ORCID Profile
0000-0003-2000-2874
Current Organisations
University of Oxford
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Menzies School of Health Research
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Publisher: Springer Science and Business Media LLC
Date: 15-08-2017
Publisher: Public Library of Science (PLoS)
Date: 10-01-2017
Publisher: Springer Science and Business Media LLC
Date: 13-06-2023
DOI: 10.1007/S43630-023-00443-Z
Abstract: UV-A- or UV-B-enriched growth light was given to basil plants at non-stress-inducing intensities. UV-A-enriched growth light gave rise to a sharp rise in the expression of PAL and CHS genes in leaves, an effect that rapidly declined after 1–2 days of exposure. On the other hand, leaves of plants grown in UV-B-enriched light had a more stable and long-lasting increase in the expression of these genes and also showed a stronger increase in leaf epidermal flavonol content. UV supplementation of growth light also led to shorter more compact plants with a stronger UV effect the younger the tissue. The effect was more prominent in plants grown under UV-B-enriched light than in those grown under UV-A. Parameters particularly affected were internode lengths, petiole lengths and stem stiffness. In fact, the bending angle of the 2nd internode was found to increase as much as 67% and 162% for plants grown in the UV-A- and UV-B-enriched treatments, respectively. The decreased stem stiffness was probably caused by both an observed smaller internode diameter and a lower specific stem weight, as well as a possible decline in lignin biosynthesis due to competition for precursors by the increased flavonoid biosynthesis. Overall, at the intensities used, UV-B wavelengths are stronger regulators of morphology, gene expression and flavonoid biosynthesis than UV-A wavelengths. Graphical abstract
Publisher: Public Library of Science (PLoS)
Date: 12-06-2018
Publisher: Springer Science and Business Media LLC
Date: 24-07-2014
Publisher: American Society of Tropical Medicine and Hygiene
Date: 07-02-2018
Abstract: Artemisinin combination therapy is recommended for the treatment of multidrug resistant Plasmodium falciparum and Plasmodium vivax . In March 2006, antimalarial policy in Indonesia was changed to a unified treatment with dihydroartemisinin-piperaquine for all species of malaria because of the low efficacy of previous drug treatments. In 2013, a randomized cross-sectional household survey in Papua was used to collect data on demographics, parasite positivity, treatment-seeking behavior, diagnosis and treatment of malaria, and household costs. Results were compared with a similar survey undertaken in 2005. A total of 800 households with 4,010 in iduals were included in the 2013 survey. The prevalence of malaria parasitemia was 12% (348/2,795). Of the in iduals who sought treatment of fever, 67% (66/98) reported attending a public provider at least once compared with 46% (349/764) before policy change ( P 0.001). During the 100 visits to healthcare providers, 95% (95) included a blood test for malaria and 74% (64/86) resulted in the recommended antimalarial for the diagnosed species, the corresponding figures before policy change were 48% (433/894) and 23% (78/336). The proportion of in iduals seeking treatment more than once fell from 14% (107/764) before policy change to 2% (2/98) after policy change ( P = 0.005). The mean indirect cost per fever episode requiring treatment seeking decreased from US$44.2 in 2005 to US$33.8 in 2013 ( P = 0.006). The implementation of a highly effective antimalarial treatment was associated with better adherence of healthcare providers in both the public and private sectors and a reduction in clinical malaria and household costs.
Publisher: Public Library of Science (PLoS)
Date: 30-11-2017
Publisher: Springer Science and Business Media LLC
Date: 24-05-2017
DOI: 10.1038/NCOMMS15159
Abstract: K13 gene mutations are a primary marker of artemisinin resistance in Plasmodium falciparum malaria that threatens the long-term clinical utility of artemisinin-based combination therapies, the cornerstone of modern day malaria treatment. Here we describe a multinational drug discovery programme that has delivered a synthetic tetraoxane-based molecule, E209, which meets key requirements of the Medicines for Malaria Venture drug candidate profiles. E209 has potent nanomolar inhibitory activity against multiple strains of P. falciparum and P. vivax in vitro , is efficacious against P. falciparum in in vivo rodent models, produces parasite reduction ratios equivalent to dihydroartemisinin and has pharmacokinetic and pharmacodynamic characteristics compatible with a single-dose cure. In vitro studies with transgenic parasites expressing variant forms of K13 show no cross-resistance with the C580Y mutation, the primary variant observed in Southeast Asia. E209 is a superior next generation endoperoxide with combined pharmacokinetic and pharmacodynamic features that overcome the liabilities of artemisinin derivatives.
Publisher: Oxford University Press (OUP)
Date: 09-1998
Publisher: Elsevier BV
Date: 06-2010
Publisher: Springer Science and Business Media LLC
Date: 20-06-2018
Publisher: Elsevier BV
Date: 06-1996
DOI: 10.1016/S0140-6736(96)91488-9
Abstract: On the western border of Thailand the efficacy of mefloquine in the treatment of falciparum malaria has declined while gametocyte carriage rates have increased, which suggests increased transmissibility of these resistant infections. We compared the following antimalarial drugs in relation to subsequent Plasmodium falciparum gametocyte carriage: mefloquine, halofantrine, quinine, and the artemisinin derivatives. Between 1990 and 1995 we assessed gametocytaemia in a series of prospective studies of antimalarial drug treatment in 5193 adults and children with acute uncomplicated falciparum malaria in an area of malarious hill forest on the western border of Thailand. Weekly parasite counts from thick and thin blood films were done during the 4-week (1990-93) or 9-week (1993-95) follow-up period. Gametocyte positivity rates and person gametocyte week (PGW) rates were calculated to measure gametocyte carriage and transmission potential. In primary P falciparum infections the gametocyte carriage rate was significantly higher after treatment with mefloquine than after treatment with the artemisinin derivatives (PGW 34.1 [95% CI 25.2-42.9] vs 3.9 [1.9-5.9] per 1000 person weeks relative risk 8.0 [4.1-15.6] p<0.0001). Recrudescent infections were associated with increased gametocyte carrier rates (relative risk 2.2 [1.6-3.0] p<0.0001), but retreatment with artemisinin derivatives reduced subsequent gametocyte carriage 18.5 fold [3.5-98] compared with mefloquine retreatment and 6.8 fold (3.1-15.1) compared with quinine retreatment (p<0.001). The introduction of the artemisinin derivatives in routine treatment at this study site in mid 1994 was associated with a reduction in the subsequent incidence of falciparum malaria of 47 (25-69)% Although environmental changes affect vector numbers, and hence malaria incidence, artemisinin derivatives were found to reduce the transmission potential of falciparum malaria. Widespread introduction of artemisinin derivatives in the treatment of falciparum malaria may prevent the spread of multidrug resistance.
Publisher: Oxford University Press (OUP)
Date: 09-1997
DOI: 10.1016/S0035-9203(97)90032-8
Abstract: On the western border of Thailand, in an area endemic for multi-drug resistant Plasmodium falciparum malaria, therapeutic responses were assessed in 1967 patients with uncomplicated falciparum malaria treated with 3 d of artesunate (total dose 12 mg/kg) plus mefloquine (total dose 25 mg/kg). The regimen was well tolerated and resulted in a rapid clinical response within 48 h, 96% of patients were aparasitaemic and 94% were afebrile. After correcting for reinfections, the cure rate by day 42 was 89% (95% confidence interval [95% CI] 87-91%). Three independent factors were found to predict recrudescence: age 40,000/microL (AHR = 1.6, 95%, CI 1.2-2.2), and pure P. falciparum infections (AHR = 1.8, 95% CI 1.3-2.7). These 3 factors combined accounted for 62% of all treatment failures. Patients who received mefloquine on admission with a high admission parasitaemia (> 40,000/microL) had a three-fold (95% CI 1.3-7) risk of subsequent recrudescence compared with those who received their mefloquine on the second or third day (P = 0.01). There has been no decline in the efficacy of the 3 d artesunate plus mefloquine regimen since it was introduced in 1992. This regimen is safe, well tolerated, and highly effective in the treatment of multi-drug resistant falciparum malaria.
Publisher: Oxford University Press (OUP)
Date: 16-11-2013
Publisher: American Society for Microbiology
Date: 11-2007
DOI: 10.1128/AAC.00486-07
Abstract: Dihydroartemisinin-piperaquine (DHP) is an important new treatment for drug-resistant malaria, although pharmacokinetic studies on the combination are limited. In Papua, Indonesia, we assessed determinants of the therapeutic efficacy of DHP for uncomplicated malaria. Plasma piperaquine concentrations were measured on day 7 and day 28, and the cumulative risk of parasitological failure at day 42 was calculated using survival analysis. Of the 598 patients in the evaluable population 342 had infections with Plasmodium falciparum , 83 with Plasmodium vivax , and 173 with a mixture of both species. The unadjusted cumulative risks of recurrence were 7.0% (95% confidence interval [CI]: 4.6 to 9.4%) for P. falciparum and 8.9% (95% CI: 6.0 to 12%) for P. vivax . After correcting for reinfections the risk of recrudescence with P. falciparum was 1.1% (95% CI: 0.1 to 2.1%). The major determinant of parasitological failure was the plasma piperaquine concentration. A concentration below 30 ng/ml on day 7 was observed in 38% (21/56) of children less than 15 years old and 22% (31/140) of adults ( P = 0.04), even though the overall dose (mg per kg of body weight) in children was 9% higher than that in adults ( P 0.001). Patients with piperaquine levels below 30 ng/ml were more likely to have a recurrence with P. falciparum (hazard ratio [HR] = 6.6 [95% CI: 1.9 to 23] P = 0.003) or P. vivax (HR = 9.0 [95% CI: 2.3 to 35] P = 0.001). The plasma concentration of piperaquine on day 7 was the major determinant of the therapeutic response to DHP. Lower plasma piperaquine concentrations and higher failure rates in children suggest that dose revision may be warranted in this age group.
Publisher: American Chemical Society (ACS)
Date: 26-06-2009
DOI: 10.1021/JP903023C
Abstract: Molecules acting as antioxidants capable of scavenging reactive oxygen species (ROS) are of the utmost importance in the living cell. The antioxidative properties of pyridoxine (vitamin B6) have recently been discovered. Previous theoretical calculations have shown a high reactivity of pyridoxine toward hydroxyl radicals, where the latter preferably abstract H from either carbon of the two methanol substituents (C8 or C9). In this study, we have explored the reactivity of pyridoxine toward further hydroxyl radicals, considering as the first step the H abstraction from either C8 or C9, also including addition reactions and cyclization. Many of the reactions display similar DeltaG, and hence, the quenching of hydroxyl radicals by pyridoxine may undergo different pathways leading to a mix of products. In addition, we observe that pyridoxine, under high hydroxyl radical concentrations, may scavenge up to eight radicals, supporting its observed high antioxidant activity.
Publisher: American Society for Microbiology
Date: 18-05-2021
DOI: 10.1128/AAC.02346-20
Abstract: Most deaths from severe falciparum malaria occur within 24 h of presentation to a hospital. Intravenous (i.v.) artesunate is the first-line treatment for severe falciparum malaria, but its efficacy may be compromised by delayed parasitological responses.
Publisher: Oxford University Press (OUP)
Date: 03-1998
DOI: 10.1016/S0035-9203(98)90750-7
Abstract: Oral artesunate is the most effective treatment for uncomplicated hyperparasitaemia in falciparum malaria. To assess the contribution of mefloquine to therapeutic efficacy in an area endemic for mefloquine-resistant Plasmodium falciparum, an open randomized comparison of a 5 d course of oral artesunate (total dose 12 mg/kg) with and without a single dose of mefloquine (25 base mg/kg) was conducted in 100 adults and children with uncomplicated hyperparasitaemia (> 4% parasitized red blood cells). Both regimens were well tolerated and gave equally rapid clinical responses (84% of patients were aparasitaemic and 96% were afebrile within 48 h), but the recrudescence rate assessed at day 42 was 6% in those receiving artesunate with mefloquine compared to 36% in those receiving artesunate alone (adjusted hazard ratio 7, 95% confidence interval [95% CI] 2-32 P < 0.01). In addition, the efficacy of a 7 d course of artesunate, with and without the addition of mefloquine, was monitored in 178 patients who were not part of the randomized comparison. The failure rate was again lower in those receiving artesunate and mefloquine--7% (95% CI 2-13) compared with 26% (95% CI 8-44) in patients treated with artesunate alone. An oral regimen of 5 d or more of artesunate, together with mefloquine (25 mg/kg) given on day 2, is an effective treatment for uncomplicated hyperparasitaemic falciparum malaria in this area of high level multidrug resistance.
Publisher: Public Library of Science (PLoS)
Date: 24-07-2020
Publisher: Public Library of Science (PLoS)
Date: 23-02-2009
Publisher: MDPI AG
Date: 14-10-2020
Abstract: Bangladesh has achieved significant progress towards malaria elimination, although health service delivery for malaria remains challenging in remote forested areas such as the Chittagong Hill Tracts (CHT). The aim of this study was to investigate perceptions of malaria and its treatment among the local population to inform contextualized strategies for rolling out radical cure for P. vivax in Bangladesh. The study comprised two sequential strands whereby the preliminary results of a qualitative strand informed the development of a structured survey questionnaire used in the quantitative strand. Results show that ethnic minority populations in the CHT live in precarious socio-economic conditions which increase their exposure to infectious diseases, and that febrile patients often self-treat, including home remedies and pharmaceuticals, before attending a healthcare facility. Perceived low quality of care and lack of communication between Bengali health providers and ethnic minority patients also affects access to public healthcare. Malaria is viewed as a condition that affects vulnerable people weakened by agricultural work and taking away blood is perceived to increase such vulnerability. Healthcare providers that initiate and sustain a dialogue about these issues with ethnic minority patients may foster the trust that is needed for local malaria elimination efforts.
Publisher: Springer Science and Business Media LLC
Date: 18-09-2015
Publisher: Elsevier BV
Date: 11-2015
Publisher: American Society of Tropical Medicine and Hygiene
Date: 11-01-2023
Abstract: Primaquine prevents relapses of Plasmodium vivax malaria but can cause severe hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The clinical and laboratory features of this outcome are usually confounded by the clinical and hemolytic effects of concomitant malaria. We describe a case of severe hemolysis occurring after a total dose of 2.04 mg/kg of primaquine used for prophylaxis in a young, G6PD-deficient (Kaiping variant), Australian man without malaria. During acute hemolysis, he had markedly elevated urinary beta-2-microglobulin, suggestive of renal tubular injury (a well-recognized complication of primaquine-induced hemolysis). He also had albuminuria and significantly increased excretion of glycocalyx metabolites, suggestive of glomerular glycocalyx degradation and injury. We show that regularly dosed paracetamol given for its putative renoprotective effect is safe in the context of severe oxidative hemolysis. Acute drug-induced hemolysis transiently increases G6PD activity. Cases such as this improve our understanding of primaquine-induced hemolysis and ultimately will help facilitate widespread safe and effective use of this critically important drug.
Publisher: Rockefeller University Press
Date: 22-10-2007
DOI: 10.1084/JEM.20070819
Abstract: Severe falciparum malaria (SM) is associated with tissue ischemia related to cytoadherence of parasitized erythrocytes to microvascular endothelium and reduced levels of NO and its precursor, l-arginine. Endothelial function has not been characterized in SM but can be improved by l-arginine in cardiovascular disease. In an observational study in Indonesia, we measured endothelial function using reactive hyperemia–peripheral arterial tonometry (RH-PAT) in 51 adults with SM, 48 patients with moderately severe falciparum malaria (MSM), and 48 controls. The mean RH-PAT index was lower in SM (1.41 95% confidence interval [CI] = 1.33–1.47) than in MSM (1.82 95% CI = 1.7–2.02) and controls (1.93 95% CI = 1.8–2.06 P & 0.0001). Endothelial dysfunction was associated with elevated blood lactate and measures of hemolysis. Exhaled NO was also lower in SM relative to MSM and controls. In an ascending dose study of intravenous l-arginine in 30 more patients with MSM, l-arginine increased the RH-PAT index by 19% (95% CI = 6–34 P = 0.006) and exhaled NO by 55% (95% CI = 32–73 P & 0.0001) without important side effects. Hypoargininemia and hemolysis likely reduce NO bioavailability. Endothelial dysfunction in malaria is nearly universal in severe disease, is reversible with l-arginine, and likely contributes to its pathogenesis. Clinical trials in SM of adjunctive agents to improve endothelial NO bioavailability, including l-arginine, are warranted.
Publisher: Oxford University Press (OUP)
Date: 15-08-2008
DOI: 10.1086/590209
Publisher: Elsevier BV
Date: 09-2006
DOI: 10.1016/J.EXPPARA.2006.02.006
Abstract: In vitro susceptibility tests provide information on the intrinsic response of Plasmodium vivax to antimalarials, free from confounding factors such as host immunity or relapse. This study examined the utility of radioisotope and PicoGreen assays as alternatives to the traditional microscopic examination for assessing response of P. vivax to antimalarial drugs. There was no significant difference in the mean chloroquine IC(50) of P. vivax (n=40) as determined by the microscopic (33.4 ng/ml), isotopic (33.6 ng/ml), and PicoGreen (39.1 ng/ml) assays, respectively (F=0.239, df=2, 51, and p=0.788). However measurement of IC(50)s by the microscopic method was slightly more successful in producing valid assays (57%), compared to the isotopic (32.5%) and PicoGreen (45.5%) methods. In a paired comparison of 20 fresh and cryopreserved isolates as examined by the microscopic method, there were no significant differences between the mean IC(50) responses (T=1.58, df=15, and p=0.34). Detailed methodologies for the short time culture of field and cryopreserved P. vivax are described. Although the microscopic in vitro assay provides a useful method for characterizing the drug susceptibility phenotype of P. vivax isolates, its utility is limited by a laborious methodology and need for highly skilled microscopists. Future efforts should focus on further development of high throughput assays such as the PicoGreen assay as described in this study.
Publisher: Wiley
Date: 11-2014
DOI: 10.1038/PSP.2014.43
Publisher: American Association for the Advancement of Science (AAAS)
Date: 21-07-2021
DOI: 10.1126/SCITRANSLMED.ABG6013
Abstract: We report an acylguanidine preclinical candidate with pharmacological features compatible with single low-dose malaria cure.
Publisher: American Chemical Society (ACS)
Date: 24-05-2011
DOI: 10.1021/CI200017F
Publisher: Oxford University Press (OUP)
Date: 15-08-2007
DOI: 10.1086/519696
Publisher: Public Library of Science (PLoS)
Date: 14-08-2013
Publisher: F1000 Research Ltd
Date: 02-06-2020
DOI: 10.12688/WELLCOMEOPENRES.15933.1
Abstract: Background: Since the coronavirus disease 2019 (COVID-19) outbreak was first reported in December 2019, many independent trials have been planned that aim to answer similar questions. Tools allowing researchers to review studies already underway can facilitate collaboration, cooperation and harmonisation. The Infectious Diseases Data Observatory (IDDO) has undertaken a living systematic review (LSR) to provide an open, accessible and frequently updated resource summarising characteristics of COVID-19 study registrations. Methods: Review of all eligible trial records identified by systematic searches as of 3 April 2020 and initial synthesis of clinical study characteristics were conducted. In partnership with Exaptive , an open access, cloud-based knowledge graph has been created using the results. Results: There were 728 study registrations which met eligibility criteria and were still active. Median (25 th , 75 th percentile) s le size was 130 (60, 400) for all studies and 134 (70, 300) for RCTs. Eight lower middle and low income countries were represented among the planned recruitment sites. Overall 109 pharmacological interventions or advanced therapy medicinal products covering 23 drug categories were studied. Majority (57%, 62/109) of them were planned only in one study arm, either alone or in combination with other interventions. There were 49 distinct combinations studied with 90% (44/49) of them administered in only one or two study arms. The data and interactive platform are available at iddo.cognitive.city/ . Conclusions: Baseline review highlighted that the majority of investigations in the first three months of the outbreak were small studies with unique treatment arms, likely to be unpowered to provide solid evidence. The continued work of this LSR will allow a more dependable overview of interventions tested, predict the likely strength of evidence generated, allow fast and informative filtering of relevant trials for specific user groups and provide the rapid guidance needed by investigators and funders to avoid duplication of efforts.
Publisher: Oxford University Press (OUP)
Date: 09-1995
DOI: 10.1016/0035-9203(95)90094-2
Abstract: To compare the therapeutic efficacy of oral artesunate and artemether in combination with mefloquine for the treatment of multidrug resistant malaria, a trial was conducted in 540 adults and children on the Thai-Myanmar border. Three regimens were compared: artesunate (4 mg/kg/d for 3 d), artemether (4 mg/kg/d for 3 d), both in combination with mefloquine (25 mg/kg), and a single dose of mefloquine (25 mg/kg). The artesunate and artemether regimens gave very similar clinical and parasitological responses, and were both very well tolerated. There was no significant adverse effect attributable to the artemisinin derivatives. Fever and parasite clearance times with mefloquine alone were significantly longer (P < 0.001). After adjusting for reinfections the failure rates were 13.9% for the artesunate combination, 12.3% for the artemether combination and 49.2% for mefloquine alone (P < 0.0001 relative risk 3.8 [95% confidence interval 2.6-5.4]). Mefloquine should no longer be used alone for the treatment of multidrug resistant falciparum malaria in this area. Three-day combination regimens with artesunate or artemether are well tolerated and more effective.
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: Public Library of Science (PLoS)
Date: 25-01-2017
Publisher: Oxford University Press (OUP)
Date: 15-02-2007
DOI: 10.1086/510756
Publisher: American Society of Tropical Medicine and Hygiene
Date: 10-2014
Publisher: EMBO
Date: 04-2022
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: 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: 29-01-2016
Publisher: Oxford University Press (OUP)
Date: 15-04-2011
Publisher: Springer Science and Business Media LLC
Date: 24-04-2015
Publisher: American Society of Tropical Medicine and Hygiene
Date: 21-08-2023
Abstract: Primaquine (PQ) kills Plasmodium vivax hypnozoites but can cause severe hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. We conducted two systematic reviews. The first used data from clinical trials to determine the variety of definitions and frequency of hematological serious adverse events (SAEs) related to PQ treatment of vivax malaria. The second used data from prospective studies and case reports to describe the clinical presentation, management, and outcome of severe PQ-associated hemolysis necessitating hospitalization. In the first review, SAEs were reported in 70 of 249 clinical trials. There were 34 hematological SAEs among 9,824 patients with P. vivax malaria treated with PQ, nine of which necessitated hospitalization or blood transfusion. Criteria used to define SAEs were erse. In the second review, 21 of 8,487 articles screened reported 163 patients hospitalized after PQ radical cure 79.9% of whom (123 of 154) were prescribed PQ at ≥ 0.5 mg/kg/day. Overall, 101 patients were categorized as having probable or possible severe PQ-associated hemolysis, 96.8% of whom were G6PD deficient ( 30% activity). The first symptoms of hemolysis were reported primarily on day 2 or 3 (45.5%), and all patients were hospitalized within 7 days of PQ commencement. A total of 57.9% of patients (77 of 133) had blood transfusion. Seven patients (6.9%) with probable or possible hemolysis died. Even when G6PD testing is available, enhanced monitoring for hemolysis is warranted after PQ treatment. Clinical review within the first 5 days of treatment may facilitate early detection and management of hemolysis. More robust definitions of severe PQ-associated hemolysis are required.
Publisher: American Society of Tropical Medicine and Hygiene
Date: 07-03-2018
Publisher: Elsevier BV
Date: 03-2007
Publisher: American Society for Clinical Investigation
Date: 15-11-2018
Publisher: Elsevier BV
Date: 07-2004
Publisher: American Society for Microbiology
Date: 10-2015
DOI: 10.1128/AAC.00874-15
Abstract: The 4-aminoquinoline naphthoquine (NQ) and the thiazine dye methylene blue (MB) have potent in vitro efficacies against Plasmodium falciparum , but susceptibility data for P. vivax are limited. The species- and stage-specific ex vivo activities of NQ and MB were assessed using a modified schizont maturation assay on clinical field isolates from Papua, Indonesia, where multidrug-resistant P. falciparum and P. vivax are prevalent. Both compounds were highly active against P. falciparum (median [range] 50% inhibitory concentration [IC 50 ]: NQ, 8.0 nM [2.6 to 71.8 nM] and MB, 1.6 nM [0.2 to 7.0 nM]) and P. vivax (NQ, 7.8 nM [1.5 to 34.2 nM] and MB, 1.2 nM [0.4 to 4.3 nM]). Stage-specific drug susceptibility assays revealed significantly greater IC 50 s in parasites exposed at the trophozoite stage than at the ring stage for NQ in P. falciparum (26.5 versus 5.1 nM, P = 0.021) and P. vivax (341.6 versus 6.5 nM, P = 0.021) and for MB in P. vivax (10.1 versus 1.6 nM, P = 0.010). The excellent ex vivo activities of NQ and MB against both P. falciparum and P. vivax highlight their potential utility for the treatment of multidrug-resistant malaria in areas where both species are endemic.
Publisher: Public Library of Science (PLoS)
Date: 29-08-2017
Publisher: Springer Science and Business Media LLC
Date: 22-08-2019
Publisher: Public Library of Science (PLoS)
Date: 04-10-2016
Publisher: Oxford University Press (OUP)
Date: 09-09-2011
Publisher: Springer Science and Business Media LLC
Date: 15-07-2015
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.PLAPHY.2018.06.025
Abstract: It has been suggested that accumulation of flavonoids could be a key step in development of plant tolerance to different environmental stresses. Moreover, it has been recognized that abiotic stresses such as drought and UV-B radiation (280-315 nm) induce phenolic compound accumulation, suggesting a role for these compounds in drought tolerance. The aim of the present study was to evaluate the effect of UV-B exposure on chili pepper (Capsicum annuum, cv. 'Coronel') plant performance, phenolic compound production, and gene expression associated with response to subsequent drought stress. Additionally, the phenotypic response to drought stress of these plants was studied. UV-B induced a reduction both in stem length, stem dry weight and number of floral primordia. The largest reduction in these variables was observed when combining UV-B and drought. UV-B-treated well-watered plants displayed fructification approximately 1 week earlier than non-UV-B-treated controls. Flavonoids measured epidermally in leaves significantly increased during UV-B treatment. Specifically, UV-B radiation significantly increased chlorogenic acid and apigenin 8-C-hexoside levels in leaves and a synergistic increase of luteolin 6-C-pentoside-8-C-hexoside was obtained by UV-B and subsequent drought stress. Gene expression of phenylalanine ammonia lyase (PAL) and chalcone synthase (CHS) genes also increased during UV-B treatments. On the other hand, expression of genes related to an oxidative response, such as mitochondrial Mn-superoxide dismutase (Mn-SOD) and peroxidase (POD) was not induced by UV-B. Drought stress in UV-B-treated plants induced mitochondrial Mn-SOD gene expression. Taken together, the UV-B treatment did not induce significant tolerance in plants towards drought stress under the conditions used.
Publisher: Springer Science and Business Media LLC
Date: 11-09-2017
Publisher: Public Library of Science (PLoS)
Date: 31-10-2007
Publisher: Public Library of Science (PLoS)
Date: 21-08-2007
Publisher: Elsevier BV
Date: 02-2021
Publisher: Public Library of Science (PLoS)
Date: 27-10-2016
Publisher: Elsevier BV
Date: 09-1996
DOI: 10.1016/S0140-6736(96)04465-0
Abstract: Previous efficacy trials of SPf66 malaria vaccine have produced conflicting results in different populations. We report a randomised double-blind trial of the SPf66 vaccine conducted in Karen children aged 2-15 living in a malarious region of northwestern Thailand. Recombinant hepatitis B vaccine was used as a comparator. The study had a power of 90% to detect an efficacy of 30%, defined as a reduction in the incidence of first cases of symptomatic falciparum malaria after three doses of vaccine. 1221 children received three immunisations and were eligible for the primary efficacy analysis. Intense active and passive case detection continued over 15 months of follow-up. The SPf66 vaccine was well tolerated, although 26 children had mild or moderately severe local or systemic allergic reactions, compared with none in the comparator group. The vaccine was immunogenic after three doses, 73% of recipients had seroconverted. There were no deaths due to malaria during the study. During the 15-month period of evaluation there were 379 first cases of symptomatic falciparum malaria (195 in the SPf66 recipients, 184 in the comparator group) an SPf66 efficacy of -9% (95% CI -33 to 14, p = 0.41). No significant differences between the two study groups in parasite density or any other measure of malaria-related morbidity were detected. These findings are consistent with a recent study showing lack of efficacy of SPf66 among Gambian infants and differ from earlier positive reports from South America and evidence of borderline efficacy from Tanzania. We conclude that SPf66 does not protect against clinical falciparum malaria and that further efficacy trials are not warranted.
Publisher: Springer Science and Business Media LLC
Date: 29-10-2010
Abstract: Severe malaria (SM) syndromes caused by Plasmodium falciparum infection result in major morbidity and mortality each year. However, only a fraction of P. falciparum infections develop into SM, implicating host genetic factors as important determinants of disease outcome. Previous studies indicate that tumour necrosis factor (TNF) and lymphotoxin alpha (LTα) may be important for the development of cerebral malaria (CM) and other SM syndromes. An extensive analysis was conducted of single nucleotide polymorphisms (SNPs) in the TNF, LTA and LTB genes in highland Papuan children and adults, a population historically unexposed to malaria that has migrated to a malaria endemic region. Generated P -values for SNPs spanning the LTA/TNF/LTB locus were corrected for multiple testing of all the SNPs and haplotype blocks within the region tested through 10,000 permutations. A global P-value of 0.05 was considered statistically significant. No associations between SNPs in the TNF/LTA/LTB locus and susceptibility to SM in highland Papuan children and adults were found. These results support the notion that unique selective pressure on the TNF/LTA/LTB locus in different populations has influenced the contribution of the gene products from this region to SM susceptibility.
Publisher: Oxford University Press (OUP)
Date: 18-12-2012
Abstract: Photomorphogenic responses triggered by low fluence rates of ultraviolet B radiation (UV-B 280–315 nm) are mediated by the UV-B photoreceptor UV RESISTANCE LOCUS8 (UVR8). Beyond our understanding of the molecular mechanisms of UV-B perception by UVR8, there is still limited information on how the UVR8 pathway functions under natural sunlight. Here, wild-type Arabidopsis (Arabidopsis thaliana) and the uvr8-2 mutant were used in an experiment outdoors where UV-A (315–400 nm) and UV-B irradiances were attenuated using plastic films. Gene expression, PYRIDOXINE BIOSYNTHESIS1 (PDX1) accumulation, and leaf metabolite signatures were analyzed. The results show that UVR8 is required for transcript accumulation of genes involved in UV protection, oxidative stress, hormone signal transduction, and defense against herbivores under solar UV. Under natural UV-A irradiance, UVR8 is likely to interact with UV-A/blue light signaling pathways to moderate UV-B-driven transcript and PDX1 accumulation. UVR8 both positively and negatively affects UV-A-regulated gene expression and metabolite accumulation but is required for the UV-B induction of phenolics. Moreover, UVR8-dependent UV-B acclimation during the early stages of plant development may enhance normal growth under long-term exposure to solar UV.
Publisher: American Society of Hematology
Date: 06-02-2017
DOI: 10.1182/BLOOD-2018-05-849307
Abstract: Platelets directly interact with and kill circulating Plasmodium parasites in patients with malaria to help control parasitemia. In vitro platelet antiplasmodicidal activity against P knowlesi involves platelet–cell binding and intracellular accumulation of PF4.
Publisher: Public Library of Science (PLoS)
Date: 22-04-2010
Publisher: Springer Science and Business Media LLC
Date: 10-08-2017
Publisher: American Chemical Society (ACS)
Date: 03-02-2011
DOI: 10.1021/JP111525P
Publisher: Springer Science and Business Media LLC
Date: 24-07-2023
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: Springer Science and Business Media LLC
Date: 20-05-2023
DOI: 10.1186/S12936-023-04578-3
Abstract: Reducing the risk of recurrent Plasmodium vivax malaria is critical for malaria control and elimination. Primaquine (PQ) is the only widely available drug against P. vivax dormant liver stages, but is recommended as a 14-day regimen, which can undermine adherence to a complete course of treatment. This is a mixed-methods study to assess socio-cultural factors influencing adherence to a 14-day PQ regimen in a 3-arm, treatment effectiveness trial in Papua, Indonesia. The qualitative strand, consisting of interviews and participant observation was triangulated with a quantitative strand in which trial participants were surveyed using a questionnaire. Trial participants differentiated between two types of malaria: tersiana and tropika , equivalent to P. vivax and Plasmodium falciparum infection, respectively. The perceived severity of both types was similar with 44.0% (267/607) perceiving tersiana vs. 45.1% (274/607) perceiving tropika as more severe. There was no perceived differentiation whether malaria episodes were due to a new infection or relapse and 71.3% (433/607) acknowledged the possibility of recurrence. Participants were familiar with malaria symptoms and delaying health facility visit by 1–2 days was perceived to increase the likelihood of a positive test. Prior to health facility visits, symptoms were treated with leftover drugs kept at home (40.4% 245/607) or bought over the counter (17.0% 103/607). Malaria was considered to be cured with ‘blue drugs’ (referring to dihydroartemisinin-piperaquine). Conversely, ‘brown drugs,’ referring to PQ, were not considered malaria medication and instead were perceived as supplements. Adherence to malaria treatment was 71.2% (131/184), in the supervised arm, 56.9% (91/160) in the unsupervised arm and 62.4% (164/263) in the control arm p = 0.019. Adherence was 47.5% (47/99) among highland Papuans, 51.7% (76/147) among lowland Papuans, and 72.9% (263/361) among non-Papuans p 0.001. Adherence to malaria treatment was a socio-culturally embedded process during which patients (re-)evaluated the characteristics of the medicines in relation to the course of the illness, their past experiences with illness, and the perceived benefits of the treatment. Structural barriers that hinder the process of patient adherence are crucial to consider in the development and rollout of effective malaria treatment policies.
Publisher: Public Library of Science (PLoS)
Date: 23-04-2021
Publisher: Elsevier BV
Date: 06-2015
Publisher: Springer Science and Business Media LLC
Date: 27-06-2016
DOI: 10.1038/NG.3599
Publisher: Public Library of Science (PLoS)
Date: 17-02-2022
DOI: 10.1371/JOURNAL.PNTD.0010174
Abstract: The introduction of novel short course treatment regimens for the radical cure of Plasmodium vivax requires reliable point-of-care diagnosis that can identify glucose-6-phosphate dehydrogenase (G6PD) deficient in iduals. While deficient males can be identified using a qualitative diagnostic test, the genetic make-up of females requires a quantitative measurement. SD Biosensor (Republic of Korea) has developed a handheld quantitative G6PD diagnostic (STANDARD G6PD test), that has approximately 90% accuracy in field studies for identifying in iduals with intermediate or severe deficiency. The device can only be considered for routine care if precision of the assay is high. Commercial lyophilised controls (ACS Analytics, USA) with high, intermediate, and low G6PD activities were assessed 20 times on 10 Biosensor devices and compared to spectrophotometry (Pointe Scientific, USA). Each device was then dispatched to one of 10 different laboratories with a standard set of the controls. Each control was tested 40 times at each laboratory by a single user and compared to spectrophotometry results. When tested at one site, the mean coefficient of variation (CV) was 0.111, 0.172 and 0.260 for high, intermediate, and low controls across all devices respectively combined G6PD Biosensor readings correlated well with spectrophotometry (r s = 0.859, p .001). When tested in different laboratories, correlation was lower (r s = 0.604, p .001) and G6PD activity determined by Biosensor for the low and intermediate controls overlapped. The use of lyophilised human blood s les rather than fresh blood may have affected these findings. Biosensor G6PD readings between sites did not differ significantly (p = 0.436), whereas spectrophotometry readings differed markedly between sites (p .001). Repeatability and inter-laboratory reproducibility of the Biosensor were good though the device did not reliably discriminate between intermediate and low G6PD activities of the lyophilized specimens. Clinical studies are now required to assess the devices performance in practice.
Publisher: Oxford University Press (OUP)
Date: 02-2009
DOI: 10.1086/596048
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: Springer Science and Business Media LLC
Date: 23-09-2022
Publisher: Springer Science and Business Media LLC
Date: 24-03-2022
DOI: 10.1186/S12936-021-03980-Z
Abstract: The duration of trial follow-up affects the ability to detect recrudescent infections following anti-malarial treatment. The aim of this study was to explore the proportions of recrudescent parasitaemia as ascribed by genotyping captured at various follow-up time-points in treatment efficacy trials for uncomplicated Plasmodium falciparum malaria. In idual patient data from 83 anti-malarial efficacy studies collated in the WorldWide Antimalarial Resistance Network (WWARN) repository with at least 28 days follow-up were available. The temporal and cumulative distributions of recrudescence were characterized using a Cox regression model with shared frailty on study-sites. Fractional polynomials were used to capture non-linear instantaneous hazard. The area under the density curve (AUC) of the constructed distribution was used to estimate the optimal follow-up period for capturing a P. falciparum malaria recrudescence. Simulation studies were conducted based on the constructed distributions to quantify the absolute overestimation in efficacy due to sub-optimal follow-up. Overall, 3703 recurrent infections were detected in 60 studies conducted in Africa (15,512 children aged 5 years) and 23 studies conducted in Asia and South America (5272 patients of all ages). Using molecular genotyping, 519 (14.0%) recurrences were ascribed as recrudescent infections. A 28 day artemether-lumefantrine (AL) efficacy trial would not have detected 58% [95% confidence interval (CI) 47–74%] of recrudescences in African children and 32% [95% CI 15–45%] in patients of all ages in Asia/South America. The corresponding estimate following a 42 day dihydroartemisinin-piperaquine (DP) efficacy trial in Africa was 47% [95% CI 19–90%] in children under 5 years old treated with 48 mg/kg total piperaquine (PIP) dose and 9% [95% CI 0–22%] in those treated with ≤ 48 mg/kg PIP dose. In absolute terms, the simulation study found that trials limited to 28 days follow-up following AL underestimated the risk of recrudescence by a median of 2.8 percentage points compared to day 63 estimates and those limited to 42 days following DP underestimated the risk of recrudescence by a median of 2.0 percentage points compared to day 42 estimates. The analysis was limited by few clinical trials following patients for longer than 42 days (9 out of 83 trials) and the imprecision of PCR genotyping which overcalls recrudescence in areas of higher transmission biasing the later distribution. Restricting follow-up of clinical efficacy trials to day 28 for AL and day 42 for DP will miss a proportion of late recrudescent treatment failures but will have a modest impact in derived efficacy. The results highlight that as genotyping methods improve consideration should be given for trials with longer duration of follow-up to detect early indications of emerging drug resistance.
Publisher: Springer Science and Business Media LLC
Date: 02-04-2019
Publisher: Springer Science and Business Media LLC
Date: 12-04-2022
DOI: 10.1186/S12936-022-04146-1
Abstract: Microscopic examination of Giemsa-stained blood films remains the reference standard for malaria parasite detection and quantification, but is undermined by difficulties in ensuring high-quality manual reading and inter-reader reliability. Automated parasite detection and quantification may address this issue. A multi-centre, observational study was conducted during 2018 and 2019 at 11 sites to assess the performance of the EasyScan Go, a microscopy device employing machine-learning-based image analysis. Sensitivity, specificity, accuracy of species detection and parasite density estimation were assessed with expert microscopy as the reference. Intra- and inter-device reliability of the device was also evaluated by comparing results from repeat reads on the same and two different devices. This study has been reported in accordance with the Standards for Reporting Diagnostic accuracy studies (STARD) checklist. In total, 2250 Giemsa-stained blood films were prepared and read independently by expert microscopists and the EasyScan Go device. The diagnostic sensitivity of EasyScan Go was 91.1% (95% CI 88.9–92.7), and specificity 75.6% (95% CI 73.1–78.0). With good quality slides sensitivity was similar (89.1%, 95%CI 86.2–91.5), but specificity increased to 85.1% (95%CI 82.6–87.4). Sensitivity increased with parasitaemia rising from 57% at 200 parasite/µL, to ≥ 90% at 200–200,000 parasite/µL. Species were identified accurately in 93% of Plasmodium falciparum s les (kappa = 0.76, 95% CI 0.69–0.83), and in 92% of Plasmodium vivax s les (kappa = 0.73, 95% CI 0.66–0.80). Parasite density estimates by the EasyScan Go were within ± 25% of the microscopic reference counts in 23% of slides. The performance of the EasyScan Go in parasite detection and species identification accuracy fulfil WHO-TDR Research Malaria Microscopy competence level 2 criteria. In terms of parasite quantification and false positive rate, it meets the level 4 WHO-TDR Research Malaria Microscopy criteria. All performance parameters were significantly affected by slide quality. Further software improvement is required to improve sensitivity at low parasitaemia and parasite density estimations. Trial registration ClinicalTrials.gov number NCT03512678.
Publisher: Elsevier BV
Date: 06-2020
Publisher: Public Library of Science (PLoS)
Date: 24-04-2009
Publisher: Elsevier BV
Date: 02-2008
Publisher: American Society for Microbiology
Date: 08-2015
DOI: 10.1128/IAI.00226-15
Abstract: Clinical illness with Plasmodium falciparum or Plasmodium vivax compromises the function of dendritic cells (DC) and expands regulatory T (Treg) cells. In iduals with asymptomatic parasitemia have clinical immunity, restricting parasite expansion and preventing clinical disease. The role of DC and Treg cells during asymptomatic Plasmodium infection is unclear. During a cross-sectional household survey in Papua, Indonesia, we examined the number and activation of blood plasmacytoid DC (pDC), CD141 + , and CD1c + myeloid DC (mDC) subsets and Treg cells using flow cytometry in 168 afebrile children (of whom 15 had P. falciparum and 36 had P. vivax infections) and 162 afebrile adults (of whom 20 had P. falciparum and 20 had P. vivax infections), alongside s les from 16 patients hospitalized with uncomplicated malaria. Unlike DC from malaria patients, DC from children and adults with asymptomatic, microscopy-positive P. vivax or P. falciparum infection increased or retained HLA-DR expression. Treg cells in asymptomatic adults and children exhibited reduced activation, suggesting increased immune responsiveness. The pDC and mDC subsets varied according to clinical immunity (asymptomatic or symptomatic Plasmodium infection) and, in asymptomatic infection, according to host age and parasite species. In conclusion, active control of asymptomatic infection was associated with and likely contingent upon functional DC and reduced Treg cell activation.
Publisher: Public Library of Science (PLoS)
Date: 09-08-2016
Publisher: Public Library of Science (PLoS)
Date: 12-03-2018
Publisher: Elsevier BV
Date: 04-2008
Abstract: The blood concentration profiles of most antimalarial drugs vary considerably between patients. The interpretation of antimalarial drug trials evaluating efficacy and effectiveness would be improved considerably if the exposure of the infecting parasite population to the antimalarial drug treatment could be measured. Artemisinin combination treatments are now recommended as first-line drugs for the treatment of falciparum malaria. Measurement of the blood, serum or plasma concentration of the slowly eliminated partner antimalarial drug on day 7 of follow-up is simpler and might be a better determinant of therapeutic response than the area under the concentration-time curve. Measurement of the day-7 drug level should be considered as a routine part of antimalarial drug trials.
Publisher: Royal Society of Chemistry (RSC)
Date: 2016
DOI: 10.1039/C6AY01342B
Abstract: Direct and indirect techniques for studying stress and acclimation responses related to pro- and anti-oxidants in plants. The larger the distance from the bull's eye, the less direct is the acquired information.
Publisher: Elsevier BV
Date: 03-2011
Publisher: Oxford University Press (OUP)
Date: 11-1999
DOI: 10.1016/S0035-9203(99)90057-3
Abstract: Genetic characterization of Plasmodium falciparum infections in north-western Thailand, a region of low transmission intensity (1 infection erson each year), has found a comparable number of parasite genotypes per infected person to regions with hyperendemic malaria. Clone multiplicity and parasite ersity were found to be homogeneous across 129 infected in iduals comprising a range of age-groups (1.32 parasite genotypes n = 98), patients (aged 2-16 years) with recrudescent infections (1.54 n = 13), and pregnant women (1.61 n = 18). In iduals belonging to groups with a high risk of infection, as deduced by clinical epidemiology, did not harbour a higher number of clones per infection, nor greater parasite ersity than low-risk groups. In fact, multiple genotype infections were as common in low-risk groups, suggesting that there is frequent transmission of polyclonal infections from a single inoculum, rather than superinfection. Such a polyclonal transmission system would enable generation of extensive parasite ersity by recombination, despite the low level of transmission. However, co-infection with P. vivax was associated with fewer P. falciparum genotypes per infection.
Publisher: Cold Spring Harbor Laboratory
Date: 05-03-2023
DOI: 10.1101/2023.03.02.23286587
Abstract: Primaquine (PQ) kills Plasmodium vivax hypnozoites but can cause haemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. We did two systematic reviews: the first used data from clinical trials to determine the spectrum of definitions and frequency of haematological serious adverse events (SAE) related to PQ treatment of vivax malaria. The second used data from prospective studies and case reports to describe the clinical presentation, management and outcome of ‘severe’ PQ-associated haemolysis necessitating hospitalisation. In the first review, SAEs were reported in 70 of 249 clinical trials. There were 34 haematological SAEs amongst 9,824 patients with vivax malaria treated with PQ, 9 of which necessitated hospitalisation or blood transfusion. Criteria used to define SAEs were erse. In the second review, 21 of 8,487 articles screened reported 163 patients hospitalised following PQ radical cure 79.9% (123/154) of whom were prescribed PQ at ≥0.5mg/kg/day. Overall, 101 patients were categorised as having probable or possible ‘severe’ PQ-associated haemolysis, 96.8% of whom were G6PD deficient ( % activity). The first symptoms of haemolysis were mostly reported on day 2 or 3 (45.5%) and all patients were hospitalised within 7 days of PQ commencement. 57.9% (77/133) of patients had blood transfusion. Seven (6.9%) patients with probable or possible haemolysis died. Even when G6PD testing is available, enhanced monitoring for haemolysis is warranted following PQ treatment. Clinical review within the first 5 days of treatment may facilitate early detection and management of haemolysis. More robust definitions of severe PQ-associated haemolysis are required. WHO-TDR, Australian National Health and Medical Research (NHMRC), The Bill & Melinda Gates Foundation.
Publisher: Elsevier BV
Date: 06-2020
Publisher: Elsevier BV
Date: 06-2015
Publisher: Elsevier BV
Date: 10-2016
Publisher: Oxford University Press (OUP)
Date: 12-02-2019
DOI: 10.1093/CID/CIZ038
Abstract: Interactions between the endothelium and infected erythrocytes play a major role in the pathogenesis of falciparum malaria, with microvascular dysfunction and parasite sequestration associated with worsening outcomes. The glycocalyx is a carbohydrate-rich layer that lines the endothelium, with multiple roles in vascular homeostasis. The role of the glycocalyx in falciparum malaria and the association with disease severity has not been investigated. We prospectively enrolled Indonesian inpatients (aged ≥18 years) with severe (SM) or moderately severe (MSM) falciparum malaria, as defined by World Health Organization criteria, and healthy controls (HCs). On enrollment, blood and urine s les were collected concurrently with measurements of vascular nitric oxide (NO) bioavailability. Urine was assayed for glycocalyx breakdown products (glycosaminoglycans) using a dimethylmethylene blue (GAG-DMMB) and liquid chromatography-tandem mass spectrometry (GAG-MS) assay. A total of 129 patients (SM = 43, MSM = 57, HC=29) were recruited. GAG-DMMB and GAG-MS (g/mol creatinine) were increased in SM (mean, 95% confidence interval: 3.98, 2.44–5.53 and 6.82, 5.19–8.44) compared to MSM patients (1.78, 1.27–2.29 and 4.87, 4.27–5.46) and HCs (0.22, 0.06–0.37 and 1.24, 0.89–1.59 P & 0.001). In SM patients, GAG-DMMB and GAG-MS were increased in those with a fatal outcome (n = 3 median, interquartile range: 6.72, 3.80–27.87 and 12.15, 7.88–17.20) compared to survivors (n = 39 3.10, 0.46–4.5 and 4.64, 2.02–15.20 P = 0.03). Glycocalyx degradation was significantly associated with parasite biomass in both MSM (r = 0.48, GAG-DMMB and r = 0.43, GAG-MS P & 0.001) and SM patients (r = 0.47, P = 0.002 and r = 0.33, P = 0.04) and inversely associated with endothelial NO bioavailability. Increased endothelial glycocalyx breakdown is associated with severe disease and a fatal outcome in adults with falciparum malaria.
Publisher: American Society for Microbiology
Date: 17-02-2022
DOI: 10.1128/IAI.00435-21
Abstract: Severe Plasmodium falciparum malaria kills many African children, and lack of antibody immunity predisposes to severe disease. A critical antibody target is the P. falciparum erythrocyte membrane 1 (PfEMP1) family of multidomain proteins, which are expressed on the infected erythrocyte surface and mediate parasite sequestration in deep organs.
Publisher: Oxford University Press (OUP)
Date: 12-2009
DOI: 10.1086/647947
Publisher: Public Library of Science (PLoS)
Date: 07-10-2020
Publisher: Elsevier BV
Date: 07-2008
DOI: 10.1053/J.AJKD.2008.03.023
Abstract: Hypertension and its cardiovascular complications affect African Americans more severely than whites, a disparity variously ascribed to low birth weight, low glomerular number, an exaggerated arteriolonephrosclerotic blood pressure response, and inflammation-induced oxidative stress. Case series. Autopsy kidneys of 107 African Americans and 87 whites aged 18 to 65 years at a single medical center between 1998 and 2005. Excluded were persons with known premorbid kidney disease pathological findings of severe arterioarteriolonephrosclerosis, nodular and diffuse diabetic glomerulosclerosis, or nonischemic cardiomyopathy. Associations of: (1) race, age, sex, birth weight, obesity, and glomerular number (predictors) with hypertension and death from coronary artery (CAD) and cerebrovascular disease (CVD outcomes) and (2) age, blood pressure, and race (predictors) with arteriolonephrosclerotic changes, including chronic tubulointerstitial inflammation (outcomes). Hypertension ascertained from chart review and heart weight. Cause of death determined from chart review and autopsy findings. Birth weight obtained from birth records (115 persons). Total glomerular number (N(glom)) estimated by using the dissector/fractionator technique. Arteriolosclerosis, glomerulosclerosis, cortical fibrosis, and chronic inflammation by using CD68 density were measured morphometrically. 59 African Americans (55%) and 32 whites (37%) were classified as hypertensive. CAD and CVD were the cause of death in 64 (33%) and 18 persons (9%), respectively. By using multiple linear regression, birth weight (P < 0.001) and sex (P < 0.01), but not race (P = 0.3) or age (P = 0.2), predicted N(glom) (P < 0.001 adjusted r(2) = 0.176). Hypertension was associated with African American race (P = 0.04), older age (P < 0.001), and male sex (P = 0.01), but not with N(glom) (P = 0.9), body mass index (P = 0.9), or birth weight (P = 0.4). Hypertension was the only significant factor associated with CAD and CVD (P < 0.001 for both). Interactions of age and blood pressure with race showed that although African Americans had more severe hypertension (P < 0.001) and arteriolosclerosis (P = 0.01) at a younger age than whites, there were no significant racial differences in degrees of arteriolosclerosis, glomerulosclerosis, cortical fibrosis, or CD68 density for any level of increased blood pressure. The study is observational and descriptive. The more severe hypertension found in African Americans could not be attributed to racial differences in N(glom) or birth weight. CAD and CVD death and increased arteriolonephrosclerosis, including CD68 density, were determined by using blood pressure without a significant interacting contribution from race.
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: MDPI AG
Date: 31-12-2020
DOI: 10.3390/PATHOGENS10010026
Abstract: Malaria elimination in the Greater Mekong Sub-Region is challenged by a rising proportion of malaria attributable to P. vivax. Primaquine (PQ) is effective in eliminating the parasite’s dormant liver stages and can prevent relapsing infections, but it induces severe haemolysis in patients with Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency, highlighting the importance of testing enzyme activity prior to treatment. A mixed-method study was conducted in south-central Vietnam to explore the factors that affect acceptability of G6PD testing, treatment-seeking behaviors, and adherence to current regimens. The majority of respondents (75.7%) were unaware of the different parasite species and rather differentiated malaria by perceived severity. People sought a diagnosis if suspected of malaria fever but not if they perceived their fevers as mild. Most respondents agreed to take prescribed medication to treat asymptomatic infection (94.1%) and to continue medication even if they felt better (91.5%). Health professionals did not have G6PD diagnostic tools nor the means to prescribe PQ safely. Adherence to treatment was linked to trust in public providers, who were perceived to make therapeutic decisions in the interest of the patient. Greater focus on providing acceptable ways of assessing G6PD deficiency will be needed to ensure the timely elimination of malaria in Vietnam.
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: 04-09-2020
DOI: 10.1186/S12936-020-03352-Z
Abstract: Microscopy performed on stained films of peripheral blood for detection, identification and quantification of malaria parasites is an essential reference standard for clinical trials of drugs, vaccines and diagnostic tests for malaria. The value of data from such research is greatly enhanced if this reference standard is consistent across time and geography. Adherence to common standards and practices is a prerequisite to achieve this. The rationale for proposed research standards and procedures for the preparation, staining and microscopic examination of blood films for malaria parasites is presented here with the aim of improving the consistency and reliability of malaria microscopy performed in such studies. These standards constitute the core of a quality management system for clinical research studies employing microscopy as a reference standard. They can be used as the basis for the design of training and proficiency testing programmes as well as for procedures and quality assurance of malaria microscopy in clinical research.
Publisher: Elsevier
Date: 2012
Publisher: American Society for Microbiology
Date: 09-2014
DOI: 10.1128/AAC.02727-13
Abstract: Renewed global efforts toward malaria eradication have highlighted the need for novel antimalarial agents with activity against multiple stages of the parasite life cycle. We have previously reported the discovery of a novel class of antimalarial compounds in the imidazolopiperazine series that have activity in the prevention and treatment of blood stage infection in a mouse model of malaria. Consistent with the previously reported activity profile of this series, the clinical candidate KAF156 shows blood schizonticidal activity with 50% inhibitory concentrations of 6 to 17.4 nM against P. falciparum drug-sensitive and drug-resistant strains, as well as potent therapeutic activity in a mouse models of malaria with 50, 90, and 99% effective doses of 0.6, 0.9, and 1.4 mg/kg, respectively. When administered prophylactically in a sporozoite challenge mouse model, KAF156 is completely protective as a single oral dose of 10 mg/kg. Finally, KAF156 displays potent Plasmodium transmission blocking activities both in vitro and in vivo . Collectively, our data suggest that KAF156, currently under evaluation in clinical trials, has the potential to treat, prevent, and block the transmission of malaria.
Publisher: Elsevier BV
Date: 09-2023
Publisher: Springer Science and Business Media LLC
Date: 30-10-2021
DOI: 10.1186/S12936-021-03959-W
Abstract: The changing global health landscape has highlighted the need for more proactive, efficient and transparent health policy-making. After more than 60 years of limited development, novel tools for vivax malaria are finally available, but need to be integrated into national policies. This paper maps the malaria policy-making processes in seven endemic countries, to identify areas where it can be improved to align with best practices and optimal efficiency. Data were collected during a workshop, convened by the Asia Pacific Malaria Elimination Network’s Vivax Working Group in 2019, and subsequent interviews with key stakeholders from Cambodia, Ethiopia, Indonesia, Pakistan, Papua New Guinea (PNG), Sri Lanka and Vietnam. Documentation of policy processes provided by respondents was reviewed. Data analysis was guided by an analytic framework focused on three a priori defined domains: “context,” “actors” and “processes”. The context of policy-making varied with available funding for malaria, population size, socio-economic status, and governance systems. There was limited documentation of the process itself or terms of reference for involved actors. In all countries, the NMP plays a critical role in initiating and informing policy change, but the involvement of other actors varied considerably. Available evidence was described as a key influencer of policy change however, the importance of local evidence and the World Health Organization’s endorsement of new treatments and diagnostics varied. The policy process itself and its complexity varied but was mostly semi-siloed from other disease specific policy processes in the wider Ministry of Health. Time taken to change and introduce a new policy guideline previously varied from 3 months to 3 years. In the medium to long term, a better alignment of anti-malarial policy-making processes with the overall health policy-making would strengthen health governance. In the immediate term, shortening the timelines for policy change will be pivotal to meet proposed malaria elimination milestones.
Publisher: American Society for Microbiology
Date: 10-2012
DOI: 10.1128/AAC.00283-12
Abstract: The declining efficacy of artemisinin derivatives against Plasmodium falciparum highlights the urgent need to identify alternative highly potent compounds for the treatment of malaria. In Papua Indonesia, where multidrug resistance has been documented against both P. falciparum and P. vivax malaria, comparative ex vivo antimalarial activity against Plasmodium isolates was assessed for the artemisinin derivatives artesunate (AS) and dihydroartemisinin (DHA), the synthetic peroxides OZ277 and OZ439, the semisynthetic 10-alkylaminoartemisinin derivatives artemisone and artemiside, and the conventional antimalarial drugs chloroquine (CQ), amodiaquine (AQ), and piperaquine (PIP). Ex vivo drug susceptibility was assessed in 46 field isolates (25 P. falciparum and 21 P. vivax ). The novel endoperoxide compounds exhibited potent ex vivo activity against both species, but significant differences in intrinsic activity were observed. Compared to AS and its active metabolite DHA, all the novel compounds showed lower or equal 50% inhibitory concentrations (IC 50 s) in both species (median IC 50 s between 1.9 and 3.6 nM in P. falciparum and 0.7 and 4.6 nM in P. vivax ). The antiplasmodial activity of novel endoperoxides showed different cross-susceptibility patterns in the two Plasmodium species: whereas their ex vivo activity correlated positively with CQ, PIP, AS, and DHA in P. falciparum , the same was not apparent in P. vivax . The current study demonstrates for the first time potent activity of novel endoperoxides against drug-resistant P. vivax . The high activity against drug-resistant strains of both Plasmodium species confirms these compounds to be promising candidates for future artemisinin-based combination therapy (ACT) regimens in regions of coendemicity.
Publisher: Springer Science and Business Media LLC
Date: 22-02-2022
DOI: 10.1186/S13104-022-05952-1
Abstract: Glucose-6-phosphate dehydrogenase (G6PD) deficiency offers some protection against malaria however, the degree of protection is poorly described and likely to vary with G6PD genotype and Plasmodium species. We present a novel approach to quantify the differential invasion rates of P. falciparum between G6PD deficient and normal red blood cells (RBCs) in an ex vivo model. A flow-cytometry based assay was developed to distinguish G6PD deficient and normal, parasitized and non-parasitized RBCs within the same s le. Venous blood collected from a G6PD heterozygous female was infected and cultured ex vivo with a laboratory strain of P. falciparum (FC27). Aliquots of infected blood were assayed at schizont and subsequent synchronized ring stages. At schizont stage, 84.9% of RBCs were G6PD deficient of which 0.4% were parasitized compared to 2.0% of normal RBCs. In the subsequent ring stage, 90.4% of RBCs were deficient and 0.2% of deficient and 0.9% of normal cells respectively were parasitized. The pooled Odds Ratio for a deficient RBC to be parasitized was 0.2 (95% confidence interval: 0.18–0.22, p 0.001) compared to a normal cell. Further studies are warranted to explore preferential parasitization with different G6PD variants and Plasmodium species.
Publisher: Springer Science and Business Media LLC
Date: 02-08-2018
Publisher: Elsevier BV
Date: 2009
DOI: 10.1016/J.PEP.2008.09.004
Abstract: In Pisum sativum, the short-chain alcohol dehydrogenase-like protein (SAD) gene family consists of at least three members (SAD-A, -B, and -C). Expression of two of these genes (SAD-A and -C) in Escherichia coli or Pichia pastoris resulted in full-length soluble proteins. Purified SAD-A was used as antigen for antibody production in rabbits. With these antibodies the recombinant SAD-C protein (which was most highly expressed of the two isoforms) was shown to be a tetramer consisting of a dimer of dimers. The SAD genes are transiently expressed in plants by short exposures to ultraviolet-B radiation (UV-B), as judged by northern blotting. In turn, mRNA accumulation leads to formation of SAD protein in leaf and stem tissue upon prolonged UV-B irradiation.
Publisher: Springer Science and Business Media LLC
Date: 05-07-2019
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: MDPI AG
Date: 06-10-2022
Abstract: Flaviviruses are a threat to public health and can cause major disease outbreaks. Tick-borne encephalitis (TBE) is caused by a flavivirus, and it is one of the most important causes of viral encephalitis in Europe and is on the rise in Sweden. As there is no antiviral treatment available, vaccination remains the best protective measure against TBE. Currently available TBE vaccines are based on formalin-inactivated virus produced in cell culture. These vaccines must be delivered by intramuscular injection, have a burdensome immunization schedule, and may exhibit vaccine failure in certain populations. This project aimed to develop an edible TBE vaccine to trigger a stronger immune response through oral delivery of viral antigens to mucosal surfaces. We demonstrated successful expression and post-translational processing of flavivirus structural proteins which then self-assembled to form virus-like particles in Nicotiana benthamiana. We performed oral toxicity tests in mice using various plant species as potential bioreactors and evaluated the immunogenicity of the resulting edible vaccine candidate. Mice immunized with the edible vaccine candidate did not survive challenge with TBE virus. Interestingly, immunization of female mice with a commercial TBE vaccine can protect their offspring against TBE virus infection.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2009
Publisher: Public Library of Science (PLoS)
Date: 07-05-2020
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: Oxford University Press (OUP)
Date: 2007
DOI: 10.1086/509809
Publisher: Elsevier BV
Date: 12-2011
Publisher: Springer Science and Business Media LLC
Date: 21-06-2016
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: Elsevier BV
Date: 10-2013
Publisher: Springer Science and Business Media LLC
Date: 07-05-2015
Publisher: Oxford University Press (OUP)
Date: 07-2010
DOI: 10.1086/653125
Publisher: Elsevier BV
Date: 04-2010
Publisher: Elsevier BV
Date: 11-2016
Publisher: Public Library of Science (PLoS)
Date: 07-08-2012
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 08-2020
Publisher: Elsevier BV
Date: 06-2018
Publisher: Oxford University Press (OUP)
Date: 14-10-2011
DOI: 10.1093/CID/CIR631
Publisher: Wiley
Date: 03-2002
Publisher: Springer Science and Business Media LLC
Date: 02-03-2016
Publisher: Springer Science and Business Media LLC
Date: 08-2019
Publisher: Springer Science and Business Media LLC
Date: 28-10-2011
Abstract: Nucleic acid lification provides the most sensitive and accurate method to detect and identify pathogens. This is primarily useful for epidemiological investigations of malaria because the infections, often with two or more Plasmodium species present simultaneously, are frequently associated with microscopically sub-patent parasite levels and cryptic mixed infections. Numerous distinct equally adequate lification-based protocols have been described, but it is unclear which to select for epidemiological surveys. Few comparative studies are available, and none that addresses the issue of inter-laboratory variability. Blood s les were collected from patients attending malaria clinics on the Thai-Myanmar border. Frozen aliquots from 413 s les were tested independently in two laboratories by nested PCR assay. Dried blood spots on filter papers from the same patients were also tested by the nested PCR assay in one laboratory and by a multiplex PCR assay in another. The aim was to determine which protocol best detected parasites below the sensitivity level of microscopic examination. As expected PCR-based assays detected a substantial number of infected s les, or mixed infections, missed by microscopy (27 and 42 for the most sensitive assay, respectively). The protocol that was most effective at detecting these, in particular mixed infections, was a nested PCR assay with in idual secondary reactions for each of the species initiated with a template directly purified from the blood s le. However, a lesser sensitivity in detection was observed when the same protocol was conducted in another laboratory, and this significantly altered the data obtained on the parasite species distribution. The sensitivity of a given PCR assay varies between laboratories. Although, the variations are relatively minor, they primarily diminish the ability to detect low-level and mixed infections and are sufficient to obviate the main rationale to use PCR assays rather than microscopy or rapid diagnostic tests. The optimal approach to standardise methodologies is to provide PCR template standards. These will help researchers in different settings to ensure that the nucleic acid lification protocols they wish to use provide the requisite level of sensitivity, and will permit comparison between sites.
Publisher: Elsevier BV
Date: 09-2023
Publisher: Informa Healthcare
Date: 08-2000
DOI: 10.1517/13543784.9.8.1815
Abstract: Artemisinin and its derivatives, artesunate and artemether, represent a new class of antimicrobial drug with potent activity against Plasmodium falciparum. Although they show excellent efficacy in both severe and uncomplicated malaria, dosage regimens still need to be optimised and pharmacokinetic profiles defined. In the treatment of uncomplicated malaria, the artemisinin drugs should be used in combination with a long acting antimalarial to protect both drugs against the emergence of resistance. In the treatment of severe malaria, parenteral artemether is at least as effective as quinine and is simpler to use. The use of rectal preparations of artesunate and artemisinin at the rural health level will facilitate early initiation of the treatment of falciparum malaria and this may reduce the proportion of patients progressing to severe disease. All of the artemisinin drugs have comparable efficacy the choice of derivative should be based upon availability, cost and quality of the preparation. Artemisinin, artesunate and artemether are well-tolerated in both adults and children, with no evidence to date of serious clinical toxicity.
Publisher: Proceedings of the National Academy of Sciences
Date: 04-11-2008
Abstract: Adherence of parasitized erythrocytes to activated endothelium causes microvascular obstruction, tissue ischemia, and clinical complications in severe malaria (SM) however, the mechanisms leading to endothelial activation remain unclear. The angiogenic factors, angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF) are modulators of endothelial activation, with Ang-2 release from Weibel–Palade bodies (WPBs) being regulated by endothelial nitric oxide (NO). We explored the relationships between endothelial NO bioavailability, Ang-2, VEGF, tissue perfusion, and clinical outcomes in SM. We measured plasma Ang-2 and VEGF, together with biomarkers of severity from 146 adults with and without SM, in parallel with longitudinal measures of endothelial function by using reactive hyperemia peripheral arterial tonometry (a measure of endothelial NO bioavailability). Regression was used to relate concentrations of Ang-2/VEGF with malaria disease severity, biomarkers of perfusion, endothelial activation, and parasite biomass. The longitudinal relationship between Ang-2 and endothelial function was assessed by using a mixed-effects model. Ang-2 concentrations were elevated in SM and associated with increased venous lactate, plasma intercellular cell adhesion molecule-1 concentrations, parasite biomass, and mortality. In contrast, VEGF concentrations were inversely associated with these biomarkers. Ang-2 concentrations were significantly better predictors of death than venous lactate ( P = 0.03). Recovery of endothelial function was associated with falling concentrations of Ang-2. Ang-2 release from endothelial cells with reduced NO bioavailability is likely to contribute to endothelial activation, sequestered parasite biomass, impaired perfusion, and poor outcome in severe falciparum malaria. Agents that improve endothelial NO, reduce WPB exocytosis, and/or antagonize Ang-2 may have therapeutic roles in SM.
Publisher: Elsevier BV
Date: 2019
Publisher: Public Library of Science (PLoS)
Date: 06-09-2023
Publisher: Springer Science and Business Media LLC
Date: 27-05-2008
Abstract: Plasmodium vivax is a major cause of malaria and is still primarily treated with chloroquine. Chloroquine inhibits the polymerization of haem to inert haemozoin. Free haem monomers are thought to catalyze oxidative damage to the Plasmodium spp. trophozoite, the stage when haemoglobin catabolism is maximal. However preliminary in vitro observations on P. vivax clinical isolates suggest that only ring stages (early trophozoites) are sensitive to chloroquine. In this study, the stage specific action of chloroquine was investigated in synchronous cryopreserved isolates of P. vivax . The in vitro chloroquine sensitivity of paired ring and trophozoite stages from 11 cryopreserved P. vivax clinical isolates from Thailand and two Plasmodium falciparum clones (chloroquine resistant K1 and chloroquine sensitive FC27) was measured using a modified WHO microtest method and fluorometric SYBR Green I Assay. The time each stage was exposed to chloroquine treatment was controlled by washing the chloroquine off at 20 hours after the beginning of treatment. Plasmodium vivax isolates added to the assay at ring stage had significantly lower median IC 50s to chloroquine than the same isolates added at trophozoite stage (median IC 50 12 nM vs 415 nM p 0.01). Although only 36% (4/11) of the SYBR Green I assays for P. vivax were successful, both microscopy and SYBR Green I assays indicated that only P. vivax trophozoites were able to develop to schizonts at chloroquine concentrations above 100 nM. Data from this study confirms the diminished sensitivity of P. vivax trophozoites to chloroquine, the stage thought to be the target of this drug. These results raise important questions about the pharmacodynamic action of chloroquine, and highlight a fundamental difference in the activity of chloroquine between P. vivax and P. falciparum .
Publisher: Public Library of Science (PLoS)
Date: 31-01-2019
Publisher: American Society for Microbiology
Date: 2011
DOI: 10.1128/AAC.01122-10
Abstract: Reports of potential drug-resistant strains of Plasmodium malariae in western Indonesia raise concerns that chloroquine resistance may be emerging in P. malariae and P. ovale . In order to assess this, in vivo and in vitro efficacy studies were conducted in patients with monoinfection in Papua, Indonesia. Consecutive patients with uncomplicated malaria due to P. ovale or P. malariae were enrolled in a prospective clinical trial, provided with supervised chloroquine treatment, and followed for 28 days. Blood from patients with P. malariae or P. ovale parasitemia greater than 1,000 per microliter underwent in vitro antimalarial drug susceptibility testing using a modified schizont maturation assay. Of the 57 evaluable patients in the clinical study ( P. malariae , n = 46 P. ovale , n = 11), none had recurrence with the same species during follow-up. The mean parasite reduction ratio at 48 h was 86 (95% confidence interval [CI], 57 to 114) for P. malariae and 150 (95% CI, 54 to 245) for P. ovale ( P = 0.18). One patient infected with P. malariae , with 93% of parasites at the trophozoite stage, was still parasitemic on day 4. In vitro drug susceptibility assays were carried out successfully for 40 isolates (34 infected with P. malariae and 6 with P. ovale ). The P. malariae infections at trophozoite stages had significantly higher chloroquine 50% effective concentrations (EC 50 s) (median, 127.9 nM [range, 7.9 to 2,980]) than those initially exposed at the ring stage (median, 14.0 nM [range, 3.5 to 27.0] P = 0.01). The EC 50 for chloroquine in P. ovale was also higher in an isolate initially at the trophozoite stage (23.2 nM) than in the three isolates predominantly at ring stage (7.8 nM). Chloroquine retains adequate efficacy against P. ovale and P. malariae , but its marked stage specificity of action may account for reports of delayed parasite clearance times.
Publisher: eLife Sciences Publications, Ltd
Date: 06-12-2022
DOI: 10.7554/ELIFE.83433
Abstract: Tafenoquine is a newly licensed antimalarial drug for the radical cure of Plasmodium vivax malaria. The mechanism of action and optimal dosing are uncertain. We pooled in idual data from 1102 patients and 72 healthy volunteers studied in the pre-registration trials. We show that tafenoquine dose is the primary determinant of efficacy. Under an Emax model, we estimate the currently recommended 300 mg dose in a 60 kg adult (5 mg/kg) results in 70% of the maximal obtainable hypnozoiticidal effect. Increasing the dose to 7.5 mg/kg (i.e. 450 mg) would result in 90% reduction in the risk of P. vivax recurrence. After adjustment for dose, the tafenoquine terminal elimination half-life, and day 7 methaemoglobin concentration, but not the parent compound exposure, were also associated with recurrence. These results suggest that the production of oxidative metabolites is central to tafenoquine’s hypnozoiticidal efficacy. Clinical trials of higher tafenoquine doses are needed to characterise their efficacy, safety and tolerability.
Publisher: American Society of Tropical Medicine and Hygiene
Date: 04-2010
Publisher: MDPI AG
Date: 03-03-2022
DOI: 10.3390/TROPICALMED7030040
Abstract: Whipple’s disease is a rare chronic infection caused by the actinomycete Tropheryma whipplei. Patients commonly present with gastrointestinal symptoms. We present a case of classic Whipple’s disease complicated by a probable Jarisch–Herxheimer reaction following the initiation of ceftriaxone treatment.
Publisher: Oxford University Press (OUP)
Date: 03-2010
DOI: 10.1086/649928
Publisher: Springer Science and Business Media LLC
Date: 04-09-2023
Publisher: Public Library of Science (PLoS)
Date: 06-2021
DOI: 10.1371/JOURNAL.PMED.1003614
Abstract: In 2017, an estimated 14 million cases of Plasmodium vivax malaria were reported from Asia, Central and South America, and the Horn of Africa. The clinical burden of vivax malaria is largely driven by its ability to form dormant liver stages (hypnozoites) that can reactivate to cause recurrent episodes of malaria. Elimination of both the blood and liver stages of the parasites (“radical cure”) is required to achieve a sustained clinical response and prevent ongoing transmission of the parasite. Novel treatment options and point-of-care diagnostics are now available to ensure that radical cure can be administered safely and effectively. We quantified the global economic cost of vivax malaria and estimated the potential cost benefit of a policy of radical cure after testing patients for glucose-6-phosphate dehydrogenase (G6PD) deficiency. Estimates of the healthcare provider and household costs due to vivax malaria were collated and combined with national case estimates for 44 endemic countries in 2017. These provider and household costs were compared with those that would be incurred under 2 scenarios for radical cure following G6PD screening: (1) complete adherence following daily supervised primaquine therapy and (2) unsupervised treatment with an assumed 40% effectiveness. A probabilistic sensitivity analysis generated credible intervals (CrIs) for the estimates. Globally, the annual cost of vivax malaria was US$359 million (95% CrI: US$222 to 563 million), attributable to 14.2 million cases of vivax malaria in 2017. From a societal perspective, adopting a policy of G6PD deficiency screening and supervision of primaquine to all eligible patients would prevent 6.1 million cases and reduce the global cost of vivax malaria to US$266 million (95% CrI: US$161 to 415 million), although healthcare provider costs would increase by US$39 million. If perfect adherence could be achieved with a single visit, then the global cost would fall further to US$225 million, equivalent to $135 million in cost savings from the baseline global costs. A policy of unsupervised primaquine reduced the cost to US$342 million (95% CrI: US$209 to 532 million) while preventing 2.1 million cases. Limitations of the study include partial availability of country-level cost data and parameter uncertainty for the proportion of patients prescribed primaquine, patient adherence to a full course of primaquine, and effectiveness of primaquine when unsupervised. Our modelling study highlights a substantial global economic burden of vivax malaria that could be reduced through investment in safe and effective radical cure achieved by routine screening for G6PD deficiency and supervision of treatment. Novel, low-cost interventions for improving adherence to primaquine to ensure effective radical cure and widespread access to screening for G6PD deficiency will be critical to achieving the timely global elimination of P . vivax .
Publisher: Springer Science and Business Media LLC
Date: 08-06-2020
DOI: 10.1186/S12936-020-03279-5
Abstract: International regulatory authorities and funders require that research be disseminated promptly and appropriately to all involved stakeholders. However, following completion of clinical trials participants often either do not receive any feedback or materials provided are not appropriate for the context. The investigators of a multicentre anti-malarial clinical trial (the IMPROV study) conducted a dissemination meeting at one of the study sites in Ethiopia trial participants and medical staff were provided feedback on the study results. This report summarizes the dissemination strategies adopted by the investigators, including a plain language visual aid and simple communication techniques. Lessons learned are reported with a discussion on the operational challenges to dissemination of clinical trials in resource limited settings.
Publisher: Springer Science and Business Media LLC
Date: 27-04-2012
Publisher: Springer Science and Business Media LLC
Date: 30-10-2019
DOI: 10.1186/S12879-019-4497-Y
Abstract: In southern Papua, Indonesia, malaria is highly prevalent in young children and is a significant cause of morbidity and early mortality. The association between malaria and delayed mortality is unknown. Routinely-collected hospital surveillance data from southern Papua, Indonesia, were used to assess the risk of recurrent malaria and mortality within 12 months of an initial presentation with malaria in all children younger than 5 years old attending the local hospital. Analysis was primarily by Kaplan Meier and Cox regression methods. In total 15,716 children presenting with malaria between April 2004 and December 2013 were included in the analysis 6184 (39.3%) with Plasmodium falciparum, 7499 (47.7%) with P. vivax , 203 (1.3%) with P. malariae, 3 with P. ovale and 1827 (11.6%) with mixed infections . Within 1 year, 48.4% (7620/15,716) of children represented a total of 16,957 times with malaria (range 1 to 11 episodes), with the incidence of malaria being greater in patients initially presenting with P. vivax infection (1334 [95%CI 1307–1361] per 1000 patient years) compared to those with P. falciparum infection (920 [896–944]). In total 266 (1.7%) children died within 1 year of their initial presentation, 129 (48.5%) within 30 days and 137 (51.5%) between 31 and 365 days. There was no significant difference in the mortality risk in patients infected with P. vivax versus P. falciparum either before 30 days (Hazard Ratio (HR) 1.02 [0.69,1.49]) or between 31 and 365 days (HR = 1.30 [0.90,1.88]). Children who died had a greater incidence of malaria, 2280 [95%CI 1946–2671] per 1000 patient years preceding their death, compared to 1141 [95%CI 1124–1158] per 1000 patient years in those surviving. Children under-5 years old with P. vivax malaria, are at significant risk of multiple representations with malaria and of dying within 1 year of their initial presentation. Preventing recurrent malaria must be a public health priority in this vulnerable population.
Publisher: Springer Science and Business Media LLC
Date: 26-10-2017
Publisher: Springer Science and Business Media LLC
Date: 05-05-2016
Publisher: Public Library of Science (PLoS)
Date: 17-12-2013
Publisher: Public Library of Science (PLoS)
Date: 26-05-2021
DOI: 10.1371/JOURNAL.PMED.1003632
Abstract: A very large biomass of intact asexual-stage malaria parasites accumulates in the spleen of asymptomatic human in iduals infected with Plasmodium vivax . The mechanisms underlying this intense tropism are not clear. We hypothesised that immature reticulocytes, in which P . vivax develops, may display high densities in the spleen, thereby providing a niche for parasite survival. We examined spleen tissue in 22 mostly untreated in iduals naturally exposed to P . vivax and Plasmodium falciparum undergoing splenectomy for any clinical indication in malaria-endemic Papua, Indonesia (2015 to 2017). Infection, parasite and immature reticulocyte density, and splenic distribution were analysed by optical microscopy, flow cytometry, and molecular assays. Nine non-endemic control spleens from in iduals undergoing spleno-pancreatectomy in France (2017 to 2020) were also examined for reticulocyte densities. There were no exclusion criteria or s le size considerations in both patient cohorts for this demanding approach. In Indonesia, 95.5% (21/22) of splenectomy patients had asymptomatic splenic Plasmodium infection (7 P . vivax , 13 P . falciparum , and 1 mixed infection). Significant splenic accumulation of immature CD71 intermediate- and high-expressing reticulocytes was seen, with concentrations 11 times greater than in peripheral blood. Accordingly, in France, reticulocyte concentrations in the splenic effluent were higher than in peripheral blood. Greater rigidity of reticulocytes in splenic than in peripheral blood, and their higher densities in splenic cords both suggest a mechanical retention process. Asexual-stage P . vivax -infected erythrocytes of all developmental stages accumulated in the spleen, with non-phagocytosed parasite densities 3,590 times (IQR: 2,600 to 4,130) higher than in circulating blood, and median total splenic parasite loads 81 (IQR: 14 to 205) times greater, accounting for 98.7% (IQR: 95.1% to 98.9%) of the estimated total-body P . vivax biomass. More reticulocytes were in contact with sinus lumen endothelial cells in P . vivax - than in P . falciparum -infected spleens. Histological analyses revealed 96% of P . vivax rings/trophozoites and 46% of schizonts colocalised with 92% of immature reticulocytes in the cords and sinus lumens of the red pulp. Larger splenic cohort studies and similar investigations in untreated symptomatic malaria are warranted. Immature CD71 + reticulocytes and splenic P . vivax- infected erythrocytes of all asexual stages accumulate in the same splenic compartments, suggesting the existence of a cryptic endosplenic lifecycle in chronic P . vivax infection. Findings provide insight into P . vivax -specific adaptions that have evolved to maximise survival and replication in the spleen.
Publisher: Oxford University Press (OUP)
Date: 02-02-2011
DOI: 10.1093/CID/CIQ249
Publisher: Massachusetts Medical Society
Date: 19-03-2009
DOI: 10.1056/NEJMC090023
Publisher: Wiley
Date: 20-05-2021
DOI: 10.1111/PPL.13448
Abstract: Acclimation of plants to water deficit involves biochemical and physiological adjustments. Here, we studied how ultraviolet (UV)‐B exposure and exogenously applied hydrogen peroxide (H 2 O 2 ) potentiates drought tolerance in tobacco ( Nicotiana tabacum L. cv. xanthi nc). Separate and combined applications for 14 days of 1.75 kJ m −2 day −1 UV‐B radiation and 0.2 mM H 2 O 2 were assessed. Both factors, in idually and combined, resulted in inhibition of growth. Furthermore, the combined treatment led to the most compacted plants. UV‐B‐ and UV‐B + H 2 O 2 ‐treated plants increased total antioxidant capacity and foliar epidermal flavonol index. H 2 O 2 ‐ and UV‐B + H 2 O 2 ‐pre‐treated plants showed cross‐tolerance to a subsequent 7‐day moderate drought treatment, which was assessed as the absence of negative impact on growth, leaf wilting, and leaf relative water content. Plant responses to the pre‐treatment were notably different: (1) H 2 O 2 increased the activity of catalase (EC 1.11.1.6), phenylalanine ammonia lyase (EC 4.3.1.5), and peroxidase activities (EC 1.11.1.7), and (2) the combined treatment induced epidermal flavonols which were key to drought tolerance. We report synergistic effects of UV‐B and H 2 O 2 on transcription accumulation of UV RESISTANCE LOCUS 8 , NAC DOMAIN PROTEIN 13 ( NAC13 ), and BRI1‐EMS‐SUPPRESSOR 1 ( BES1 ). Our data demonstrate a pre‐treatment‐dependent response to drought for NAC13 , BES1 , and CHALCONE SYNTHASE transcript accumulation. This study highlights the potential of combining UV‐B and H 2 O 2 to improve drought tolerance which could become a useful tool to reduce water use.
Publisher: Wiley
Date: 2020
DOI: 10.1002/CTI2.1209
Publisher: Public Library of Science (PLoS)
Date: 11-06-2008
Publisher: Public Library of Science (PLoS)
Date: 13-12-2019
Publisher: Springer Science and Business Media LLC
Date: 18-05-2022
DOI: 10.1186/S13063-022-06364-Z
Abstract: Plasmodium vivax forms dormant liver stages that can reactivate weeks or months following an acute infection. Recurrent infections are often associated with a febrile illness and can cause a cumulative risk of severe anaemia, direct and indirect mortality, and onward transmission of the parasite. There is an increased risk of P. vivax parasitaemia following falciparum malaria suggesting a rationale for universal use of radically curative treatment in patients with P. falciparum malaria even in the absence of detectable P. vivax parasitaemia in areas that are co-endemic for both species. This is a multicentre, health care facility-based, randomized, controlled, open-label trial in Bangladesh, Indonesia and Ethiopia. Patients with uncomplicated falciparum malaria, G6PD activity of ≥70% of the adjusted male median (AMM) and haemoglobin levels ≥8g/dl are recruited into the study and randomized to either receive standard schizonticidal treatment plus 7-day high dose primaquine (total dose 7mg/kg) or standard care in a 1:1 ratio. Patients are followed up weekly until day 63. The primary endpoint is the incidence risk of any P. vivax parasitemia on day 63. Secondary endpoints include incidence risk on day 63 of symptomatic P. vivax malaria and the risk of any P. falciparum parasitaemia. Secondary safety outcomes include the proportion of adverse events and serious adverse events, the incidence risk of severe anaemia (Hb g/dl and g/dl) and/or the risk for blood transfusion, the incidence risk of ≥ 25% fall in haemoglobin with and without haemoglobinuria, and the incidence risk of ≥ 25% fall in haemoglobin to under 7g/dl with and without haemoglobinuria. This study evaluates the potential benefit of a universal radical cure for both P. vivax and P. falciparum in different endemic locations. If found safe and effective universal radical cure could represent a cost-effective approach to clear otherwise unrecognised P. vivax infections and hence accelerate P. vivax elimination. NCT03916003 . Registered on 12 April 2019.
Publisher: Springer Science and Business Media LLC
Date: 04-05-2009
Publisher: Elsevier BV
Date: 02-2016
Publisher: Springer Science and Business Media LLC
Date: 25-11-2014
DOI: 10.1038/NCOMMS6521
Abstract: The quest for new antimalarial drugs, especially those with novel modes of action, is essential in the face of emerging drug-resistant parasites. Here we describe a new chemical class of molecules, pyrazoleamides, with potent activity against human malaria parasites and showing remarkably rapid parasite clearance in an in vivo model. Investigations involving pyrazoleamide-resistant parasites, whole-genome sequencing and gene transfers reveal that mutations in two proteins, a calcium-dependent protein kinase (PfCDPK5) and a P-type cation-ATPase (PfATP4), are necessary to impart full resistance to these compounds. A pyrazoleamide compound causes a rapid disruption of Na + regulation in blood-stage Plasmodium falciparum parasites. Similar effect on Na + homeostasis was recently reported for spiroindolones, which are antimalarials of a chemical class quite distinct from pyrazoleamides. Our results reveal that disruption of Na + homeostasis in malaria parasites is a promising mode of antimalarial action mediated by at least two distinct chemical classes.
Publisher: Elsevier BV
Date: 04-2014
Publisher: American Society for Clinical Investigation
Date: 22-07-2021
Publisher: Oxford University Press (OUP)
Date: 09-2000
DOI: 10.1016/S0035-9203(00)90080-4
Abstract: Following a marked decline in the efficacy in vivo of mefloquine between 1990 and 1994, a combination of artesunate (4 mg/kg/d for 3 d) and mefloquine (25 mg/kg) has been used as first line treatment of uncomplicated falciparum malaria in c s for displaced persons located along the north-western border of Thailand. Antimalarial drug susceptibility of fresh isolates of Plasmodium falciparum from this population was evaluated using a radioisotope microdilution assay between 1995 and 1999. In total, 268 isolates were collected, of which 189 were from primary infections and 79 from recrudescent infections. The geometric mean 50% inhibitory concentration (IC50) values from primary infections were: dihydroartemisinin 1.2 ng/mL, artesunate 1.6 ng/mL, artemether 4.8 ng/mL, atovaquone 0.4 ng/mL, lumefantrine 32 ng/mL, chloroquine 149 ng/mL, quinine 354 ng/mL, mefloquine 27 ng/mL and halofantrine 4.1 ng/mL. A significant positive correlation was found between the susceptibility in vitro to artesunate and quinine (r = 0.43, P < 0.001), mefloquine (r = 0.46, P < 0.001), and halofantrine (r = 0.51, P < 0.001). These levels of resistance in vitro are among the highest reported and confirm continuing high level multidrug resistance in this area. Despite intensive use of the combination between 1995 and 1999 there has been a significant improvement in mefloquine sensitivity (P < 0.001) and artesunate sensitivity (P < 0.001). This supports observations in vivo that the combination of artesunate and mefloquine has reversed the previous decline in mefloquine sensitivity.
Publisher: American Society of Tropical Medicine and Hygiene
Date: 08-07-2020
Publisher: Wiley
Date: 23-09-2021
DOI: 10.1111/PPL.13551
Abstract: During recent years, we have advanced our understanding of plant molecular responses to ultraviolet radiation (UV, 280–400 nm) however, how plants respond to UV radiation under different spectral light qualities is poorly understood. In this study, cucumber plants ( Cucumis sativus “Lausanna RZ F1”) were grown under monochromatic blue, green, red, and broadband white light in combination with UV radiation. The effects of light quality and UV radiation on acclimatory responses were assessed by measuring transcript accumulation of ELONGATED HYPOCOTYL 5 ( HY5 ), CHALCONE SYNTHASE 2 ( CHS2 ), and LIGHT HARVESTING COMPLEX II ( LHCII ), and the accumulation of flavonoids and hydroxycinnamic acids in the leaves. The growth light backgrounds differentially regulated gene expression and metabolite accumulation. While HY5 and CHS2 transcripts were induced by blue and white light, LHCII was induced by white and red light. Furthermore, UV radiation antagonized the effects of blue, red, green, and white light on transcript accumulation in a gene‐dependent manner. Plants grown under blue light with supplementary UV radiation increased phenylalanine, flavonol disaccharide I and caffeic acid contents compared to those exposed only to blue light. UV radiation also induced the accumulation of flavonol disaccharide I and II, ferulic acid hexose and coumaric acid hexose in plants grown under green light. Our findings provide a further understanding of plant responses to UV radiation in combination with different light spectra and contribute to the design of light recipes for horticultural practices that aim to modify plant metabolism and ultimately improve crop quality.
Publisher: Springer Science and Business Media LLC
Date: 18-05-2011
Abstract: Quantitative data are lacking on published malaria research. The purpose of the study is to characterize trends in malaria-related literature from 1990 to 2009 in 11 Asian-Pacific countries that are committed to malaria elimination as a national goal. A systematic search was conducted for articles published from January 1990 to December 2009 in PubMed/MEDLINE using terms for malaria and 11 target countries (Bhutan, China, North Korea, Indonesia, Malaysia, Philippines, Solomon Islands, South Korea, Sri Lanka, Thailand and Vanuatu). The references were collated and categorized according to subject, Plasmodium species, and whether they contained original or derivative data. 2,700 articles published between 1990 and 2009 related to malaria in the target countries. The annual output of malaria-related papers increased linearly whereas the overall biomedical output from these countries grew exponentially. The percentage of malaria-related publications was nearly 3% (111/3741) of all biomedical publications in 1992 and decreased to less than 1% (118/12171 p 0.001) in 2009. Thailand had the highest absolute output of malaria-related papers (n = 1211), followed by China (n = 609) and Indonesia (n = 346). Solomon Islands and Vanuatu had lower absolute numbers of publications, but both countries had the highest number of publications per capita (1.3 and 2.5 papers/1,000 population). The largest percentage of papers concerned the epidemiology and control of malaria (53%) followed by studies of drugs and drug resistance (47%). There was an increase in the proportion of articles relating to epidemiology, entomology, biology, molecular biology, pathophysiology and diagnostics from the first to the second decade, whereas the percentage of papers on drugs, clinical aspects of malaria, immunology, and social sciences decreased. The proportion of malaria-related publications out of the overall biomedical output from the 11 target Asian-Pacific countries is decreasing. The discovery and evaluation of new, safe and effective drugs and vaccines is paramount. In addition the elimination of malaria will require operational research to implement and scale up interventions.
Publisher: Elsevier BV
Date: 03-2014
Publisher: American Society of Tropical Medicine and Hygiene
Date: 08-07-2020
Publisher: American Astronomical Society
Date: 02-2023
Abstract: Using data from the Green Bank Telescope (GBT) Observations of TMC-1: Hunting for Aromatic Molecules (GOTHAM) survey, we report the first astronomical detection of the C 10 H − anion. The astronomical observations also provided the necessary data to refine the spectroscopic parameters of C 10 H − . From the velocity stacked data and the matched filter response, C 10 H − is detected at σ confidence level at a column density of 4.04 − 2.23 + 10.67 × 10 11 cm −2 . A dedicated search for the C 10 H radical was also conducted toward TMC-1. In this case, the stacked molecular emission of C 10 H was detected at a ∼3.2 σ confidence interval at a column density of 2.02 − 0.82 + 2.68 × 10 11 cm −2 . However, as the determined confidence level is currently σ , we consider the identification of C 10 H as tentative. The full GOTHAM data set was also used to better characterize the physical parameters including column density, excitation temperature, line width, and source size for the C 4 H, C 6 H, and C 8 H radicals and their respective anions, and the measured column densities were compared to the predictions from a gas/grain chemical formation model and from a machine learning analysis. Given the measured values, the C 10 H − /C 10 H column density ratio is ∼ 2.0 − 1.6 + 5.9 —the highest value measured between an anion and neutral species to date. Such a high ratio is at odds with current theories for interstellar anion chemistry. For the radical species, both models can reproduce the measured abundances found from the survey however, the machine learning analysis matches the detected anion abundances much better than the gas/grain chemical model, suggesting that the current understanding of the formation chemistry of molecular anions is still highly uncertain.
Publisher: American Society for Microbiology
Date: 09-2011
DOI: 10.1128/AAC.01375-10
Abstract: Ferroquine (FQ SSR97193), a ferrocene-containing 4-aminoquinoline derivate, has potent in vitro efficacy against chloroquine (CQ)-resistant Plasmodium falciparum and CQ-sensitive P. vivax . In the current study, ex vivo FQ activity was tested in multidrug-resistant P. falciparum and P. vivax field isolates using a schizont maturation assay. Although FQ showed excellent activity against CQ-sensitive and -resistant P. falciparum and P. vivax (median 50% inhibitory concentrations [IC 50 s], 9.6 nM and 18.8 nM, respectively), there was significant cross-susceptibility with the quinoline-based drugs chloroquine, amodiaquine, and piperaquine (for P. falciparum , r = 0.546 to 0.700, P 0.001 for P. vivax , r = 0.677 to 0.821, P 0.001). The observed ex vivo cross-susceptibility is likely to reflect similar mechanisms of drug uptake/efflux and modes of drug action of this drug class. However, the potent activity of FQ against resistant isolates of both P. falciparum and P. vivax highlights a promising role for FQ as a lead antimalarial against CQ-resistant Plasmodium and a useful partner drug for artemisinin-based combination therapy.
Publisher: Springer Science and Business Media LLC
Date: 2003
DOI: 10.2165/00003495-200363060-00006
Abstract: Atovaquone roguanil is a fixed-dose combination tablet of two antimalarial agents and is highly effective for the prevention of Plasmodium falciparum malaria. In combination with proguanil, the ability of atovaquone to inhibit parasitic mitochondrial electron transport is markedly enhanced. Both atovaquone and proguanil are active against hepatic (pre-erythrocytic) stages of P. falciparum, thereby providing causal prophylaxis and eliminating the need to continue post-travel treatment beyond 7 days. Both agents are also active against erythrocytic stages of P. falciparum, thereby providing suppressive prophylaxis. Atovaquone roguanil is highly effective against drug-resistant strains of P. falciparum, and cross-resistance has not been observed between atovaquone and other antimalarial agents. In comparative, randomised clinical trials, there were no cases of P. falciparum malaria in nonimmune adults, adolescents and children (>/=11 kg) visiting malaria-endemic regions for </=28 days and receiving atovaquone roguanil (250/100 mg in adults and dosage based on bodyweight in children /=11 kg) from endemic regions who may carry some immunity to malaria (semi-immune), the prophylactic efficacy rating for atovaquone roguanil based on placebo-controlled trials was 95-100%. Atovaquone roguanil is generally well tolerated by both adults and children. The most common treatment-related adverse events in placebo-controlled trials were headache and abdominal pain, which occurred at a rate similar to that observed with placebo. Atovaquone roguanil therapy was associated with significantly fewer gastrointestinal adverse events than chloroquine plus proguanil, and significantly fewer neuropsychiatric adverse events than mefloquine in nonimmune in iduals. Significantly fewer recipients of atovaquone roguanil discontinued treatment because of adverse events than in iduals receiving chloroquine plus proguanil or mefloquine (p < 0.05). Atovaquone roguanil is a fixed-dose combination antimalarial tablet that provides effective prophylaxis of P. falciparum malaria, including drug-resistant strains. Both atovaquone and proguanil are effective against hepatic stages of P. falciparum, which means that treatment need only continue for 7 days after leaving a malaria-endemic region. Atovaquone roguanil was generally well tolerated and was associated with fewer gastrointestinal adverse events than chloroquine plus proguanil, and fewer neuropsychiatric adverse events than mefloquine. Thus, atovaquone roguanil provides effective prophylaxis of P. falciparum malaria and compared with other commonly used antimalarial agents has an improved tolerability profile, and, overall, a more convenient dosage regimen, particularly in the post-travel period.
Publisher: American Society for Microbiology
Date: 11-2004
DOI: 10.1128/AAC.48.11.4271-4280.2004
Abstract: To determine the optimum duration of follow-up for the assessment of drug efficacy against Plasmodium falciparum malaria, 96 trial arms from randomized controlled trials (RCTs) with follow-up of 28 days or longer that were conducted between 1990 and 2003 were analyzed. These trials enrolled 13,772 patients, and participating patients comprised 23% of all patients enrolled in RCTs over the past 40 years 61 (64%) trial arms were conducted in areas where the rate of malaria transmission was low, and 58 (50%) trial arms were supported by parasite genotyping to distinguish true recrudescences from reinfections. The median overall failure rate reported was 10% (range, 0 to 47%). The widely used day 14 assessment had a sensitivity of between 0 and 37% in identifying treatment failures and had no predictive value. Assessment at day 28 had a sensitivity of 66% overall (28 to 100% in in idual trials) but could be used to predict the true failure rate if either parasite genotyping was performed ( r 2 = 0.94) or if the entomological inoculation rate was known. In the assessment of drug efficacy against falciparum malaria, 28 days should be the minimum period of follow-up.
Publisher: Springer Science and Business Media LLC
Date: 22-04-2009
Abstract: Analytical approaches for the interpretation of anti-malarial clinical trials vary considerably. The aim of this study was to quantify the magnitude of the differences between efficacy estimates derived from these approaches and identify the factors underlying these differences. Data from studies conducted in Africa and Thailand were compiled and the risk estimates of treatment failure, adjusted and unadjusted by genotyping, were derived by three methods (intention to treat (ITT), modified intention to treat (mITT) and per protocol (PP)) and then compared. 29 clinical trials (15 from Africa and 14 from Thailand) with a total of 65 treatment arms (38 from Africa and 27 from Thailand) were included in the analysis. Of the 15,409 patients enrolled, 2,637 (17.1%) had incomplete follow up for the unadjusted analysis and 4,489 (33.4%) for the adjusted analysis. Estimates of treatment failure were consistently higher when derived from the ITT or PP analyses compared to the mITT approach. In the unadjusted analyses the median difference between the ITT and mITT estimates was greater in Thai studies (11.4% [range 2.1–31.8]) compared to African Studies (1.8% [range 0–11.7]). In the adjusted analyses the median difference between PP and mITT estimates was 1.7%, but ranged from 0 to 30.9%. The discrepancy between estimates was correlated significantly with the proportion of patients with incomplete follow-up p 0.0001. The proportion of studies with a major difference ( 5%) between adjusted PP and mITT was 28% (16/57), with the risk difference greater in African (37% 14/38) compared to Thai studies (11% 2/19). In the African studies, a major difference in the adjusted estimates was significantly more likely in studies in high transmission sites (62% 8/13) compared to studies in moderate transmission sites (24% 6/25) p = 0.035. Estimates of anti-malarial clinical efficacy vary significantly depending on the analytical methodology from which they are derived. In order to monitor temporal and spatial trends in anti-malarial efficacy, standardized analytical tools need to be applied in a transparent and systematic manner.
Publisher: Elsevier BV
Date: 08-2017
Publisher: Springer Science and Business Media LLC
Date: 07-2019
DOI: 10.1039/C9PP00151D
Abstract: UV-B exposure of plants regulates expression of numerous genes concerned with various responses. Sudden exposure of non-acclimated plants to high fluence rate, short wavelength UV-B induces expression via stress-related signaling pathways that are not specific to the UV-B stimulus, whereas low fluence rates of UV-B can regulate expression via the UV-B photoreceptor UV RESISTANCE LOCUS 8 (UVR8). However, there is little information about whether non-stressful, low fluence rate UV-B treatments can activate gene expression independently of UVR8. Here, transcriptomic analysis of wild-type and uvr8 mutant Arabidopsis exposed to low fluence rate UV-B showed that numerous genes were regulated independently of UVR8. Moreover, nearly all of these genes were distinct to those induced by stress treatments. A small number of genes were expressed at all UV-B fluence rates employed and may be concerned with activation of eustress responses that facilitate acclimation to changing conditions. Expression of the gene encoding the transcription factor ARABIDOPSIS NAC DOMAIN CONTAINING PROTEIN 13 (ANAC13) was studied to characterise a low fluence rate, UVR8-independent response. ANAC13 is induced by as little as 0.1 μmol m-2 s-1 UV-B and its regulation is independent of components of the canonical UVR8 signaling pathway COP1 and HY5/HYH. Furthermore, UV-B induced expression of ANAC13 is independent of the photoreceptors CRY1, CRY2, PHOT1 and PHOT2 and phytochromes A, B, D and E. ANAC13 expression is induced over a range of UV-B wavelengths at low doses, with maximum response at 310 nm. This study provides a basis for further investigation of UVR8 and stress independent, low fluence rate UV-B signaling pathway(s).
Publisher: Springer Science and Business Media LLC
Date: 17-08-2012
Abstract: Primaquine has been the only widely available hypnozoitocidal anti-malarial drug for half a century. Despite this its clinical efficacy is poorly characterized resulting in a lack of consensus over the optimal regimen for the radical cure of Plasmodium vivax . Published studies since 1950 of the use of primaquine regimens for preventing P. vivax relapse were reviewed. Data were extracted systematically from available papers. Primaquine regimens were categorized according to the total dose administered: very low (≤2.5 mg/kg), low ( .5 mg/kg- 5.0 mg/kg) and high (≥ 5.0 mg/kg). The risk of recurrent infection were summarized across geographical regions and the odds ratios between treatment regimens calculated after stratifying by total treatment dose and duration of study follow up. Data could be retrieved from 87 clinical trials presenting data in 59,735 patients enrolled into 156 treatment arms, conducted in 20 countries. There was marked heterogeneity in study design, particularly primaquine dosing and duration of follow up. The median rate of recurrence following very low dose of primaquine (n = 44) was 25% (range 0-90%) at 4–6 months, compared to 6.7 % (range 0-59%) following low dose primaquine (n = 82). High dose primaquine regimens were assessed in 28 treatment arms, and were associated with a median recurrence rate of 0% (Range: 0-15%) at one month. In 18 studies with control arms, the effectiveness of a very low dose primaquine regimen was no different from patients who did not receive primaquine (OR = 0.60, 95%CI 0.33-1.09, p = 0.09), whereas for the low dose regimens a significant difference was reported in 50% (6/12) of studies (overall OR = 0.14, 95%CI: 0.06-0.35, p 0.001). Two studies enrolling 171 patients demonstrated high effectiveness of high dose primaquine compared to a control arm (OR = 0.03 (95%CI: 0.01-0.13) p 0.0001). Low dose regimens retain adequate efficacy in some areas, but this is not uniform. The efficacy and safety of pragmatic high dose primaquine regimens needs to be assessed in a range of endemic and geographical locations. Such studies will require a prolonged period of follow up and comparison with control arms to account for confounding factors.
Publisher: F1000 Research Ltd
Date: 16-01-2023
DOI: 10.12688/WELLCOMEOPENRES.18681.1
Abstract: We describe the MalariaGEN Pf7 data resource, the seventh release of Plasmodium falciparum genome variation data from the MalariaGEN network. It comprises over 20,000 s les from 82 partner studies in 33 countries, including several malaria endemic regions that were previously underrepresented. For the first time we include dried blood spot s les that were sequenced after selective whole genome lification, necessitating new methods to genotype copy number variations. We identify a large number of newly emerging crt mutations in parts of Southeast Asia, and show ex les of heterogeneities in patterns of drug resistance within Africa and within the Indian subcontinent. We describe the profile of variations in the C-terminal of the csp gene and relate this to the sequence used in the RTS,S and R21 malaria vaccines. Pf7 provides high-quality data on genotype calls for 6 million SNPs and short indels, analysis of large deletions that cause failure of rapid diagnostic tests, and systematic characterisation of six major drug resistance loci, all of which can be freely downloaded from the MalariaGEN website.
Publisher: Public Library of Science (PLoS)
Date: 17-01-2014
Publisher: American Chemical Society (ACS)
Date: 24-06-2013
DOI: 10.1021/CI4001822
Publisher: Public Library of Science (PLoS)
Date: 17-12-2013
Publisher: Public Library of Science (PLoS)
Date: 12-10-2023
Publisher: Oxford University Press (OUP)
Date: 07-2008
DOI: 10.1086/588711
Publisher: American Society of Tropical Medicine and Hygiene
Date: 05-07-2018
Publisher: Public Library of Science (PLoS)
Date: 31-12-2015
Publisher: American Chemical Society (ACS)
Date: 04-02-2019
DOI: 10.1021/ACS.JMEDCHEM.8B01799
Abstract: A series of 3,3'-disubstituted 5,5'-bi(1,2,4-triazine) derivatives was synthesized and screened against the erythrocytic stage of Plasmodium falciparum 3D7 line. The most potent dimer, 6k, with an IC
Publisher: Oxford University Press (OUP)
Date: 15-10-2018
Abstract: This study identified CD16+ DCs as the only blood DC subset distinctively activated during primary blood-stage human Plasmodium infection. As TNF/IL-10 coproducers, CD16+ DCs contribute to early inflammatory processes, yet P falciparum restimulation skewed cytokine responses further towards IL-10 production.
Publisher: Faculty of Medicine, Universitas Indonesia
Date: 11-2006
Publisher: Elsevier BV
Date: 11-2021
Publisher: Oxford University Press (OUP)
Date: 05-2008
DOI: 10.1086/586743
Publisher: Springer Science and Business Media LLC
Date: 19-04-2013
Abstract: Parasitaemia on Day 3 has been proposed as a useful alert of potential artemisinin resistance, however, the normal variation of parasite clearance observed in artemisinin-based combination therapy clinical trials is poorly documented. The trends in early parasitological response following treatment with an artemisinin anti-malarial regimen were reviewed. A PubMed literature search identified all studies using an artemisinin regimen for uncomplicated falciparum malaria published between January 2000 and December 2011. Data from clinical studies were extracted for analysis using a standardized questionnaire. In total 65,078 patients were enrolled into 213 clinical trials with 413 treatment arms containing either an artemisinin derivative alone (n=26) or in combination with a partner drug (n=387). The proportion of patients remaining parasitaemic at 24, 48 and 72 hours was documented in 115 (28%), 167 (40%) and 153 (37%) treatment arms, respectively. Excluding resistance studies in Cambodia, the median proportion of patients still parasitaemic was 53.8% [range 3–95, IQR=30.5-69.2] on Day 1, 6% [range 0–65.9, IQR=2-11.5] on Day 2 and 0 [range 0–12.6, IQR=0-2] on Day 3. Comparing studies from 2000 to 2005 and 2006 to 2011, the median proportion of patients reported to remain parasitaemic at 72 hours decreased in Africa (1.2% vs 0%, p=0.007), but increased in Asia (0.4% vs 3.9%, p=0.076). In 95% of studies the proportion of patients with peripheral parasitaemia was less than 6% at 72 hours. These results highlight the normal distribution of early parasitological responses following ACT, and the influence that heterogeneity in study design, host and parasite factors have in confounding a surveillance system based on Day 3 parasite positivity. Greater understanding of factors influencing parasite clearance is crucial, but will require analysis of pooled data from in idual patient records.
Publisher: Public Library of Science (PLoS)
Date: 24-07-2013
Publisher: Springer Science and Business Media LLC
Date: 12-2015
Publisher: Oxford University Press (OUP)
Date: 19-11-2018
Abstract: Neutrophil activation results in Plasmodium parasite killing in vitro, but neutrophil products including neutrophil extracellular traps (NETs) mediate host organ damage and may contribute to severe malaria. The role of NETs in the pathogenesis of severe malaria has not been examined. In Papua, Indonesia, we enrolled adults with symptomatic Plasmodium falciparum (n = 47 uncomplicated, n = 8 severe), Plasmodium vivax (n = 37), or Plasmodium malariae (n = 14) malaria asymptomatic P falciparum (n = 19) or P vivax (n = 21) parasitemia and healthy adults (n = 23) without parasitemia. Neutrophil activation and NETs were quantified by immunoassays and microscopy and correlated with parasite biomass and disease severity. In patients with symptomatic malaria, neutrophil activation and NET counts were increased in all 3 Plasmodium species. In falciparum malaria, neutrophil activation and NET counts positively correlated with parasite biomass (Spearman rho = 0.41, P = .005 and r2 = 0.26, P = .002, respectively) and were significantly increased in severe disease. In contrast, NETs were inversely associated with parasitemia in adults with asymptomatic P falciparum infection (r2 = 0.24, P = .031) but not asymptomatic P vivax infection. Although NETs may inhibit parasite growth in asymptomatic P falciparum infection, neutrophil activation and NET release may contribute to pathogenesis in severe falciparum malaria. Agents with potential to attenuate these processes should be evaluated.
Publisher: Elsevier BV
Date: 12-2012
Publisher: Elsevier BV
Date: 10-2010
Publisher: Elsevier
Date: 2012
Publisher: American Chemical Society (ACS)
Date: 21-01-2014
DOI: 10.1021/JP4104118
Publisher: Blue Eyes Intelligence Engineering and Sciences Engineering and Sciences Publication - BEIESP
Date: 30-11-2019
DOI: 10.35940/IJRTE.B2530.118419
Abstract: recently, a rapidly increasing type of education that is mostly adopted by higher education in developed countries is known as E-learning. The aim of the research was to evaluating students’ satisfaction of e-Learning. In the current research, both the theory of technology acceptance model (TAM) and the method of employed structural equation modelling (SEM) with Smart PLS were used to examine the process of students' adoption. It has been found that the learning satisfaction was positively influenced by the perceived ease of use (PEOU), perceived usefulness (PU) and intention to use (IU) as witnessed among university students. Significant and positive perceptions towards e-learning and intend to practice it by university students in Malaysia have been observed by this research.
Publisher: Public Library of Science (PLoS)
Date: 04-01-2013
Publisher: Springer Science and Business Media LLC
Date: 06-06-2023
DOI: 10.1186/S12936-023-04583-6
Abstract: The World Health Organization (WHO) recommends that when peripheral malarial parasitaemia is quantified by thick film microscopy, an actual white blood cell (WBC) count from a concurrently collected blood s le is used in calculations. However, in resource-limited settings an assumed WBC count is often used instead. The aim of this study was to describe the variability in WBC count during acute uncomplicated malaria, and estimate the impact of using an assumed value of WBC on estimates of parasite density and clearance. Uncomplicated malaria drug efficacy studies that measured WBC count were selected from the WorldWide Antimalarial Resistance Network data repository for an in idual patient data meta-analysis of WBC counts. Regression models with random intercepts for study-site were used to assess WBC count variability at presentation and during follow-up. Inflation factors for parasitaemia density, and clearance estimates were calculated for methods using assumed WBC counts (8000 cells/µL and age-stratified values) using estimates derived from the measured WBC value as reference. Eighty-four studies enrolling 27,656 patients with clinically uncomplicated malaria were included. Geometric mean WBC counts (× 1000 cells/µL) in age groups 1, 1–4, 5–14 and ≥ 15 years were 10.5, 8.3, 7.1, 5.7 and 7.5, 7.0, 6.5, 6.0 for in iduals with falciparum (n = 24,978) and vivax (n = 2678) malaria, respectively. At presentation, higher WBC counts were seen among patients with higher parasitaemia, severe anaemia and, for in iduals with vivax malaria, in regions with shorter regional relapse periodicity. Among falciparum malaria patients, using an assumed WBC count of 8000 cells/µL resulted in parasite density underestimation by a median (IQR) of 26% (4–41%) in infants 1 year old but an overestimation by 50% (16–91%) in adults aged ≥ 15 years. Use of age-stratified assumed WBC values removed systematic bias but did not improve precision of parasitaemia estimation. Imprecision of parasite clearance estimates was only affected by the within-patient WBC variability over time, and remained 10% for 79% of patients. Using an assumed WBC value for parasite density estimation from a thick smear may lead to underdiagnosis of hyperparasitaemia and could adversely affect clinical management but does not result in clinically consequential inaccuracies in the estimation of the prevalence of prolonged parasite clearance and artemisinin resistance.
Publisher: Wiley
Date: 06-05-2014
DOI: 10.1111/PCE.12341
Abstract: Wavelengths in the ultraviolet (UV) region of the solar spectrum, UV-B (280-315 nm) and UV-A (315-400 nm), are key environmental signals modifying several aspects of plant physiology. Despite significant advances in the understanding of plant responses to UV-B and the identification of signalling components involved, there is limited information on the molecular mechanisms that control UV-B signalling in plants under natural sunlight. Here, we aimed to corroborate the previous suggested role for RADICAL-INDUCED CELL DEATH1 (RCD1) in UV-B signalling under full spectrum sunlight. Wild-type Arabidopsis thaliana and the rcd1-1 mutant were used in an experimental design outdoors where UV-B and UV-A irradiances were manipulated using plastic films, and gene expression, PYRIDOXINE BIOSYNTHESIS1 (PDX1) accumulation and metabolite profiles were analysed in the leaves. At the level of transcription, RCD1 was not directly involved in the solar UV-B regulation of genes with functions in UV acclimation, hormone signalling and stress-related markers. Furthermore, RCD1 had no role on PDX1 accumulation but modulated the UV-B induction of flavonoid accumulation in leaves of Arabidopsis exposed to solar UV. We conclude that RCD1 does not play an active role in UV-B signalling but rather modulates UV-B responses under full spectrum sunlight.
Publisher: Springer Science and Business Media LLC
Date: 20-02-2020
DOI: 10.1186/S12916-020-1497-0
Abstract: An acute episode of malaria can be followed by multiple recurrent episodes either due to re-infection, recrudescence of a partially treated parasite or, in the case of Plasmodium vivax or P. ovale , relapse from the dormant liver stage of the parasite. The aim of this study was to quantify the impact of recurrent malaria episodes on morbidity and mortality in Papua, Indonesia. We undertook a retrospective analysis of routinely collected data from malaria patients attending the primary referral hospital in Papua, Indonesia, between April 2004 and December 2013. Multi-state modelling was used to estimate the effect of recurring malaria episodes on re-presentation and admission to hospital and death. The risks of early (≤ 14 days) and late (15 to 365 days) hospital admission and death were estimated separately in our study to distinguish between the direct and indirect effects of malaria recurrence on adverse outcomes. A total of 68,361 patients were included in the analysis, of whom 37,168 (54.4%) presented initially with P. falciparum , 22,209 (32.5%) with P. vivax , and 8984 (13.1%) with other species. During 12 months of follow-up after each of the first four malaria episodes, 10,868 (15.9%) patients were admitted to hospital and 897 (1.3%) died. The risk of re-presenting to the hospital with malaria increased from 34.7% (95% CI 34.4%, 35.1%) at first episode to 58.6% (57.5%, 59.6%) following the third episode of malaria. After adjusting for co-factors, infection with P. vivax was a significant risk factor for re-presentation (hazard ratio (HR) = 1.48 (95% CI 1.44, 1.51)) and late admission to hospital (HR = 1.17 (1.11, 1.22)). Patients infected with P. falciparum had a greater overall rate of mortality within 14 days (HR = 1.54 (1.25, 1.92)), but after multiple episodes of malaria , there was a trend towards a higher rate of early death in patients infected with P. vivax compared to P. falciparum (HR = 1.91 (0.73, 4.97)). Compared to patients initially infected with P. falciparum, those infected with P. vivax had significantly more re-presentations to hospital with malaria, and this contributed to a high risk of inpatient admission and death. These findings highlight the importance of radical cure of P. vivax to eliminate the dormant liver stages that trigger relapses.
Publisher: Springer Science and Business Media LLC
Date: 14-07-2022
DOI: 10.1186/S12936-022-04236-0
Abstract: Malaria remains endemic in Bangladesh, with the majority of cases occurring in forested, mountainous region in the Chittagong Hill Tracts (CHT). This area is home to Bengali and erse groups of indigenous people (Pahari) residing largely in mono-ethnic villages. 1002 in iduals of the 9 most prominent Pahari and the Bengali population were randomly selected and screened by RDT and qPCR. Parasites were genotyped by msp2 and deep sequencing of 5 licons ( ama1-D3, cpmp, cpp, csp , and msp7 ) for Plasmodium falciparum (n = 20), and by microsatellite (MS) typing of ten loci and licon sequencing of msp1 for Plasmodium vivax (n = 21). Population structure was analysed using STRUCTURE software. Identity-by-state (IBS) was calculated as a measure of parasite relatedness and used to generate relatedness networks. The prevalence of P. falciparum and P. vivax infection was 0.7% by RDT ( P. falciparum 6/1002 P. vivax 0/1002, mixed: 1/1002) and 4% by qPCR ( P. falciparum 21/1002 P. vivax 16/1002, mixed: 5/1002). Infections were highly clustered, with 64% (27/42) of infections occurring in only two Pahari groups, the Khumi and Mro. Diversity was high expected heterozygosity was 0.93 for P. falciparum and 0.81 for P. vivax . 85.7% (18/21) of P. vivax and 25% (5/20) of P. falciparum infections were polyclonal. No population structure was evident for either species, suggesting high transmission and gene flow among Pahari groups. High subclinical infection prevalence and genetic ersity mirror ongoing transmission. Control activities should be specifically directed to Pahari groups at greatest risk.
Publisher: Springer Science and Business Media LLC
Date: 16-06-2016
Publisher: Oxford University Press (OUP)
Date: 16-12-2021
DOI: 10.1093/IJE/DYAB259
Publisher: IEEE
Date: 07-2009
DOI: 10.1109/AHS.2009.24
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: 29-05-2012
Publisher: BMJ
Date: 19-08-2014
Publisher: Public Library of Science (PLoS)
Date: 14-09-2020
Publisher: Oxford University Press (OUP)
Date: 06-2006
DOI: 10.1086/503423
Publisher: Elsevier BV
Date: 12-2021
Publisher: AMPCo
Date: 09-02-2020
DOI: 10.5694/MJA2.50474
Publisher: Elsevier BV
Date: 03-2020
Publisher: Public Library of Science (PLoS)
Date: 14-05-2020
Publisher: Elsevier BV
Date: 09-2023
Publisher: Informa UK Limited
Date: 16-03-2016
DOI: 10.1080/08870446.2016.1146719
Abstract: The current article details a position statement and recommendations for future research and practice on planning and implementation intentions in health contexts endorsed by the Synergy Expert Group. The group comprised world-leading researchers in health and social psychology and behavioural medicine who convened to discuss priority issues in planning interventions in health contexts and develop a set of recommendations for future research and practice. The expert group adopted a nominal groups approach and voting system to elicit and structure priority issues in planning interventions and implementation intentions research. Forty-two priority issues identified in initial discussions were further condensed to 18 key issues, including definitions of planning and implementation intentions and 17 priority research areas. Each issue was subjected to voting for consensus among group members and formed the basis of the position statement and recommendations. Specifically, the expert group endorsed statements and recommendations in the following areas: generic definition of planning and specific definition of implementation intentions, recommendations for better testing of mechanisms, guidance on testing the effects of moderators of planning interventions, recommendations on the social aspects of planning interventions, identification of the preconditions that moderate effectiveness of planning interventions and recommendations for research on how people use plans.
Publisher: Springer Science and Business Media LLC
Date: 10-10-2023
Publisher: Research Square Platform LLC
Date: 12-09-2019
Abstract: Objective: Electronic data collection (EDC) has become a suitable alternative to paper based data collection (PBDC) in biomedical research even in resource poor settings. During a survey in Nepal, data were collected using both systems and data entry errors compared between both methods. Collected data were checked for completeness, values outside of realistic ranges, internal logic and date variables for reasonable time frames. Variables were grouped into 5 categories and the number of discordant entries were compared between both systems, overall and per variable category. Results: Data from 52 variables collected from 358 participants were available. Discrepancies between both data sets were found in 12.6% of all entries (2352/18,616). Differences between data points were identified in 18.0% (643/3,580) of continuous variables, 15.8% of time variables (113/716), 13.0% of date variables (140/1,074), 12.0% of text variables (86/716), and 10.9% of categorical variables (1,370/12,530). Overall 64% (1,499/2,352) of all discrepancies were due to data omissions, 76.6% (1,148/1,499) of missing entries were among categorical data. Omissions in PBDC (n=1002) were twice as frequent as in EDC (n=497, p .001). Data omissions, specifically among categorical variables were identified as the greatest source of error. If designed accordingly, EDC can address this short fall effectively.
Publisher: Research Square Platform LLC
Date: 12-09-2019
Abstract: Objective: Electronic data collection (EDC) has become a suitable alternative to paper based data collection (PBDC) in biomedical research even in resource poor settings. During a survey in Nepal, data were collected using both systems and data entry errors compared between both methods. Collected data were checked for completeness, values outside of realistic ranges, internal logic and date variables for reasonable time frames. Variables were grouped into 5 categories and the number of discordant entries were compared between both systems, overall and per variable category. Results: Data from 52 variables collected from 358 participants were available. Discrepancies between both data sets were found in 12.6% of all entries (2352/18,616). Differences between data points were identified in 18.0% (643/3,580) of continuous variables, 15.8% of time variables (113/716), 13.0% of date variables (140/1,074), 12.0% of text variables (86/716), and 10.9% of categorical variables (1,370/12,530). Overall 64% (1,499/2,352) of all discrepancies were due to data omissions, 76.6% (1,148/1,499) of missing entries were among categorical data. Omissions in PBDC (n=1002) were twice as frequent as in EDC (n=497, p .001). Data omissions, specifically among categorical variables were identified as the greatest source of error. If designed accordingly, EDC can address this short fall effectively.
Publisher: Research Square Platform LLC
Date: 11-10-2019
Abstract: Objective: Electronic data collection (EDC) has become a suitable alternative to paper based data collection (PBDC) in biomedical research even in resource poor settings. During a survey in Nepal, data were collected using both systems and data entry errors compared between both methods. Collected data were checked for completeness, values outside of realistic ranges, internal logic and date variables for reasonable time frames. Variables were grouped into 5 categories and the number of discordant entries were compared between both systems, overall and per variable category. Results: Data from 52 variables collected from 358 participants were available. Discrepancies between both data sets were found in 12.6% of all entries (2352/18,616). Differences between data points were identified in 18.0% (643/3,580) of continuous variables, 15.8% of time variables (113/716), 13.0% of date variables (140/1,074), 12.0% of text variables (86/716), and 10.9% of categorical variables (1,370/12,530). Overall 64% (1,499/2,352) of all discrepancies were due to data omissions, 76.6% (1,148/1,499) of missing entries were among categorical data. Omissions in PBDC (n=1002) were twice as frequent as in EDC (n=497, p .001). Data omissions, specifically among categorical variables were identified as the greatest source of error. If designed accordingly, EDC can address this short fall effectively.
Publisher: American Society for Microbiology
Date: 09-2015
DOI: 10.1128/AAC.01048-15
Abstract: Chloroquine (CQ) has been the mainstay of malaria treatment for more than 60 years. However, the emergence and spread of CQ resistance now restrict its use to only a few areas where malaria is endemic. The aim of the present study was to investigate whether a novel combination of a CQ-like moiety and an imipramine-like pharmacophore can reverse CQ resistance ex vivo . Between March to October 2011 and January to September 2013, two “reversed chloroquine” (RCQ) compounds (PL69 and PL106) were tested against multidrug-resistant field isolates of Plasmodium falciparum ( n = 41) and Plasmodium vivax ( n = 45) in Papua, Indonesia, using a modified ex vivo schizont maturation assay. The RCQ compounds showed high efficacy against both CQ-resistant P. falciparum and P. vivax field isolates. For P. falciparum , the median 50% inhibitory concentrations (IC 50 s) were 23.2 nM for PL69 and 26.6 nM for PL106, compared to 79.4 nM for unmodified CQ ( P 0.001 and P = 0.036, respectively). The corresponding values for P. vivax were 19.0, 60.0, and 60.9 nM ( P 0.001 and P = 0.018, respectively). There was a significant correlation between IC 50 s of CQ and PL69 (Spearman's rank correlation coefficient [ r s ] = 0.727, P 0.001) and PL106 ( r s = 0.830, P 0.001) in P. vivax but not in P. falciparum . Both RCQs were equally active against the ring and trophozoite stages of P. falciparum , but in P. vivax , PL69 and PL106 showed less potent activity against trophozoite stages (median IC 50 s, 130.2 and 172.5 nM) compared to ring stages (median IC 50 s, 17.6 and 91.3 nM). RCQ compounds have enhanced ex vivo activity against CQ-resistant clinical isolates of P. falciparum and P. vivax , suggesting the potential use of reversal agents in antimalarial drug development. Interspecies differences in RCQ compound activity may indicate differences in CQ pharmacokinetics between the two Plasmodium species.
Publisher: Research Square Platform LLC
Date: 30-08-2019
Abstract: Objective: Electronic data collection (EDC) has become a suitable alternative to paper based data collection (PBDC) in biomedical research even in resource poor settings. During a survey in Nepal, data were collected using both systems and data entry errors compared between both methods. Collected data were checked for completeness, values outside of realistic ranges, internal logic and date variables for reasonable time frames. Variables were grouped into 5 categories and the number of discordant entries were compared between both systems, overall and per variable category. Results: Data from 52 variables collected from 358 participants were available. Discrepancies between both data sets were found in 12.6% of all entries (2352/18,616). Differences between data points were identified in 18.0% (643/3,580) of continuous variables, 15.8% of time variables (113/716), 13.0% of date variables (140/1,074), 12.0% of text variables (86/716), and 10.9% of categorical variables (1,370/12,530). Overall 64% (1,499/2,352) of all discrepancies were due to data omissions, 76.6% (1,148/1,499) of missing entries were among categorical data. Omissions in PBDC (n=1002) were twice as frequent as in EDC (n=497, p .001). Data omissions, specifically among categorical variables were identified as the greatest source of error. If designed accordingly, EDC can address this short fall effectively.
Publisher: Elsevier BV
Date: 11-2023
Publisher: Public Library of Science (PLoS)
Date: 09-07-2020
Publisher: Elsevier BV
Date: 2019
Publisher: Springer Science and Business Media LLC
Date: 12-2015
Publisher: Public Library of Science (PLoS)
Date: 11-05-2022
DOI: 10.1371/JOURNAL.PNTD.0010406
Abstract: Primaquine and tafenoquine are the only licensed drugs with activity against Plasmodium vivax hypnozoites but cause haemolysis in patients with glucose–6–phosphate dehydrogenase (G6PD) deficiency. Malaria also causes haemolysis, leading to the replacement of older erythrocytes with low G6PD activity by reticulocytes and young erythrocytes with higher activity. Aim of this study was to assess the impact of acute malaria on G6PD activity. Selected patients with uncomplicated malaria were recruited in Bangladesh (n = 87), Indonesia (n = 75), and Ethiopia (n = 173) G6PD activity was measured at the initial presentation with malaria and a median of 176 days later (range 140 to 998) in the absence of malaria. Among selected participants (deficient participants preferentially enrolled in Bangladesh but not at other sites) G6PD activity fell between malaria and follow up by 79.1% (95%CI: 40.4 to 117.8) in 6 participants classified as deficient ( % activity), 43.7% (95%CI: 34.2 to 53.1) in 39 in iduals with intermediate activity (30% to %), and by 4.5% (95%CI: 1.4 to 7.6) in 290 G6PD normal (≥70%) participants. In Bangladesh and Indonesia G6PD activity was significantly higher during acute malaria than when the same in iduals were retested during follow up (40.9% (95%CI: 33.4–48.1) and 7.4% (95%CI: 0.2 to 14.6) respectively), whereas in Ethiopia G6PD activity was 3.6% (95%CI: -1.0 to -6.1) lower during acute malaria. The change in G6PD activity was apparent in patients presenting with either P . vivax or P . falciparum infection. Overall, 66.7% (4/6) severely deficient participants and 87.2% (34/39) with intermediate deficiency had normal activities when presenting with malaria. These findings suggest that G6PD activity rises significantly and at clinically relevant levels during acute malaria. Prospective case-control studies are warranted to confirm the degree to which the predicted population attributable risks of drug induced haemolysis is lower than would be predicted from cross sectional surveys.
Publisher: Elsevier BV
Date: 07-2019
Publisher: American Society for Microbiology
Date: 12-2000
DOI: 10.1128/AAC.44.12.3414-3424.2000
Abstract: Antimalarial resistance develops and spreads when spontaneously occurring mutant malaria parasites are selected by concentrations of antimalarial drug which are sufficient to eradicate the more sensitive parasites but not those with the resistance mutation(s). Mefloquine, a slowly eliminated quinoline-methanol compound, is the most widely used drug for the treatment of multidrug-resistant falciparum malaria. It has been used at doses ranging between 15 and 25 mg of base/kg of body weight. Resistance to mefloquine has developed rapidly on the borders of Thailand, where the drug has been deployed since 1984. Mathematical modeling with population pharmacokinetic and in vivo and in vitro pharmacodynamic data from this region confirms that, early in the evolution of resistance, conventional assessments of the therapeutic response ≤28 days after treatment underestimate considerably the level of resistance. Longer follow-up is required. The model indicates that initial deployment of a lower (15-mg/kg) dose of mefloquine provides a greater opportunity for the selection of resistant mutants and would be expected to lead more rapidly to resistance than de novo use of the higher (25-mg/kg) dose.
Publisher: Public Library of Science (PLoS)
Date: 06-09-2012
Publisher: American Society of Tropical Medicine and Hygiene
Date: 05-10-2016
Publisher: Wiley
Date: 2020
DOI: 10.1002/CTI2.1144
Publisher: Springer Science and Business Media LLC
Date: 17-06-2015
DOI: 10.1038/NATURE14451
Publisher: Elsevier
Date: 2012
Publisher: eLife Sciences Publications, Ltd
Date: 16-11-2022
Publisher: Elsevier BV
Date: 11-2012
Publisher: Massachusetts Medical Society
Date: 27-05-2021
DOI: 10.1056/NEJMC2023884
Publisher: Springer Science and Business Media LLC
Date: 06-03-2018
Publisher: Springer Science and Business Media LLC
Date: 02-08-2008
Abstract: Malaria is a very important cause of anaemia in tropical countries. Anaemia is assessed either by measurement of the haematocrit or the haemoglobin concentration. For comparisons across studies, it is often necessary to derive one measure from the other. Data on patients with slide-confirmed uncomplicated falciparum malaria were pooled from 85 antimalarial drug trials conducted in 25 different countries, to assess the haemoglobin/haematocrit relationship at different time points in malaria. Using a linear random effects model, a conversion equation for haematocrit was derived based on 3,254 measurements from various time points (ranging from day 0 to day 63) from 1,810 patients with simultaneous measurements of both parameters. Haemoglobin was also estimated from haematocrit with the commonly used threefold conversion. A good fit was obtained using Haematocrit = 5.62 + 2.60 * Haemoglobin. On average, haematocrit/3 levels were slightly higher than haemoglobin measurements with a mean difference (± SD) of -0.69 (± 1.3) for children under the age of 5 (n = 1,440 measurements from 449 patients). Based on this large data set, an accurate and robust conversion factor both in acute malaria and in convalescence was obtained. The commonly used threefold conversion is also valid.
Publisher: Springer Science and Business Media LLC
Date: 02-08-2008
Abstract: Multidrug resistance has emerged to both Plasmodium vivax and Plasmodium falciparum and yet the comparative epidemiology of these infections is poorly defined. All laboratory-confirmed episodes of malaria in Timika, Papua, Indonesia, presenting to community primary care clinics and an inpatient facility were reviewed over a two-year period. In addition information was gathered from a house-to-house survey to quantify the prevalence of malaria and treatment-seeking behaviour of people with fever. Between January 2004 and December 2005, 99,158 laboratory-confirmed episodes of malaria were reported, of which 58% (57,938) were attributable to P. falciparum and 37% (36,471) to P. vivax . Malaria was most likely to be attributable to pure P. vivax in children under one year of age (55% 2,684/4,889). In the household survey, the prevalence of asexual parasitaemia was 7.5% (290/3,890) for P. falciparum and 6.4% (248/3,890) for P. vivax . The prevalence of P. falciparum infection peaked in young adults aged 15–25 years (9.8% 69/707), compared to P. vivax infection which peaked in children aged 1 to 4 years (9.5% 61/642). Overall 35% (1,813/5,255) of people questioned reported a febrile episode in the preceding month. Of the 60% of people who were estimated to have had malaria, only 39% would have been detected by the surveillance network. The overall incidence of malaria was therefore estimated as 876 per 1,000 per year (Range: 711–906). In this region of multidrug-resistant P. vivax and P. falciparum , both species are associated with substantial morbidity, but with significant differences in the age-related risk of infection.
Publisher: Elsevier BV
Date: 02-2013
DOI: 10.1016/J.TPLANTS.2012.09.003
Abstract: Ultraviolet-B (UV-B) radiation has long been perceived as a stressor. However, a conceptual U-turn has taken place, and UV-B damage is now considered rare. We question whether UV-stress and UV-B-induced reactive oxygen species (ROS) are still relevant concepts, and if ROS-mediated signaling contributes to UV-B acclimation. Measurements of antioxidants and of antioxidant genes show that both low and high UV-B doses alter ROS metabolism. Yet, there is no evidence that ROS control gene expression under low UV-B. Instead, expression of antioxidant genes is linked to the UV RESISTANCE LOCUS 8 pathway. We hypothesize that low UV-B doses cause 'eustress' (good stress) and that stimuli-specific signaling pathways pre-dispose plants to a state of low alert that includes activation of antioxidant defenses.
Publisher: American Society for Microbiology
Date: 08-2017
DOI: 10.1128/AAC.00355-17
Abstract: High-grade chloroquine (CQ) resistance has emerged in both Plasmodium falciparum and P. vivax . The aim of the present study was to investigate the phenotypic differences of CQ resistance in both of these species and the ability of known CQ resistance reversal agents (CQRRAs) to alter CQ susceptibility. Between April 2015 and April 2016, the potential of verapamil (VP), mibefradil (MF), L703,606 (L7), and primaquine (PQ) to reverse CQ resistance was assessed in 46 P. falciparum and 34 P. vivax clinical isolates in Papua, Indonesia, where CQ resistance is present in both species, using a modified schizont maturation assay. In P. falciparum , CQ 50% inhibitory concentrations (IC 50 s) were reduced when CQ was combined with VP (1.4-fold), MF (1.2-fold), L7 (4.2-fold), or PQ (1.8-fold). The degree of CQ resistance reversal in P. falciparum was highly correlated with CQ susceptibility for all CQRRAs ( R 2 = 0.951, 0.852, 0.962, and 0.901 for VP, MF, L7, and PQ, respectively), in line with observations in P. falciparum laboratory strains. In contrast, no reduction in the CQ IC 50 s was observed with any of the CQRRAs in P. vivax , even in those isolates with high chloroquine IC 50 s. The differential effect of CQRRAs in P. falciparum and P. vivax suggests significant differences in CQ kinetics and, potentially, the likely mechanism of CQ resistance between these two species.
Publisher: Springer Science and Business Media LLC
Date: 16-03-2018
DOI: 10.1186/S12936-018-2266-9
Abstract: First-line schizontocidal treatment for uncomplicated malaria in the Republic of the Sudan is artesunate (total dose 12 mg/kg) plus Sulphadoxine yrimethamine (25/1.25 mg/kg) (AS/SP). Patients with Plasmodium vivax are also treated with 14 days primaquine (total dose 3.5 mg/kg) (PQ). The aim of this study was to assess the efficacy of the national policy. Patients above 1 year, with microscopy-confirmed, Plasmodium falciparum and/or P. vivax malaria were treated with AS/SP. Patients with P. falciparum were randomized to no primaquine (Pf-noPQ) or a single 0.25 mg/kg dose of PQ (Pf-PQ1). Patients with P. vivax received 14 days unsupervised 3.5 mg/kg PQ (Pv-PQ14) on day 2 or at the end of follow up (Pv-noPQ). Primary endpoint was the risk of recurrent parasitaemia at day 42. G6PD activity was measured by spectrophotometry and the Accessbio Biosensor™. 231 patients with P. falciparum (74.8%), 77 (24.9%) with P. vivax and 1 (0.3%) patient with mixed infection were enrolled. The PCR corrected cumulative risk of recurrent parasitaemia on day 42 was 3.8% (95% CI 1.2–11.2%) in the Pf-noPQ arm compared to 0.9% (95% CI 0.1–6.0%) in the Pf-PQ1 arm (HR = 0.25 [95% CI 0.03–2.38], p = 0.189). The corresponding risks of recurrence were 13.4% (95% CI 5.2–31.9%) in the Pv-noPQ arm and 5.3% (95% CI 1.3–19.4%) in the Pv-PQ14 arm (HR 0.36 [95% CI 0.1–2.0], p = 0.212). Two (0.9%) patients had G6PD enzyme activity below 10%, 19 (8.9%) patients below 60% of the adjusted male median. Correlation between spectrophotometry and Biosensor™ was low (r s = 0.330, p 0.001). AS/SP remains effective for the treatment of P. falciparum and P. vivax . The addition of PQ reduced the risk of recurrent P. falciparum and P. vivax by day 42, although this did not reach statistical significance. The version of the Biosensor™ assessed is not suitable for routine use. Trial registration t2/show/NCT02592408
Publisher: Public Library of Science (PLoS)
Date: 08-01-2015
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: Public Library of Science (PLoS)
Date: 04-10-2019
Publisher: American Society for Microbiology
Date: 03-2008
DOI: 10.1128/AAC.01334-07
Abstract: In Papua, Indonesia, the antimalarial susceptibility of Plasmodium vivax ( n = 216) and P. falciparum ( n = 277) was assessed using a modified schizont maturation assay for chloroquine, amodiaquine, artesunate, lumefantrine, mefloquine, and piperaquine. The most effective antimalarial against P. vivax and P. falciparum was artesunate, with geometric mean 50% inhibitory concentrations (IC 50 s) (95% confidence intervals [CI]) of 1.31 nM (1.07 to 1.59) and 0.64 nM (0.53 to 0.79), respectively. In contrast, the geometric mean chloroquine IC 50 for P. vivax was 295 nM (227 to 384) compared to only 47.4 nM (42.2 to 53.3) for P. falciparum . Two factors were found to significantly influence the in vitro drug response of P. vivax : the initial stage of the parasite and the duration of the assay. Isolates of P. vivax initially at the trophozoite stage had significantly higher chloroquine IC 50 s (478 nM [95% CI, 316 to 722]) than those initially at the ring stage (84.7 nM [95% CI, 45.7 to 157] P 0.001). Synchronous isolates of P. vivax and P. falciparum which reached the target of 40% schizonts in the control wells within 30 h had significantly higher geometric mean chloroquine IC 50 s (435 nM [95% CI, 169 to 1,118] and 55.9 nM [95% CI, 48 to 64.9], respectively) than isolates that took more than 30 h (39.9 nM [14.6 to 110.4] and 36.9 nM [31.2 to 43.7] P 0.005). The results demonstrate the marked stage-specific activity of chloroquine with P. vivax and suggest that susceptibility to chloroquine may be associated with variable growth rates. These findings have important implications for the phenotypic and downstream genetic characterization of P. vivax .
Publisher: Springer Science and Business Media LLC
Date: 12-2014
Publisher: Oxford University Press (OUP)
Date: 24-07-2016
Publisher: Springer Science and Business Media LLC
Date: 06-09-2007
Publisher: Wiley
Date: 25-09-2016
DOI: 10.1111/PBI.12479
Publisher: Wiley
Date: 24-03-2020
DOI: 10.1111/PCE.13752
Publisher: MDPI AG
Date: 22-05-2021
Abstract: Malaria in Bhutan has fallen significantly over the last decade. As Bhutan attempts to eliminate malaria in 2022, this study aimed to characterize the space–time clustering of malaria from 2010 to 2019. Malaria data were obtained from the Bhutan Vector-Borne Disease Control Program data repository. Spatial and space–time cluster analyses of Plasmodium falciparum and Plasmodium vivax cases were conducted at the sub-district level from 2010 to 2019 using Kulldorff’s space–time scan statistic. A total of 768 confirmed malaria cases, including 454 (59%) P. vivax cases, were reported in Bhutan during the study period. Significant temporal clusters of cases caused by both species were identified between April and September. The most likely spatial clusters were detected in the central part of Bhutan throughout the study period. The most likely space–time cluster was in Sarpang District and neighboring districts between January 2010 to June 2012 for cases of infection with both species. The most likely cluster for P. falciparum infection had a radius of 50.4 km and included 26 sub-districts with a relative risk (RR) of 32.7. The most likely cluster for P. vivax infection had a radius of 33.6 km with 11 sub-districts and RR of 27.7. Three secondary space–time clusters were detected in other parts of Bhutan. Spatial and space–time cluster analysis identified high-risk areas and periods for both P. vivax and P. falciparum malaria. Both malaria types showed significant spatial and spatiotemporal variations. Operational research to understand the drivers of residual transmission in hotspot sub-districts will help to overcome the final challenges of malaria elimination in Bhutan.
Publisher: BMJ
Date: 05-2008
Abstract: Demand for organisational ethics capacity is growing in health organisations, particularly among managers. The role of clinical ethicists in, and perspective on, organisational ethics has not been well described or documented in the literature. To describe clinical ethicists' perspectives on organisational ethics issues in their hospitals, their institutional role in relation to organisational ethics, and their perceived effectiveness in helping to address organisational ethics issues. Qualitative case study involving semi-structured interviews with 18 clinical ethicists across 13 health organisations in Toronto, Canada. From the clinical ethicists' perspective, the most pressing organisational ethics issues in their organisations are: resource allocation, staff moral distress linked to the organisation's moral climate, conflicts of interest, and clinical issues with a significant organisational dimension. Clinical ethicists were consulted in particular on issues related to staff moral distress and clinical issues with an organisational dimension. Some ethicists described being increasingly consulted on resource allocation, conflicts of interest, and other corporate decisions. Many clinical ethicists felt they lacked sufficient knowledge and understanding of organisational decision-making processes, training in organisational ethics, and access to organisational ethics tools to deal effectively with the increasing demand for organisational ethics support. Growing demand for organisational ethics expertise in healthcare institutions is reshaping the role of clinical ethicists. Effectiveness in organisational ethics entails a re-evaluation of clinical ethics training to include capacity building in organisational ethics and organisational decision-making processes as a complement to traditional clinical ethics education.
Publisher: Springer Science and Business Media LLC
Date: 18-11-2014
Publisher: Oxford University Press (OUP)
Date: 15-11-2009
DOI: 10.1086/644641
Publisher: Springer Science and Business Media LLC
Date: 15-09-2007
Abstract: Accurate diagnosis of Plasmodium spp. is essential for the rational treatment of malaria. Despite its many disadvantages, microscopic examination of blood smears remains the current "gold standard" for malaria detection and speciation. PCR assays offer an alternative to microscopy which has been shown to have superior sensitivity and specificity. Unfortunately few comparative studies have been done on the various molecular based speciation methods. The sensitivity, specificity and cost effectiveness of three molecular techniques were compared for the detection and speciation of Plasmodium falciparum and Plasmodium vivax from dried blood spots collected from 136 patients in western Thailand. The results from the three molecular speciation techniques (nested PCR, multiplex PCR, and real-time PCR) were used to develop a molecular consensus (two or more identical PCR results) as an alternative gold standard. According to the molecular consensus, 9.6% (13/136) of microscopic diagnoses yielded false negative results. Multiplex PCR failed to detect P. vivax in three mixed isolates, and the nested PCR gave a false positive P. falciparum result in one case. Although the real-time PCR melting curve analysis was the most expensive method, it was 100% sensitive and specific and least time consuming of the three molecular techniques investigated. Although microscopy remains the most appropriate method for clinical diagnosis in a field setting, its use as a gold standard may result in apparent false positive results by superior techniques. Future studies should consider using more than one established molecular methods as a new gold standard to assess novel malaria diagnostic kits and PCR assays.
Publisher: Springer Science and Business Media LLC
Date: 25-07-2015
Publisher: Public Library of Science (PLoS)
Date: 2030
Publisher: Elsevier
Date: 2012
Publisher: Public Library of Science (PLoS)
Date: 12-03-2015
Publisher: Public Library of Science (PLoS)
Date: 29-05-2019
Publisher: Oxford University Press (OUP)
Date: 07-2010
DOI: 10.1086/653211
Publisher: Cold Spring Harbor Laboratory
Date: 27-02-2021
DOI: 10.1101/2021.02.26.432958
Abstract: Acclimation of plants to water deficit involves biochemical and physiological adjustments. Here, we studied how UV-B exposure and exogenously applied hydrogen peroxide (H 2 O 2 ) potentiates drought tolerance in tobacco ( Nicotiana tabacum L.). Separate and combined applications for 14 days of 1.75 kJ m −2 day −1 UV-B radiation and 0.2 mM H 2 O 2 were assessed. Both factors, in idually and combined, resulted in inhibition of growth. Furthermore, the combined treatment led to the most compacted plants. UV-B- and UV-B+H 2 O 2 -treated plants increased total antioxidant capacity and foliar epidermal flavonol content. H 2 O 2 - and UV-B+H 2 O 2 -pre-treated plants showed cross-tolerance to a subsequent 7-day drought treatment. Plant responses to the pre-treatment were notably different: i) H 2 O 2 increased the activity of catalase, phenylalanine ammonia lyase and peroxidase activities, and ii) the combined treatment induced epidermal flavonols which were key to drought tolerance. We report synergistic effects of UV-B and H 2 O 2 on transcription accumulation of UV RESISTANCE LOCUS 8, NAC DOMAIN PROTEIN 13 ( NAC13 ), and BRI1-EMS-SUPPRESSOR 1 ( BES1 ). Our data demonstrate a pre-treatment-dependent response to drought for NAC13, BES1 and CHALCONE SYNTHASE transcript accumulation. This study highlights the potential of combining UV-B and H 2 O 2 to improve drought tolerance which could become a useful tool to reduce water use.
Publisher: American Society for Microbiology
Date: 12-2010
DOI: 10.1128/AAC.00801-10
Abstract: Pyronaridine, a Mannich base antimalarial, has demonstrated high in vivo and in vitro efficacy against chloroquine-resistant Plasmodium falciparum . Although this drug has the potential to become a prominent artemisinin combination therapy, little is known about its efficacy against drug-resistant Plasmodium vivax . The in vitro antimalarial susceptibility of pyronaridine was assessed in multidrug-resistant P. vivax ( n = 99) and P. falciparum ( n = 90) isolates from Papua, Indonesia, using a schizont maturation assay. The median 50% inhibitory concentration (IC 50 ) of pyronaridine was 1.92 nM (range, 0.24 to 13.8 nM) against P. falciparum and 2.58 nM (range, 0.13 to 43.6 nM) against P. vivax , with in vitro susceptibility correlating significantly with chloroquine, amodiaquine, and piperaquine ( r s [Spearman's rank correlation coefficient] = 0.45 to 0.62 P 0.001). P. falciparum parasites initially at trophozoite stage had higher IC 50 s of pyronaridine than those exposed at the ring stage (8.9 nM [range, 0.6 to 8.9 nM] versus 1.6 nM [range, 0.6 to 8.9 nM], respectively P = 0.015), although this did not reach significance for P. vivax (4.7 nM [range, 1.4 to 18.7 nM] versus 2.5 nM [range, 1.4 to 15.6 nM], respectively P = 0.085). The excellent in vitro efficacy of pyronaridine against both chloroquine-resistant P. vivax and P. falciparum highlights the suitability of the drug as a novel partner for artemisinin-based combination therapy in regions where the two species are coendemic.
Publisher: American Chemical Society (ACS)
Date: 04-10-2016
Publisher: Springer Science and Business Media LLC
Date: 16-09-2022
DOI: 10.1186/S12916-022-02504-Z
Abstract: In 2012, the World Health Organization (WHO) recommended single low-dose (SLD, 0.25 mg/kg) primaquine to be added as a Plasmodium (P.) falciparum gametocytocide to artemisinin-based combination therapy (ACT) without glucose-6-phosphate dehydrogenase (G6PD) testing, to accelerate malaria elimination efforts and avoid the spread of artemisinin resistance. Uptake of this recommendation has been relatively slow primarily due to safety concerns. A systematic review and in idual patient data (IPD) meta-analysis of single-dose (SD) primaquine studies for P. falciparum malaria were performed. Absolute and fractional changes in haemoglobin concentration within a week and adverse effects within 28 days of treatment initiation were characterised and compared between primaquine and no primaquine arms using random intercept models. Data comprised 20 studies that enrolled 6406 participants, of whom 5129 (80.1%) had received a single target dose of primaquine ranging between 0.0625 and 0.75 mg/kg. There was no effect of primaquine in G6PD-normal participants on haemoglobin concentrations. However, among 194 G6PD-deficient African participants, a 0.25 mg/kg primaquine target dose resulted in an additional 0.53 g/dL (95% CI 0.17–0.89) reduction in haemoglobin concentration by day 7, with a 0.27 (95% CI 0.19–0.34) g/dL haemoglobin drop estimated for every 0.1 mg/kg increase in primaquine dose. Baseline haemoglobin, young age, and hyperparasitaemia were the main determinants of becoming anaemic (Hb 10 g/dL), with the nadir observed on ACT day 2 or 3, regardless of G6PD status and exposure to primaquine. Time to recovery from anaemia took longer in young children and those with baseline anaemia or hyperparasitaemia. Serious adverse haematological events after primaquine were few (9/3, 113, 0.3%) and transitory. One blood transfusion was reported in the primaquine arms, and there were no primaquine-related deaths. In controlled studies, the proportions with either haematological or any serious adverse event were similar between primaquine and no primaquine arms. Our results support the WHO recommendation to use 0.25 mg/kg of primaquine as a P. falciparum gametocytocide, including in G6PD-deficient in iduals. Although primaquine is associated with a transient reduction in haemoglobin levels in G6PD-deficient in iduals, haemoglobin levels at clinical presentation are the major determinants of anaemia in these patients. PROSPERO, CRD42019128185
Publisher: Springer Science and Business Media LLC
Date: 30-08-2012
Publisher: Wiley
Date: 11-2008
DOI: 10.1111/J.1600-0463.2008.00900.X
Abstract: Development of transgenic edible plants, to be used as production, storage and delivery systems for recombinant vaccine antigens, is a promising strategy to obtain cost effective vaccines against infectious diseases, not least for use in developing countries. Therefore, we used Agrobacterium tumefaciens-mediated gene transfer to introduce the p24 gag gene encoding the nucleocapsid protein from HIV-1 subtype C into the Arabidopsis thaliana plant genome. Eighteen plant lines were confirmed positive for the p24 gene by PCR four of these lines showed an apparent homozygous phenotype when grown on selective medium and these lines also showed transcription of the p24 gene into its corresponding mRNA. The mRNA in all four cases generated the p24 protein in plants, as verified by Western blot analysis. The plants were shown to contain between 0.2 mug and 0.5 mug p24 protein per g of fresh tissue. Analysis of the localisation of the p24 protein showed that stem tissue contained the largest amount of protein, more than twice as much as leaf tissue, whereas no p24 protein was detected in roots. By using Southern blotting, we found that 4, 2-3, 2 and 1 T-DNA insertion events took place in the four lines 1, 2, 7, and 10, respectively. The genetic insertions of line 1 were stable from the T(2) to the T(5) generation and gave rise to the p24 protein in all cases, as verified by Western blotting. In mice fed with fresh transgenic A. thaliana (line 10), anti-gag IgG was obtained in serum after a booster injection with recombinant p37Gag. No immune response was observed after equal booster injection of untreated mice or mice fed with A. thaliana WT plants.
Publisher: Springer Science and Business Media LLC
Date: 06-09-2022
DOI: 10.1186/S12936-022-04268-6
Abstract: Circulating myeloid-derived-suppressor-cells (MDSC) with immunosuppressive function are increased in human experimental Plasmodium falciparum infection, but have not been studied in clinical malaria. Using flow-cytometry, circulating polymorphonuclear-MDSC were evaluated in cryopreserved s les from patients with uncomplicated Plasmodium vivax (n = 8) and uncomplicated (n = 4) and severe (n = 16) falciparum malaria from Papua, Indonesia. The absolute number of circulating polymorphonuclear-MDSC were significantly elevated in severe falciparum malaria patients compared to controls (n = 10). Polymorphonuclear-MDSC levels in uncomplicated vivax malaria were also elevated to levels comparable to that seen in severe falciparum malaria. Control of expansion of immunosuppressive MDSC may be important for development of effective immune responses in falciparum and vivax malaria.
Publisher: American Chemical Society (ACS)
Date: 25-09-2012
DOI: 10.1021/CI300264U
Abstract: Homology models of CYP26B1 (cytochrome P450RAI2) and CYP26B1 spliced variant were derived using the crystal structure of cyanobacterial CYP120A1 as template for the model building. The quality of the homology models generated were carefully evaluated, and the natural substrate all-trans-retinoic acid (atRA), several tetralone-derived retinoic acid metabolizing blocking agents (RAMBAs), and a well-known potent inhibitor of CYP26B1 (R115866) were docked into the homology model of full-length cytochrome P450 26B1. The results show that in the model of the full-length CYP26B1, the protein is capable of distinguishing between the natural substrate (atRA), R115866, and the tetralone derivatives. The spliced variant of CYP26B1 model displays a reduced affinity for atRA compared to the full-length enzyme, in accordance with recently described experimental information.
Publisher: Elsevier BV
Date: 04-1997
DOI: 10.1016/S0166-6851(96)02822-8
Abstract: The pfmdr 1 gene encodes a Plasmodium falciparum homologue of the human P-glycoprotein expressed on the surface of the parasite food vacuole. Variation in copy number and specific codon mutations of pfmdr 1 have been implicated in the development of parasite resistance to antimalarial drugs. We describe here the technique of Tandem-Competitive Polymerase Chain Reaction (TC-PCR), which allows accurate measurement of pfmdr 1 copy number in parasite DNA obtained directly from small quantities (100 microliters) of red blood cells. We reliably quantified pfmdr1 in previously well characterised strains of Plasmodium falciparum with differing pfmdr1 gene copy numbers using starting amounts of between 3,000 and 40,000 gene copies. We then used TC-PCR to determine pfmdr1 gene copy number in field specimens of venous blood taken from 10 patients with malaria contracted along the Thai-Burmese border. In this region of high grade parasite resistance to mefloquine greater than 70% of s les had a copy number greater than 1 of pfmdr1 determined with a repeatability coefficient of 0.58.
Publisher: Wiley
Date: 12-01-2021
DOI: 10.1002/APP5.314
Abstract: New diagnostics and treatment options for the radical cure of Plasmodium vivax malaria are now available. At the 2019 annual meeting of the Vivax Working Group of the Asia Pacific Malaria Elimination Network, participants took part in a roundtable discussion to identify further evidence required to introduce these new tools into policy and practice. Key gaps identified were accuracy and reliability of glucose‐6‐phosphate‐dehydrogenase deficiency tests, health system capacity, and feasibility and cost effectiveness of novel treatment strategies in routine clinical practice. As expected, there were differences in the priorities between country partners and researcher partners. To achieve the 2030 target for the regional elimination of malaria, evidence to address these issues should be generated as a matter of priority. Review of global guidelines alongside locally generated data will help to ensure the timely revision and optimisation of national treatment guidelines that will be vital to meet regional elimination goals.
Publisher: American Society for Microbiology
Date: 07-2008
DOI: 10.1128/AAC.00169-08
Abstract: Recent studies using laboratory clones have demonstrated that several antiretroviral protease inhibitors (PIs) inhibit the growth of Plasmodium falciparum at concentrations that may be of clinical significance, especially during human immunodeficiency virus type 1 (HIV-1) and malaria coinfection. Using clinical isolates, we now demonstrate the in vitro effectiveness of two HIV-1 aspartic PIs, saquinavir (SQV) and ritonavir (RTV), against P. vivax ( n = 30) and P. falciparum ( n = 20) from populations subjected to high levels of mefloquine and artesunate pressure on the Thailand-Myanmar border. The median 50% inhibitory concentration values of P. vivax to RTV and SQV were 2,233 nM (range, 732 to 7,738 nM) and 4,230 nM (range, 1,326 to 8,452 nM), respectively, both within the therapeutic concentration range commonly found for patients treated with these PIs. RTV was fourfold more effective at inhibiting P. vivax than it was at inhibiting P. falciparum , compared to a twofold difference in SQV sensitivity. An increased P. falciparum mdr1 copy number was present in 33% (3/9) of isolates and that of P. vivax mdr1 was present in 9% of isolates (2/22), but neither was associated with PI sensitivity. The inter- Plasmodium sp. variations in PI sensitivity indicate key differences between P. vivax and P. falciparum . PI-containing antiretroviral regimens may demonstrate prophylactic activity against both vivax and falciparum malaria in HIV-infected patients who reside in areas where multidrug-resistant P. vivax or P. falciparum is found.
Publisher: Elsevier BV
Date: 12-2021
Publisher: Oxford University Press (OUP)
Date: 04-2007
Publisher: Oxford University Press (OUP)
Date: 24-03-2018
DOI: 10.1093/CID/CIY236
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: Springer Science and Business Media LLC
Date: 27-03-2013
Publisher: Springer Science and Business Media LLC
Date: 12-2010
Abstract: New diagnoses of tuberculosis (TB) present important opportunities to detect and treat HIV. Rates of HIV and TB in Indonesia's easternmost Papua Province exceed national figures, but data on co-infection rates and outcomes are lacking. We aimed to measure TB-HIV co-infection rates, examine longitudinal trends, compare management with World Health Organisation (WHO) recommendations, and document progress and outcome. Adults with newly-diagnosed smear-positive pulmonary TB managed at the Timika TB clinic, Papua Province, were offered voluntary counselling and testing for HIV in accordance with Indonesian National Guidelines, using a point-of-care antibody test. Positive tests were confirmed with 2 further rapid tests. Study participants were assessed using clinical, bacteriological, functional and radiological measures and followed up for 6 months. Of 162 participants, HIV status was determined in 138 (85.2%), of whom 18 (13.0%) were HIV+. Indigenous Papuans were significantly more likely to be HIV+ than Non-Papuans (Odds Ratio [OR] 4.42, 95% confidence interval [CI] 1.38-14.23). HIV prevalence among people with TB was significantly higher than during a 2003-4 survey at the same TB clinic, and substantially higher than the Indonesian national estimate of 3%. Compared with HIV- study participants, those with TB-HIV co-infection had significantly lower exercise tolerance (median difference in 6-minute walk test: 25 m, p = 0.04), haemoglobin (mean difference: 1.3 g/dL, p = 0.002), and likelihood of cavitary disease (OR 0.35, 95% CI 0.12-1.01), and increased occurrence of pleural effusion (OR 3.60, 95% CI 1.70-7.58), higher rates of hospitalisation or death (OR 11.80, 95% CI 1.82-76.43), but no difference in the likelihood of successful 6-month treatment outcome. Adherence to WHO guidelines was limited by the absence of integration of TB and HIV services, specifically, with no on-site ART prescriber available. Only six people had CD4+ T-cell counts recorded, 11 were prescribed co-trimoxazole and 4 received ART before, during or after TB treatment, despite ART being indicated in 14 according to 2006 WHO guidelines. TB-HIV co-infection in southern Papua, Indonesia, is a serious emerging problem especially among the Indigenous population, and has risen rapidly in the last 5 years. Major efforts are required to incorporate new WHO recommendations on TB-HIV management into national guidelines, and support their implementation in community settings.
Publisher: Oxford University Press (OUP)
Date: 06-03-2013
Publisher: Public Library of Science (PLoS)
Date: 19-01-2016
Publisher: Springer Science and Business Media LLC
Date: 02-2019
DOI: 10.1039/C8PP00480C
Abstract: Expression of cucumber (Cucumis sativus) genes encoding the phenylpropanoid and flavonoid biosynthetic enzymes phenylalanine ammonia lyase (PAL), cinnamic acid 4-hydroxylase (C4H), and chalcone synthase (CHS), was studied under control light conditions (photosynthetically active radiation, PAR) in root, stem, and leaf. Furthermore, the expression was quantified in leaves illuminated with PAR and supplemental ultraviolet-A (315-400 nm) or ultraviolet-B (280-315 nm) radiation. The expression patterns of all twelve CsPAL, three CsC4H, and three CsCHS genes were established. Among the genes regulated by UV two general expression patterns emerge. One pattern applies to genes primarily regulated by enriched UV-A illumination (pattern 1). Another pattern (pattern 2) was found for the genes regulated by enriched UV-B. Three of the pattern 2 genes (CsPAL4, CsPAL10, and CsCHS2) displayed a particular sub-pattern (pattern 2b) with transcription enriched by at least 30-fold. In contrast to the other genes studied, the promoters of the genes regulated according to pattern 2b contained a combination of a number of cis-acting regulatory elements (MREs, ACEs, and G-boxes) that may be of importance for the particularly high enhancement of expression under UV-B-containing light. The regulation of phenylpropanoid and flavonoid biosynthesis genes in cucumber resembles that of a number of other plants. However, cucumber, due to its greater size, is an attractive species for combining more detailed studies of the morphology, physiological parameters and fine regulation of spatial and temporal expression of key genes. This, in turn, can facilitate the quantitative investigation of the relationships among different promoter motifs, the expression levels of each of these three genes, and metabolite accumulation profiles.
Publisher: Elsevier BV
Date: 09-2018
Publisher: Springer Science and Business Media LLC
Date: 10-05-2013
Publisher: Springer Science and Business Media LLC
Date: 08-06-2022
DOI: 10.1186/S12916-022-02394-1
Abstract: In Papua (Indonesia), infants with P. falciparum and/or P. vivax malaria are at risk of severe anaemia and death. We hypothesized that in an area of high malaria transmission, intermittent screening and treatment of infants with malaria (ISTi) will reduce morbidity compared to passive case detection (PCDi). We conducted a cluster randomised, open label, superiority trial. A total of 21 clusters of village health posts (VHP) were randomised 1:1 to either IST for infants coinciding with 4 routine immunisation visits or PCDi. Healthy term infants born to consenting mothers enrolled into a maternal malaria cluster randomised trial were included in the study and followed for 12 months. Point of care malaria rapid diagnostic tests were used to detect peripheral parasitaemia at 2, 3, 4 and 9 months old in all infants in ISTi clusters and when symptomatic in PCDi clusters. Infants with detected peripheral parasitaemia were treated with dihydroartemisinin-piperaquine. The co-primary outcomes were the incidence rate of clinical malaria in the first year of life and the prevalence of parasitaemia at age 12 months. The incidence rate ratio and prevalence ratio between ISTi and PCDi were estimated using mixed-effects Poisson and log-binomial regression modelling (accounting for clustering at VHP level). Between May 2014 and February 2017, 757 infants were enrolled into the study, 313 into 10 ISTi clusters, and 444 into 11 PCDi clusters. Overall, 132 episodes of parasitaemia were detected, of whom 17 (12.9%) were in symptomatic infants. Over 12 months, the incidence rate (IR) of clinical malaria was 24 [95% CI, 10–50] per 1000 children-years at risk in the ISTi arm and 19 [95% CI, 8,38] per 1000 children-years in the PCDi arm (adjusted incidence rate ratio [aIRR] 1.77 [95% CI, 0.62–5.01] p = 0.280). The prevalence of parasitaemia at 12 months was 13% (33/254) in the IST clusters and 15% (57/379) in the PCD clusters (adjusted prevalence ratio (aPR) = 0.92 (95% CI, 0.70–1.21), p = 0.55). There was no difference in the risk of anaemia between treatment arms. In high malaria transmission area outside of Africa, our study suggests that compared to PCDi, ISTi offers no significant benefit in reducing the risk of clinical malaria in infants born to women receiving effective protection from malaria during pregnancy. ClinicalTrials.gov NCT 02001428 , registered on 20 Nov 2013.
Publisher: Elsevier BV
Date: 05-2009
Abstract: Long considered a benign infection, Plasmodium vivax is now recognized as a cause of severe and fatal malaria, despite its low parasite biomass, the increased deformability of vivax-infected red blood cells and an apparent paucity of parasite sequestration. Severe anemia is associated with recurrent bouts of hemolysis of predominantly uninfected erythrocytes with increased fragility, and lung injury is associated with inflammatory increases in alveolar-capillary membrane permeability. Although rare, vivax-associated coma challenges our understanding of pathobiology caused by Plasmodium spp. Host and parasite factors contribute to the risk of severe disease, and comorbidities might contribute to vivax mortality. In this review, we discuss potential mechanisms underlying the syndromes of uncomplicated and severe vivax malaria, identifying key areas for future research.
Publisher: Public Library of Science (PLoS)
Date: 29-04-2016
Publisher: Springer Science and Business Media LLC
Date: 12-05-2021
DOI: 10.1186/S12936-021-03743-W
Abstract: The radical cure of Plasmodium vivax requires treatment with an 8-aminoquinoline drug, such as primaquine and tafenoquine, to eradicate liver hypnozoite stages, which can reactivate to cause relapsing infections. Safe treatment regimens require prior screening of patients for glucose-6-phosphate dehydrogenase (G6PD) deficiency to avoid potential life-threatening drug induced haemolysis. Testing is rarely available in malaria endemic countries, but will be needed to support routine use of radical cure. This study investigates end-user perspectives in Bangladesh on the introduction of a quantitative G6PD test (SD Biosensor STANDARD™ G6PD analyser) to support malaria elimination. The perspectives of users on the SD Biosensor test were analysed using semi-structured interviews and focus group discussions with health care providers and malaria programme officers in Bangladesh. Key emerging themes regarding the feasibility of introducing this test into routine practice, including perceived barriers, were analysed. In total 63 participants were interviewed. Participants emphasized the life-saving potential of the biosensor, but raised concerns including the impact of limited staff time, high workload and some technical aspects of the device. Participants highlighted that there are both too few and too many P. vivax patients to implement G6PD testing owing to challenges of funding, workload and complex testing infrastructure. Implementing the biosensor would require flexibility and improvisation to deal with remote sites, overcoming a low index of suspicion and mutual interplay of declining patient numbers and reluctance to test. This approach would generate new forms of evidence to justify introduction in policy and carefully consider questions of deployment given declining patient numbers. The results of the study show that, in an elimination context, the importance of malaria needs to be maintained for both policy makers and the affected communities, in this case by ensuring P. vivax , PQ treatment, and G6PD deficiency remain visible. Availability of new technologies, such as the biosensor, will fuel ongoing debates about priorities for allocating resources that must be adapted to a constantly evolving target. Technical and logistical concerns regarding the biosensor should be addressed by future product designs, adequate training, strengthened supply chains, and careful planning of communication, advocacy and staff interactions at all health system levels.
Publisher: Springer Science and Business Media LLC
Date: 05-04-2017
Publisher: WHO Press
Date: 27-09-2019
Publisher: Oxford University Press (OUP)
Date: 23-10-2017
DOI: 10.1093/CID/CIX779
Publisher: Public Library of Science (PLoS)
Date: 13-02-2017
Publisher: Oxford University Press (OUP)
Date: 15-04-2007
DOI: 10.1086/512677
Publisher: Public Library of Science (PLoS)
Date: 18-07-2012
Publisher: Elsevier BV
Date: 08-2022
DOI: 10.1016/J.PLANTSCI.2022.111326
Abstract: Ultraviolet radiation (UV, 280-400 nm) as an environmental signal triggers metabolic acclimatory responses. However, how different light qualities affect UV acclimation during growth is poorly understood. Here, cucumber plants (Cucumis sativus) were grown under blue, green, red, or white light in combination with UV. Their effects on leaf metabolites were determined using untargeted metabolomics. Blue and white growth light triggered increased levels of compounds related to primary and secondary metabolism, including amino acids, phenolics, hormones, and compounds related to sugar metabolism and the TCA cycle. In contrast, supplementary UV in a blue or white light background decreased leaf content of amino acids, phenolics, sugars, and TCA-related compounds, without affecting abscisic acid, auxin, zeatin, or jasmonic acid levels. However, in plants grown under green light, UV induced increased levels of phenolics, hormones (auxin, zeatin, dihydrozeatin-7-N-dihydrozeatin, jasmonic acid), amino acids, sugars, and TCA cycle-related compounds. Plants grown under red light with UV mainly showed decreased sugar content. These findings highlight the importance of the blue light component for metabolite accumulation. Also, data on interactions of UV with green light on the one hand, and blue or white light on the other, further contributes to our understanding of light quality regulation of plant metabolism.
Publisher: Public Library of Science (PLoS)
Date: 11-11-2020
DOI: 10.1371/JOURNAL.PNTD.0008838
Abstract: The widespread use of primaquine (PQ) radical cure for P . vivax , is constrained by concerns over its safety. We used routinely collected patient data to compare the overall morbidity and mortality in patients treated with and without PQ without prior testing of Glucose-6-Phosphate-Dehydrogenase (G6PD) deficiency in Papua, Indonesia, where there is a low prevalence of G6PD deficiency. Records were collated from patients older than 1 year, with P . vivax infection, who were treated with an artemisinin combination therapy (ACT). The risks of re-presentation, hospitalization, major fall in haemoglobin and death within 30 days were quantified and compared between patients treated with and without PQ using a Cox regression model. In total 26,216 patients with P . vivax malaria presented to the hospital with malaria during the study period. Overall 27.56% (95% Confidence Interval (95%CI): 26.96–28.16) of 21,344 patients treated with PQ re-presented with any illness within 30 days and 1.69% (1.51–1.88) required admission to hospital. The corresponding risks were higher in the 4,872 patients not treated with PQ Adjusted Hazard Ratio (AHR) = 0.84 (0.79–0.91 p .001) and 0.54 (0.41–0.70 p .001) respectively. By day 30, 14.15% (12.45–16.05) of patients who had received PQ had a fall in haemoglobin (Hb) below 7g/dl compared to 20.43% (16.67–24.89) of patients treated without PQ AHR = 0.66 (0.45–0.97 p = 0.033). A total of 75 (0.3%) patients died within 30 days of treatment with a mortality risk of 0.27% (0.21–0.35) in patients treated with PQ, compared to 0.38% (0.24–0.60) without PQ AHR = 0.79 (0.43–1.45 p = 0.448). In Papua, Indonesia routine administration of PQ radical cure without prior G6PD testing, was associated with lower risk of all cause hospitalization and other serious adverse clinical outcomes. In areas where G6PD testing is not available or cannot be delivered reliably, the risks of drug induced haemolysis should be balanced against the potential benefits of reducing recurrent P . vivax malaria and its associated morbidity and mortality.
Publisher: Oxford University Press (OUP)
Date: 11-08-2020
Abstract: Since the World Health Organization recommended single low-dose (0.25 mg/kg) primaquine (PQ) in combination with artemisinin-based combination therapies (ACTs) in areas of low transmission or artemisinin-resistant Plasmodium falciparum, several single-site studies have been conducted to assess efficacy. An in idual patient meta-analysis to assess gametocytocidal and transmission-blocking efficacy of PQ in combination with different ACTs was conducted. Random effects logistic regression was used to quantify PQ effect on (1) gametocyte carriage in the first 2 weeks post treatment and (2) the probability of infecting at least 1 mosquito or of a mosquito becoming infected. In 2574 participants from 14 studies, PQ reduced PCR-determined gametocyte carriage on days 7 and 14, most apparently in patients presenting with gametocytemia on day 0 (odds ratio [OR], 0.22 95% confidence interval [CI], .17–.28 and OR, 0.12 95% CI, .08–.16, respectively). Rate of decline in gametocyte carriage was faster when PQ was combined with artemether-lumefantrine (AL) compared to dihydroartemisinin-piperaquine (DP) (P = .010 for day 7). Addition of 0.25 mg/kg PQ was associated with near complete prevention of transmission to mosquitoes. Transmission blocking is achieved with 0.25 mg/kg PQ. Gametocyte persistence and infectivity are lower when PQ is combined with AL compared to DP.
Publisher: Oxford University Press (OUP)
Date: 04-2023
DOI: 10.1093/JTM/TAAD044
Publisher: Oxford University Press (OUP)
Date: 12-06-2013
Publisher: Springer Science and Business Media LLC
Date: 12-2018
Publisher: Elsevier BV
Date: 09-2019
Publisher: Cold Spring Harbor Laboratory
Date: 27-05-2018
DOI: 10.1101/331850
Abstract: The first line treatment for uncomplicated falciparum malaria is artemisinin-based combination therapy (ACT), which consists of an artemisinin derivative co-administered with a longer acting partner drug. However, the spread of Plasmodium falciparum resistant to both artemisinin and its partner drugs poses a major global threat to malaria control activities. Novel strategies are needed to retard and reverse the spread of these resistant parasites. One such strategy is triple artemisinin-based combination therapy (TACT). We developed a mechanistic within-host mathematical model to investigate the efficacy of a TACT (dihydroartemisinin-piperaquine-mefloquine - DHA-PQ-MQ), for use in South-East Asia, where DHA and PQ resistance are now increasingly prevalent. Comprehensive model simulations were used to explore the degree to which the underlying resistance influences the parasitological outcomes. The effect of MQ dosing on the efficacy of TACT was quantified at varying degrees of DHA and PQ resistance. To incorporate interactions between drugs, a novel model is presented for the combined effect of DHA-PQ-MQ, which illustrates how the interactions can influence treatment efficacy. When combined with a standard regimen of DHA and PQ, the administration of three 8.3 mg/kg doses of MQ was sufficient to achieve parasitological efficacy greater than that currently recommended by WHO guidelines.
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: Wiley
Date: 07-09-2010
Publisher: Public Library of Science (PLoS)
Date: 19-11-2020
DOI: 10.1371/JOURNAL.PMED.1003393
Abstract: There is a high risk of Plasmodium vivax parasitaemia following treatment of falciparum malaria. Our study aimed to quantify this risk and the associated determinants using an in idual patient data meta-analysis in order to identify populations in which a policy of universal radical cure, combining artemisinin-based combination therapy (ACT) with a hypnozoitocidal antimalarial drug, would be beneficial. A systematic review of Medline, Embase, Web of Science, and the Cochrane Database of Systematic Reviews identified efficacy studies of uncomplicated falciparum malaria treated with ACT that were undertaken in regions coendemic for P . vivax between 1 January 1960 and 5 January 2018. Data from eligible studies were pooled using standardised methodology. The risk of P . vivax parasitaemia at days 42 and 63 and associated risk factors were investigated by multivariable Cox regression analyses. Study quality was assessed using a tool developed by the Joanna Briggs Institute. The study was registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42018097400). In total, 42 studies enrolling 15,341 patients were included in the analysis, including 30 randomised controlled trials and 12 cohort studies. Overall, 14,146 (92.2%) patients had P . falciparum monoinfection and 1,195 (7.8%) mixed infection with P . falciparum and P . vivax . The median age was 17.0 years (interquartile range [IQR] = 9.0–29.0 years range = 0–80 years), with 1,584 (10.3%) patients younger than 5 years. 2,711 (17.7%) patients were treated with artemether-lumefantrine (AL, 13 studies), 651 (4.2%) with artesunate-amodiaquine (AA, 6 studies), 7,340 (47.8%) with artesunate-mefloquine (AM, 25 studies), and 4,639 (30.2%) with dihydroartemisinin-piperaquine (DP, 16 studies). 14,537 patients (94.8%) were enrolled from the Asia-Pacific region, 684 (4.5%) from the Americas, and 120 (0.8%) from Africa. At day 42, the cumulative risk of vivax parasitaemia following treatment of P . falciparum was 31.1% (95% CI 28.9–33.4) after AL, 14.1% (95% CI 10.8–18.3) after AA, 7.4% (95% CI 6.7–8.1) after AM, and 4.5% (95% CI 3.9–5.3) after DP. By day 63, the risks had risen to 39.9% (95% CI 36.6–43.3), 42.4% (95% CI 34.7–51.2), 22.8% (95% CI 21.2–24.4), and 12.8% (95% CI 11.4–14.5), respectively. In multivariable analyses, the highest rate of P . vivax parasitaemia over 42 days of follow-up was in patients residing in areas of short relapse periodicity (adjusted hazard ratio [AHR] = 6.2, 95% CI 2.0–19.5 p = 0.002) patients treated with AL (AHR = 6.2, 95% CI 4.6–8.5 p 0.001), AA (AHR = 2.3, 95% CI 1.4–3.7 p = 0.001), or AM (AHR = 1.4, 95% CI 1.0–1.9 p = 0.028) compared with DP and patients who did not clear their initial parasitaemia within 2 days (AHR = 1.8, 95% CI 1.4–2.3 p 0.001). The analysis was limited by heterogeneity between study populations and lack of data from very low transmission settings. Study quality was high. In this meta-analysis, we found a high risk of P . vivax parasitaemia after treatment of P . falciparum malaria that varied significantly between studies. These P . vivax infections are likely attributable to relapses that could be prevented with radical cure including a hypnozoitocidal agent however, the benefits of such a novel strategy will vary considerably between geographical areas.
Publisher: Public Library of Science (PLoS)
Date: 29-01-2020
Publisher: American Chemical Society (ACS)
Date: 25-10-2011
DOI: 10.1021/JP205724K
Publisher: Springer Science and Business Media LLC
Date: 25-01-2017
DOI: 10.1038/NATURE21038
Publisher: Elsevier BV
Date: 05-2021
Publisher: Elsevier BV
Date: 08-2004
DOI: 10.1016/J.TMAID.2004.02.006
Abstract: Travellers to malaria-endemic destinations are at risk of significant disease and, sometimes, death. Current malaria protection strategies, including chemoprophylaxis, can never be completely effective. In some cases, protective measures are discontinued or misapplied while the risk of infection still exists. In others, suboptimal measures are used, or even no measures at all, because of poor information or inappropriate risk-benefit assessment. In very rare cases, inexplicable failure of prophylaxis occurs. If malaria is contracted whilst abroad the danger to the in idual is often further compounded by a lack of high-quality medical facilities and an uncertain supply of effective drugs for treatment. The advent of newer, well tolerated, drugs for treating malaria provides an opportunity to review the role of standby emergency self-medication in travellers visiting or staying (for work or other reasons) in areas where there is a risk of contracting malaria. This article was prepared following a meeting convened in London on Africa Malaria Day in 2002, in which the current opinions of experts in travel medicine and specifically malaria were discussed. It reviews opinion on the current effectiveness and acceptance of prevention strategies, as well as the role of standby emergency medication for falciparum malaria.
Publisher: Springer Science and Business Media LLC
Date: 13-11-2013
Publisher: Oxford University Press (OUP)
Date: 12-07-2013
Publisher: Elsevier BV
Date: 11-2023
Publisher: Oxford University Press (OUP)
Date: 15-11-2008
DOI: 10.1086/592451
Publisher: American Society for Microbiology
Date: 10-2014
DOI: 10.1128/JCM.01060-14
Abstract: A case of fever, sepsis, and chest lesions evident on a computed tomography scan of an indigenous man in northern Australia following burns to the feet is described. Sputum PCR testing revealed Mycobacterium leprae , and a fine-needle aspirate of the chest lesions demonstrated Cryptococcus coinfection.
Publisher: Oxford University Press (OUP)
Date: 15-07-2008
DOI: 10.1086/589287
Abstract: The reported case-fatality rate associated with severe malaria varies widely. Whether age is an independent risk factor is uncertain. In a large, multicenter treatment trial conducted in Asia, the presenting manifestations and outcome of severe malaria were analyzed in relation to age. Among 1050 patients with severe malaria, the mortality increased stepwise, from 6.1% in children (age, 50 years (P<0.001). Compared with adults aged 21-50 years, the decreased risk of death among children (adjusted odds ratio, 0.06 95% confidence interval, 0.01-0.23 P 50 years (adjusted odds ratio, 1.88 95% confidence interval, 1.01-3.52 P<0.001) was independent of the variation in presenting manifestations. The incidence of anemia and convulsions decreased with age, whereas the incidence of hyperparasitemia, jaundice, and renal insufficiency increased with age. Coma and metabolic acidosis did not vary with age and were the strongest predictors of a fatal outcome. The number of severity signs at hospital admission also had a strong prognostic value. Presenting syndromes in severe malaria depend on age, although the incidence and the strong prognostic significance of coma and acidosis are similar at all ages. Age is an independent risk factor for a fatal outcome of the disease.
Publisher: Wiley
Date: 17-05-2014
DOI: 10.1016/J.FEBSLET.2014.05.005
Abstract: Solar UV-B (280-315 nm) radiation is a developmental signal in plants but may also cause oxidative stress when combined with other environmental factors. Using computer modeling and in solution experiments we show that UV-B is capable of photosensitizing hydroxyl radical production from hydrogen peroxide. We present evidence that the oxidative effect of UV-B in leaves is at least twofold: (i) it increases cellular hydrogen peroxide concentrations, to a larger extent in pyridoxine antioxidant mutant pdx1.3-1 Arabidopsis and (ii) is capable of a partial photo-conversion of both 'natural' and 'extra' hydrogen peroxide to hydroxyl radicals. As stress conditions other than UV can increase cellular hydrogen peroxide levels, synergistic deleterious effects of various stresses may be expected already under ambient solar UV-B.
Publisher: Elsevier BV
Date: 10-2014
Publisher: American Society for Microbiology
Date: 09-2018
DOI: 10.1128/AAC.00012-18
Abstract: The 2-aminopyridine MMV048 was the first drug candidate inhibiting Plasmodium phosphatidylinositol 4-kinase (PI4K), a novel drug target for malaria, to enter clinical development. In an effort to identify the next generation of PI4K inhibitors, the series was optimized to improve properties such as solubility and antiplasmodial potency across the parasite life cycle, leading to the 2-aminopyrazine UCT943.
Publisher: American Society for Microbiology
Date: 03-2009
DOI: 10.1128/AAC.01511-08
Abstract: Amodiaquine retains efficacy against infection by chloroquine-resistant Plasmodium falciparum however, little information is available on its efficacy against infection by chloroquine-resistant Plasmodium vivax . Patients presenting to a rural clinic with a pure P. vivax infection that recurred after recent antimalarial treatment were retreated, this time with amodiaquine monotherapy, and the risk of further recurrence within 4 weeks was assessed. Of the 87 patients with pure P. vivax infection, 15 patients did not complete a full course of treatment, 4 of whom were intolerant to treatment. In the 72 patients completing treatment, 91% (63 of 69) had cleared their parasitemia within 48 h with no early treatment failure. Follow-up to day 28 or recurrent parasitemia was achieved for 56 patients (78%). The cumulative incidence of treatment failure by day 28 was 22.8% (95% confidence interval, 7.3 to 38%). The in vitro sensitivity profile was determined for a separate set of isolates from outpatients with pure P. vivax infection. The median 50% inhibitory concentration of amodiaquine was 11.3 nM (range, 0.37 to 95.8) and was correlated significantly with that of chloroquine (Spearman rank correlation coefficient, 0.602 P 0.001) Although amodiaquine results in a rapid clinical response, the risk of recurrence by day 28 is unacceptably high, reducing its suitability as an alternative treatment of infection by chloroquine-resistant P. vivax in this region.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 20-03-2013
DOI: 10.1126/SCITRANSLMED.3005029
Abstract: ELQ-300, an investigational drug for treating and preventing malaria, shows potent transmission-blocking activity in rodent models of malaria.
Publisher: Springer Science and Business Media LLC
Date: 06-08-2009
Publisher: Springer Science and Business Media LLC
Date: 12-2008
Publisher: American Society for Microbiology
Date: 17-02-2021
DOI: 10.1128/AAC.01150-20
Abstract: Dihydroartemisinin-piperaquine (DP) is a long-acting artemisinin combination treatment that provides effective chemoprevention and has been proposed as an alternative antimalarial drug for intermittent preventive therapy in pregnancy (IPTp). Several pharmacokinetic studies have shown that dose adjustment may not be needed for the treatment of malaria in pregnancy with DP.
Publisher: Springer Science and Business Media LLC
Date: 28-01-2019
DOI: 10.1038/S41598-018-37005-8
Abstract: UVR8 (UV RESISTANCE LOCUS 8) is a UV-B photoreceptor responsible for initiating UV-B signalling in plants. UVR8 is a homodimer in its signalling inactive form. Upon absorption of UV radiation, the protein monomerizes into its photoactivated state. In the monomeric form, UVR8 binds the E3 ubiquitin ligase COP1 (CONSTITUTIVELY PHOTOMORPHOGENIC 1), triggering subsequent UV-B-dependent photomorphogenic development in plants. Recent in vivo experiments have shown that the UVR8 C-terminal region (aa 397–423 UVR8 C27 ) alone is sufficient to regulate the activity of COP1. In this work, CD spectroscopy and NMR experiments showed that the UVR8 C27 domain was non-structured but gained secondary structure at higher temperatures leading to increased order. Bias-exchange metadynamics simulations were also performed to evaluate the free energy landscape of UVR8 C27 . An inverted free energy landscape was revealed, with a disordered structure in the global energy minimum. Flanking the global energy minimum, more structured states were found at higher energies. Furthermore, stabilization of the low energy disordered state was attributed to a proline residue, P411, as evident from P411A mutant data. P411 is also a key residue in UVR8 binding to COP1. UVR8 C27 is therefore structurally competent to function as a molecular switch for interaction of UVR8 with different binding partners since at higher free energies different structural conformations are being induced in this peptide. P411 has a key role for this function.
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: Elsevier BV
Date: 06-2001
Abstract: The rising prevalence of multidrug resistant falciparum malaria is occurring at an alarming rate and has serious implications for the health of many of the world's poorest countries. The dangers of not changing treatment practices immediately are huge and irreversible, threatening to both exacerbate the scale and scope of the malaria pandemic, and deprive policymakers of future options against the disease. If a health care disaster is to be avoided then massive and long term funding is urgently required. Funds need to be applied in a cohesive manner, accountable to funding bodies and tailored to the specifics of each endemic region. The key elements of such an approach should be improving early diagnosis and treatment of infection and the deployment of combination regimens containing an artemisinin derivative. These short term measures will need to be accompanied by a longer term strategy to encourage antimalarial drug research and development.
Publisher: Springer Science and Business Media LLC
Date: 27-11-2019
DOI: 10.1186/S12874-019-0856-Z
Abstract: Antimalarial clinical efficacy studies for uncomplicated Plasmodium falciparum malaria frequently encounter situations in which molecular genotyping is unable to discriminate between parasitic recurrence, either new infection or recrudescence. The current WHO guideline recommends excluding these in iduals with indeterminate outcomes in a complete case (CC) analysis. Data from the four artemisinin-based combination (4ABC) trial was used to compare the performance of multiple imputation (MI) and inverse probability weighting (IPW) against the standard CC analysis for dealing with indeterminate recurrences. 3369 study participants from the multicentre study (4ABC trial) with molecularly defined parasitic recurrence treated with three artemisinin-based combination therapies were used to represent a complete dataset. A set proportion of recurrent infections (10, 30 and 45%) were reclassified as missing using two mechanisms: a completely random selection (mechanism 1) missingness weakly dependent (mechanism 2a) and strongly dependent (mechanism 2b) on treatment and transmission intensity. The performance of MI, IPW and CC approaches in estimating the Kaplan-Meier (K-M) probability of parasitic recrudescence at day 28 was then compared. In addition, the maximum likelihood estimate of the cured proportion was presented for further comparison (analytical solution). Performance measures (bias, relative bias, standard error and coverage) were reported as an average from 1000 simulation runs. The CC analyses resulted in absolute underestimation of K-M probability of day 28 recrudescence by up to 1.7% and were associated with reduced precision and poor coverage across all the scenarios studied. Both MI and IPW method performed better (greater consistency and greater efficiency) compared to CC analysis. In the absence of censoring, the analytical solution provided the most consistent and accurate estimate of cured proportion compared to the CC analyses. The widely used CC approach underestimates antimalarial failure IPW and MI procedures provided efficient and consistent estimates and should be considered when reporting the results of antimalarial clinical trials, especially in areas of high transmission, where the proportion of indeterminate outcomes could be large. The analytical solution estimating the cured proportion could provide an alternative approach, in scenarios with minimal censoring due to loss to follow-up or new infections.
Publisher: Elsevier BV
Date: 03-2021
Publisher: Oxford University Press (OUP)
Date: 28-08-2015
Publisher: Springer Science and Business Media LLC
Date: 30-07-2020
DOI: 10.1186/S12916-020-01710-X
Abstract: The COVID-19 pandemic has resulted in millions of infections, hundreds of thousands of deaths and major societal disruption due to lockdowns and other restrictions introduced to limit disease spread. Relatively little attention has been paid to understanding how the pandemic has affected treatment, prevention and control of malaria, which is a major cause of death and disease and predominantly affects people in less well-resourced settings. Recent successes in malaria control and elimination have reduced the global malaria burden, but these gains are fragile and progress has stalled in the past 5 years. Withdrawing successful interventions often results in rapid malaria resurgence, primarily threatening vulnerable young children and pregnant women. Malaria programmes are being affected in many ways by COVID-19. For prevention of malaria, insecticide-treated nets need regular renewal, but distribution c aigns have been delayed or cancelled. For detection and treatment of malaria, in iduals may stop attending health facilities, out of fear of exposure to COVID-19, or because they cannot afford transport, and health care workers require additional resources to protect themselves from COVID-19. Supplies of diagnostics and drugs are being interrupted, which is compounded by production of substandard and falsified medicines and diagnostics. These disruptions are predicted to double the number of young African children dying of malaria in the coming year and may impact efforts to control the spread of drug resistance. Using ex les from successful malaria control and elimination c aigns, we propose strategies to re-establish malaria control activities and maintain elimination efforts in the context of the COVID-19 pandemic, which is likely to be a long-term challenge. All sectors of society, including governments, donors, private sector and civil society organisations, have crucial roles to play to prevent malaria resurgence. Sparse resources must be allocated efficiently to ensure integrated health care systems that can sustain control activities against COVID-19 as well as malaria and other priority infectious diseases. As we deal with the COVID-19 pandemic, it is crucial that other major killers such as malaria are not ignored. History tells us that if we do, the consequences will be dire, particularly in vulnerable populations.
Publisher: Springer Science and Business Media LLC
Date: 29-09-2015
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2011
Publisher: Cold Spring Harbor Laboratory
Date: 27-02-2021
DOI: 10.1101/2021.02.27.432481
Abstract: Ultraviolet (UV)-A- or UV-B-enrichment of growth light resulted in a stocky cucumber ( Cucumis sativus L.) phenotype exhibiting decreased stem and petiole lengths and leaf area. Effects were larger in plants grown in UV-B- than in UV-A-enriched light. In plants grown in UV-A-enriched light, decreases in stem and petiole lengths were similar independently of tissue age. In the presence of UV-B radiation, stems and petioles were progressively shorter the younger the tissue. Also, plants grown under UV-A-enriched light significantly reallocated photosynthate from shoot to root and also had thicker leaves with decreased specific leaf area. Our data therefore imply different morphological plant regulatory mechanisms under UV-A and UV-B radiation. There was no evidence of stress in the UV-exposed plants, neither in photosynthetic parameters, total chlorophyll content, nor in accumulation of damaged DNA (cyclobutane pyrimidine dimers). The ABA content of the plants also was consistent with non-stress conditions. Parameters such as total leaf antioxidant activity, leaf adaxial epidermal flavonol content and foliar total UV-absorbing pigment levels revealed successful UV acclimation of the plants. Thus, the stocky UV-phenotype was displayed by healthy cucumber plants, implying a strong morphological response and regulatory adjustment as part of UV acclimation processes involving UV-A and/or UV-B photoreceptors.
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: Oxford University Press (OUP)
Date: 15-02-2010
DOI: 10.1086/650301
Publisher: American Society for Microbiology
Date: 11-2018
DOI: 10.1128/AAC.01068-18
Abstract: The first line treatment for uncomplicated falciparum malaria is artemisinin-based combination therapy (ACT), which consists of an artemisinin derivative coadministered with a longer-acting partner drug. However, the spread of Plasmodium falciparum resistant to both artemisinin and its partner drugs poses a major global threat to malaria control activities.
Publisher: Springer Science and Business Media LLC
Date: 24-10-2015
Publisher: MDPI AG
Date: 14-09-2022
DOI: 10.3390/PATHOGENS11091045
Abstract: Low glucose-6-phosphate dehydrogenase enzyme (G6PD) activity is a key determinant of drug-induced haemolysis. More than 230 clinically relevant genetic variants have been described. We investigated the variation in G6PD activity within and between different genetic variants. In this systematic review, in idual patient data from studies reporting G6PD activity measured by spectrophotometry and corresponding the G6PD genotype were pooled (PROSPERO: CRD42020207448). G6PD activity was converted into percent normal activity applying study-specific definitions of 100%. In total, 4320 in iduals from 17 studies across 10 countries were included, where 1738 (40.2%) had one of the 24 confirmed G6PD mutations, and 61 observations (3.5%) were identified as outliers. The median activity of the hemi-/homozygotes with A-(c.202G A/c.376A G) was 29.0% (range: 1.7% to 76.6%), 10.2% (range: 0.0% to 32.5%) for Mahidol, 16.9% (range 3.3% to 21.3%) for Mediterranean, 9.0% (range: 2.9% to 23.2%) for Vanua Lava, and 7.5% (range: 0.0% to 18.3%) for Viangchan. The median activity in heterozygotes was 72.1% (range: 16.4% to 127.1%) for A-(c.202G A/c.376A G), 54.5% (range: 0.0% to 112.8%) for Mahidol, 37.9% (range: 20.7% to 80.5%) for Mediterranean, 53.8% (range: 10.9% to 82.5%) for Vanua Lava, and 52.3% (range: 4.8% to 78.6%) for Viangchan. A total of 99.5% of hemi/homozygotes with the Mahidol mutation and 100% of those with the Mediterranean, Vanua Lava, and Viangchan mutations had % activity. For A-(c.202G A/c.376A G), 55% of hemi/homozygotes had % activity. The G6PD activity for each variant spanned the current classification thresholds used to define clinically relevant categories of enzymatic deficiency.
Publisher: Oxford University Press (OUP)
Date: 22-04-2016
DOI: 10.1093/CID/CIW121
Publisher: Oxford University Press (OUP)
Date: 30-05-2014
Publisher: Wiley
Date: 15-02-2010
Publisher: Springer Science and Business Media LLC
Date: 07-06-2009
Publisher: Oxford University Press (OUP)
Date: 22-02-2011
Abstract: The pea (Pisum sativum) tetrameric short-chain alcohol dehydrogenase-like protein (SAD) family consists of at least three highly similar members (SAD-A, -B, and -C). According to mRNA data, environmental stimuli induce SAD expression. The aim of this study was to characterize the SAD proteins by examining their catalytic function, distribution in pea, and induction in different tissues. In enzyme activity assays using a range of potential substrates, the SAD-C enzyme was shown to reduce one- or two-ring-membered quinones lacking long hydrophobic hydrocarbon tails. Immunological assays using a specific antiserum against the protein demonstrated that different tissues and cell types contain small amounts of SAD protein that was predominantly located within epidermal or subepidermal cells and around vascular tissue. Particularly high local concentrations were observed in the protoderm of the seed cotyledonary axis. Two bow-shaped rows of cells in the ovary and the placental surface facing the ovule also exhibited considerable SAD staining. Ultraviolet-B irradiation led to increased staining in epidermal and subepidermal cells of leaves and stems. The different localization patterns of SAD suggest functions both in development and in responses to environmental stimuli. Finally, the pea SAD-C promoter was shown to confer heterologous wound-induced expression in Arabidopsis (Arabidopsis thaliana), which confirmed that the inducibility of its expression is regulated at the transcriptional level.
Publisher: Public Library of Science (PLoS)
Date: 07-06-2011
Publisher: Wiley
Date: 19-11-2019
DOI: 10.1111/PBI.13287
Publisher: Elsevier BV
Date: 07-2009
Publisher: Oxford University Press (OUP)
Date: 15-06-2023
Abstract: The decline of malaria in Southeast Asia means other causes of fever are increasingly relevant, but often undiagnosed. The objective of this study was to assess the feasibility of point-of-care tests to diagnose acute febrile illnesses in primary care settings. A mixed-methods study was conducted at nine rural health centres in western Cambodia. Workshops introduced health workers to the STANDARD(TM) Q Dengue Duo, STANDARD(TM) Q Malaria/CRP Duo and a multiplex biosensor detecting antibodies and/or antigens of eight pathogens. Sixteen structured observation checklists assessed users’ performances and nine focus group discussions explored their opinions. All three point-of-care tests were performed well under assessment, but s le collection was difficult for the dengue test. Respondents expressed that the diagnostics were useful and could be integrated into routine clinical care, but were not as convenient to perform as standard malaria rapid tests. Health workers recommended that the most valued point-of-care tests would directly inform clinical management (e.g. a decision to refer a patient or to provide/withhold antibiotics). Deployment of new point-of-care tests to health centres could be feasible and acceptable if they are user-friendly, selected for locally circulating pathogens and are accompanied by disease-specific education and simple management algorithms.
Publisher: American Society for Microbiology
Date: 11-2018
DOI: 10.1128/AAC.01941-18
Publisher: MDPI AG
Date: 27-04-2023
DOI: 10.3390/PATHOGENS12050650
Abstract: Plasmodium vivax malaria continues to cause a significant burden of disease in the Asia-Pacific, the Horn of Africa, and the Americas. In addition to schizontocidal treatment, the 8-aminoquinoline drugs are crucial for the complete removal of the parasite from the human host (radical cure). While well tolerated in most recipients, 8-aminoquinolines can cause severe haemolysis in glucose-6-phosphate dehydrogenase (G6PD) deficient patients. G6PD deficiency is one of the most common enzymopathies worldwide therefore, the WHO recommends routine testing to guide 8-aminoquinoline based treatment for vivax malaria whenever possible. In practice, this is not yet implemented in most malaria endemic countries. This review provides an update of the characteristics of the most used G6PD diagnostics. We describe the current state of policy and implementation of routine point-of-care G6PD testing in malaria endemic countries and highlight key knowledge gaps that hinder broader implementation. Identified challenges include optimal training of health facility staff on point-of-care diagnostics, quality control of novel G6PD diagnostics, and culturally appropriate information and communication with affected communities around G6PD deficiency and implications for treatment.
Publisher: Springer Science and Business Media LLC
Date: 09-2012
Publisher: The Royal Society
Date: 14-04-2010
Abstract: Malaria parasites vary in phenotypic traits of biomedical or biological interest such as growth rate, virulence, sex ratio and drug resistance, and there is considerable interest in identifying the genes that underlie this variation. An important first step is to determine trait heritability ( H 2 ). We evaluate two approaches to measuring H 2 in natural parasite populations using relatedness inferred from genetic marker data. We collected single-clone Plasmodium falciparum infections from 185 patients from the Thailand–Burma border, monitored parasite clearance following treatment with artemisinin combination therapy (ACT), measured resistance to six antimalarial drugs and genotyped parasites using 335 microsatellites. We found strong relatedness structure. There were 27 groups of two to eight clonally identical (CI) parasites, and 74 per cent of parasites showed significant relatedness to one or more other parasites. Initially, we used matrices of allele sharing and variance components (VC) methods to estimate H 2 . Inhibitory concentrations (IC 50 ) for six drugs showed significant H 2 (0.24 to 0.79, p = 0.06 to 2.85 × 10 −9 ), demonstrating that this study design has adequate power. However, a phenotype of current interest—parasite clearance following ACT—showed no detectable heritability ( H 2 = 0–0.09, ns) in this population. The existence of CI parasites allows the use of a simple ANOVA approach for quantifying H 2 , analogous to that used in human twin studies. This gave similar results to the VC method and requires considerably less genotyping information. We conclude (i) that H 2 can be effectively measured in malaria parasite populations using minimal genotype data, allowing rational design of genome-wide association studies and (ii) while drug response (IC 50 ) shows significant H 2 , parasite clearance following ACT was not heritable in the population studied.
Publisher: Wiley
Date: 07-03-2012
DOI: 10.1111/J.1399-3054.2012.01591.X
Abstract: Lolium perenne (cv. AberDart) was grown at 14 locations along a latitudinal gradient across Europe (37-68°N) to study the impact of ultraviolet radiation (UV) and climate on aboveground growth and foliar UV-B absorbing compounds. At each location, plants were grown outdoors for 5 weeks in a replicated UV-B filtration experiment consisting of open, UV-B transparent (cellulose diacetate) and UV-B opaque (polyester) environments. Fourier transform-infrared spectroscopy was used to compare plant metabolite profiles in relation to treatment and location. UV radiation and climatic parameters were determined for each location from online sources and the data were assessed using a combination of anova and multiple regression analyses. Most of the variation in growth between the locations was attributable to the combination of climatic parameters, with minimum temperature identified as an important growth constraint. However, no single environmental parameter could consistently account for the variability in plant growth. Concentrations of foliar UV-B absorbing compounds showed a positive trend with solar UV across the latitudinal gradient however, this relationship was not consistent in all treatments. The most striking experimental outcome from this study was the effect of presence or absence of filtration frames on UV-absorbing compounds. Overall, the study demonstrates the value of an European approach in studying the impacts of natural UV across a large latitudinal gradient. We have shown the feasibility of coordinated UV filtration at multiple sites but have also highlighted the need for open controls and careful interpretation of plant responses.
Publisher: Public Library of Science (PLoS)
Date: 05-03-2020
Publisher: Springer Science and Business Media LLC
Date: 04-02-2019
DOI: 10.1038/S41598-018-38053-W
Abstract: Direct and indirect roles of vitamin B 6 in leaf acclimation to supplementary UV-B radiation are shown in vitamin B 6 deficient Arabidopsis thaliana mutant rsr4-1 and C24 wild type. Responses to 4 days of 3.9 kJ m −2 d −1 biologically effective UV-B dose were compared in terms of leaf photochemistry, vitamer content, and antioxidant enzyme activities complemented with a comprehensive study of vitamer ROS scavenging capacities. Under UV-B, rsr4-1 leaves lost more (34%) photochemical yield than C24 plants (24%). In the absence of UV-B, rsr4-1 leaves contained markedly less pyridoxal-5′-phosphate (PLP) than C24 ones, but levels increased up to the C24 contents in response to UV-B. Activities of class-III ascorbate and glutathione peroxidases increased in C24 leaves upon the UV-B treatment but not in the rsr4-1 mutant. SOD activities remained the same in C24 but decreased by more than 50% in rsr4-1 under UV-B. Although PLP was shown to be an excellent antioxidant in vitro , our results suggest that the UV-B protective role of B 6 vitamers is realized indirectly, via supporting peroxidase defence rather than by direct ROS scavenging. We hypothesize that the two defence pathways are linked through the PLP-dependent biosynthesis of cystein and heme, affecting peroxidases.
Publisher: Public Library of Science (PLoS)
Date: 19-06-2017
Publisher: Oxford University Press (OUP)
Date: 16-05-2018
DOI: 10.1093/CID/CIY403
Abstract: In Papua, splenectomized in iduals have greater risk of malaria in the 12 months following splenectomy but not of mortality. Malaria risk was higher for Plasmodium vivax than P. falciparum. Early radical cure and prophylaxis are warranted in malaria endemic areas.
Publisher: American Society of Tropical Medicine and Hygiene
Date: 02-09-2020
Publisher: Oxford University Press (OUP)
Date: 03-06-2013
Publisher: Oxford University Press (OUP)
Date: 12-2005
DOI: 10.1086/497697
Publisher: American Society of Tropical Medicine and Hygiene
Date: 02-07-2014
Publisher: Elsevier BV
Date: 08-2005
Publisher: American Society for Microbiology
Date: 03-2011
DOI: 10.1128/AAC.01220-10
Abstract: Histone acetylation plays an important role in regulating gene transcription and silencing in Plasmodium falciparum . Histone deacetylase (HDAC) inhibitors, particularly those of the hydroxamate class, have been shown to have potent in vitro activity against drug-resistant and -sensitive laboratory strains of P. falciparum , raising their potential as a new class of antimalarial compounds. In the current study, stage-specific ex vivo susceptibility profiles of representative hydroxamate-based HDAC inhibitors suberoylanilide hydroxamic acid (SAHA), 2-ASA-9, and 2-ASA-14 (2-ASA-9 and 2-ASA-14 are 2-aminosuberic acid-based HDAC inhibitors) were assessed in multidrug-resistant clinical isolates of P. falciparum ( n = 24) and P. vivax ( n = 25) from Papua, Indonesia, using a modified schizont maturation assay. Submicromolar concentrations of SAHA, 2-ASA-9, and 2-ASA-14 inhibited the growth of both P. falciparum (median 50% inhibitory concentrations [IC 50 s] of 310, 533, and 266 nM) and P. vivax (median IC 50 s of 170, 503, and 278 nM). Inverse correlation patterns between HDAC inhibitors and chloroquine for P. falciparum and mefloquine for P. vivax indicate species-specific susceptibility profiles for HDAC inhibitors. These HDAC inhibitors were also found to be potent ex vivo against P . vivax schizont maturation, comparable to that in P. falciparum , suggesting that HDAC inhibitors may be promising candidates for antimalarial therapy in geographical locations where both species are endemic. Further studies optimizing the selectivity and in vivo efficacy of HDAC inhibitors in Plasmodium spp. and defining drug interaction with common antimalarial compounds are warranted to investigate the role of HDAC inhibitors in antimalarial therapy.
Publisher: American Chemical Society (ACS)
Date: 02-05-2008
DOI: 10.1021/CT800033X
Publisher: Springer Science and Business Media LLC
Date: 08-2018
DOI: 10.1039/C8PP00138C
Abstract: The photoreceptor UV RESISTANCE LOCUS 8 (UVR8) activates photomorphogenic responses when plants are exposed to ultraviolet-B (UV-B) light. However, whereas the absorption spectrum of UVR8 peaks at 280 nm, action spectra for several photomorphogenic UV-B responses show maximal photon effectiveness at 290-300 nm. To investigate this apparent discrepancy we measured the effectiveness of UV wavelengths in initiating two responses in Arabidopsis: photoconversion of homodimeric UVR8 into the monomeric form, which is active in signaling, and accumulation of transcripts of the ELONGATED HYPOCOTYL 5 (HY5) transcription factor, which has a key role in UVR8-mediated responses. When purified UVR8 or Arabidopsis leaf extracts were exposed to UV light monomerisation was maximal at approximately 280 nm, which correlates with the UVR8 absorption spectrum. When intact plants were exposed to UV, monomerisation was most strongly initiated at approximately 290 nm, and this shift in maximal effectiveness could be explained by strong absorption or reflectance at 280 nm by leaf tissue. Notably, the action spectrum for accumulation of HY5 transcripts in the same leaf tissue s les used to assay UVR8 dimer/monomer status peaked at approximately 300 nm. Possible reasons for the difference in maximal photon effectiveness of UVR8 monomerisation and HY5 transcript accumulation in leaf tissue are discussed.
Publisher: Springer Science and Business Media LLC
Date: 08-11-2016
Publisher: Public Library of Science (PLoS)
Date: 02-11-2018
Publisher: Springer Science and Business Media LLC
Date: 17-05-2019
Publisher: SAGE Publications
Date: 11-02-2023
DOI: 10.1177/17407745231154215
Abstract: The COVID-19 pandemic and resulting restrictions, particularly travel restrictions, have had significant impact on the conduct of global clinical trials. Our clinical trials programme, which relied on in-person visits for training, monitoring and capacity building across nine low- and middle-income countries, had to adapt to those unprecedented operational challenges. We report the adaptation of our working model with a focus on the operational areas of training, monitoring and cross-site collaboration. Adaptations include changing training strategies from in-person site visits with three or four team members to a multi-pronged virtual approach, with generic online training for good clinical practice, the development of a library of study-specific training videos, and interactive virtual training sessions, including practical laboratory-focused training sessions. We also report changes from in-person monitoring to remote monitoring as well as the development of a more localized network of clinical trial monitors to support hybrid models with in-person and remote monitoring depending on identified risks at each site. We established a virtual network across different trial and study sites with the objective to further build capacity for good clinical practice–compliant antimalarial trials and foster cross-country and cross-study site collaboration. The forced adaptation of these new strategies has come with advantages that we did not envisage initially. This includes improved, more frequent engagement through the established network with opportunities for increased south-to-south support and a substantially reduced carbon footprint and budget savings. Our new approach is challenging for study sites with limited prior experience but this can be overcome with hybrid models. Capacity building for laboratory-based work remains difficult using a virtual environment. The changes to our working model are likely to last, even after the end of the pandemic, providing a more sustainable and equitable approach to our research.
Publisher: Wiley
Date: 18-11-2016
DOI: 10.1111/APM.12605
Publisher: Public Library of Science (PLoS)
Date: 17-06-2008
Publisher: Elsevier BV
Date: 02-2022
Publisher: American Society of Tropical Medicine and Hygiene
Date: 15-06-2022
Publisher: Emerald
Date: 20-11-2009
Publisher: Oxford University Press (OUP)
Date: 15-06-2009
DOI: 10.1086/599041
Publisher: Wiley
Date: 24-11-2006
Publisher: Springer Science and Business Media LLC
Date: 07-03-2022
DOI: 10.1186/S12916-022-02265-9
Abstract: Plasmodium falciparum malaria is associated with anaemia-related morbidity, attributable to host, parasite and drug factors. We quantified the haematological response following treatment of uncomplicated P. falciparum malaria to identify the factors associated with malarial anaemia. In idual patient data from eligible antimalarial efficacy studies of uncomplicated P. falciparum malaria, available through the WorldWide Antimalarial Resistance Network data repository prior to August 2015, were pooled using standardised methodology. The haematological response over time was quantified using a multivariable linear mixed effects model with nonlinear terms for time, and the model was then used to estimate the mean haemoglobin at day of nadir and day 7. Multivariable logistic regression quantified risk factors for moderately severe anaemia (haemoglobin 7 g/dL) at day 0, day 3 and day 7 as well as a fractional fall ≥ 25% at day 3 and day 7. A total of 70,226 patients, recruited into 200 studies between 1991 and 2013, were included in the analysis: 50,859 (72.4%) enrolled in Africa, 18,451 (26.3%) in Asia and 916 (1.3%) in South America. The median haemoglobin concentration at presentation was 9.9 g/dL (range 5.0–19.7 g/dL) in Africa, 11.6 g/dL (range 5.0–20.0 g/dL) in Asia and 12.3 g/dL (range 6.9–17.9 g/dL) in South America. Moderately severe anaemia (Hb 7g/dl) was present in 8.4% (4284/50,859) of patients from Africa, 3.3% (606/18,451) from Asia and 0.1% (1/916) from South America. The nadir haemoglobin occurred on day 2 post treatment with a mean fall from baseline of 0.57 g/dL in Africa and 1.13 g/dL in Asia. Independent risk factors for moderately severe anaemia on day 7, in both Africa and Asia, included moderately severe anaemia at baseline (adjusted odds ratio (AOR) = 16.10 and AOR = 23.00, respectively), young age (age 1 compared to ≥ 12 years AOR = 12.81 and AOR = 6.79, respectively), high parasitaemia (AOR = 1.78 and AOR = 1.58, respectively) and delayed parasite clearance (AOR = 2.44 and AOR = 2.59, respectively). In Asia, patients treated with an artemisinin-based regimen were at significantly greater risk of moderately severe anaemia on day 7 compared to those treated with a non-artemisinin-based regimen (AOR = 2.06 [95%CI 1.39–3.05], p 0.001). In patients with uncomplicated P. falciparum malaria, the nadir haemoglobin occurs 2 days after starting treatment. Although artemisinin-based treatments increase the rate of parasite clearance, in Asia they are associated with a greater risk of anaemia during recovery.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Start Date: 2022
End Date: 2025
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2016
End Date: 2023
Funder: Wellcome Trust
View Funded ActivityStart Date: 2021
End Date: 2023
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2017
End Date: 2022
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2019
End Date: 2022
Funder: National Health and Medical Research Council
View Funded Activity