Research Articles (UP Centre for Sustainable Malaria Control (UP CSMC))

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A potent and selective reaction hijacking inhibitor of Plasmodium falciparum tyrosine tRNA synthetase exhibits single dose oral efficacy in vivo
(Public Library of Science, 2024-12-09) Xie, Stanley C.; Tai, Chia-Wei; Morton, Craig J.; Ma, Liting; Huang, Shih-Chung; Wittlin, Sergio; Du, Yawei; Hu, Yongbo; Dogovski, Con; Salimimarand, Mina; Griffin, Robert; England, Dylan; De la Cruz, Elisa; Yeo, Tomas; Burkhard, Anna Y.; Striepen, Josefine; Schindler, Kyra A.; Crespo, Benigno; Gamo, Francisco J.; Khandokar, Yogesh; Hutton, Craig A.; Rabie, Tayla Anne; Birkholtz, Lyn-Marie; Famodimu, Mufuliat T.; Delves, Michael J.; Bolsher, Judith; Koolen, Karin M.J.; Van der Laak, Rianne; Aguiar, Anna C.C.; Pereira, Dhelio B.; Guido, Rafael V.C.; Creek, Darren J.; Fidock, David A.; Dick, Lawrence R.; Brand, Stephen L.; Gould, Alexandra E.; Langston, Steven; Griffin, Michael D.W.; Tilley, Leann
The Plasmodium falciparum cytoplasmic tyrosine tRNA synthetase (PfTyrRS) is an attractive drug target that is susceptible to reaction-hijacking by AMP-mimicking nucleoside sulfamates. We previously identified an exemplar pyrazolopyrimidine ribose sulfamate, ML901, as a potent reaction hijacking inhibitor of PfTyrRS. Here we examined the stage specificity of action of ML901, showing very good activity against the schizont stage, but lower trophozoite stage activity. We explored a series of ML901 analogues and identified ML471, which exhibits improved potency against trophozoites and enhanced selectivity against a human cell line. Additionally, it has no inhibitory activity against human ubiquitin-activating enzyme (UAE) in vitro. ML471 exhibits low nanomolar activity against asexual blood stage P. falciparum and potent activity against liver stage parasites, gametocytes and transmissible gametes. It is fast-acting and exhibits a long in vivo half-life. ML471 is well-tolerated and shows single dose oral efficacy in the SCID mouse model of P. falciparum malaria. We confirm that ML471 is a reaction hijacking inhibitor that is converted into a tight binding Tyr-ML471 conjugate by the PfTyrRS enzyme. A crystal structure of the PfTyrRS/ Tyr-ML471 complex offers insights into improved potency, while molecular docking into UAE provides a rationale for improved selectivity.
The prevalence of childhood asthma, respiratory symptoms and associated air pollution sources among adolescent learners in selected schools in Vhembe District, South Africa
(MDPI, 2024-11-20) Rathogwa-Takalani, Funzani; Mudau, Thabelo Rodney; Patrick, Sean Mark; Shirinde, Joyce; Voyi, K.V.V. (Kuku); joyce.shirinde@up.ac.za
This study investigated the prevalence of childhood asthma and respiratory symptoms with their associated air pollution sources among adolescents aged 13–14 years residing in a Malaria-endemic region. METHODS : A cross-sectional survey was conducted with 2855 adolescents from fourteen (14) selected schools in communities exposed to high levels of air pollution from indoor residual spraying (IRS) that is used for malaria vector control in the Vhembe region. Data were collected using a self-administered standardized International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. Statistical software STATA version 17 was used to analyze the data. Binary logistic regression was used to determine the relationship between air pollution sources and childhood asthma/symptoms. RESULTS : The prevalences of asthma, ‘wheeze ever’ and ‘wheeze in the past’ were 18.91%, 37.69% and 24.69%, respectively. The results from the adjusted binary logistic regression model indicated that exposure to tobacco smoke (OR = 1.84; 95% CI: 1.08–3.16), smoking a water pipe (OR = 1.65; 95% CI: 1.16–2.36) and the use of paraffin as fuel for heating (OR = 1.70; 95% CI: 0.97–2.88) and cooking (OR = 0.48; 95% CI: 0.29–1.00) were significant risk factors for asthma. Trucks passing through the streets, having a cat at home and using open fires were significantly associated with ‘wheeze in the past’. Finally, using gas for cooking (OR = 0.72; 95% CI: 0.53–0.99), open fires for heating (OR = 0.53; 95% CI: 0.35–0.80) and smoking a water pipe (OR = 2.47; 95% CI: 1.78–3.44) were associated with ‘wheeze ever’. CONCLUSIONS : School children living in these communities had an increased risk of developing asthma and presenting with wheezing due to exposure to environmental air pollution sources.
Synthesis and SAR studies of acyl-thiourea platinum(II) complexes yield analogs with dual-stage antiplasmodium activity
(American Chemical Society, 2025-03) Ishmail, Fatima-Zahra; Coertzen, Dina; Tshabalala, Sizwe; Leshabane, Meta Kgaogelo; Da Rocha, Shanté; Njoroge, Mathew; Gibhard, Liezl; Birkholtz, Lyn-Marie; Woodland, John G.; Egan, Timothy J.; Wicht, Kathryn J.; Chibale, Kelly
Mixed-ligand platinum(II) complexes incorporating bipyridine and acyl-thiourea ligands were synthesized and evaluated for their in vitro growth inhibitory activity against the human malaria parasite Plasmodium falciparum (Pf). The substituents at four distinct sites were varied to identify structure–activity relationships for this series. Most complexes displayed potent PfNF54 activity with IC50 values in the nanomolar range and favorable cytotoxicity profiles. Five complexes (C1, C11, C12, C15, and C17) exhibited activity against both the asexual blood and sexual (gametocyte) stage parasites, with another complex (C8) exhibiting activity against late-stage gametocytes only. In addition, the complexes showed comparable ABS potency against the PfK1 multidrug-resistant strain. The pharmacokinetic parameters of one analog (C6), which displayed good solubility and mouse microsomal metabolic stability, were measured. This work demonstrates the potential of acyl-thiourea platinum(II) complexes as selective, multistage-active antiplasmodium compounds as part of the search for new antimalarial agents.
Eliminating malaria transmission requires targeting immature and mature gametocytes through lipoidal uptake of antimalarials
(Nature Research, 2024-11-15) Naude, Mariska; Van Heerden, Ashleigh; Reader, Janette; Van der Watt, Mariette Elizabeth; Niemand, Jandeli; Joubert, Dore; Siciliano, Giulia; Alano, Pietro; Njoroge, Mathew; Chibale, Kelly; Herreros, Esperanza; Leroy, Didier; Birkholtz, Lyn-Marie
Novel antimalarial compounds targeting both the pathogenic and transmissible stages of the human malaria parasite, Plasmodium falciparum, would greatly benefit malaria elimination strategies. However, most compounds affecting asexual blood stage parasites show severely reduced activity against gametocytes. The impact of this activity loss on a compound’s transmission-blocking activity is unclear. Here, we report the systematic evaluation of the activity loss against gametocytes and investigate the confounding factors contributing to this. A threshold for acceptable activity loss between asexual blood stage parasites and gametocytes was defined, with near-equipotent compounds required to prevent continued gametocyte maturation and onward transmission. Target abundance is not predictive of gametocytocidal activity, but instead, lipoidal uptake is the main barrier of dual activity and is influenced by distinct physicochemical properties. This study provides guidelines for the required profiles of potential dual-active antimalarial agents and facilitates the development of effective transmission-blocking compounds.
Evaluation of the malaria case surveillance system in KwaZulu-Natal Province, South Africa, 2022 : a focus on DHIS2
(BioMed Central, 2024-02-14) Mabona, Maxwell; Zwane, Thembekile; Raman, Jaishree; Kuonza, Lazarus R.; Mhlongo, Babongile; Phafane, Poncho
BACKGROUND South Africa set a target to eliminate malaria by 2023, with KwaZulu-Natal (KZN) Province the malariaendemic province closest to achieving this goal. Objective two of the National Malaria Elimination Strategic Plan (NMESP) focused on strengthening surveillance systems to support the country’s elimination efforts. Regular evaluations of the malaria surveillance systems against the targets of the NMESP objective are crucial in improving their performance and impact. This study aimed to assess whether the malaria surveillance system in KwaZulu-Natal Province meets the NMESP surveillance objective and goals. METHODS A mixed-methods cross-sectional study design was used to evaluate the malaria surveillance system, focusing on the District Health Information System 2 (DHIS2). The study assessed the data quality, timeliness, simplicity, and acceptability of the system. Key personnel from KZN’s Provincial malaria control programme were interviewed using self-administered questionnaires to evaluate their perception of the system’s simplicity and acceptability. Malaria case data from January 2016 to December 2020 were extracted from the DHIS2 and evaluated for data quality and timeliness. RESULTS The survey respondents generally found the DHIS2-based surveillance system acceptable (79%, 11/14) and easy to use (71%, 10/14), stating that they could readily find, extract, and share data (64%, 9/14). Overall data quality was good (88.9%), although some variables needed for case classification had low completeness and data availability. However, case notifications were not timely, with only 61% (2 622/4 329) of cases notified within 24 h of diagnosis. During the 5-year study period, the DHIS2 captured 4 333 malaria cases. The majority of cases (81%, 3 489/4 330) were categorized as imported, and predominately in males (67%, 2 914/4 333). CONCLUSION While the malaria surveillance system in KZN Province largely met the NMESP surveillance strategic goals, it failed to achieve the overarching surveillance objective of 100% notification of cases within 24 h of diagnosis. The majority of reported cases in KZN Province were classified as imported, emphasizing the importance of complete data for accurate case classification. Engaging with healthcare professionals responsible for case notification and disseminating aggregated data back to them is needed to encourage and improve notification timeliness.
Helminth parasites of impalas, Aepyceros melampus, in eastern southern Africa, collected during 1973 to 2007
(Medpharm Publications, 2024-03) Horak, Ivan Gerard; Junker, K.; Braack, L.E.O.; Gallivan, G.J.
This paper summarises published and unpublished data on helminths collected systematically from 424 impalas at 11 localities in eastern southern Africa, from St. Lucia in KwaZulu-Natal (KZN) to the Tuli Block in north-eastern Botswana. It includes data on collections in the Kruger National Park (KNP) in the drought of 1982, and in 1992/93 following the 1991/92 drought. Thirty-three species of nematodes, plus six taxa identified only to the generic level, three taxa of trematodes, and three species of cestodes were collected. Helminth species richness was highest in the southern KNP and lowest in the Tuli Block. The prevalence and intensity of infection of several helminths also declined from KZN and the southern KNP to the drier areas in the north and west. With the exception of St. Lucia and Nylsvley, > 80% of the helminths collected at each locality were collected in the southern KNP. St. Lucia was the most dissimilar locality; of the 20 helminths collected, five were unique. Ten of 33 species of nematodes, the paramphistomines (Trematoda) and the cestode Stilesia hepatica were collected at seven or more localities. Six of the most common nematodes, Cooperia hungi, Cooperioides hamiltoni, Impalaia tuberculata, Longistrongylus sabie, Strongyloides papillosus and Trichostrongylus deflexus are primarily parasites of impalas in the southern KNP, whereas many of the helminths collected at only one or two localities are parasites of other hosts. Nematode burdens were increased in the drought affected impalas in 1982, but helminth burdens decreased in 1992/93 following a dry cycle.
Genetic complexity alters drug susceptibility of asexual and gametocyte stages of Plasmodium falciparum to antimalarial candidates
(American Society for Microbiology, 2024-03) Greyling, Nicola; Van der Watt, Mariette Elizabeth; Gwarinda, Hazel B.; Van Heerden, Ashleigh; Greenhouse, Bryan; Leroy, Didier; Niemand, Jandeli; Birkholtz, Lyn-Marie; lbirkholtz@up.ac.za
Malaria elimination requires interventions able to target both the asexual blood stage (ABS) parasites and transmissible gametocyte stages of Plasmodium falciparum. Lead antimalarial candidates are evaluated against clinical isolates to address key concerns regarding efficacy and to confirm that the current, circulating parasites from endemic regions lack resistance against these candidates. While this has largely been performed on ABS parasites, limited data are available on the transmission-blocking efficacy of compounds with multistage activity. Here, we evaluated the efficacy of lead antimalarial candidates against both ABS parasites and late-stage gametocytes side-by-side, against clinical P. falciparum isolates from southern Africa. We additionally correlated drug efficacy to the genetic diversity of the clinical isolates as determined with a panel of well-characterized, genome-spanning microsatellite markers. Our data indicate varying sensitivities of the isolates to key antimalarial candidates, both for ABS parasites and gametocyte stages. While ABS parasites were efficiently killed, irrespective of genetic complexity, antimalarial candidates lost some gametocytocidal efficacy when the gametocytes originated from genetically complex, multiple-clone infections. This suggests a fitness benefit to multiclone isolates to sustain transmission and reduce drug susceptibility. In conclusion, this is the first study to investigate the efficacy of antimalarial candidates on both ABS parasites and gametocytes from P. falciparum clinical isolates where the influence of parasite genetic complexity is highlighted, ultimately aiding the malaria elimination agenda
Association between prenatal exposure to indoor residual spraying insecticides and infection rates among South African children participating in the Venda Health Examination of Mothers, Babies and their Environment (VHEMBE)
(Elsevier, 2024-03) Davis, Brooklyn; Eskenazi, Brenda; Bornman, Maria S. (Riana); Obida, Muvhulawa; Chevrier, Jonathan
Please read abstract in the article.
Towards integrated malaria molecular surveillance in Africa
(Elsevier, 2024-11) Dada, Nsa; Simpson, Victoria J.; Amenga-Etego, Lucas N.; Oriero, Eniyou; Miotto, Olivo; Torok, Mili Estee; Juma, Elijah O.; Williams, Nana Aba; Rajatileka, Shavanthi; Ariani, Cristina V.; Raman, Jaishree; Ishengoma, Deus S.
Integrated malaria molecular surveillance (iMMS) systems are essential for Africa's expanding malaria genomics initiatives. Here we highlight a few initiatives and demonstrate how iMMS can support evidence-based decisions and policies for National Malaria Programs and other malaria control stakeholders. We conclude with key considerations for advancing these malaria genomics initiatives towards sustainable iMMS.
House screening reduces exposure to indoor host-seeking and biting malaria vectors : evidence from rural South-East Zambia
(MDPI, 2024-01-15) Saili, Kochelani; De Jager, Christiaan; Masaninga, Freddie; Sangoro, Onyango P.; Nkya, Theresia E.; Likulunga, Likulunga Emmanuel; Chirwa, Jacob; Hamainza, Busiku; Chanda, Emmanuel; Fillinger, Ulrike; Mutero, Clifford Maina; tiaan.dejager@up.ac.za
This study evaluated the impact of combining house screens with long-lasting insecticidal nets (LLINs) on mosquito host-seeking, resting, and biting behavior. Intervention houses received house screens and LLINs, while control houses received only LLINs. Centre for Disease Control light traps, pyrethrum spray collections and human landing catches were used to assess the densities of indoor and outdoor host-seeking, indoor resting, and biting behavior of malaria vectors in 15 sentinel houses per study arm per sampling method. The protective efficacy of screens and LLINs was estimated through entomological inoculation rates (EIRs). There were 68% fewer indoor host-seeking Anopheles funestus (RR = 0.32, 95% CI 0.20–0.51, p < 0.05) and 63% fewer An. arabiensis (RR = 0.37, 95% CI 0.22–0.61, p < 0.05) in screened houses than unscreened houses. There was a significantly higher indoor biting rate for unscreened houses (6.75 bites/person/h [b/p/h]) than for screened houses (0 b/p/h) (χ2 = 6.67, df = 1, p < 0.05). The estimated indoor EIR in unscreened houses was 2.91 infectious bites/person/six months, higher than that in screened houses (1.88 infectious bites/person/six months). Closing eaves and screening doors and windows has the potential to reduce indoor densities of malaria vectors and malaria transmission.
The Tuberculosis drug candidate SQ109 and its analogs have multistage activity against Plasmodium falciparum
(American Chemical Society, 2024-08) Watson, Savannah Jade; Van der Watt, Mariette Elizabeth; Theron, Anjo; Reader, Janette; Tshabalala, Sizwe; Erlank, Erica; Koekemoer, Lizette L.; Naude, Mariska; Stampolaki, Marianna; Adewole, Feyisola; Sadowska, Katie; Pérez-Lozano, Pilar; Turcu, Andreea L.; Vázquez, Santiago; Ko, Jihee; Mazurek, Ben; Singh, Davinder; Malwal, Satish R.; Njoroge, Mathew; Chibale, Kelly; Onajole, Oluseye K.; Kolocouris, Antonios; Oldfield, Eric; Birkholtz, Lyn-Marie; lynmarie.birkholtz@up.ac.za
Toward repositioning the antitubercular clinical candidate SQ109 as an antimalarial, analogs were investigated for structure−activity relationships for activity against asexual blood stages of the human malaria parasite Plasmodium falciparum pathogenic forms, as well as transmissible, sexual stage gametocytes. We show that equipotent activity (IC50) in the 100−300 nM range could be attained for both asexual and sexual stages, with the activity of most compounds retained against a multidrug-resistant strain. The multistage activity profile relies on high lipophilicity ascribed to the adamantane headgroup, and antiplasmodial activity is critically dependent on the diamine linker. Frontrunner compounds showed conserved activity against genetically diverse southern African clinical isolates. We additionally validated that this series could block transmission to mosquitoes, marking these compounds as novel chemotypes with multistage antiplasmodial activity.
Exploring the modulatory influence on the antimalarial activity of amodiaquine using scaffold hybridisation with ferrocene integration
(Elsevier, 2024-05) Mbaba, Mziyanda; Golding, Taryn M.; Omondi, Reinner O.; Mohunlal, Roxanne; Egan, Timothy J.; Reader, Janette; Birkholtz, Lyn-Marie; Smith, Gregory S.
Amodiaquine (AQ) is a potent antimalarial drug used in combination with artesunate as part of artemisinin-based combination therapies (ACTs) for malarial treatment. Due to the rising emergence of resistant malaria parasites, some of which have been reported for ACT, the usefulness of AQ as an efficacious therapeutic drug is threatened. Employing the organometallic hybridisation approach, which has been shown to restore the antimalarial activity of chloroquine in the form of an organometallic hybrid clinical candidate ferroquine (FQ), the present study utilises this strategy to modulate the biological performance of AQ by incorporating ferrocene. Presently, we have conceptualised ferrocenyl AQ derivatives and have developed facile, practical routes for their synthesis. A tailored library of AQ derivatives was assembled and their antimalarial activity evaluated against chemosensitive (NF54) and multidrug-resistant (K1) strains of the malaria parasite, Plasmodium falciparum. The compounds generally showed enhanced or comparable activities to those of the reference clinical drugs chloroquine and AQ, against both strains, with higher selectivity for the sensitive phenotype, mostly in the double-digit nanomolar IC50 range. Moreover, representative compounds from this series show the potential to block malaria transmission by inhibiting the growth of stage II/III and V gametocytes in vitro. Preliminary mechanistic insights also revealed hemozoin inhibition as a potential mode of action.
Community perceptions, acceptability, and the durability of house screening interventions against exposure to malaria vectors in Nyimba district, Zambia
(BMC, 2024-01) Saili, Kochelani; De Jager, Christiaan; Masaninga, Freddie; Chisanga, Brian; Sinyolo, Andy; Chiwaula, Japhet; Chirwa, Jacob; Hamainza, Busiku; Chanda, Emmanuel; Bakyaita, Nathan N.; Mutero, Clifford Maina
BACKGOUND: House screening remains conspicuously absent in national malaria programs despite its recognition by the World Health Organization as a supplementary malaria vector-control intervention. This may be attributed, in part, to the knowledge gap in screen durability or longevity in local climatic conditions and community acceptance under specific cultural practices and socio-economic contexts. The objectives of this study were to assess the durability of window and door wire mesh screens a year after full house screening and to assess the acceptability of the house screening intervention to the participants involved. METHODS: This study was conducted in Nyimba district, Zambia and used both quantitative and qualitative methods of data collection and analysis. Both direct observation and questionnaires were employed to assess the durability of the screens and the main reasons for damage. Findings on damage were summarized as percentages. Focus group discussions were used to assess people’s knowledge, perceptions, and acceptability of the closing eaves and house screening intervention. Deductive coding and inductive coding were used to analyse the qualitative data. RESULTS: A total of 321 out of 400 (80.3%) household owners of screened houses were interviewed. Many window screens (90.3%) were intact. In sharp contrast, most door screens were torn (n=150; 46.7%) or entirely removed (n=55; 17.1%). Most doors (n=114; 76%) had their wire mesh damaged or removed on the bottom half. Goats (25.4%), rust (17.6%) and children (17.1%) were cited most as the cause of damage to door screens. The focus group discussion elicited positive experiences from the participants following the closing of eaves and screening of their windows and doors, ranging from sleeping peacefully due to reduced mosquito biting and/or nuisance and having fewer insects in the house. Participants linked house screening to reduced malaria in their households and community. CONCLUSION: This study demonstrated that in rural south-east Zambia, closing eaves and screening windows and doors was widely accepted. Participants perceived that house screening reduced human-vector contact, reduced the malaria burden and nuisance biting from other potentially disease carrying insects. However, screened doors are prone to damage, mainly by children, domestic animals, rust, and termites.
Anopheles rufipes implicated in malaria transmission both indoors and outdoors alongside Anopheles funestus and Anopheles arabiensis in rural south-east Zambia
(BMC, 2023-03-16) Saili, Kochelani; De Jager, Christiaan; Sangoro, Onyango P.; Nkya, Theresia E.; Masaninga, Freddie; Mwenya, Mwansa; Sinyolo, Andy; Hamainza, Busiku; Chanda, Emmanuel; Fillinger, Ulrike; Mutero, Clifford Maina
BACKGROUND : The primary malaria vector-control interventions, indoor residual spraying and long-lasting insecticidal nets, are effective against indoor biting and resting mosquito species. Consequently, outdoor biting and resting malaria vectors might elude the primary interventions and sustain malaria transmission. Varied vector biting and resting behaviour calls for robust entomological surveillance. This study investigated the bionomics of malaria vectors in rural south-east Zambia, focusing on species composition, their resting and host-seeking behaviour and sporozoite infection rates. METHODS : The study was conducted in Nyimba District, Zambia. Randomly selected households served as sentinel houses for monthly collection of mosquitoes indoors using CDC-light traps (CDC-LTs) and pyrethrum spray catches (PSC), and outdoors using only CDC-LTs for 12 months. Mosquitoes were identified using morphological taxonomic keys. Specimens belonging to the Anopheles gambiae complex and Anopheles funestus group were further identified using molecular techniques. Plasmodium falciparum sporozoite infection was determined using sandwich enzymelinked immunosorbent assays. RESULTS : From 304 indoor and 257 outdoor light trap-nights and 420 resting collection, 1409 female Anopheles species mosquitoes were collected and identified morphologically; An. funestus (n = 613; 43.5%), An. gambiae sensu lato (s.l.)(n = 293; 20.8%), Anopheles pretoriensis (n = 282; 20.0%), Anopheles maculipalpis (n = 130; 9.2%), Anopheles rufipes (n = 55; 3.9%), Anopheles coustani s.l. (n = 33; 2.3%), and Anopheles squamosus (n = 3, 0.2%). Anopheles funestus sensu stricto (s.s.) (n = 144; 91.1%) and Anopheles arabiensis (n = 77; 77.0%) were the dominant species within the An. funestus group and An. gambiae complex, respectively. Overall, outdoor CDC-LTs captured more Anopheles mosquitoes (mean = 2.25, 95% CI 1.22–3,28) than indoor CDC-LTs (mean = 2.13, 95% CI 1.54–2.73). Fewer resting mosquitoes were collected with PSC (mean = 0.44, 95% CI 0.24–0.63). Sporozoite infectivity rates for An. funestus, An. arabiensis and An. rufipes were 2.5%, 0.57% and 9.1%, respectively. Indoor entomological inoculation rates (EIRs) for An. funestus s.s, An. arabiensis and An. rufipes were estimated at 4.44, 1.15 and 1.20 infectious bites/person/year respectively. Outdoor EIRs for An. funestus s.s. and An. rufipes at 7.19 and 4.31 infectious bites/person/year, respectively. CONCLUSION : The findings of this study suggest that An. rufipes may play an important role in malaria transmission alongside An. funestus s.s. and An. arabiensis in the study location.
Correlating the density and refractive index of ternary liquid mixtures
(Springer, 2023-11) Dzingai, Pethile; Focke, Walter Wilhelm; Ramjee, Shatish; Khosa, Pretty; Nobunga, Ripfumelo A.; walter.focke@up.ac.za
Some physical properties of ideal solutions, e.g. the molar volume and the molar refraction, vary linearly with composition. Others can be expressed, either as ratios or as products of two other properties which vary with composition in this way. It is postulated that the nonideal behaviour of real solutions can be adequately modelled by substituting these linear functions with higher order Scheffé polynomials. A suite of such models is presented for which the parameters are fully determined by knowledge of pure component properties and binary behaviour. Their binary data representation ability, and capacity to predict ternary properties, was tested using density and refractive index data for the acetic acid–ethanolwater ternary system as well as fourteen additional ternary data sets. Model performance was ranked on the basis of the Akaike Information criterion. With respect to predicting ternary density and refractive index behaviour from knowledge of binary data, it was found that lower-order models outperformed higher order models.
Species composition, seasonal abundance, and biting behavior of malaria vectors in rural Conhane Village, Southern Mozambique
(MDPI, 2023-02-17) Salome, Graca; Riddin, Megan A.; Braack, L.E.O.
Malaria vector surveillance provides important data to inform the effective planning of vector control interventions at a local level. The aim of this study was to determine the species diversity and abundance, biting activity, and Plasmodium infectivity of Anopheles mosquitoes from a rural village in southern Mozambique. Human landing catches were performed monthly between December 2020 and August 2021. All collected Anopheles were identified to the species level and tested for the presence of malaria parasites. Eight Anopheles species were identified among the 1802 collected anophelines. Anopheles gambiae sensu lato (s.l.) were the most abundant (51.9%) and were represented by Anopheles quadriannulatus and Anopheles arabiensis. Anopheles funestus s.l. represented 4.5%. The biting activity of An. arabiensis was more pronounced early in the evening and outdoors, whereas that of An. funestus sensu stricto (s.s.) was more intense late in the night, with no significant differences in location. One An. funestus s.s. and one An. arabiensis, both collected outdoors, were infected with Plasmodium falciparum. The overall entomologic inoculation rate was estimated at 0.015 infective bites per person per night. The significant outdoor and early evening biting activity of An. arabiensis and An. funestus found in this village may negatively impact the effectiveness of current vector control interventions. Additional vector control tools that can target these mosquitoes are needed.
hERG, Plasmodium life cycle, and cross resistance profiling of new azabenzimidazole analogues of astemizole
(American Chemical Society, 2024-03) Mambwe, Dickson; Coertzen, Dina; Leshabane, Meta Kgaogelo; Mulubwa, Mwila; Njoroge, Mathew; Gibhard, Liezl; Girling, Gareth; Wicht, Kathryn J.; Lee, Marcus C.S.; Wittlin, Sergio; Moreira, Diogo Rodrigo Magalhaes; Birkholtz, Lyn-Marie; Chibale, Kelly
Please read abstract in the article.
Characterizing the thermal phase behaviour of fipronil polymorphs
(Springer, 2023-07) Moyo, Dennis Simbarashe; Van der Merwe, Elizabet Margaretha; Rademeyer, Melanie; Malan, F.P. (Frederick); Atanasova, Maria T.; Mapossa, António Benjamim; Focke, Walter Wilhelm; dennis.moyo@up.ac.za
This manuscript reports the investigation of the polymorphic behaviour of fipronil using a systematic comparison of the thermochemical and structural properties of different crystal forms obtained in this study as well as those previously reported in literature. The analytical techniques employed include DSC, TGA, PXRD, SCXRD and hot stage microscopy. DSC proved particularly useful because it made it possible to differentiate between the two different crystal forms found in the as-received neat fipronil. The DSC scans revealed the presence of two polymorphs which had melting endotherms with peak maxima at ca. 196 °C and 205 °C, respectively. These polymorphs were successfully separated via sublimation and resulted in a metastable, lower melting polymorph in the sublimate and a thermodynamically stable, higher melting form in the sublimation residue. Clear evidence for the instability of the lower melting polymorph was found when the endotherms were examined under a range of heating rates. The proportion of the metastable form appeared to increase as the rate was increased, indicating that the metastable form underwent a solid–solid phase transition to the stable form at low heating rates. Recrystallization of fipronil from different solvents yielded five different forms. TGA curves revealed that all forms, except the acetone-derived one, were solvate pseudo-polymorphs that showed solvent loss between 60 and 100 °C. The acetone-derived sample was a hemihydrate that only started to show mass loss at 120 °C. SCXRD studies revealed that three of the five forms have similar structural characteristics, while the other two forms differ notably from each other and the rest of the structures. Despite these structural differences, all five forms exhibit near-identical intra- and intermolecular hydrogen bond networks.
Maternal exposure to pyrethroid insecticides during pregnancy and respiratory allergy symptoms among children participating in the Venda Health Examination of Mothers, Babies and their Environment (VHEMBE)
(Elsevier, 2024-02) Elsiwi, Basant; Eskenazi, Brenda; Bornman, Maria S. (Riana); Obida, Muvhulawa; Kim, Joanne; Moodie, Erica E.M.; Mann, Koren K.; Chevrier, Jonathan
BACKGROUND : Pyrethroid insecticides use for indoor residual spraying (IRS) in malaria-endemic areas results in high levels of exposure to local populations. Pyrethroids may cause asthma and respiratory allergies but no prior study has investigated this question in an IRS area. METHODS : We measured maternal urinary concentrations of pyrethroid metabolites (cis-DBCA, cis-DCCA, trans-DCCA, 3-PBA) in samples collected at delivery from 751 mothers participating in the Venda Health Examination of Mothers, Babies, and their Environment (VHEMBE), a birth cohort study based in Limpopo, South Africa. At 3.5-year and 5-year follow-up visits, caregivers of 647 and 620 children, respectively, were queried about children's respiratory allergy symptoms based on validated instruments. We applied marginal structural models for repeated outcomes to estimate associations between biomarker concentrations and asthma diagnosis as well as respiratory allergy symptoms at ages 3.5 and 5 years. RESULTS : We found that a10-fold increase in maternal urinary cis-DCCA, trans-DCCA and 3-PBA concentrations were associated with more than a doubling in the risk of doctor-diagnosed asthma (cis-DCCA: RR = 2.1, 95% CI = 1.3, 3.3; trans-DCCA: RR = 2.1, 95% CI = 1.1, 3.9; 3-PBA: RR = 2.4, 95% CI = 1.0, 5.8) and an about 80% increase in the risk of wheezing or whistling in the chest (cis-DCCA: RR = 1.8, 95% CI = 1.1, 3.0; trans-DCCA: RR = 1.7, 95% CI = 1.1, 2.6; 3-PBA: RR = 1.8, 95% CI = 1.0, 3.3) and suspected asthma (cis-DCCA: RR = 1.8, 95% CI = 1.1, 3.1; trans-DCCA: RR = 1.8, 95% CI = 1.1, 2.8). We also observed that higher concentrations of cis-DBCA and 3-PBA were related to increases in the risks of dry cough at night (RR = 3.5, 95% CI = 1.3, 9.5) and seasonal rhinoconjunctivitis (RR = 2.0, 95% CI = 1.1, 3.9), respectively. CONCLUSION : Maternal exposure to pyrethroids may increase the risk of asthma and other respiratory allergy symptoms among preschool children from an IRS area.
The association between long-term DDT or DDE exposures and an altered sperm epigenome-a cross-sectional study of Greenlandic Inuit and South African VhaVenda men
(National Institute of Environmental Health Sciences, 2024-01) Lismer, Ariane; Shao, Xiaojian; Dumargne, Marie-Charlotte; Lafleur, Christine; Lambrot, Romain; Chan, Donovan; Toft, Gunnar; Bonde, Jens Peter; Macfarlane, Amanda J.; Bornman, Maria S. (Riana); Aneck-Hahn, Natalie Hildegard; Patrick, Sean Mark; Bailey, Janice M.; De Jager, Christiaan; Dumeaux, Vanessa; Trasler, Jacquetta M.; Kimmins, Sarah
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