ORCID Profile
0000-0002-4638-536X
Current Organisation
Menzies School of Health Research
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Publisher: Elsevier BV
Date: 10-2008
Publisher: Springer Science and Business Media LLC
Date: 15-08-2017
Publisher: Public Library of Science (PLoS)
Date: 12-10-2020
Publisher: Public Library of Science (PLoS)
Date: 16-05-2017
Publisher: Public Library of Science (PLoS)
Date: 31-12-2008
Publisher: Springer Science and Business Media LLC
Date: 25-11-2013
DOI: 10.1038/SREP03318
Publisher: Public Library of Science (PLoS)
Date: 29-04-2016
Publisher: Public Library of Science (PLoS)
Date: 18-07-2011
Publisher: Oxford University Press (OUP)
Date: 22-04-2016
DOI: 10.1093/CID/CIW121
Publisher: Springer Science and Business Media LLC
Date: 05-06-2008
DOI: 10.1038/GENE.2008.38
Publisher: Frontiers Media SA
Date: 11-08-2022
DOI: 10.3389/FCIMB.2022.953187
Abstract: Although the power of genetic surveillance tools has been acknowledged widely, there is an urgent need in malaria endemic countries for feasible and cost-effective tools to implement in national malaria control programs (NMCPs) that can generate evidence to guide malaria control and elimination strategies, especially in the case of Plasmodium vivax . Several genetic surveillance applications (‘use cases’) have been identified to align research, technology development, and public health efforts, requiring different types of molecular markers. Here we present a new highly-multiplexed deep sequencing assay (Pv AmpliSeq). The assay targets the 33-SNP vivaxGEN-geo panel for country-level classification, and a newly designed 42-SNP within-country barcode for analysis of parasite dynamics in Vietnam and 11 putative drug resistance genes in a highly multiplexed NGS protocol with easy workflow, applicable for many different genetic surveillance use cases. The Pv AmpliSeq assay was validated using: 1) isolates from travelers and migrants in Belgium, and 2) routine collections of the national malaria control program at sentinel sites in Vietnam. The assay targets 229 licons and achieved a high depth of coverage (mean 595.7 ± 481) and high accuracy (mean error-rate of 0.013 ± 0.007). P. vivax parasites could be characterized from dried blood spots with a minimum of 5 parasites/µL and 10% of minority-clones. The assay achieved good spatial specificity for between-country prediction of origin using the 33-SNP vivaxGEN-geo panel that targets rare alleles specific for certain countries and regions. A high resolution for within-country ersity in Vietnam was achieved using the designed 42-SNP within-country barcode that targets common alleles (median MAF 0.34, range 0.01-0.49. Many variants were detected in (putative) drug resistance genes, with different predominant haplotypes in the pvmdr1 and pvcrt genes in different provinces in Vietnam. The capacity of the assay for high resolution identity-by-descent (IBD) analysis was demonstrated and identified a high rate of shared ancestry within Gia Lai Province in the Central Highlands of Vietnam, as well as between the coastal province of Binh Thuan and Lam Dong. Our approach performed well in geographically differentiating isolates at multiple spatial scales, detecting variants in putative resistance genes, and can be easily adjusted to suit the needs in other settings in a country or region. We prioritize making this tool available to researchers and NMCPs in endemic countries to increase ownership and ensure data usage for decision-making and malaria policy.
Publisher: Springer Science and Business Media LLC
Date: 05-04-2017
Publisher: Public Library of Science (PLoS)
Date: 29-02-2012
Publisher: Elsevier BV
Date: 11-2012
Publisher: Oxford University Press (OUP)
Date: 29-04-2009
DOI: 10.1093/HMG/DDP192
Publisher: Elsevier BV
Date: 03-2012
Publisher: Springer Science and Business Media LLC
Date: 08-07-2019
DOI: 10.1038/S41598-019-46398-Z
Abstract: The zoonotic Plasmodium knowlesi parasite is the most common cause of human malaria in Malaysia. Genetic analysis has shown that the parasites are ided into three subpopulations according to their geographic origin (Peninsular or Borneo) and, in Borneo, their macaque host ( Macaca fascicularis or M . nemestrina ). Whilst evidence suggests that genetic exchange events have occurred between the two Borneo subpopulations, the picture is unclear in less studied Peninsular strains. One difficulty is that P . knowlesi infected in iduals tend to present with low parasitaemia leading to s les with insufficient DNA for whole genome sequencing. Here, using a parasite selective whole genome lification approach on unprocessed blood s les, we were able to analyse recent genomes sourced from both Peninsular Malaysia and Borneo. The analysis provides evidence that recombination events are present in the Peninsular Malaysia parasite subpopulation, which have acquired fragments of the M . nemestrina associated subpopulation genotype, including the DBPβ and NBPXa erythrocyte invasion genes. The NBPXb invasion gene has also been exchanged within the macaque host-associated subpopulations of Malaysian Borneo. Our work provides strong evidence that exchange events are far more ubiquitous than expected and should be taken into consideration when studying the highly complex P . knowlesi population structure.
Publisher: Cold Spring Harbor Laboratory
Date: 10-09-2020
DOI: 10.1101/2020.09.10.291005
Abstract: Plasmodium vivax has been recently discovered as a significant cause of malaria in Mauritania, although very rare elsewhere in West Africa. It has not been known if this is a recently introduced or locally remnant parasite population, nor whether the genetic structure reflects epidemic or endemic transmission. To investigate the P. vivax population genetic structure in Mauritania and compare with populations previously analysed elsewhere, multi-locus genotyping was undertaken on 100 clinical isolates, using a genome-wide panel of 38 single nucleotide polymorphisms (SNPs), plus seven SNPs in drug resistance genes. The Mauritanian P. vivax population is shown to be genetically erse and ergent from populations elsewhere, indicated consistently by genetic distance matrix analysis, principal components analyses, and fixation indices. Only one isolate had a genotype clearly indicating recent importation, from a southeast Asian source. There was no linkage disequilibrium in the local parasite population, and only a small number of infections appeared to be closely genetically related, indicating that there is ongoing genetic recombination consistent with endemic transmission. The P. vivax ersity in a remote mining town was similar to that in the capital Nouakchott, with no indication of local substructure or of epidemic population structure. Drug resistance alleles were virtually absent in Mauritania, in contrast with P. vivax in other areas of the world. The molecular epidemiology indicates that there is long-standing endemic transmission that will be very challenging to eliminate. The virtual absence of drug resistance alleles suggests that most infections have been untreated, and that this endemic infection has been more neglected in comparison to P. falciparum locally or to P. vivax elsewhere. Plasmodium vivax is a widespread cause of malaria in Mauritania, in contrast to its rarity elsewhere throughout West Africa. To investigate whether the parasite may be recently introduced or epidemic, multi-locus genotyping was performed on 100 Mauritanian P. vivax malaria cases. Analysis of a genome-wide panel of single nucleotide polymorphisms showed the P. vivax population to be genetically erse and ergent from populations elsewhere, indicating that there has been long-standing endemic transmission. Almost all infections appear to be locally acquired, with the exception of one that was presumably imported with a genotype similar to infections seen in Southeast Asia. The Mauritanian P. vivax population shows no linkage disequilibrium, and very few infections have closely related genotypes, indicating ongoing recombination. The parasite showed no indication of local substructure or epidemic population structure. Drug resistance alleles were virtually absent, suggesting that most infections have been untreated historically. The molecular epidemiology indicates that there has been long-standing endemic transmission of this neglected parasite that requires special attention for control.
Publisher: Springer Science and Business Media LLC
Date: 30-09-2015
DOI: 10.1038/NATURE15390
Publisher: Public Library of Science (PLoS)
Date: 09-11-2016
Publisher: Cold Spring Harbor Laboratory
Date: 07-11-2019
DOI: 10.1101/824730
Abstract: MalariaGEN is a data-sharing network that enables groups around the world to work together on the genomic epidemiology of malaria. Here we describe a new release of curated genome variation data on 7,000 Plasmodium falciparum s les from MalariaGEN partner studies in 28 malaria-endemic countries. High-quality genotype calls on 3 million single nucleotide polymorphisms (SNPs) and short indels were produced using a standardised analysis pipeline. Copy number variants associated with drug resistance and structural variants that cause failure of rapid diagnostic tests were also analysed. Almost all s les showed genetic evidence of resistance to at least one antimalarial drug, and some s les from Southeast Asia carried markers of resistance to six commonly-used drugs. Genes expressed during the mosquito stage of the parasite life-cycle are prominent among loci that show strong geographic differentiation. By continuing to enlarge this open data resource we aim to facilitate research into the evolutionary processes affecting malaria control and to accelerate development of the surveillance toolkit required for malaria elimination.
Publisher: Springer Science and Business Media LLC
Date: 28-11-2008
Publisher: Springer Science and Business Media LLC
Date: 12-2015
Publisher: Elsevier BV
Date: 08-2018
Publisher: Springer Science and Business Media LLC
Date: 23-12-2022
DOI: 10.1038/S42003-022-04352-2
Abstract: Traditionally, patient travel history has been used to distinguish imported from autochthonous malaria cases, but the dormant liver stages of Plasmodium vivax confound this approach. Molecular tools offer an alternative method to identify, and map imported cases. Using machine learning approaches incorporating hierarchical fixation index and decision tree analyses applied to 799 P. vivax genomes from 21 countries, we identified 33-SNP, 50-SNP and 55-SNP barcodes (GEO33, GEO50 and GEO55), with high capacity to predict the infection’s country of origin. The Matthews correlation coefficient (MCC) for an existing, commonly applied 38-SNP barcode (BR38) exceeded 0.80 in 62% countries. The GEO panels outperformed BR38, with median MCCs 0.80 in 90% countries at GEO33, and 95% at GEO50 and GEO55. An online, open-access, likelihood-based classifier framework was established to support data analysis (vivaxGEN-geo). The SNP selection and classifier methods can be readily amended for other use cases to support malaria control programs.
Publisher: Elsevier BV
Date: 09-2019
Publisher: Elsevier BV
Date: 02-2017
DOI: 10.1016/J.IJPARA.2016.08.006
Abstract: Molecular approaches have an increasingly recognized utility in surveillance of malaria parasite populations, not only in defining prevalence and incidence with higher sensitivity than traditional methods, but also in monitoring local and regional parasite transmission patterns. In this review, we provide an overview of population genetic and genomic studies of human-infecting Plasmodium species, highlighting recent advances in the field. In accordance with the renewed impetus for malaria eradication, many studies are now using genetic and genomic epidemiology to support local evidence-based intervention strategies. Microsatellite genotyping remains a popular approach for both Plasmodium falciparum and Plasmodium vivax. However, with the increasing availability of whole genome sequencing data enabling effective single nucleotide polymorphism-based panels tailored to a given study question and setting, this approach is gaining popularity. The availability of new reference genomes for Plasmodium malariae and Plasmodium ovale should see a surge in similar molecular studies on these currently neglected species. Genomic studies are revealing new insights into important adaptive mechanisms of the parasite including antimalarial drug resistance. The advent of new methodologies such as selective whole genome lification for dealing with extensive human DNA in low density field isolates should see genome-wide approaches becoming routine for parasite surveillance once the economic costs outweigh the current cost benefits of targeted approaches.
Publisher: Oxford University Press (OUP)
Date: 24-07-2016
Publisher: Oxford University Press (OUP)
Date: 19-10-2012
DOI: 10.1093/CID/CIS902
Abstract: Plasmodium knowlesi commonly causes severe malaria in Malaysian Borneo, with high case-fatality rates reported. We compared risk, spectrum, and outcome of severe disease from P. knowlesi, Plasmodium falciparum, and Plasmodium vivax and outcomes following introduction of protocols for early referral and intravenous artesunate for all severe malaria. From September 2010 to October 2011 we prospectively assessed nonpregnant patients aged ≥12 years admitted to Queen Elizabeth Hospital (QEH), Sabah, with polymerase chain reaction-confirmed Plasmodium monoinfection. Standardized referral and prereferral intravenous artesunate were instituted at district hospitals. Severe malaria occurred in 38 of 130 (29%) patients with P. knowlesi, 13 of 122 (11%) with P. falciparum, and 7 of 43 (16%) with P. vivax. The commonest severity criteria in knowlesi malaria included parasitemia >100 000/µL (n = 18), jaundice (n = 20), respiratory distress (n = 14), hypotension (n = 13), and acute kidney injury (n = 9). On multivariate analysis, P. knowlesi was associated with a 2.96-fold (95% confidence interval, 1.19-7.38-fold) greater risk of severity than P. falciparum (P = .020) only parasitemia and schizontemia >10% independently predicted knowlesi severity. Risk of severe knowlesi malaria increased 11-fold with parasitemia >20 000/µL, and 28-fold with parasitemia >100 000/µL. Nearly all (92%) knowlesi malaria patients received oral artemisinin therapy 36 of 38 (95%) and 39 of 92 (42%) with severe and nonsevere disease, respectively, also received ≥1 dose of intravenous artesunate. No deaths occurred from any species. Plasmodium knowlesi is the commonest cause of severe malaria at QEH, with parasitemia the major risk factor for severity. Early referral and treatment with artesunate was highly effective for severe malaria from all species and associated with zero mortality.
Publisher: Public Library of Science (PLoS)
Date: 16-12-2020
DOI: 10.1371/JOURNAL.PNTD.0008945
Abstract: Plasmodium vivax has been recently discovered as a significant cause of malaria in Mauritania, although very rare elsewhere in West Africa. It has not been known if this is a recently introduced or locally remnant parasite population, nor whether the genetic structure reflects epidemic or endemic transmission. To investigate the P . vivax population genetic structure in Mauritania and compare with populations previously analysed elsewhere, multi-locus genotyping was undertaken on 100 clinical isolates, using a genome-wide panel of 38 single nucleotide polymorphisms (SNPs), plus seven SNPs in drug resistance genes. The Mauritanian P . vivax population is shown to be genetically erse and ergent from populations elsewhere, indicated consistently by genetic distance matrix analysis, principal components analyses, and fixation indices. Only one isolate had a genotype clearly indicating recent importation, from a southeast Asian source. There was no linkage disequilibrium in the local parasite population, and only a small number of infections appeared to be closely genetically related, indicating that there is ongoing genetic recombination consistent with endemic transmission. The P . vivax ersity in a remote mining town was similar to that in the capital Nouakchott, with no indication of local substructure or of epidemic population structure. Drug resistance alleles were virtually absent in Mauritania, in contrast with P . vivax in other areas of the world. The molecular epidemiology indicates that there is long-standing endemic transmission that will be very challenging to eliminate. The virtual absence of drug resistance alleles suggests that most infections have been untreated, and that this endemic infection has been more neglected in comparison to P . vivax elsewhere.
Publisher: Public Library of Science (PLoS)
Date: 04-01-2013
Publisher: Springer Science and Business Media LLC
Date: 10-02-2012
Abstract: Genome and transcriptome studies of Plasmodium nucleic acids obtained from parasitized whole blood are greatly improved by depletion of human DNA or enrichment of parasite DNA prior to next-generation sequencing and microarray hybridization. The most effective method currently used is a two-step procedure to deplete leukocytes: centrifugation using density gradient media followed by filtration through expensive, commercially available columns. This method is not easily implemented in field studies that collect hundreds of s les and simultaneously process s les for multiple laboratory analyses. Inexpensive syringes, hand-packed with CF11 cellulose powder, were recently shown to improve ex vivo cultivation of Plasmodium vivax obtained from parasitized whole blood. This study was undertaken to determine whether CF11 columns could be adapted to isolate Plasmodium falciparum DNA from parasitized whole blood and achieve current quantity and purity requirements for Illumina sequencing. The CF11 procedure was compared with the current two-step standard of leukocyte depletion using parasitized red blood cells cultured in vitro and parasitized blood obtained ex vivo from Cambodian patients with malaria. Procedural variations in centrifugation and column size were tested, along with a range of blood volumes and parasite densities. CF11 filtration reliably produces 500 nanograms of DNA with less than 50% human DNA contamination, which is comparable to that obtained by the two-step method and falls within the current quality control requirements for Illumina sequencing. In addition, a centrifuge-free version of the CF11 filtration method to isolate P. falciparum DNA at remote and minimally equipped field sites in malaria-endemic areas was validated. CF11 filtration is a cost-effective, scalable, one-step approach to remove human DNA from P. falciparum -infected whole blood s les.
Publisher: Cold Spring Harbor Laboratory
Date: 23-03-2020
DOI: 10.1101/2020.03.23.003293
Abstract: Plasmodium vivax malaria is much less common in Africa than the rest of the world because the parasite relies primarily on the Duffy antigen/chemokine receptor ( DARC ) to invade human erythrocytes, and the majority of Africans are Duffy negative. Recently, there has been a dramatic increase in the reporting of P. vivax cases in Africa, with a high number of them being in Duffy negative in iduals, potentially indicating P. vivax has evolved an alternative invasion mechanism that can overcome Duffy negativity. Here, we analyzed single nucleotide polymorphism (SNP) and copy number variation (CNV) in Whole Genome Sequence (WGS) data from 44 P. vivax s les isolated from symptomatic malaria patients in southwestern Ethiopia, where both Duffy positive and Duffy negative in iduals are found. A total of 236,351 SNPs were detected, of which 21.9% was nonsynonymous and 78.1% was synonymous mutations. The largest number of SNPs were detected on chromosomes 9 (33,478 SNPs 14% of total) and 10 (28,133 SNPs 11.9%). There were particularly high levels of polymorphism in erythrocyte binding gene candidates including reticulocyte binding protein 2c ( RBP 2c), merozoite surface protein 1 ( MSP 1), and merozoite surface protein 3 ( MSP 3.5, MSP 3.85 and MSP 3.9). Thirteen genes related to immunogenicity and erythrocyte binding function were detected with significant signals of positive selection. Variation in gene copy number was also concentrated in genes involved in host-parasite interactions, including the expansion of the Duffy binding protein gene ( PvDBP ) on chromosome 6 and several PIR genes. Based on the phylogeny constructed from the whole genome sequences, the expansion of these genes was an independent process among the P. vivax lineages in Ethiopia. We further inferred transmission patterns of P. vivax infections among study sites and showed various levels of gene flow at a small geographical scale. The genomic features of P. vivax provided baseline data for future comparison with those in Duffy-negative in iduals, and allowed us to develop a panel of informative Single Nucleotide Polymorphic markers diagnostic at a micro-geographical scale.
Publisher: Springer Science and Business Media LLC
Date: 25-01-2017
DOI: 10.1038/NATURE21038
Publisher: Public Library of Science (PLoS)
Date: 27-10-2016
Publisher: Elsevier BV
Date: 04-2019
Publisher: American Society for Microbiology
Date: 18-07-2023
DOI: 10.1128/AAC.01610-22
Abstract: Increasing reports of resistance to a frontline malaria blood-stage treatment, chloroquine (CQ), raises concerns for the elimination of Plasmodium vivax . The absence of an effective molecular marker of CQ resistance in P. vivax greatly constrains surveillance of this emerging threat.
Publisher: Public Library of Science (PLoS)
Date: 12-05-2017
Publisher: eLife Sciences Publications, Ltd
Date: 2016
Publisher: Public Library of Science (PLoS)
Date: 03-2016
Publisher: Springer Science and Business Media LLC
Date: 18-02-2009
DOI: 10.1038/EJHG.2009.8
Publisher: Public Library of Science (PLoS)
Date: 14-09-2020
Publisher: Public Library of Science (PLoS)
Date: 15-01-2009
Publisher: Springer Science and Business Media LLC
Date: 12-2008
DOI: 10.1038/NATURE07632
Publisher: Public Library of Science (PLoS)
Date: 06-06-2011
Publisher: Springer Science and Business Media LLC
Date: 12-2018
Publisher: Springer Science and Business Media LLC
Date: 27-07-2020
DOI: 10.1186/S12936-020-03330-5
Abstract: The Asia–Pacific region faces formidable challenges in achieving malaria elimination by the proposed target in 2030. Molecular surveillance of Plasmodium parasites can provide important information on malaria transmission and adaptation, which can inform national malaria control programmes (NMCPs) in decision-making processes. In November 2019 a parasite genotyping workshop was held in Jakarta, Indonesia, to review molecular approaches for parasite surveillance and explore ways in which these tools can be integrated into public health systems and inform policy. The meeting was attended by 70 participants from 8 malaria-endemic countries and partners of the Asia Pacific Malaria Elimination Network. The participants acknowledged the utility of multiple use cases for parasite genotyping including: quantifying the prevalence of drug resistant parasites, predicting risks of treatment failure, identifying major routes and reservoirs of infection, monitoring imported malaria and its contribution to local transmission, characterizing the origins and dynamics of malaria outbreaks, and estimating the frequency of Plasmodium vivax relapses. However, the priority of each use case varies with different endemic settings. Although a one-size-fits-all approach to molecular surveillance is unlikely to be applicable across the Asia–Pacific region, consensus on the spectrum of added-value activities will help support data sharing across national boundaries. Knowledge exchange is needed to establish local expertise in different laboratory-based methodologies and bioinformatics processes. Collaborative research involving local and international teams will help maximize the impact of analytical outputs on the operational needs of NMCPs. Research is also needed to explore the cost-effectiveness of genetic epidemiology for different use cases to help to leverage funding for wide-scale implementation. Engagement between NMCPs and local researchers will be critical throughout this process.
Publisher: Springer Science and Business Media LLC
Date: 12-09-2023
Publisher: Elsevier BV
Date: 10-2011
DOI: 10.1016/J.EURONEURO.2011.08.008
Abstract: The spectrum of disorders of the brain is large, covering hundreds of disorders that are listed in either the mental or neurological disorder chapters of the established international diagnostic classification systems. These disorders have a high prevalence as well as short- and long-term impairments and disabilities. Therefore they are an emotional, financial and social burden to the patients, their families and their social network. In a 2005 landmark study, we estimated for the first time the annual cost of 12 major groups of disorders of the brain in Europe and gave a conservative estimate of €386 billion for the year 2004. This estimate was limited in scope and conservative due to the lack of sufficiently comprehensive epidemiological and/or economic data on several important diagnostic groups. We are now in a position to substantially improve and revise the 2004 estimates. In the present report we cover 19 major groups of disorders, 7 more than previously, of an increased range of age groups and more cost items. We therefore present much improved cost estimates. Our revised estimates also now include the new EU member states, and hence a population of 514 million people. To estimate the number of persons with defined disorders of the brain in Europe in 2010, the total cost per person related to each disease in terms of direct and indirect costs, and an estimate of the total cost per disorder and country. The best available estimates of the prevalence and cost per person for 19 groups of disorders of the brain (covering well over 100 specific disorders) were identified via a systematic review of the published literature. Together with the twelve disorders included in 2004, the following range of mental and neurologic groups of disorders is covered: addictive disorders, affective disorders, anxiety disorders, brain tumor, childhood and adolescent disorders (developmental disorders), dementia, eating disorders, epilepsy, mental retardation, migraine, multiple sclerosis, neuromuscular disorders, Parkinson's disease, personality disorders, psychotic disorders, sleep disorders, somatoform disorders, stroke, and traumatic brain injury. Epidemiologic panels were charged to complete the literature review for each disorder in order to estimate the 12-month prevalence, and health economic panels were charged to estimate best cost-estimates. A cost model was developed to combine the epidemiologic and economic data and estimate the total cost of each disorder in each of 30 European countries (EU27+Iceland, Norway and Switzerland). The cost model was populated with national statistics from Eurostat to adjust all costs to 2010 values, converting all local currencies to Euro, imputing costs for countries where no data were available, and aggregating country estimates to purchasing power parity adjusted estimates for the total cost of disorders of the brain in Europe 2010. The total cost of disorders of the brain was estimated at €798 billion in 2010. Direct costs constitute the majority of costs (37% direct healthcare costs and 23% direct non-medical costs) whereas the remaining 40% were indirect costs associated with patients' production losses. On average, the estimated cost per person with a disorder of the brain in Europe ranged between €285 for headache and €30,000 for neuromuscular disorders. The European per capita cost of disorders of the brain was €1550 on average but varied by country. The cost (in billion €PPP 2010) of the disorders of the brain included in this study was as follows: addiction: €65.7 anxiety disorders: €74.4 brain tumor: €5.2 child/adolescent disorders: €21.3 dementia: €105.2 eating disorders: €0.8 epilepsy: €13.8 headache: €43.5 mental retardation: €43.3 mood disorders: €113.4 multiple sclerosis: €14.6 neuromuscular disorders: €7.7 Parkinson's disease: €13.9 personality disorders: €27.3 psychotic disorders: €93.9 sleep disorders: €35.4 somatoform disorder: €21.2 stroke: €64.1 traumatic brain injury: €33.0. It should be noted that the revised estimate of those disorders included in the previous 2004 report constituted €477 billion, by and large confirming our previous study results after considering the inflation and population increase since 2004. Further, our results were consistent with administrative data on the health care expenditure in Europe, and comparable to previous studies on the cost of specific disorders in Europe. Our estimates were lower than comparable estimates from the US. This study was based on the best currently available data in Europe and our model enabled extrapolation to countries where no data could be found. Still, the scarcity of data is an important source of uncertainty in our estimates and may imply over- or underestimations in some disorders and countries. Even though this review included many disorders, diagnoses, age groups and cost items that were omitted in 2004, there are still remaining disorders that could not be included due to limitations in the available data. We therefore consider our estimate of the total cost of the disorders of the brain in Europe to be conservative. In terms of the health economic burden outlined in this report, disorders of the brain likely constitute the number one economic challenge for European health care, now and in the future. Data presented in this report should be considered by all stakeholder groups, including policy makers, industry and patient advocacy groups, to reconsider the current science, research and public health agenda and define a coordinated plan of action of various levels to address the associated challenges. Political action is required in light of the present high cost of disorders of the brain. Funding of brain research must be increased care for patients with brain disorders as well as teaching at medical schools and other health related educations must be quantitatively and qualitatively improved, including psychological treatments. The current move of the pharmaceutical industry away from brain related indications must be halted and reversed. Continued research into the cost of the many disorders not included in the present study is warranted. It is essential that not only the EU but also the national governments forcefully support these initiatives.
Publisher: Springer Science and Business Media LLC
Date: 13-03-2009
Publisher: Elsevier BV
Date: 12-2021
Publisher: Public Library of Science (PLoS)
Date: 07-05-2020
Publisher: Oxford University Press (OUP)
Date: 13-11-2007
DOI: 10.1093/HMG/DDM331
Publisher: Public Library of Science (PLoS)
Date: 11-08-2011
Publisher: Cold Spring Harbor Laboratory
Date: 24-09-2019
DOI: 10.1101/776781
Abstract: Imported cases present a considerable challenge to the elimination of malaria. Traditionally, patient travel history has been used to identify imported cases, but the long-latency liver stages confound this approach in Plasmodium vivax . Molecular tools to identify and map imported cases offer a more robust approach, that can be combined with drug resistance and other surveillance markers in high-throughput, population-based genotyping frameworks. Using a machine learning approach incorporating hierarchical FST (HFST) and decision tree (DT) analysis applied to 831 P. vivax genomes from 20 countries, we identified a 28-Single Nucleotide Polymorphism (SNP) barcode with high capacity to predict the country of origin. The Matthews correlation coefficient (MCC), which provides a measure of the quality of the classifications, ranging from −1 (total disagreement) to 1 (perfect prediction), exceeded 0.9 in 15 countries in cross-validation evaluations. When combined with an existing 37-SNP P. vivax barcode, the 65-SNP panel exhibits MCC scores exceeding 0.9 in 17 countries with up to 30% missing data. As a secondary objective, several genes were identified with moderate MCC scores (median MCC range from 0.54-0.68), amenable as markers for rapid testing using low-throughput genotyping approaches. A likelihood-based classifier framework was established, that supports analysis of missing data and polyclonal infections. To facilitate investigator-lead analyses, the likelihood framework is provided as a web-based, open-access platform (vivaxGEN-geo) to support the analysis and interpretation of data produced either at the 28-SNP core or full 65-SNP barcode. These tools can be used by malaria control programs to identify the main reservoirs of infection so that resources can be focused to where they are needed most.
Publisher: Cold Spring Harbor Laboratory
Date: 12-2022
DOI: 10.1101/2022.11.30.22282917
Abstract: Increasing reports of resistance to a frontline malaria blood-stage treatment, chloroquine (CQ), raise concerns for the elimination of Plasmodium vivax . The absence of an effective molecular marker of CQ resistance in P. vivax greatly constrains surveillance of this emerging threat. A recent genetic cross between CQ sensitive (CQS) and CQ resistant (CQR) NIH-1993 strains of P. vivax linked a moderate CQR phenotype with two candidate markers in P. vivax CQ resistance transporter gene ( pvcrt-o ): MS334 and In9 pvcrt . Longer TGAAGH motifs at MS334 were associated with CQ resistance, as were shorter motifs at the In9 pvcrt locus. In this study, high-grade CQR clinical isolates of P. vivax from Malaysia were used to investigate the association between the MS334 and In9 pvcrt variants and treatment efficacy. Amongst a total of 49 independent monoclonal P. vivax isolates assessed, high-quality MS334 and In9 pvcrt sequences could be derived from 30 (61%) and 23 (47%), respectively. Five MS334 and six In9 pvcrt alleles were observed, with allele frequencies ranging from 2 to 76% and 3 to 71%, respectively. None of the clinical isolates had the same variant as the NIH-1993 CQR strain, and none were associated with CQ treatment failure (all p .05). Our findings suggest that the pvcrt-o MS334 and In9 pvcrt markers cannot be used universally as markers of CQ treatment efficacy in an area of high-grade CQ resistance. Further studies applying hypothesis-free genome-wide approaches are warranted to identify more effective CQR markers for P. vivax .
Publisher: Public Library of Science (PLoS)
Date: 23-04-2021
Publisher: Public Library of Science (PLoS)
Date: 31-03-2017
Publisher: Oxford University Press (OUP)
Date: 13-09-2012
DOI: 10.1093/BIOINFORMATICS/BTS557
Abstract: Summary: There is an immediate need for tools to both analyse and visualize in real-time single-nucleotide polymorphisms, insertions and deletions, and other structural variants from new sequence file formats. We have developed VarB software that can be used to visualize variant call format files in real time, as well as identify regions under balancing selection and informative markers to differentiate user-defined groups (e.g. populations). We demonstrate its utility using sequence data from 50 Plasmodium falciparum isolates comprising two different continents and confirm known signals from genomic regions that contain important antigenic and anti-malarial drug-resistance genes. Availability and implementation: The C++-based software VarB and user manual are available from arb. Contact: taane.clark@lshtm.ac.uk
Publisher: Cold Spring Harbor Laboratory
Date: 17-07-2019
DOI: 10.1101/621813
Abstract: The rapid and aggressive spread of artemisinin-resistant Plasmodium falciparum carrying the kelch13 C580Y mutation is a growing threat to malaria elimination in Southeast Asia, but there is no evidence of their spread to other regions. We conducted cross-sectional surveys in 2016 and 2017 at two clinics in Wewak, Papua New Guinea (PNG) where we identified three infections caused by C580Y mutants among 239 genotyped clinical s les. One of these mutants exhibited the highest survival rate (6.8%) among all parasites surveyed in ring-stage survival assays (RSA) for artemisinin. Analyses of kelch13 flanking regions, and comparisons of deep sequencing data from 389 clinical s les from PNG, Indonesian Papua and Western Cambodia, suggested an independent origin of the Wewak C580Y mutation, showing that the mutants possess several distinctive genetic features. Identity by descent (IBD) showed that multiple portions of the mutants’ genomes share a common origin with parasites found in Indonesian Papua, comprising several mutations within genes previously associated with drug resistance, such as mdr1, ferredoxin, atg18 and pnp. These findings suggest that a P. falciparum lineage circulating on the island of New Guinea has gradually acquired a complex ensemble of variants, including kelch13 C580Y, which have affected the parasites’ drug sensitivity. This worrying development reinforces the need for increased surveillance of the evolving parasite populations on the island, to contain the spread of resistance.
Publisher: Elsevier BV
Date: 10-2015
Publisher: Springer Science and Business Media LLC
Date: 12-07-2016
Publisher: Public Library of Science (PLoS)
Date: 04-2010
Publisher: Apollo - University of Cambridge Repository
Date: 2020
DOI: 10.17863/CAM.60046
Publisher: Public Library of Science (PLoS)
Date: 23-06-2022
DOI: 10.1371/JOURNAL.PNTD.0010492
Abstract: Plasmodium vivax is the most widespread cause of human malaria. Recent reports of drug resistant vivax malaria and the challenge of eradicating the dormant liver forms increase the importance of vaccine development against this relapsing disease. P . vivax reticulocyte binding protein 1a (PvRBP1a) is a potential vaccine candidate, which is involved in red cell tropism, a crucial step in the merozoite invasion of host reticulocytes. As part of the initial evaluation of the PvRBP1a vaccine candidate, we investigated its genetic ersity and antigenicity using geographically erse clinical isolates. We analysed pvrbp1a genetic polymorphisms using 202 vivax clinical isolates from six countries. Pvrbp1a was separated into six regions based on specific domain features, sequence conserved olymorphic regions, and the reticulocyte binding like (RBL) domains. In the fragmented gene sequence analysis, PvRBP1a region II (RII) and RIII (head and tail structure homolog, 152–625 aa.) showed extensive polymorphism caused by random point mutations. The haplotype network of these polymorphic regions was classified into three clusters that converged to independent populations. Antigenicity screening was performed using recombinant proteins PvRBP1a-N (157–560 aa.) and PvRBP1a-C (606–962 aa.), which contained head and tail structure region and sequence conserved region, respectively. Sensitivity against PvRBP1a-N (46.7%) was higher than PvRBP1a-C (17.8%). PvRBP1a-N was reported as a reticulocyte binding domain and this study identified a linear epitope with moderate antigenicity, thus an attractive domain for merozoite invasion-blocking vaccine development. However, our study highlights that a global PvRBP1a-based vaccine design needs to overcome several difficulties due to three distinct genotypes and low antigenicity levels.
Publisher: SAGE Publications
Date: 06-01-2017
Abstract: Multiple sclerosis (MS) is an inflammatory and neurodegenerative demyelinating disease of the central nervous system (CNS), most likely autoimmune in origin, usually beginning in early adulthood. The aetiology of the disease is not well understood it is viewed currently as a multifactorial disease which results from complex interactions between genetic predisposition and environmental factors, of which a few are potentially modifiable. Improving our understanding of these factors can lead to new and more effective approaches to patient counselling and, possibly, prevention and management of the disease. The 2016 focused workshop of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) addressed the topic of environmental, modifiable risk factors for MS, gathering experts from around the world, to collate experimental and clinical research into environmental factors that have been associated with the disease onset and, in a few cases, disease activity and progression. A number of factors, including infections, vitamin D deficiency, diet and lifestyle factors, stress and comorbidities, were discussed. The meeting provided a forum to analyse available evidence, to identify inconsistencies and gaps in current knowledge and to suggest avenues for future research.
Publisher: Springer Science and Business Media LLC
Date: 27-06-2016
DOI: 10.1038/NG.3599
Publisher: Springer Science and Business Media LLC
Date: 28-04-2013
DOI: 10.1038/NG.2624
Publisher: Oxford University Press (OUP)
Date: 16-08-2009
DOI: 10.1093/BIOINFORMATICS/BTP488
Abstract: Summary: Array-based comparative genomic hybridization (CGH) technology is used to discover and validate genomic structural variation, including copy number variants, insertions, deletions and other structural variants (SVs). The visualization and summarization of the array CGH data outputs, potentially across many s les, is an important process in the identification and analysis of SVs. We have developed a software tool for SV analysis using data from array CGH technologies, which is also amenable to short-read sequence data. Availability and implementation: SnoopCGH is written in java and is available from snoopcgh.sourceforge.net/ Contact: jg10@sanger.ac.uk tc5@sanger.ac.uk
Publisher: Springer Science and Business Media LLC
Date: 26-10-2008
Publisher: Public Library of Science (PLoS)
Date: 09-07-2020
Publisher: Cold Spring Harbor Laboratory
Date: 29-07-2022
DOI: 10.1101/2022.07.27.501805
Abstract: 2. Here we present the R package - MinSNPs. This is designed to assemble resolution optimised sets of single nucleotide polymorphisms (SNPs) from alignments such as genome wide orthologous SNP matrices. We also demonstrate a pipeline for assembling such matrices from multiple bio-projects, so as to facilitate SNP set derivation from globally representative data sets. MinSNPs can derive sets of SNPs optimised for discriminating any user-defined combination of sequences from all others. Alternatively, SNP sets may be optimised to discriminate all from all, i.e., to maximise ersity. MinSNPs encompasses functions that facilitate rapid and flexible SNP mining, and clear and comprehensive presentation of the results. The MinSNPs running time scales in a linear fashion with input data volume, and the numbers of SNPs and SNPs sets specified in the output. MinSNPs was tested using a previously reported orthologous SNP matrix of Staphylococcus aureus . and an orthologous SNP matrix of 3,279 genomes with 164,335 SNPs assembled from four S. aureus short read genomic data sets. MinSNPs demonstrated efficacy in deriving discriminatory SNP sets for potential surveillance targets and in identifying SNP sets optimised to discriminate isolates from different clonal complexes (CC). MinSNPs was also tested with a large Plasmodium vivax orthologous SNP matrix. A set of five SNPs was derived that reliably indicated the country of origin within 3 south-east Asian countries. In summary, we report the capacity to assemble comprehensive SNP matrices that effectively capture microbial genomic ersity, and to rapidly and flexibly mine these entities for optimised surveillance marker sets. 3. We present the R package “MinSNPs”. This derives resolution optimised SNP sets from datasets of genome sequence variation. Such SNP sets can underpin targeted genetic analysis for high throughput surveillance of microbial variants of public health concern. MinSNPs supports considerable flexibility in search methods. The package allows non-specialist bioinformaticians to easily and quickly convert global scale data of intra-specific genomic variation into SNP sets precisely and efficiently directed towards many microbial genetic analysis tasks. 4. The source code for minSNPs is available from GitHub under MIT Licence (URLs – udwigHoon/minSNPs and mirrored in ackage=minSNPs ) Staphylococcus aureus (STARRS data set) Orthologous SNP Matrix (URL - 0.1371/journal.pone.0245790.s005 ) Plasmodium vivax data set (VCF file) (URL - esource/24 ) Staphylococcus aureus short read sequences (fastq) from bioprojects: PRJEB40888 (or STARRS)( ioproject/PRJEB40888 ), PRJEB3174 ( ioproject/PRJEB3174 ), PRJEB32286 ( ioproject/PRJEB32286 ), and PRJNA400143 ( ioproject/PRJNA400143 )
Publisher: Public Library of Science (PLoS)
Date: 23-04-2021
DOI: 10.1371/JOURNAL.PMED.1003576
Abstract: Glucose-6-phosphate dehydrogenase (G6PD) activity is dependent upon G6PD genotype and age of the red blood cell (RBC) population, with younger RBCs having higher activity. Peripheral parasitemia with Plasmodium spp. induces hemolysis, replacing older RBCs with younger cells with higher G6PD activity. This study aimed to assess whether G6PD activity varies between in iduals with and without malaria or a history of malaria. In iduals living in the Chittagong Hill Tracts of Bangladesh were enrolled into 3 complementary studies: (i) a prospective, single-arm clinical efficacy trial of patients ( n = 175) with uncomplicated malaria done between 2014 and 2015, (ii) a cross-sectional survey done between 2015 and 2016 ( n = 999), and (iii) a matched case–control study of aparasitemic in iduals with and without a history of malaria done in 2020 ( n = 506). G6PD activity was compared between in iduals with and without malaria diagnosed by microscopy, rapid diagnostic test (RDT), or polymerase chain reaction (PCR), and in aparasitemic participants with and without a history of malaria. In the cross-sectional survey and clinical trial, 15.5% (182/1,174) of participants had peripheral parasitemia detected by microscopy or RDT, 3.1% (36/1,174) were positive by PCR only, and 81.4% (956/1,174) were aparasitemic. Aparasitemic in iduals had significantly lower G6PD activity (median 6.9 U/g Hb, IQR 5.2–8.6) than those with peripheral parasitemia detected by microscopy or RDT (7.9 U/g Hb, IQR 6.6–9.8, p 0.001), but G6PD activity similar to those with parasitemia detected by PCR alone (submicroscopic parasitemia) (6.1 U/g Hb, IQR 4.8–8.6, p = 0.312). In total, 7.7% (14/182) of patients with malaria had G6PD activity 70% compared to 25.0% (248/992) of participants with submicroscopic or no parasitemia (odds ratio [OR] 0.25, 95% CI 0.14–0.44, p 0.001). In the case–control study, the median G6PD activity was 10.3 U/g Hb (IQR 8.8–12.2) in 253 patients with a history of malaria and 10.2 U/g Hb (IQR 8.7–11.8) in 253 in iduals without a history of malaria ( p = 0.323). The proportion of in iduals with G6PD activity 70% was 11.5% (29/253) in the cases and 15.4% (39/253) in the controls (OR 0.7, 95% CI 0.41–1.23, p = 0.192). Limitations of the study included the non-contemporaneous nature of the clinical trial and cross-sectional survey. Patients with acute malaria had significantly higher G6PD activity than in iduals without malaria, and this could not be accounted for by a protective effect of G6PD deficiency. G6PD-deficient patients with malaria may have higher than expected G6PD enzyme activity and an attenuated risk of primaquine-induced hemolysis compared to the risk when not infected.
Publisher: Public Library of Science (PLoS)
Date: 15-12-2020
DOI: 10.1371/JOURNAL.PPAT.1009133
Abstract: The rapid and aggressive spread of artemisinin-resistant Plasmodium falciparum carrying the C580Y mutation in the kelch13 gene is a growing threat to malaria elimination in Southeast Asia, but there is no evidence of their spread to other regions. We conducted cross-sectional surveys in 2016 and 2017 at two clinics in Wewak, Papua New Guinea (PNG) where we identified three infections caused by C580Y mutants among 239 genotyped clinical s les. One of these mutants exhibited the highest survival rate (6.8%) among all parasites surveyed in ring-stage survival assays (RSA) for artemisinin. Analyses of kelch13 flanking regions, and comparisons of deep sequencing data from 389 clinical s les from PNG, Indonesian Papua and Western Cambodia, suggested an independent origin of the Wewak C580Y mutation, showing that the mutants possess several distinctive genetic features. Identity by descent (IBD) showed that multiple portions of the mutants’ genomes share a common origin with parasites found in Indonesian Papua, comprising several mutations within genes previously associated with drug resistance, such as mdr1 , ferredoxin , atg18 and pnp . These findings suggest that a P . falciparum lineage circulating on the island of New Guinea has gradually acquired a complex ensemble of variants, including kelch13 C580Y, which have affected the parasites’ drug sensitivity. This worrying development reinforces the need for increased surveillance of the evolving parasite populations on the island, to contain the spread of resistance.
Publisher: Proceedings of the National Academy of Sciences
Date: 17-12-2012
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.
Publisher: Springer Science and Business Media LLC
Date: 06-01-2021
DOI: 10.1186/S12936-020-03551-8
Abstract: Although autochthonous malaria cases are no longer reported in Anhui Province, China, imported malaria has become a major health concern. The proportion of reported malaria cases caused by Plasmodium ovale spp. increased to levels higher than expected during 2012 to 2019, and showed two peaks, 19.69% in 2015 and 19.35% in 2018. A case-based retrospective study was performed using data collected from the China Information System for Disease Control and Prevention (CISDCP) and Information System for Parasitic Disease Control and Prevention (ISPDCP) from 2012 to 2019 to assess the trends and differences between Plasmodium ovale curtisi ( P. o. curtisi ) and Plasmodium ovale wallikeri ( P. o. wallikeri ) . Epidemiological characteristics were analyzed using descriptive statistics. Plasmodium o. curtisi and P. o. wallikeri were found to simultaneously circulate in 14 African countries. Among 128 patients infected with P. ovale spp., the proportion of co-infection cases was 10.16%. Six cases of co-infection with P. ovale spp. and P. falciparum were noted , each presenting with two clinical attacks (the first attack was due to P. falciparum and the second was due to P. ovale spp.) at different intervals. Accurate identification of the infecting species was achieved among only 20.00% of cases of P. ovale spp. infection. At the reporting units, 32.17% and 6.96% of cases of P. ovale spp. infection were misdiagnosed as P. vivax and P. falciparum infections, respectively. The present results indicate that the potential of P. ovale spp. to co-infect with other Plasmodium species has been previously underestimated, as is the incidence of P. ovale spp. in countries where malaria is endemic. P. o. curtisi may have a long latency period of 3 years and potentially cause residual foci, thus posing challenges to the elimination of malaria in P. ovale spp.-endemic areas. Considering the low rate of species identification, more sensitive point-of-care detection methods need to be developed for P. ovale spp. and introduced in non-endemic areas.
Publisher: Springer Science and Business Media LLC
Date: 03-07-2018
DOI: 10.1038/S41467-018-04965-4
Abstract: The incidence of Plasmodium vivax infection has declined markedly in Malaysia over the past decade despite evidence of high-grade chloroquine resistance. Here we investigate the genetic changes in a P. vivax population approaching elimination in 51 isolates from Sabah, Malaysia and compare these with data from 104 isolates from Thailand and 104 isolates from Indonesia. Sabah displays extensive population structure, mirroring that previously seen with the emergence of artemisinin-resistant P. falciparum founder populations in Cambodia. Fifty-four percent of the Sabah isolates have identical genomes, consistent with a rapid clonal expansion. Across Sabah, there is a high prevalence of loci known to be associated with antimalarial drug resistance. Measures of differentiation between the three countries reveal several gene regions under putative selection in Sabah. Our findings highlight important factors pertinent to parasite resurgence and molecular cues that can be used to monitor low-endemic populations at the end stages of P. vivax elimination.
Publisher: F1000 Research Ltd
Date: 14-04-2022
DOI: 10.12688/WELLCOMEOPENRES.17795.1
Abstract: This report describes the MalariaGEN Pv4 dataset, a new release of curated genome variation data on 1,895 s les of Plasmodium vivax collected at 88 worldwide locations between 2001 and 2017. It includes 1,370 new s les contributed by MalariaGEN and VivaxGEN partner studies in addition to previously published s les from these and other sources. We provide genotype calls at over 4.5 million variable positions including over 3 million single nucleotide polymorphisms (SNPs), as well as short indels and tandem duplications. This enlarged dataset highlights major compartments of parasite population structure, with clear differentiation between Africa, Latin America, Oceania, Western Asia and different parts of Southeast Asia. Each s le has been classified for drug resistance to sulfadoxine, pyrimethamine and mefloquine based on known markers at the dhfr , dhps and mdr1 loci. The prevalence of all of these resistance markers was much higher in Southeast Asia and Oceania than elsewhere. This open resource of analysis-ready genome variation data from the MalariaGEN and VivaxGEN networks is driven by our collective goal to advance research into the complex biology of P. vivax and to accelerate genomic surveillance for malaria control and elimination.
Publisher: Oxford University Press (OUP)
Date: 15-02-2009
DOI: 10.1086/596320
Publisher: Wiley
Date: 14-07-2015
DOI: 10.1002/HBM.22835
Publisher: Elsevier BV
Date: 03-2018
Publisher: Canadian Science Publishing
Date: 02-1990
DOI: 10.1139/O90-077
Abstract: The hepatic glycine cleavage system (GCS) is the principal route for the metabolism of glycine in mammals. Flux through the GCS in isolated rat hepatocytes was stimulated by about 100% by glucagon (10 −7 M), forskolin (10 −4 M), and dibutyryl cAMP (10 −4 M). The stimulation of flux through the GCS by these agents was accompanied by marked elevation of cellular cAMP levels. A significant correlation was observed between increased cellular cAMP levels induced by glucagon and stimulation of flux through the GCS by glucagon. Exclusion of calcium from the incubation medium reduced the basal flux by 38%, but did not affect the degree of stimulation of flux through the GCS by glucagon. A single intraperitoneal injection of glucagon to rats prior to isolation of hepatocytes resulted in a 76% stimulation of flux through the GCS. These hepatocytes with stimulated flux through the GCS showed reduced sensitivity for further stimulation by glucagon. Half-maximal stimulation of flux through the GCS occurred at 3.8 ± 1.1 and 8.5 ± 1.4 nM glucagon in hepatocytes isolated from control and glucagon-injected rats, respectively. We conclude that cAMP is involved in the regulation of flux through the GCS by gluagon.Key words: amino acid, metabolism, liver, mitochondria, hormones.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-04-2016
Publisher: F1000 Research Ltd
Date: 24-02-2021
DOI: 10.12688/WELLCOMEOPENRES.16168.1
Abstract: MalariaGEN is a data-sharing network that enables groups around the world to work together on the genomic epidemiology of malaria. Here we describe a new release of curated genome variation data on 7,000 Plasmodium falciparum s les from MalariaGEN partner studies in 28 malaria-endemic countries. High-quality genotype calls on 3 million single nucleotide polymorphisms (SNPs) and short indels were produced using a standardised analysis pipeline. Copy number variants associated with drug resistance and structural variants that cause failure of rapid diagnostic tests were also analysed. Almost all s les showed genetic evidence of resistance to at least one antimalarial drug, and some s les from Southeast Asia carried markers of resistance to six commonly-used drugs. Genes expressed during the mosquito stage of the parasite life-cycle are prominent among loci that show strong geographic differentiation. By continuing to enlarge this open data resource we aim to facilitate research into the evolutionary processes affecting malaria control and to accelerate development of the surveillance toolkit required for malaria elimination.
Publisher: F1000 Research Ltd
Date: 13-07-2021
DOI: 10.12688/WELLCOMEOPENRES.16168.2
Abstract: MalariaGEN is a data-sharing network that enables groups around the world to work together on the genomic epidemiology of malaria. Here we describe a new release of curated genome variation data on 7,000 Plasmodium falciparum s les from MalariaGEN partner studies in 28 malaria-endemic countries. High-quality genotype calls on 3 million single nucleotide polymorphisms (SNPs) and short indels were produced using a standardised analysis pipeline. Copy number variants associated with drug resistance and structural variants that cause failure of rapid diagnostic tests were also analysed. Almost all s les showed genetic evidence of resistance to at least one antimalarial drug, and some s les from Southeast Asia carried markers of resistance to six commonly-used drugs. Genes expressed during the mosquito stage of the parasite life-cycle are prominent among loci that show strong geographic differentiation. By continuing to enlarge this open data resource we aim to facilitate research into the evolutionary processes affecting malaria control and to accelerate development of the surveillance toolkit required for malaria elimination.
Publisher: American Society for Microbiology
Date: 2016
DOI: 10.1128/AAC.02207-15
Abstract: Chloroquine (CQ)-resistant Plasmodium vivax is present in most countries where P. vivax infection is endemic, but the underlying molecular mechanisms responsible remain unknown. Increased expression of P. vivax crt-o ( pvcrt-o ) has been correlated with in vivo CQ resistance in an area with low-grade resistance. We assessed pvcrt-o expression in isolates from Papua (Indonesia), where P. vivax is highly CQ resistant. Ex vivo drug susceptibilities to CQ, amodiaquine, piperaquine, mefloquine, and artesunate were determined using a modified schizont maturation assay. Expression levels of pvcrt-o were measured using a novel real-time quantitative reverse transcription-PCR method. Large variations in pvcrt-o expression were observed across the 51 isolates evaluated, with the fold change in expression level ranging from 0.01 to 59 relative to that seen with the P. vivax β-tubulin gene and from 0.01 to 24 relative to that seen with the P. vivax aldolase gene. Expression was significantly higher in isolates with the majority of parasites at the ring stage of development (median fold change, 1.7) compared to those at the trophozoite stage (median fold change, 0.5 P 0.001). Twenty-nine isolates fulfilled the criteria for ex vivo drug susceptibility testing and showed high variability in CQ responses (median, 107.9 [range, 6.5 to 345.7] nM). After controlling for the parasite stage, we found that pvcrt-o expression levels did not correlate with the ex vivo response to CQ or with that to any of the other antimalarials tested. Our results highlight the importance of development-stage composition for measuring pvcrt-o expression and suggest that pvcrt-o transcription is not a primary determinant of ex vivo drug susceptibility. A comprehensive transcriptomic approach is warranted for an in-depth investigation of the role of gene expression levels and P. vivax drug resistance.
Publisher: Springer Science and Business Media LLC
Date: 28-08-2015
Publisher: Oxford University Press (OUP)
Date: 16-06-2010
DOI: 10.1093/BIOINFORMATICS/BTQ327
Abstract: Motivation: Quantifying differences in linkage disequilibrium (LD) between sub-groups can highlight genetic regions or sites under selection and/or associated with disease, and may have utility in trans-ethnic mapping studies. Results: We present a novel pseudo Bayes factor (PBF) approach that assess differences in covariance of genotype frequencies from single nucleotide polymorphism (SNP) data from a genome-wide study. The magnitude of the PBF reflects the strength of evidence for a difference, while accounting for the s le size and number of SNPs, without the requirement for permutation testing to establish statistical significance. Application of the PBF to HapMap and Gambian malaria SNP data reveals regional LD differences, some known to be under selection. Availability and implementation: The PBF approach has been implemented in the BALD (Bayesian analysis of LD differences) C++ software, and is available from homepages.lshtm.ac.uk/tgclark/downloads Contact: taane.clark@lshtm.ac.uk
Publisher: Cold Spring Harbor Laboratory
Date: 16-03-2023
DOI: 10.1101/2023.03.13.23287179
Abstract: Challenges in understanding the origin of recurrent Plasmodium vivax infections constrains the surveillance of antimalarial efficacy and transmission of this neglected parasite. Recurrent infections within an in idual may arise from activation of dormant liver stages (relapse), blood-stage treatment failure (recrudescence) or new inoculations (reinfection). Molecular inference of familial relatedness (identity-by-descent or IBD) based on whole genome sequence data, together with analysis of the intervals between parasitaemic episodes (“time-to-event” analysis), can help resolve the probable origin of recurrences. Whole genome sequencing of predominantly low-density P. vivax infections is challenging, so an accurate and scalable genotyping method to determine the origins of recurrent parasitaemia would be of significant benefit. We have developed a P. vivax genome-wide informatics pipeline to select specific microhaplotype panels that can capture IBD within small, lifiable segments of the genome. Using a global set of 615 P. vivax genomes, we derived a panel of 100 microhaplotypes, each comprising 3-10 high frequency SNPs within bp sequence windows. This panel exhibits high ersity in regions of the Asia-Pacific, Latin America and the horn of Africa (median H E = 0.70-0.81) and it captured 89% (273/307) of the polyclonal infections detected with genome-wide datasets. Using data simulations, we demonstrate lower error in estimating pairwise IBD using microhaplotypes, relative to traditional biallelic SNP barcodes. Our panel exhibited high accuracy in predicting the country of origin (median Matthew’s correlation coefficient .9 in 90% countries tested) and it also captured local infection outbreak and bottlenecking events. The informatics pipeline is available open-source and yields microhaplotypes that can be readily transferred to high-throughput licon sequencing assays for surveillance in malaria-endemic regions.
Publisher: Springer Science and Business Media LLC
Date: 27-03-2013
Publisher: Public Library of Science (PLoS)
Date: 17-12-2013
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Sarah Auburn.