179 results on '"Flegg, Jennifer A."'
Search Results
152. MOESM2 of Agent-based models of malaria transmission: a systematic review
- Author
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Smith, Neal, Trauer, James, Gambhir, Manoj, Richards, Jack, Maude, Richard, Keith, Jonathan, and Flegg, Jennifer
- Subjects
parasitic diseases ,3. Good health - Abstract
Additional file 2. Key characteristics of individual-based models of malaria.
153. MOESM5 of Agent-based models of malaria transmission: a systematic review
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Smith, Neal, Trauer, James, Gambhir, Manoj, Richards, Jack, Maude, Richard, Keith, Jonathan, and Flegg, Jennifer
- Subjects
3. Good health - Abstract
Additional file 5. Overview of ensemble and comparative models.
154. MOESM4 of Agent-based models of malaria transmission: a systematic review
- Author
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Smith, Neal, Trauer, James, Gambhir, Manoj, Richards, Jack, Maude, Richard, Keith, Jonathan, and Flegg, Jennifer
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Data_FILES ,3. Good health - Abstract
Additional file 4. Overview of elements of spatial models.
155. MOESM4 of Agent-based models of malaria transmission: a systematic review
- Author
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Smith, Neal, Trauer, James, Gambhir, Manoj, Richards, Jack, Maude, Richard, Keith, Jonathan, and Flegg, Jennifer
- Subjects
Data_FILES ,3. Good health - Abstract
Additional file 4. Overview of elements of spatial models.
156. MOESM2 of Agent-based models of malaria transmission: a systematic review
- Author
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Smith, Neal, Trauer, James, Gambhir, Manoj, Richards, Jack, Maude, Richard, Keith, Jonathan, and Flegg, Jennifer
- Subjects
parasitic diseases ,3. Good health - Abstract
Additional file 2. Key characteristics of individual-based models of malaria.
157. MOESM3 of Agent-based models of malaria transmission: a systematic review
- Author
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Smith, Neal, Trauer, James, Gambhir, Manoj, Richards, Jack, Maude, Richard, Keith, Jonathan, and Flegg, Jennifer
- Subjects
3. Good health - Abstract
Additional file 3. Adapted PRISMA search flow diagram of study selection.
158. MOESM1 of Agent-based models of malaria transmission: a systematic review
- Author
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Smith, Neal, Trauer, James, Gambhir, Manoj, Richards, Jack, Maude, Richard, Keith, Jonathan, and Flegg, Jennifer
- Subjects
Data_FILES ,3. Good health - Abstract
Additional file 1. Systematic review search strategies.
159. MOESM5 of Agent-based models of malaria transmission: a systematic review
- Author
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Smith, Neal, Trauer, James, Gambhir, Manoj, Richards, Jack, Maude, Richard, Keith, Jonathan, and Flegg, Jennifer
- Subjects
3. Good health - Abstract
Additional file 5. Overview of ensemble and comparative models.
160. MOESM3 of Agent-based models of malaria transmission: a systematic review
- Author
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Smith, Neal, Trauer, James, Gambhir, Manoj, Richards, Jack, Maude, Richard, Keith, Jonathan, and Flegg, Jennifer
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3. Good health - Abstract
Additional file 3. Adapted PRISMA search flow diagram of study selection.
161. Estimation of Plasmodium falciparum allele and multi-SNP haplotype and genotype frequencies
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Taylor, Aimee Rebecca, Holmes, Christopher, Guérin, Philippe, and Flegg, Jennifer
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614.5 - Abstract
Malaria kills hundreds of thousands of people each year, yet is entirely curable given prompt treatment. Malaria parasites evolve resistance to antimalarial drugs, hence routine surveillance of antimalarial resistance is vital. The surveillance of parasite genetic markers of resistance provides an economical adjunct to clinical efficacy trials, and has the potential to resolve drug specific resistance ahead of clinical failure. To monitor spatiotemporal changes using genetic markers, frequencies of alleles and/or haplotypes and genotypes spanning multiple single nucleotide polymorphisms (SNPs) are required. However, multiclonal infections complicate frequency estimation, especially in highly endemic regions. With the aim of harnessing the full potential of genetic markers for the surveillance of antimalarial resistance, a statistical model to estimate frequencies is proposed. The model builds upon existing methods (reviewed in chapter 2), without reliance upon experimentally-derived estimates of the sample-wise multiplicities of infection (MOIs). Its ability to generate precise and accurate estimates within a Bayesian framework is documented in chapter 3. In chapter 4, the model is applied to data collected from a cohort of children enrolled in a longitudinal trial in Uganda, generating valuable insight into haplotype frequency trends. In chapter 5, the model is extended to investigate inter-child variability in the aforesaid cohort, revealing a small amount of inter-child variation. In chapter 6, the model is modified to enable the analysis of short-read sequencing data, with application to data from malaria patients in Northern Ghana, providing insight into the extent of within-host diversity and anti-folate resistance in the region. In summary, this thesis documents the development, application, extension and modification of a model designed to estimate population-level frequencies of P. falciparum alleles and multi-SNP haplotypes and genotypes within a Bayesian framework. It is hoped that the model and its proposed framework will provide a practical tool for surveillance of antimalarial resistance, as well as a foundation on which to develop further methods.
- Published
- 2016
162. Cyclin A2 modulates kinetochore--microtubule attachment in meiosis II.
- Author
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Qing-Hua Zhang, Wai Shan Yuen, Adhikari, Deepak, Flegg, Jennifer A., FitzHarris, Greg, Conti, Marco, Sicinski, Piotr, Nabti, Ibtissem, Marangos, Petros, and Carroll, John
- Subjects
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CYCLINS , *KINETOCHORE , *MEIOSIS - Abstract
Cyclin A2 is a crucial mitotic Cdk regulatory partner that coordinates entry into mitosis and is then destroyed in prometaphase within minutes of nuclear envelope breakdown. The role of cyclin A2 in female meiosis and its dynamics during the transition from meiosis I (MI) to meiosis II (MII) remain unclear. We found that cyclin A2 decreases in prometaphase I but recovers after the first meiotic division and persists, uniquely for metaphase, in MII-arrested oocytes. Conditional deletion of cyclin A2 from mouse oocytes has no discernible effect on MI but leads to disrupted MII spindles and increased merotelic attachments. On stimulation of exit from MII, there is a dramatic increase in lagging chromosomes and an inhibition of cytokinesis. These defects are associated with an increase in microtubule stability in MII spindles, suggesting that cyclin A2 mediates the fidelity of MII by maintaining microtubule dynamics during the rapid formation of the MII spindle. [ABSTRACT FROM AUTHOR]
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- 2017
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163. Patient-specific Boolean models of signalling networks guide personalised treatments
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Montagud, Arnau, Béal, Jonas, Tobalina, Luis, Traynard, Pauline, Subramanian, Vigneshwari, Szalai, Bence, Alföldi, Róbert, Puskás, László, Valencia, Alfonso, Barillot, Emmanuel, Saez-Rodriguez, Julio, Calzone, Laurence, Barcelona Supercomputing Center, and Flegg, Jennifer
- Subjects
Male ,Informàtica::Aplicacions de la informàtica::Bioinformàtica [Àrees temàtiques de la UPC] ,Prostate cancer ,General Immunology and Microbiology ,Carcinogenesis ,General Neuroscience ,Boolean models ,Prostatic Neoplasms ,Precision oncology ,General Medicine ,Prostate--Cancer ,Personalized medicine ,General Biochemistry, Genetics and Molecular Biology ,Cancer genes ,Humans ,Personalised treatments ,HSP90 Heat-Shock Proteins ,Precision Medicine ,Càncer ,Signal Transduction - Abstract
Prostate cancer is the second most occurring cancer in men worldwide. To better understand the mechanisms of tumorigenesis and possible treatment responses, we developed a mathematical model of prostate cancer which considers the major signalling pathways known to be deregulated. We personalised this Boolean model to molecular data to reflect the heterogeneity and specific response to perturbations of cancer patients. 488 prostate samples were used to build patient-specific models and compared to available clinical data. Additionally, eight prostate cell-line-specific models were built to validate our approach with dose-response data of several drugs. The effects of single and combined drugs were tested in these models under different growth conditions. We identified 15 actionable points of interventions in one cell-line-specific model whose inactivation hinders tumorigenesis. To validate these results, we tested nine small molecule inhibitors of five of those putative targets and found a dose-dependent effect on four of them, notably those targeting HSP90 and PI3K. These results highlight the predictive power of our personalised Boolean models and illustrate how they can be used for precision oncology. This work has been partially supported by the European Commission under the PrECISE project (H2020-PHC-668858), the INFORE project (H2020-ICT-825070) and the PerMedCoE (H2020-ICT-951773) Peer Reviewed "Article signat per 12 autors/es: Arnau Montagud, Jonas Béal, Luis Tobalina, Pauline Traynard, Vigneshwari Subramanian, Bence Szalai, Róbert Alföldi, László Puskás, Alfonso Valencia, Emmanuel Barillot, Julio Saez-Rodriguez, Laurence Calzone"
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- 2022
164. Synergistic interventions to control COVID-19: Mass testing and isolation mitigates reliance on distancing
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Tiffany L. Bogich, Cécile Viboud, Chris P. Jewell, James D. Nichols, Rebecca K. Borchering, Michael J. Tildesley, Emily Howerton, Michael C. Runge, Ottar N. Bjørnstad, Matthew J. Ferrari, William J. M. Probert, Katriona Shea, and Flegg, Jennifer A.
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medicine.medical_specialty ,Isolation (health care) ,QH301-705.5 ,Cost-Benefit Analysis ,Population ,Physical Distancing ,Psychological intervention ,Models, Biological ,Cellular and Molecular Neuroscience ,COVID-19 Testing ,Pandemic ,Genetics ,medicine ,Humans ,Computer Simulation ,Biology (General) ,education ,Molecular Biology ,Pandemics ,Ecology, Evolution, Behavior and Systematics ,Preventive healthcare ,education.field_of_study ,Ecology ,Cost–benefit analysis ,SARS-CoV-2 ,Public health ,COVID-19 ,Computational Biology ,Test (assessment) ,Computational Theory and Mathematics ,Risk analysis (engineering) ,Modeling and Simulation ,Communicable Disease Control ,Business ,RA ,Research Article - Abstract
Stay-at-home orders and shutdowns of non-essential businesses are powerful, but socially costly, tools to control the pandemic spread of SARS-CoV-2. Mass testing strategies, which rely on widely administered frequent and rapid diagnostics to identify and isolate infected individuals, could be a potentially less disruptive management strategy, particularly where vaccine access is limited. In this paper, we assess the extent to which mass testing and isolation strategies can reduce reliance on socially costly non-pharmaceutical interventions, such as distancing and shutdowns. We develop a multi-compartmental model of SARS-CoV-2 transmission incorporating both preventative non-pharmaceutical interventions (NPIs) and testing and isolation to evaluate their combined effect on public health outcomes. Our model is designed to be a policy-guiding tool that captures important realities of the testing system, including constraints on test administration and non-random testing allocation. We show how strategic changes in the characteristics of the testing system, including test administration, test delays, and test sensitivity, can reduce reliance on preventative NPIs without compromising public health outcomes in the future. The lowest NPI levels are possible only when many tests are administered and test delays are short, given limited immunity in the population. Reducing reliance on NPIs is highly dependent on the ability of a testing program to identify and isolate unreported, asymptomatic infections. Changes in NPIs, including the intensity of lockdowns and stay at home orders, should be coordinated with increases in testing to ensure epidemic control; otherwise small additional lifting of these NPIs can lead to dramatic increases in infections, hospitalizations and deaths. Importantly, our results can be used to guide ramp-up of testing capacity in outbreak settings, allow for the flexible design of combined interventions based on social context, and inform future cost-benefit analyses to identify efficient pandemic management strategies., Author summary The global spread of SARS-CoV-2 and the strategies used to manage it have come at significant societal costs. We analyze how mixed control strategies, which utilize interventions that prevent new infections from occurring (e.g., distancing or shut-downs) and others that actively search for and isolate existing infections (here, mass testing), can achieve improved public health outcomes while avoiding severe socio-economic burdens. Our results suggest that increasing testing capacity, including the number of tests available and the speed at which test results are provided, can reduce reliance on costly preventative interventions. Such reduction is possible with more isolation of active infections, including those without reported symptoms. However, failing to maintain preventative interventions without sufficient testing capacity can lead to large increases in infection burdens. By defining the combined effect of these interventions through mathematical models, this study provides insight into relaxation of distancing measures, and lays the groundwork for future public health economics analyses on the cost-effectiveness of combined management strategies.
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- 2021
165. Evaluation of a Bayesian hierarchical pharmacokinetic-pharmacodynamic model for predicting parasitological outcomes in Phase 2 studies of new antimalarial drugs.
- Author
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Tully MK, Dini S, Flegg JA, McCarthy JS, Price DJ, and Simpson JA
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- Humans, Malaria, Falciparum drug therapy, Malaria, Falciparum parasitology, Plasmodium falciparum drug effects, Adult, Parasitemia drug therapy, Parasitemia parasitology, Malaria drug therapy, Male, Computer Simulation, Female, Antimalarials pharmacokinetics, Antimalarials therapeutic use, Antimalarials pharmacology, Bayes Theorem
- Abstract
The rise of multidrug-resistant malaria requires accelerated development of novel antimalarial drugs. Pharmacokinetic-pharmacodynamic (PK-PD) models relate blood antimalarial drug concentrations with the parasite-time profile to inform dosing regimens. We performed a simulation study to assess the utility of a Bayesian hierarchical mechanistic PK-PD model for predicting parasite-time profiles for a Phase 2 study of a new antimalarial drug, cipargamin. We simulated cipargamin concentration- and malaria parasite-profiles based on a Phase 2 study of eight volunteers who received cipargamin 7 days after inoculation with malaria parasites. The cipargamin profiles were generated from a two-compartment PK model and parasite profiles from a previously published biologically informed PD model. One thousand PK-PD data sets of eight patients were simulated, following the sampling intervals of the Phase 2 study. The mechanistic PK-PD model was incorporated in a Bayesian hierarchical framework, and the parameters were estimated. Population PK model parameters describing absorption, distribution, and clearance were estimated with minimal bias (mean relative bias ranged from 1.7% to 8.4%). The PD model was fitted to the parasitaemia profiles in each simulated data set using the estimated PK parameters. Posterior predictive checks demonstrate that our PK-PD model adequately captures the simulated PD profiles. The bias of the estimated population average PD parameters was low-moderate in magnitude. This simulation study demonstrates the viability of our PK-PD model to predict parasitological outcomes in Phase 2 volunteer infection studies. This work will inform the dose-effect relationship of cipargamin, guiding decisions on dosing regimens to be evaluated in Phase 3 trials., Competing Interests: The authors declare no conflict of interest.
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- 2024
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166. Mathematical assessment of the role of intervention programs for malaria control.
- Author
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Korsah MA, Johnston ST, Tiedje KE, Day KP, Flegg JA, and Walker CR
- Abstract
Malaria remains a global health problem despite the many attempts to control and eradicate it. There is an urgent need to understand the current transmission dynamics of malaria and to determine the interventions necessary to control malaria. In this paper, we seek to develop a fit-for-purpose mathematical model to assess the interventions needed to control malaria in an endemic setting. To achieve this, we formulate a malaria transmission model to analyse the spread of malaria in the presence of interventions. A sensitivity analysis of the model is performed to determine the relative impact of the model parameters on disease transmission. We explore how existing variations in the recruitment and management of intervention strategies affect malaria transmission. Results obtained from the study imply that the discontinuation of existing interventions has a significant effect on malaria prevalence. Thus, the maintenance of interventions is imperative for malaria elimination and eradication. In a scenario study aimed at assessing the impact of long-lasting insecticidal nets (LLINs), indoor residual spraying (IRS), and localized individual measures, our findings indicate that increased LLINs utilization and extended IRS coverage (with longer-lasting insecticides) cause a more pronounced reduction in symptomatic malaria prevalence compared to a reduced LLINs utilization and shorter IRS coverage. Additionally, our study demonstrates the impact of localized preventive measures in mitigating the spread of malaria when compared to the absence of interventions.
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- 2023
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167. Updating estimates of Plasmodium knowlesi malaria risk in response to changing land use patterns across Southeast Asia.
- Author
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Tobin RJ, Harrison LE, Tully MK, Lubis IND, Noviyanti R, Anstey NM, Rajahram GS, Grigg MJ, Flegg JA, Price DJ, and Shearer FM
- Abstract
Background: Plasmodium knowlesi is a zoonotic parasite that causes malaria in humans. The pathogen has a natural host reservoir in certain macaque species and is transmitted to humans via mosquitoes of the Anopheles Leucosphyrus Group. The risk of human P. knowlesi infection varies across Southeast Asia and is dependent upon environmental factors. Understanding this geographic variation in risk is important both for enabling appropriate diagnosis and treatment of the disease and for improving the planning and evaluation of malaria elimination. However, the data available on P. knowlesi occurrence are biased towards regions with greater surveillance and sampling effort. Predicting the spatial variation in risk of P. knowlesi malaria requires methods that can both incorporate environmental risk factors and account for spatial bias in detection., Methods & Results: We extend and apply an environmental niche modelling framework as implemented by a previous mapping study of P. knowlesi transmission risk which included data up to 2015. We reviewed the literature from October 2015 through to March 2020 and identified 264 new records of P. knowlesi , with a total of 524 occurrences included in the current study following consolidation with the 2015 study. The modelling framework used in the 2015 study was extended, with changes including the addition of new covariates to capture the effect of deforestation and urbanisation on P. knowlesi transmission., Discussion: Our map of P. knowlesi relative transmission suitability estimates that the risk posed by the pathogen is highest in Malaysia and Indonesia, with localised areas of high risk also predicted in the Greater Mekong Subregion, The Philippines and Northeast India. These results highlight areas of priority for P. knowlesi surveillance and prospective sampling to address the challenge the disease poses to malaria elimination planning.
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- 2023
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168. Spatiotemporal spread of Plasmodium falciparum mutations for resistance to sulfadoxine-pyrimethamine across Africa, 1990-2020.
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Flegg JA, Humphreys GS, Montanez B, Strickland T, Jacome-Meza ZJ, Barnes KI, Raman J, Guerin PJ, Hopkins Sibley C, and Dahlström Otienoburu S
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- Bayes Theorem, Drug Combinations, Drug Resistance genetics, Female, Humans, Mutation, Plasmodium falciparum genetics, Pregnancy, Pyrimethamine pharmacology, Pyrimethamine therapeutic use, South Africa, Sulfadoxine, Tetrahydrofolate Dehydrogenase genetics, Antimalarials pharmacology, Antimalarials therapeutic use, Malaria drug therapy, Malaria, Falciparum drug therapy, Malaria, Falciparum epidemiology, Malaria, Falciparum prevention & control
- Abstract
Background: Sulfadoxine-pyrimethamine (SP) is recommended in Africa in several antimalarial preventive regimens including Intermittent Preventive Treatment in pregnant women (IPTp), Intermittent Preventive Treatment in infants (IPTi) and Seasonal Malaria Chemoprevention (SMC). The effectiveness of SP-based preventive treatments are threatened in areas where Plasmodium falciparum resistance to SP is high. The prevalence of mutations in the dihydropteroate synthase gene (pfdhps) can be used to monitor SP effectiveness. IPTi-SP is recommended only in areas where the prevalence of the pfdhps540E mutation is below 50%. It has also been suggested that IPTp-SP does not have a protective effect in areas where the pfdhps581G mutation, exceeds 10%. However, pfdhps mutation prevalence data in Africa are extremely heterogenous and scattered, with data completely missing from many areas., Methods and Findings: The WWARN SP Molecular Surveyor database was designed to summarize dihydrofolate reductase (pfdhfr) and pfdhps gene mutation prevalence data. In this paper, pfdhps mutation prevalence data was used to generate continuous spatiotemporal surface maps of the estimated prevalence of the SP resistance markers pfdhps437G, pfdhps540E, and pfdhps581G in Africa from 1990 to 2020 using a geostatistical model, with a Bayesian inference framework to estimate uncertainty. The maps of estimated prevalence show an expansion of the pfdhps437G mutations across the entire continent over the last three decades. The pfdhps540E mutation emerged from limited foci in East Africa to currently exceeding 50% estimated prevalence in most of East and South East Africa. pfdhps540E distribution is expanding at low or moderate prevalence in central Africa and a predicted focus in West Africa. Although the pfdhps581G mutation spread from one focus in East Africa in 2000, to exceeding 10% estimated prevalence in several foci in 2010, the predicted distribution of the marker did not expand in 2020, however our analysis indicated high uncertainty in areas where pfdhps581G is present. Uncertainty was higher in spatial regions where the prevalence of a marker is intermediate or where prevalence is changing over time., Conclusions: The WWARN SP Molecular Surveyor database and a set of continuous spatiotemporal surface maps were built to provide users with standardized, current information on resistance marker distribution and prevalence estimates. According to the maps, the high prevalence of pfdhps540E mutation was to date restricted to East and South East Africa, which is reassuring for continued use of IPTi and SMC in West Africa, but continuous monitoring is needed as the pfdhps540E distribution is expanding. Several foci where pfdhps581G prevalence exceeded 10% were identified. More data on the pfdhps581G distribution in these areas needs to be collected to guide IPTp-SP recommendations. Prevalence and uncertainty maps can be utilized together to strategically identify sites where increased surveillance can be most informative. This study combines a molecular marker database and predictive modelling to highlight areas of concern, which can be used to support decisions in public health, highlight knowledge gaps in certain regions, and guide future research., Competing Interests: The authors have declared that no competing interests exist.
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- 2022
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169. COVID-19 morbidity in Afghanistan: a nationwide, population-based seroepidemiological study.
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Saeedzai SA, Sahak MN, Arifi F, Abdelkreem Aly E, Gurp MV, White LJ, Chen S, Barakat A, Azim G, Rasoly B, Safi S, Flegg JA, Ahmed N, Ahadi MJ, Achakzai NM, and AbouZeid A
- Subjects
- Adult, Afghanistan epidemiology, Antibodies, Viral, Cross-Sectional Studies, Humans, Prevalence, SARS-CoV-2, Seroepidemiologic Studies, Young Adult, COVID-19 epidemiology
- Abstract
Objective: The primary objectives were to determine the magnitude of COVID-19 infections in the general population and age-specific cumulative incidence, as determined by seropositivity and clinical symptoms of COVID-19, and to determine the magnitude of asymptomatic or subclinical infections., Design, Setting and Participants: We describe a population-based, cross-sectional, age-stratified seroepidemiological study conducted throughout Afghanistan during June/July 2020. Participants were interviewed to complete a questionnaire, and rapid diagnostic tests were used to test for SARS-CoV-2 antibodies. This national study was conducted in eight regions of Afghanistan plus Kabul province, considered a separate region. The total sample size was 9514, and the number of participants required in each region was estimated proportionally to the population size of each region. For each region, 31-44 enumeration areas (EAs) were randomly selected, and a total of 360 clusters and 16 households per EA were selected using random sampling. To adjust the seroprevalence for test sensitivity and specificity, and seroreversion, Bernoulli's model methodology was used to infer the population exposure in Afghanistan., Outcome Measures: The main outcome was to determine the prevalence of current or past COVID-19 infection., Results: The survey revealed that, to July 2020, around 10 million people in Afghanistan (31.5% of the population) had either current or previous COVID-19 infection. By age group, COVID-19 seroprevalence was reported to be 35.1% and 25.3% among participants aged ≥18 and 5-17 years, respectively. This implies that most of the population remained at risk of infection. However, a large proportion of the population had been infected in some localities, for example, Kabul province, where more than half of the population had been infected with COVID-19., Conclusion: As most of the population remained at risk of infection at the time of the study, any lifting of public health and social measures needed to be considered gradually., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2022
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170. A Multiscale Mathematical Model of Plasmodium Vivax Transmission.
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Anwar MN, Hickson RI, Mehra S, McCaw JM, and Flegg JA
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- Animals, Humans, Mathematical Concepts, Models, Biological, Models, Theoretical, Plasmodium vivax, Anopheles, Malaria, Malaria, Vivax
- Abstract
Malaria is caused by Plasmodium parasites which are transmitted to humans by the bite of an infected Anopheles mosquito. Plasmodium vivax is distinct from other malaria species in its ability to remain dormant in the liver (as hypnozoites) and activate later to cause further infections (referred to as relapses). Mathematical models to describe the transmission dynamics of P. vivax have been developed, but most of them fail to capture realistic dynamics of hypnozoites. Models that do capture the complexity tend to involve many governing equations, making them difficult to extend to incorporate other important factors for P. vivax, such as treatment status, age and pregnancy. In this paper, we have developed a multiscale model (a system of integro-differential equations) that involves a minimal set of equations at the population scale, with an embedded within-host model that can capture the dynamics of the hypnozoite reservoir. In this way, we can gain key insights into dynamics of P. vivax transmission with a minimum number of equations at the population scale, making this framework readily scalable to incorporate more complexity. We performed a sensitivity analysis of our multiscale model over key parameters and found that prevalence of P. vivax blood-stage infection increases with both bite rate and number of mosquitoes but decreases with hypnozoite death rate. Since our mathematical model captures the complex dynamics of P. vivax and the hypnozoite reservoir, it has the potential to become a key tool to inform elimination strategies for P. vivax., (© 2022. The Author(s).)
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- 2022
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171. Detection and identification of cis-regulatory elements using change-point and classification algorithms.
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Maderazo D, Flegg JA, Algama M, Ramialison M, and Keith J
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- Bayes Theorem, Binding Sites, Genome, Human, Humans, Algorithms, Regulatory Sequences, Nucleic Acid genetics
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Background: Transcriptional regulation is primarily mediated by the binding of factors to non-coding regions in DNA. Identification of these binding regions enhances understanding of tissue formation and potentially facilitates the development of gene therapies. However, successful identification of binding regions is made difficult by the lack of a universal biological code for their characterisation., Results: We extend an alignment-based method, changept, and identify clusters of biological significance, through ontology and de novo motif analysis. Further, we apply a Bayesian method to estimate and combine binary classifiers on the clusters we identify to produce a better performing composite., Conclusions: The analysis we describe provides a computational method for identification of conserved binding sites in the human genome and facilitates an alternative interrogation of combinations of existing data sets with alignment data., (© 2022. The Author(s).)
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- 2022
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172. Antibody Dynamics for Plasmodium vivax Malaria: A Mathematical Model.
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Mehra S, McCaw JM, Flegg MB, Taylor PG, and Flegg JA
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- Humans, Antibodies, Protozoan blood, Malaria, Vivax epidemiology, Malaria, Vivax immunology, Malaria, Vivax transmission, Models, Biological
- Abstract
Malaria is a mosquito-borne disease that, despite intensive control and mitigation initiatives, continues to pose an enormous public health burden. Plasmodium vivax is one of the principal causes of malaria in humans. Antibodies, which play a fundamental role in the host response to P. vivax, are acquired through exposure to the parasite. Here, we introduce a stochastic, within-host model of antibody responses to P. vivax for an individual in a general transmission setting. We begin by developing an epidemiological framework accounting for P. vivax infections resulting from new mosquito bites (primary infections), as well as the activation of dormant-liver stages known as hypnozoites (relapses). By constructing an infinite server queue, we obtain analytic results for the distribution of relapses in a general transmission setting. We then consider a simple model of antibody kinetics, whereby antibodies are boosted with each infection, but are subject to decay over time. By embedding this model for antibody kinetics in the epidemiological framework using a generalised shot noise process, we derive analytic expressions governing the distribution of antibody levels for a single individual in a general transmission setting. Our work provides a means to explore exposure-dependent antibody dynamics for P. vivax, with the potential to address key questions in the context of serological surveillance and acquired immunity.
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- 2021
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173. Influencing public health policy with data-informed mathematical models of infectious diseases: Recent developments and new challenges.
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Alahmadi A, Belet S, Black A, Cromer D, Flegg JA, House T, Jayasundara P, Keith JM, McCaw JM, Moss R, Ross JV, Shearer FM, Tun STT, Walker CR, White L, Whyte JM, Yan AWC, and Zarebski AE
- Subjects
- Bayes Theorem, Humans, Models, Biological, Communicable Diseases epidemiology, Health Policy, Models, Theoretical, Public Health statistics & numerical data
- Abstract
Modern data and computational resources, coupled with algorithmic and theoretical advances to exploit these, allow disease dynamic models to be parameterised with increasing detail and accuracy. While this enhances models' usefulness in prediction and policy, major challenges remain. In particular, lack of identifiability of a model's parameters may limit the usefulness of the model. While lack of parameter identifiability may be resolved through incorporation into an inference procedure of prior knowledge, formulating such knowledge is often difficult. Furthermore, there are practical challenges associated with acquiring data of sufficient quantity and quality. Here, we discuss recent progress on these issues., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)
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- 2020
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174. An Activation-Clearance Model for Plasmodium vivax Malaria.
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Mehra S, McCaw JM, Flegg MB, Taylor PG, and Flegg JA
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- Animals, Anopheles parasitology, Carrier State parasitology, Computer Simulation, Disease Reservoirs parasitology, Humans, Insect Bites and Stings parasitology, Kinetics, Liver parasitology, Malaria, Vivax epidemiology, Malaria, Vivax transmission, Markov Chains, Mathematical Concepts, Probability, Recurrence, Stochastic Processes, Malaria, Vivax parasitology, Models, Biological, Plasmodium vivax pathogenicity
- Abstract
Malaria is an infectious disease with an immense global health burden. Plasmodium vivax is the most geographically widespread species of malaria. Relapsing infections, caused by the activation of liver-stage parasites known as hypnozoites, are a critical feature of the epidemiology of Plasmodium vivax. Hypnozoites remain dormant in the liver for weeks or months after inoculation, but cause relapsing infections upon activation. Here, we introduce a dynamic probability model of the activation-clearance process governing both potential relapses and the size of the hypnozoite reservoir. We begin by modelling activation-clearance dynamics for a single hypnozoite using a continuous-time Markov chain. We then extend our analysis to consider activation-clearance dynamics for a single mosquito bite, which can simultaneously establish multiple hypnozoites, under the assumption of independent hypnozoite behaviour. We derive analytic expressions for the time to first relapse and the time to hypnozoite clearance for mosquito bites establishing variable numbers of hypnozoites, both of which are quantities of epidemiological significance. Our results extend those in the literature, which were limited due to an assumption of collective dormancy. Our within-host model can be embedded readily in multiscale models and epidemiological frameworks, with analytic solutions increasing the tractability of statistical inference and analysis. Our work therefore provides a foundation for further work on immune development and epidemiological-scale analysis, both of which are important for achieving the goal of malaria elimination.
- Published
- 2020
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175. A Current Perspective on Wound Healing and Tumour-Induced Angiogenesis.
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Flegg JA, Menon SN, Byrne HM, and McElwain DLS
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- Animals, Biomechanical Phenomena, Computer Simulation, Humans, Mathematical Concepts, Oxygen physiology, Stochastic Processes, Models, Biological, Neoplasms blood supply, Neovascularization, Pathologic, Neovascularization, Physiologic, Wound Healing physiology
- Abstract
Angiogenesis, or capillary growth from pre-existing vasculature, is an essential component of several physiological processes, both vital and pathological. These include dermal wound healing and tumour growth that together pose some of the most significant challenges to healthcare systems worldwide. Over the last few decades, mathematical modelling has proven to be a valuable tool for unravelling the complex network of interactions that underlie such processes. Moreover, theoretical frameworks that describe some of the mechanical and chemical aspects of angiogenesis inherent in wound healing and tumour growth have revealed intriguing similarities between the two processes. In this review, we highlight some of the significant contributions made by mathematical models of tumour-induced and wound healing angiogenesis and illustrate how advances in each field have been made using insights from the other. We also detail some open problems that could be addressed through a combination of theoretical and experimental approaches.
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- 2020
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176. Agent-based models of malaria transmission: a systematic review.
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Smith NR, Trauer JM, Gambhir M, Richards JS, Maude RJ, Keith JM, and Flegg JA
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- Animals, Humans, Disease Transmission, Infectious, Host-Parasite Interactions, Malaria transmission, Models, Statistical, Mosquito Vectors physiology
- Abstract
Background: Much of the extensive research regarding transmission of malaria is underpinned by mathematical modelling. Compartmental models, which focus on interactions and transitions between population strata, have been a mainstay of such modelling for more than a century. However, modellers are increasingly adopting agent-based approaches, which model hosts, vectors and/or their interactions on an individual level. One reason for the increasing popularity of such models is their potential to provide enhanced realism by allowing system-level behaviours to emerge as a consequence of accumulated individual-level interactions, as occurs in real populations., Methods: A systematic review of 90 articles published between 1998 and May 2018 was performed, characterizing agent-based models (ABMs) relevant to malaria transmission. The review provides an overview of approaches used to date, determines the advantages of these approaches, and proposes ideas for progressing the field., Results: The rationale for ABM use over other modelling approaches centres around three points: the need to accurately represent increased stochasticity in low-transmission settings; the benefits of high-resolution spatial simulations; and heterogeneities in drug and vaccine efficacies due to individual patient characteristics. The success of these approaches provides avenues for further exploration of agent-based techniques for modelling malaria transmission. Potential extensions include varying elimination strategies across spatial landscapes, extending the size of spatial models, incorporating human movement dynamics, and developing increasingly comprehensive parameter estimation and optimization techniques., Conclusion: Collectively, the literature covers an extensive array of topics, including the full spectrum of transmission and intervention regimes. Bringing these elements together under a common framework may enhance knowledge of, and guide policies towards, malaria elimination. However, because of the diversity of available models, endorsing a standardized approach to ABM implementation may not be possible. Instead it is recommended that model frameworks be contextually appropriate and sufficiently described. One key recommendation is to develop enhanced parameter estimation and optimization techniques. Extensions of current techniques will provide the robust results required to enhance current elimination efforts.
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- 2018
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177. Baseline data of parasite clearance in patients with falciparum malaria treated with an artemisinin derivative: an individual patient data meta-analysis.
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Abdulla S, Ashley EA, Bassat Q, Bethell D, Björkman A, Borrmann S, D'Alessandro U, Dahal P, Day NP, Diakite M, Djimde AA, Dondorp AM, Duong S, Edstein MD, Fairhurst RM, Faiz MA, Falade C, Flegg JA, Fogg C, Gonzalez R, Greenwood B, Guérin PJ, Guthmann JP, Hamed K, Hien TT, Htut Y, Juma E, Lim P, Mårtensson A, Mayxay M, Mokuolu OA, Moreira C, Newton P, Noedl H, Nosten F, Ogutu BR, Onyamboko MA, Owusu-Agyei S, Phyo AP, Premji Z, Price RN, Pukrittayakamee S, Ramharter M, Sagara I, Se Y, Suon S, Stepniewska K, Ward SA, White NJ, and Winstanley PA
- Subjects
- Adolescent, Adult, Aged, Animals, Child, Child, Preschool, Clinical Trials as Topic, Drug Resistance, Female, Humans, Infant, Male, Middle Aged, Plasmodium falciparum drug effects, Young Adult, Antimalarials administration & dosage, Artemisinins administration & dosage, Blood parasitology, Malaria, Falciparum drug therapy, Parasitemia drug therapy, Plasmodium falciparum isolation & purification
- Abstract
Background: Artemisinin resistance in Plasmodium falciparum manifests as slow parasite clearance but this measure is also influenced by host immunity, initial parasite biomass and partner drug efficacy. This study collated data from clinical trials of artemisinin derivatives in falciparum malaria with frequent parasite counts to provide reference parasite clearance estimates stratified by location, treatment and time, to examine host factors affecting parasite clearance, and to assess the relationships between parasite clearance and risk of recrudescence during follow-up., Methods: Data from 24 studies, conducted from 1996 to 2013, with frequent parasite counts were pooled. Parasite clearance half-life (PC1/2) was estimated using the WWARN Parasite Clearance Estimator. Random effects regression models accounting for study and site heterogeneity were used to explore factors affecting PC1/2 and risk of recrudescence within areas with reported delayed parasite clearance (western Cambodia, western Thailand after 2000, southern Vietnam, southern Myanmar) and in all other areas where parasite populations are artemisinin sensitive., Results: PC1/2 was estimated in 6975 patients, 3288 of whom also had treatment outcomes evaluate d during 28-63 days follow-up, with 93 (2.8 %) PCR-confirmed recrudescences. In areas with artemisinin-sensitive parasites, the median PC1/2 following three-day artesunate treatment (4 mg/kg/day) ranged from 1.8 to 3.0 h and the proportion of patients with PC1/2 >5 h from 0 to 10 %. Artesunate doses of 4 mg/kg/day decreased PC1/2 by 8.1 % (95 % CI 3.2-12.6) compared to 2 mg/kg/day, except in populations with delayed parasite clearance. PC1/2 was longer in children and in patients with fever or anaemia at enrolment. Long PC1/2 (HR = 2.91, 95 % CI 1.95-4.34 for twofold increase, p < 0.001) and high initial parasitaemia (HR = 2.23, 95 % CI 1.44-3.45 for tenfold increase, p < 0.001) were associated independently with an increased risk of recrudescence. In western Cambodia, the region with the highest prevalence of artemisinin resistance, there was no evidence for increasing PC1/2 since 2007., Conclusions: Several factors affect PC1/2. As substantial heterogeneity in parasite clearance exists between locations, early detection of artemisinin resistance requires reference PC1/2 data. Studies with frequent parasite count measurements to characterize PC1/2 should be encouraged. In western Cambodia, where PC1/2 values are longest, there is no evidence for recent emergence of higher levels of artemisinin resistance.
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- 2015
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178. Bayesian hierarchical regression on clearance rates in the presence of "lag" and "tail" phases with an application to malaria parasites.
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Fogarty CB, Fay MP, Flegg JA, Stepniewska K, Fairhurst RM, and Small DS
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- Bias, Biometry methods, Computer Simulation, Data Interpretation, Statistical, Humans, Incidence, Linear Models, Malaria, Falciparum diagnosis, Parasite Load statistics & numerical data, Reproducibility of Results, Risk Assessment methods, Sensitivity and Specificity, Bayes Theorem, Malaria, Falciparum epidemiology, Malaria, Falciparum parasitology, Parasite Load methods, Plasmodium falciparum isolation & purification, Regression Analysis
- Abstract
We present a principled technique for estimating the effect of covariates on malaria parasite clearance rates in the presence of "lag" and "tail" phases through the use of a Bayesian hierarchical linear model. The hierarchical approach enables us to appropriately incorporate the uncertainty in both estimating clearance rates in patients and assessing the potential impact of covariates on these rates into the posterior intervals generated for the parameters associated with each covariate. Furthermore, it permits us to incorporate information about individuals for whom there exists only one observation time before censoring, which alleviates a systematic bias affecting inference when these individuals are excluded. We use a changepoint model to account for both lag and tail phases, and hence base our estimation of the parasite clearance rate only on observations within the decay phase. The Bayesian approach allows us to treat the delineation between lag, decay, and tail phases within an individual's clearance profile as themselves being random variables, thus taking into account the additional uncertainty of boundaries between phases. We compare our method to existing methodology used in the antimalarial research community through a simulation study and show that it possesses desirable frequentist properties for conducting inference. We use our methodology to measure the impact of several covariates on Plasmodium falciparum clearance rate data collected in 2009 and 2010. Though our method was developed with this application in mind, it can be easily applied to any biological system exhibiting these hindrances to estimation., (© 2015, The International Biometric Society.)
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- 2015
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179. The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria: a meta-analysis of individual patient data.
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Adjuik MA, Allan R, Anvikar AR, Ashley EA, Ba MS, Barennes H, Barnes KI, Bassat Q, Baudin E, Björkman A, Bompart F, Bonnet M, Borrmann S, Brasseur P, Bukirwa H, Checchi F, Cot M, Dahal P, D'Alessandro U, Deloron P, Desai M, Diap G, Djimde AA, Dorsey G, Doumbo OK, Espié E, Etard JF, Fanello CI, Faucher JF, Faye B, Flegg JA, Gaye O, Gething PW, González R, Grandesso F, Guerin PJ, Guthmann JP, Hamour S, Hasugian AR, Hay SI, Humphreys GS, Jullien V, Juma E, Kamya MR, Karema C, Kiechel JR, Kremsner PG, Krishna S, Lameyre V, Ibrahim LM, Lee SJ, Lell B, Mårtensson A, Massougbodji A, Menan H, Ménard D, Menéndez C, Meremikwu M, Moreira C, Nabasumba C, Nambozi M, Ndiaye JL, Nikiema F, Nsanzabana C, Ntoumi F, Ogutu BR, Olliaro P, Osorio L, Ouédraogo JB, Penali LK, Pene M, Pinoges L, Piola P, Price RN, Roper C, Rosenthal PJ, Rwagacondo CE, Same-Ekobo A, Schramm B, Seck A, Sharma B, Sibley CH, Sinou V, Sirima SB, Smith JJ, Smithuis F, Somé FA, Sow D, Staedke SG, Stepniewska K, Swarthout TD, Sylla K, Talisuna AO, Tarning J, Taylor WR, Temu EA, Thwing JI, Tjitra E, Tine RC, Tinto H, Vaillant MT, Valecha N, Van den Broek I, White NJ, Yeka A, and Zongo I
- Subjects
- Africa, Dose-Response Relationship, Drug, Drug Combinations, Female, Humans, Male, Middle Aged, Recurrence, Risk Factors, Treatment Outcome, Amodiaquine administration & dosage, Antimalarials administration & dosage, Artemisinins administration & dosage, Malaria, Falciparum drug therapy
- Abstract
Background: Artesunate-amodiaquine (AS-AQ) is one of the most widely used artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum malaria in Africa. We investigated the impact of different dosing strategies on the efficacy of this combination for the treatment of falciparum malaria., Methods: Individual patient data from AS-AQ clinical trials were pooled using the WorldWide Antimalarial Resistance Network (WWARN) standardised methodology. Risk factors for treatment failure were identified using a Cox regression model with shared frailty across study sites., Results: Forty-three studies representing 9,106 treatments from 1999-2012 were included in the analysis; 4,138 (45.4%) treatments were with a fixed dose combination with an AQ target dose of 30 mg/kg (FDC), 1,293 (14.2%) with a non-fixed dose combination with an AQ target dose of 25 mg/kg (loose NFDC-25), 2,418 (26.6%) with a non-fixed dose combination with an AQ target dose of 30 mg/kg (loose NFDC-30), and the remaining 1,257 (13.8%) with a co-blistered non-fixed dose combination with an AQ target dose of 30 mg/kg (co-blistered NFDC). The median dose of AQ administered was 32.1 mg/kg [IQR: 25.9-38.2], the highest dose being administered to patients treated with co-blistered NFDC (median = 35.3 mg/kg [IQR: 30.6-43.7]) and the lowest to those treated with loose NFDC-25 (median = 25.0 mg/kg [IQR: 22.7-25.0]). Patients treated with FDC received a median dose of 32.4 mg/kg [IQR: 27-39.0]. After adjusting for reinfections, the corrected antimalarial efficacy on day 28 after treatment was similar for co-blistered NFDC (97.9% [95% confidence interval (CI): 97.0-98.8%]) and FDC (98.1% [95% CI: 97.6%-98.5%]; P = 0.799), but significantly lower for the loose NFDC-25 (93.4% [95% CI: 91.9%-94.9%]), and loose NFDC-30 (95.0% [95% CI: 94.1%-95.9%]) (P < 0.001 for all comparisons). After controlling for age, AQ dose, baseline parasitemia and region; treatment with loose NFDC-25 was associated with a 3.5-fold greater risk of recrudescence by day 28 (adjusted hazard ratio, AHR = 3.51 [95% CI: 2.02-6.12], P < 0.001) compared to FDC, and treatment with loose NFDC-30 was associated with a higher risk of recrudescence at only three sites., Conclusions: There was substantial variation in the total dose of amodiaquine administered in different AS-AQ combination regimens. Fixed dose AS-AQ combinations ensure optimal dosing and provide higher antimalarial treatment efficacy than the loose individual tablets in all age categories.
- Published
- 2015
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