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Jennifer A. Flegg

Bio: Jennifer A. Flegg is an academic researcher from University of Melbourne. The author has contributed to research in topics: Malaria & Medicine. The author has an hindex of 24, co-authored 60 publications receiving 3445 citations. Previous affiliations of Jennifer A. Flegg include Monash University & University of Oxford.


Papers
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Journal ArticleDOI
TL;DR: Prolonged courses of artemisinin-based combination therapies are currently efficacious in areas where standard 3-day treatments are failing, and the incidence of pretreatment and post-treatment gametocytemia was higher among patients with slow parasite clearance, suggesting greater potential for transmission.
Abstract: BACKGROUND: Artemisinin resistance in Plasmodium falciparum has emerged in Southeast Asia and now poses a threat to the control and elimination of malaria. Mapping the geographic extent of resistance is essential for planning containment and elimination strategies. METHODS: Between May 2011 and April 2013, we enrolled 1241 adults and children with acute, uncomplicated falciparum malaria in an open-label trial at 15 sites in 10 countries (7 in Asia and 3 in Africa). Patients received artesunate, administered orally at a daily dose of either 2 mg per kilogram of body weight per day or 4 mg per kilogram, for 3 days, followed by a standard 3-day course of artemisinin-based combination therapy. Parasite counts in peripheral-blood samples were measured every 6 hours, and the parasite clearance half-lives were determined. RESULTS: The median parasite clearance half-lives ranged from 1.9 hours in the Democratic Republic of Congo to 7.0 hours at the Thailand-Cambodia border. Slowly clearing infections (parasite clearance half-life >5 hours), strongly associated with single point mutations in the "propeller" region of the P. falciparum kelch protein gene on chromosome 13 (kelch13), were detected throughout mainland Southeast Asia from southern Vietnam to central Myanmar. The incidence of pretreatment and post-treatment gametocytemia was higher among patients with slow parasite clearance, suggesting greater potential for transmission. In western Cambodia, where artemisinin-based combination therapies are failing, the 6-day course of antimalarial therapy was associated with a cure rate of 97.7% (95% confidence interval, 90.9 to 99.4) at 42 days. CONCLUSIONS: Artemisinin resistance to P. falciparum, which is now prevalent across mainland Southeast Asia, is associated with mutations in kelch13. Prolonged courses of artemisinin-based combination therapies are currently efficacious in areas where standard 3-day treatments are failing. (Funded by the U.K. Department of International Development and others; ClinicalTrials.gov number, NCT01350856.).

1,777 citations

Journal ArticleDOI
TL;DR: Assessment of the spread of artemisinin-resistant P falciparum in Myanmar finds Artemisinin resistance extends across much of Myanmar, and Appropriate therapeutic regimens should be tested urgently and implemented comprehensively if spread of warfarin resistance to other regions is to be avoided.
Abstract: Summary Background Emergence of artemisinin resistance in southeast Asia poses a serious threat to the global control of Plasmodium falciparum malaria. Discovery of the K13 marker has transformed approaches to the monitoring of artemisinin resistance, allowing introduction of molecular surveillance in remote areas through analysis of DNA. We aimed to assess the spread of artemisinin-resistant P falciparum in Myanmar by determining the relative prevalence of P falciparum parasites carrying K13-propeller mutations. Methods We did this cross-sectional survey at malaria treatment centres at 55 sites in ten administrative regions in Myanmar, and in relevant border regions in Thailand and Bangladesh, between January, 2013, and September, 2014. K13 sequences from P falciparum infections were obtained mainly by passive case detection. We entered data into two geostatistical models to produce predictive maps of the estimated prevalence of mutations of the K13 propeller region across Myanmar. Findings Overall, 371 (39%) of 940 samples carried a K13-propeller mutation. We recorded 26 different mutations, including nine mutations not described previously in southeast Asia. In seven (70%) of the ten administrative regions of Myanmar, the combined K13-mutation prevalence was more than 20%. Geospatial mapping showed that the overall prevalence of K13 mutations exceeded 10% in much of the east and north of the country. In Homalin, Sagaing Region, 25 km from the Indian border, 21 (47%) of 45 parasite samples carried K13-propeller mutations. Interpretation Artemisinin resistance extends across much of Myanmar. We recorded P falciparum parasites carrying K13-propeller mutations at high prevalence next to the northwestern border with India. Appropriate therapeutic regimens should be tested urgently and implemented comprehensively if spread of artemisinin resistance to other regions is to be avoided. Funding Wellcome Trust–Mahidol University–Oxford Tropical Medicine Research Programme and the Bill & Melinda Gates Foundation.

385 citations

Journal ArticleDOI
TL;DR: Replication and validation studies are needed to refine the location of loci responsible for artemisinin resistance and to understand the mechanism behind it; however, two SNPs on chromosomes 10 and 13 may be useful markers of delayed parasite clearance in surveillance for artesunate resistance in Southeast Asia.
Abstract: The recent emergence of artemisinin-resistant Plasmodium falciparum malaria in western Cambodia could threaten prospects for malaria elimination. Identification of the genetic basis of resistance would provide tools for molecular surveillance, aiding efforts to contain resistance. Clinical trials of artesunate efficacy were conducted in Bangladesh, in northwestern Thailand near the Myanmar border, and at two sites in western Cambodia. Parasites collected from trial participants were genotyped at 8,079 single nucleotide polymorphisms (SNPs) using a P. falciparum-specific SNP array. Parasite genotypes were examined for signatures of recent positive selection and association with parasite clearance phenotypes to identify regions of the genome associated with artemisinin resistance. Four SNPs on chromosomes 10 (one), 13 (two), and 14 (one) were significantly associated with delayed parasite clearance. The two SNPs on chromosome 13 are in a region of the genome that appears to be under strong recent positive selection in Cambodia. The SNPs on chromosomes 10 and 13 lie in or near genes involved in postreplication repair, a DNA damage-tolerance pathway. Replication and validation studies are needed to refine the location of loci responsible for artemisinin resistance and to understand the mechanism behind it; however, two SNPs on chromosomes 10 and 13 may be useful markers of delayed parasite clearance in surveillance for artemisinin resistance in Southeast Asia.

266 citations

Journal ArticleDOI
TL;DR: The parasite clearance estimator provides a consistent, reliable and accurate method to estimate the lag phase and malaria parasite clearance rate and could be used to detect early signs of emerging resistance to artemisinin derivatives and other compounds which affect ring-stage clearance.
Abstract: Background A significant reduction in parasite clearance rates following artesunate treatment of falciparum malaria, and increased failure rates following artemisinin combination treatments (ACT), signaled emergent artemisinin resistance in Western Cambodia. Accurate measurement of parasite clearance is therefore essential to assess the spread of artemisinin resistance in Plasmodium falciparum. The slope of the log-parasitaemia versus time relationship is considered to be the most robust measure of anti-malarial effect. However, an initial lag phase of numerical instability often precedes a steady exponential decline in the parasite count after the start of anti-malarial treatment. This lag complicates the clearance estimation, introduces observer subjectivity, and may influence the accuracy and consistency of reported results.

254 citations

Journal ArticleDOI
Jane Achan, Ishag Adam1, Emmanuel Arinaitwe, Elizabeth A. Ashley2, Ghulam Rahim Awab3, Ghulam Rahim Awab2, Mamadou S. Ba4, Karen I. Barnes5, Quique Bassat, Steffen Borrmann6, Steffen Borrmann7, Teun Bousema8, Teun Bousema9, Prabin Dahal10, Umberto D'Alessandro8, Umberto D'Alessandro11, Timothy M. E. Davis12, Arjen M. Dondorp, Grant Dorsey13, Chris Drakeley8, Caterina I. Fanello2, Babacar Faye4, Jennifer A. Flegg10, Oumar Gaye4, Peter W. Gething10, Raquel González, Philippe J Guerin10, Simon I. Hay10, Tran Tinh Hien10, Tran Tinh Hien14, Bart Janssens15, Moses R. Kamya16, Corine Karema, Harin Karunajeewa12, Moussa Koné, Bertrand Lell17, Kevin Marsh7, Kevin Marsh10, Mayfong Mayxay18, Mayfong Mayxay19, Clara Menéndez20, Petra F. Mens21, Martin M Meremikwu22, Clarissa Moreira10, Clarissa Moreira7, Ivo Mueller23, Ivo Mueller24, Carolyn Nabasumba, Michael Nambozi, Jean Louis Ndiaye4, Paul N. Newton18, Paul N. Newton10, Thuy Nguyen10, François Nosten2, François Nosten10, Christian Nsanzabana10, Sabah A. Omar25, Jean-Bosco Ouédraogo, Louis K. Penali, Mbaye Pene4, Aung Pyae Phyo2, Patrice Piola26, Ric N. Price27, Ric N. Price10, P. Sasithon2, Philip J. Rosenthal13, Albert Same-Ekobo, Patrick Sawa25, Henk D. F. H. Schallig, Seif Shekalaghe28, Carol Hopkins Sibley29, Jeff Smith, Frank Smithuis15, Anyirékun Fabrice Somé, Kasia Stepniewska10, Ambrose O. Talisuna30, Joel Tarning2, Joel Tarning10, Emiliana Tjitra, Roger Tine4, Halidou Tinto, Neena Valecha31, Michel Van Herp15, Michèle van Vugt, Nicholas J. White10, Nicholas J. White2, Charles J. Woodrow10, William Yavo, Adoke Yeka, Issaka Zongo 
TL;DR: In this paper, the influence of different dosing schedules on Dihydroartemisinin-piperaquine (DP) clinical efficacy was investigated, and a multivariable model was used to identify risk factors for parasite recrudescence.
Abstract: Background:Dihydroartemisinin-piperaquine (DP) is increasingly recommended for antimalarial treatment in many endemic countries; however, concerns have been raised over its potential under dosing in young children. We investigated the influence of different dosing schedules on DP's clinical efficacy.Methods and Findings:A systematic search of the literature was conducted to identify all studies published between 1960 and February 2013, in which patients were enrolled and treated with DP. Principal investigators were approached and invited to share individual patient data with the WorldWide Antimalarial Resistance Network (WWARN). Data were pooled using a standardised methodology. Univariable and multivariable risk factors for parasite recrudescence were identified using a Cox's regression model with shared frailty across the study sites. Twenty-four published and two unpublished studies (n = 7,072 patients) were included in the analysis. After correcting for reinfection by parasite genotyping, Kaplan-Meier survival estimates were 97.7% (95% CI 97.3%-98.1%) at day 42 and 97.2% (95% CI 96.7%-97.7%) at day 63. Overall 28.6% (979/3,429) of children aged 1 to 5 years received a total dose of piperaquine below 48 mg/kg (the lower limit recommended by WHO); this risk was 2.3-2.9-fold greater compared to that in the other age groups and was associated with reduced efficacy at day 63 (94.4% [95% CI 92.6%-96.2%], p<0.001). After adjusting for confounding factors, the mg/kg dose of piperaquine was found to be a significant predictor for recrudescence, the risk increasing by 13% (95% CI 5.0%-21%) for every 5 mg/kg decrease in dose; p = 0.002. In a multivariable model increasing the target minimum total dose of piperaquine in children aged 1 to 5 years old from 48 mg/kg to 59 mg/kg would halve the risk of treatment failure and cure at least 95% of patients; such an increment was not associated with gastrointestinal toxicity in the ten studies in which this could be assessed.Conclusions:DP demonstrates excellent efficacy in a wide range of transmission settings; however, treatment failure is associated with a lower dose of piperaquine, particularly in young children, suggesting potential for further dose optimisation.Please see later in the article for the Editors' Summary.

127 citations


Cited by
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01 Jan 2016
TL;DR: The table of integrals series and products is universally compatible with any devices to read and is available in the book collection an online access to it is set as public so you can get it instantly.
Abstract: Thank you very much for downloading table of integrals series and products. Maybe you have knowledge that, people have look hundreds times for their chosen books like this table of integrals series and products, but end up in harmful downloads. Rather than reading a good book with a cup of coffee in the afternoon, instead they cope with some harmful virus inside their laptop. table of integrals series and products is available in our book collection an online access to it is set as public so you can get it instantly. Our book servers saves in multiple locations, allowing you to get the most less latency time to download any of our books like this one. Merely said, the table of integrals series and products is universally compatible with any devices to read.

4,085 citations

Journal ArticleDOI
TL;DR: Prolonged courses of artemisinin-based combination therapies are currently efficacious in areas where standard 3-day treatments are failing, and the incidence of pretreatment and post-treatment gametocytemia was higher among patients with slow parasite clearance, suggesting greater potential for transmission.
Abstract: BACKGROUND: Artemisinin resistance in Plasmodium falciparum has emerged in Southeast Asia and now poses a threat to the control and elimination of malaria. Mapping the geographic extent of resistance is essential for planning containment and elimination strategies. METHODS: Between May 2011 and April 2013, we enrolled 1241 adults and children with acute, uncomplicated falciparum malaria in an open-label trial at 15 sites in 10 countries (7 in Asia and 3 in Africa). Patients received artesunate, administered orally at a daily dose of either 2 mg per kilogram of body weight per day or 4 mg per kilogram, for 3 days, followed by a standard 3-day course of artemisinin-based combination therapy. Parasite counts in peripheral-blood samples were measured every 6 hours, and the parasite clearance half-lives were determined. RESULTS: The median parasite clearance half-lives ranged from 1.9 hours in the Democratic Republic of Congo to 7.0 hours at the Thailand-Cambodia border. Slowly clearing infections (parasite clearance half-life >5 hours), strongly associated with single point mutations in the "propeller" region of the P. falciparum kelch protein gene on chromosome 13 (kelch13), were detected throughout mainland Southeast Asia from southern Vietnam to central Myanmar. The incidence of pretreatment and post-treatment gametocytemia was higher among patients with slow parasite clearance, suggesting greater potential for transmission. In western Cambodia, where artemisinin-based combination therapies are failing, the 6-day course of antimalarial therapy was associated with a cure rate of 97.7% (95% confidence interval, 90.9 to 99.4) at 42 days. CONCLUSIONS: Artemisinin resistance to P. falciparum, which is now prevalent across mainland Southeast Asia, is associated with mutations in kelch13. Prolonged courses of artemisinin-based combination therapies are currently efficacious in areas where standard 3-day treatments are failing. (Funded by the U.K. Department of International Development and others; ClinicalTrials.gov number, NCT01350856.).

1,777 citations

Journal ArticleDOI
02 Jan 2014-Nature
TL;DR: Strong correlations between the presence of a mutant allele, in vitro parasite survival rates and in vivo parasite clearance rates indicate that K13-propeller mutations are important determinants of artemisinin resistance.
Abstract: Plasmodium falciparum resistance to artemisinin derivatives in southeast Asia threatens malaria control and elimination activities worldwide. To monitor the spread of artemisinin resistance, a molecular marker is urgently needed. Here, using whole-genome sequencing of an artemisinin-resistant parasite line from Africa and clinical parasite isolates from Cambodia, we associate mutations in the PF3D7_1343700 kelch propeller domain ('K13-propeller') with artemisinin resistance in vitro and in vivo. Mutant K13-propeller alleles cluster in Cambodian provinces where resistance is prevalent, and the increasing frequency of a dominant mutant K13-propeller allele correlates with the recent spread of resistance in western Cambodia. Strong correlations between the presence of a mutant allele, in vitro parasite survival rates and in vivo parasite clearance rates indicate that K13-propeller mutations are important determinants of artemisinin resistance. K13-propeller polymorphism constitutes a useful molecular marker for large-scale surveillance efforts to contain artemisinin resistance in the Greater Mekong Subregion and prevent its global spread.

1,639 citations

Journal ArticleDOI
TL;DR: In this Perspective, applications of fluorine in the construction of bioisosteric elements designed to enhance the in vitro and in vivo properties of a molecule are summarized.
Abstract: The electronic properties and relatively small size of fluorine endow it with considerable versatility as a bioisostere and it has found application as a substitute for lone pairs of electrons, the hydrogen atom, and the methyl group while also acting as a functional mimetic of the carbonyl, carbinol, and nitrile moieties. In this context, fluorine substitution can influence the potency, conformation, metabolism, membrane permeability, and P-gp recognition of a molecule and temper inhibition of the hERG channel by basic amines. However, as a consequence of the unique properties of fluorine, it features prominently in the design of higher order structural metaphors that are more esoteric in their conception and which reflect a more sophisticated molecular construction that broadens biological mimesis. In this Perspective, applications of fluorine in the construction of bioisosteric elements designed to enhance the in vitro and in vivo properties of a molecule are summarized.

1,199 citations

Book
01 Jun 2009
TL;DR: The United Nations Children's Fund (UNICEF) as mentioned in this paper was originally created to provide relief for children in countries devastated by the destruction of World War II, and in 1965, it was awarded the Nobel Prize for Peace for its humanitarian efforts.
Abstract: The United Nations Children's Fund, or UNICEF, was originally created to provide relief for children in countries devastated by the destruction of World War II. After 1950, UNICEF turned to focus on general programs for the improvement of children's welfare worldwide, and in 1965, it was awarded the Nobel Prize for Peace for its humanitarian efforts. The organization concentrates on areas in which relatively small expenditures can have a significant impact on the lives of the most disadvantaged children in developing countries, such as the prevention and treatment of disease, child healthcare, malnutrition, illiteracy, and other welfare services.

1,156 citations