating and circulating regulatory T cells have been implicated as being key players. The final sections of the review are focused on an update of the immunotherapy of established and advanced disease, as well as on the search for novel, reliable lesional and systemic biomarkers with the potential to guide patient management.
Effects of anti-pseudomonal agents, individually and in combination, with or without clarithromycin, on growth and biofilm formation by antibiotic-susceptible and -resistant strains of Pseudomonas aeruginosa, and the impact of exposure to cigarette smoke condensate
(MDPI, 2025-03) Cholo, Moloko C.; Feldman, Charles; Anderson, Ronald; Sekalo, Lebogang; Moloko, Naledi; Richards, Guy A.; moloko.cholo@up.ac.za
BACKGROUND/OBJECTIVES : Pseudomonas aeruginosa (Psa) can circumvent antimicrobial chemotherapy, an ability enhanced by cigarette smoking (CS). This study probed potential benefits of combinations of anti-pseudomonal agents, and potential augmentation by a macrolide, in the absence or presence of cigarette smoke condensate (CSC). METHODS : Two susceptible (WT: wild-type and DS: drug-sensitive) and one multidrug-resistant (MDR) strains of Psa were treated with amikacin, cefepime, and ciprofloxacin, individually and in combination, and with and without clarithromycin, followed by the measurement of planktonic growth and biofilm formation by spectrophotometry. Antibiotic interactions were determined using the fractional inhibitory concentration index (FICI) method. Effects on preformed biofilm density were measured following the addition of antibiotics: all procedures were performed in the absence and presence of CSC. RESULTS : The minimal inhibitory concentrations (MICs) of the three agents ranged from 0.125 mg/L to 1 mg/L (WT and DS strains) and 16 mg/L to 64 mg/L (MDR strain), with all resistant to clarithromycin (125 mg/L). MIC values closely correlated with the antibiotic concentrations required to inhibit biofilm formation. FICI revealed synergism between most combinations, with augmentation by clarithromycin. Amikacin had the greatest effect on biofilm density, which was potentiated by combination with the other antibiotics, particularly clarithromycin. Exposure to CSC had variable, albeit modest, effects on bacterial growth and biofilm formation, but low concentrations increased biofilm mass and attenuated synergistic antimicrobial interactions and effects on biofilm density. CONCLUSIONS : Amikacin, cefepime, and ciprofloxacin, especially with clarithromycin, exhibit synergistic anti-pseudomonal activity and decrease preformed biofilm density. CSC attenuated these effects, illustrating the pro-infective potential of CS.
Pembrolizumab 400 mg every 6 weeks as first-line therapy for advanced melanoma (KEYNOTE-555) : results from cohort B of an open-label, phase 1 study
(Public Library of Science, 2024-11-12) Cohen, Graham; Rapoport, Bernardo Leon; Chan, Sze W.; Ruff, Paul; Arance, Ana; Eizmendi, Karmele Mujika; Houghton, Baerin; Brown, Michael P.; Zielinski, Robert M.; Couselo, Eva Munoz; Lyle, Megan; Anderson, James R.; Jain, Lokesh; De Alwis, Dinesh; Lala, Mallika; Akala, Omobaloji; Chartash, Elliot; Jacobs, Conrad
Intravenous pembrolizumab 400 mg every 6 weeks was approved across tumor types based on pharmacokinetic modeling, which showed exposures consistent with previous standard dosing of 200 mg or 2 mg/kg every 3 weeks, and early results of cohort B of the phase 1 KEYNOTE-555 study. Results after ≥1 year of potential follow-up for all patients in cohort B of KEYNOTE-555 are presented. Patients aged ≥18 years with previously untreated stage III/IV melanoma received pembrolizumab 400 mg every 6 weeks for ≤18 cycles. The primary endpoint was objective response rate per RECIST v1.1 by blinded independent central review. Secondary endpoints included duration of response, progression-free survival, pharmacokinetics, and safety. Overall, 101 patients received pembrolizumab. Median projected follow-up was 21.9 months (range, 17.0–25.7). The objective response rate was 50.5% (95% CI: 40.4–60.6; 19 complete responses, 32 partial responses). Median duration of response was not reached (NR; range, 2.4+ to 21.0+ months). Median progression-free survival was 13.8 months (95% CI: 4.1–NR). Observed pharmacokinetic exposures were consistent with model predictions for pembrolizumab 400 mg every 6 weeks and other approved and tested schedules (2 mg/kg or 200 mg every 3 weeks). Grade 3–4 treatment-related adverse events occurred in 13 patients (12.9%). No deaths were considered treatment related. These results support the pharmacokinetic modeling and demonstrate that the benefit-risk profile of pembrolizumab 400 mg Q6W is consistent with that of 200 mg or 2 mg/kg every 3 weeks. Clinically meaningful objective response rate and durable progression-free survival within the expected range for first-line pembrolizumab were observed.
Pro-inflammatory interactions of streptolysin O toxin with human neutrophils in vitro
(Taylor and Francis Group, 2024-12) Joseph, Darren; Theron, Annette J.; Feldman, C.; Anderson, Ronald; Tintinger, Gregory
The recent global resurgence of severe infections caused by the Group A streptococcus (GAS) pathogen, Streptococcus pyogenes, has focused attention on this microbial pathogen, which produces an array of virulence factors, such as the pore-forming toxin, streptolysin O (SOT). Importantly, the interactions of SOT with human neutrophils (PMN), are not well understood. The current study was designed to investigate the effects of pretreatment of isolated human PMN with purified SOT on several pro-inflammatory activities, including generation of reactive oxygen species (ROS), degranulation (elastase release), influx of extracellular calcium (Ca2þ) and release of extracellular DNA (NETosis), using chemiluminescence, spectrophotometric and fluorimetric procedures, respectively. Exposure of PMN to SOT alone caused modest production of ROS and elastase release, while pretreatment with the toxin caused significant augmentation of chemoattractant (fMLP)-activated ROS generation and release of elastase by activated PMN. These effects of treatment of PMN with SOT were associated with both a marked and sustained elevation of cytosolic Ca2þconcentrations and significant increases in the concentrations of extracellular DNA, indicative of NETosis. The current study has identified a potential role for SOT in augmenting the Ca2þ-dependent pro-inflammatory interactions of PMN, which, if operative in a clinical setting, may contribute to hyper-activation of PMN and GAS-mediated tissue injury.

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