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Frontiers in Genetics 2022infects millions and kills thousands of people annually the world over. With the emergence of artemisinin and/or multidrug resistant strains of the pathogen, it has...
infects millions and kills thousands of people annually the world over. With the emergence of artemisinin and/or multidrug resistant strains of the pathogen, it has become even more challenging to control and eliminate the disease. Multiomics studies of the parasite have started to provide a glimpse into the confounding genetics and mechanisms of artemisinin resistance and identified mutations in Kelch13 (K13) as a molecular marker of resistance. Over the years, thousands of genomes and transcriptomes of artemisinin-resistant/sensitive isolates have been documented, supplementing the search for new genes/pathways to target artemisinin-resistant isolates. This meta-analysis seeks to recap the genetic landscape and the transcriptional deregulation that demarcate artemisinin resistance in the field. To explore the genetic territory of artemisinin resistance, we use genomic single-nucleotide polymorphism (SNP) datasets from 2,517 isolates from 15 countries from the MalariaGEN Network (The Pf3K project, pilot data release 4, 2015) to dissect the prevalence, geographical distribution, and co-existing patterns of genetic markers associated with/enabling artemisinin resistance. We have identified several mutations which co-exist with the established markers of artemisinin resistance. Interestingly, K13-resistant parasites harbor α-ß hydrolase and putative HECT domain-containing protein genes with the maximum number of SNPs. We have also explored the multiple, publicly available transcriptomic datasets to identify genes from key biological pathways whose consistent deregulation may be contributing to the biology of resistant parasites. Surprisingly, glycolytic and pentose phosphate pathways were consistently downregulated in artemisinin-resistant parasites. Thus, this meta-analysis highlights the genetic and transcriptomic features of resistant parasites to propel further exploratory studies in the community to tackle artemisinin resistance.
PubMed: 35464842
DOI: 10.3389/fgene.2022.824483 -
Parasites & Vectors Dec 2022The production of Plasmodium gametocytes in vitro is a real challenge. Many protocols have been described, but few have resulted in the production of viable and... (Review)
Review
BACKGROUND
The production of Plasmodium gametocytes in vitro is a real challenge. Many protocols have been described, but few have resulted in the production of viable and infectious gametocytes in sufficient quantities to conduct research on-but not limited to-transmission-blocking drug and vaccine development. The aim of this review was to identify and discuss gametocyte production protocols that have been developed over the last two decades.
METHODS
We analyzed the original gametocyte production protocols published from 2000 onwards based on a literature search and a thorough review. A systematic review was performed of relevant articles identified in the PubMed, Web of Sciences and ScienceDirect databases.
RESULTS
A total 23 studies on the production of Plasmodium gametocytes were identified, 19 involving in vitro Plasmodium falciparum, one involving Plasmodium knowlesi and three involving ex vivo Plasmodium vivax. Of the in vitro studies, 90% used environmental stressors to trigger gametocytogenesis. Mature gametocytemia of up to 4% was reported.
CONCLUSIONS
Several biological parameters contribute to an optimal production in vitro of viable and infectious mature gametocytes. The knowledge gained from this systematic review on the molecular mechanisms involved in gametocytogenesis enables reproducible gametocyte protocols with transgenic parasite lines to be set up. This review highlights the need for additional gametocyte production protocols for Plasmodium species other than P. falciparum.
Topics: Humans; Malaria, Falciparum; Plasmodium falciparum; Plasmodium knowlesi; Plasmodium vivax; Systematic Reviews as Topic
PubMed: 36471426
DOI: 10.1186/s13071-022-05566-3 -
The Lancet Regional Health. Southeast... Jul 2022The long-term maintenance of parasite biomass below the detection threshold of microscopy may stymie malaria elimination. Variation in microscopists' competencies to...
BACKGROUND
The long-term maintenance of parasite biomass below the detection threshold of microscopy may stymie malaria elimination. Variation in microscopists' competencies to detect and correctly identify parasite species reflect in microscopy sensitivity, resulting in incorrect species-specific burden.
METHODS
The study estimated SMI pooled burden from published reports using a random effect model & identifies their hotspots in India. The study applied a prediction model for the first time on Indian data, emphasizing the importance of such models that can predict PCR-prevalence from slide- prevalence.
FINDINGS
A total of 17,449 samples from 39 districts were examined for by microscopy and PCR. The overall heterogeneity in clinic-based and community-based studies was 91% and 96%, respectively, with the pooled prevalence of 3.63%. The SMI prevalence in individual studies ranged from 38.4% to 0.4%. Sensitivity of microscopy for mono- (91%) was found to be better than mono- (82 %). But surprisingly, it was much lower for mixed PfPv (45%).
INTERPRETATION
Primary regional data in the form of SMIs hot spots should be generated from countries on the verge of malaria elimination, and genetic monitoring should be integrated into national programs, particularly in key areas for successful malaria elimination.
FUNDING
Not applicable.
PubMed: 37383294
DOI: 10.1016/j.lansea.2022.05.001 -
PloS One 2020Plasmodium ovale can infect humans, causing malaria disease. We aimed to investigate the severity and mortality of severe P. ovale infection to increase the awareness of... (Meta-Analysis)
Meta-Analysis
Plasmodium ovale can infect humans, causing malaria disease. We aimed to investigate the severity and mortality of severe P. ovale infection to increase the awareness of physicians regarding the prognosis of this severe disease and outcome-related deaths in countries in which this disease is endemic. Articles that were published in the PubMed, Scopus, and ISI Web of Science databases prior to January 5, 2020 and reported the prevalence of severe P. ovale infection were systematically searched and reviewed. Studies that mainly reported severe P. ovale infection according to the 2014 WHO criteria for the treatment of malaria were included. Two reviewers selected, identified, assessed, and extracted data from studies independently. The pooled prevalence of severe P. ovale mono-infections was estimated using the command "metaprop case population, random/fixed", which yielded the pooled estimate, 95% confidence interval (CI) and the I2 value, indicating the level of heterogeneity. Meta-analyses of the proportions were performed using a random-effects model to explore the different proportions of severity between patients with P. ovale and those with other Plasmodium species infections. Among the eight studies that were included and had a total of 1,365 ovale malaria cases, the pooled prevalence of severe P. ovale was 0.03 (95% CI = 0.03-0.05%, I2 = 54.4%). Jaundice (1.1%), severe anemia (0.88%), and pulmonary impairments (0.59%) were the most common severe complications found in patients infected with P. ovale. The meta-analysis demonstrated that a smaller proportion of patients with P. ovale than of patients with P. falciparum had severe infections (P-value = 0.01, OR = 0.36, 95% CI = 0.16-0.81, I2 = 72%). The mortality rate of severe P. ovale infections was 0.15% (2/1,365 cases). Although severe complications of P. ovale infections in patients are rare, it is very important to increase the awareness of physicians regarding the prognosis of severe P. ovale infections in patients, especially in a high-risk population.
Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Female; Humans; Infant; Malaria; Male; Middle Aged; Plasmodium falciparum; Plasmodium ovale; Prevalence
PubMed: 32559238
DOI: 10.1371/journal.pone.0235014 -
Infection Jun 2024Despite the significant burden of Plasmodium falciparum (Pf) malaria and the licensure of two vaccines for use in infants and young children that are partially effective... (Meta-Analysis)
Meta-Analysis
Protective efficacy and safety of radiation-attenuated and chemo-attenuated Plasmodium Falciparum sporozoite vaccines against controlled and natural malaria infection: a systematic review and meta-analysis of randomized controlled trials.
BACKGROUND AND OBJECTIVE
Despite the significant burden of Plasmodium falciparum (Pf) malaria and the licensure of two vaccines for use in infants and young children that are partially effective in preventing clinical malaria caused by Pf, a highly effective vaccine against Pf infection is still lacking. Live attenuated vaccines using Pf sporozoites as the immunogen (PfSPZ Vaccines) hold promise for addressing this gap. Here we review the safety and efficacy of two of the most promising PfSPZ approaches: PfSPZ Vaccine (radiation attenuated PfSPZ) and PfSPZ-CVac (chemo-attenuated PfSPZ).
METHODS
We conducted a systematic review and meta-analysis by searching PubMed, EMBASE, SCOPUS, CENTRAL, and WOS until 22nd December 2021. We included randomized controlled trials (RCTs) of these two vaccine approaches that measured protection against parasitaemia following controlled human malaria infection (CHMI) in malaria-naive and malaria-exposed adults or following exposure to naturally transmitted Pf malaria in African adults and children (primary outcome) and that also measured the incidence of solicited and unsolicited adverse events as indicators of safety and tolerability after vaccination (secondary outcome). We included randomized controlled trials (RCTs) that measured the detected parasitaemia after vaccination (primary outcome) and the incidence of various solicited and unsolicited adverse events (secondary outcome). The quality of the included RCTs using the Cochrane ROB 1 tool and the quality of evidence using the GRADE system were evaluated. We pooled dichotomous data using the risk ratio (RR) for development of parasitemia in vaccinees relative to controls as a measure of vaccine efficacy (VE), including the corresponding confidence interval (CI). This study was registered with PROSPERO (CRD42022308057).
RESULTS
We included 19 RCTs. Pooled RR favoured PfSPZ Vaccine (RR: 0.65 with 95% CI [0.53, 0.79], P = 0.0001) and PfSPZ-table (RR: 0.42 with 95% CI [0.27, 0.67], P = 0.0002) for preventing parasitaemia, relative to normal saline placebo. Pooled RR showed no difference between PfSPZ Vaccine and the control in the occurrence of any solicited adverse event (RR: 1.00 with 95% CI [0.82, 1.23], P = 0.98), any local solicited adverse events (RR: 0.73 with 95% CI [0.49, 1.08], P = 0.11), any systemic solicited adverse events (RR: 0.94 with 95% CI [0.75, 1.17], P = 0.58), and any unsolicited adverse event (RR: 0.93 with 95% CI [0.78, 1.10], P = 0.37).
CONCLUSION
PfSPZ and PfSPZ-CVacs showed comparable efficacy. Therefore, they can introduce a promising strategy for malaria prophylaxis, but more large-scale field trials are required to sustain efficacy and yield clinically applicable findings.
Topics: Humans; Malaria Vaccines; Malaria, Falciparum; Parasitemia; Plasmodium falciparum; Randomized Controlled Trials as Topic; Sporozoites; Vaccines, Attenuated
PubMed: 38319556
DOI: 10.1007/s15010-024-02174-4 -
Journal of Infection and Public Health May 2022A wide spread of chloroquine resistance prompted its discontinued use for treatment of uncomplicated malaria in several African countries. However, disappearances of... (Review)
Review
Molecular surveillance of chloroquine-resistant Plasmodium falciparum in sub-Saharan African countries after withdrawal of chloroquine for treatment of uncomplicated malaria: A systematic review.
BACKGROUND
A wide spread of chloroquine resistance prompted its discontinued use for treatment of uncomplicated malaria in several African countries. However, disappearances of chloroquine-resistant parasites have been reported in areas with restricted use of chloroquine. This review reports the current prevalence of chloroquine-resistant Plasmodium falciparum using Pfcrt K76T and Pfmdr1 N86Y genotypes.
METHODS
A PROSPERO registered systematic review searched evidence from PubMed/MEDLINE, Science Direct and Google Scholar. The search included studies on chloroquine-resistant/ susceptible P. falciparum in humans between January 1st, 2000 and May 15th, 2020. The search was conducted on 15th of May, 2020.
RESULTS
Out of 519 searched records, 15 studies qualified for final analysis with 8040 samples genotyped for Pfcrt K76T. Of 8040, 43.6% (837/1572; 95%CI: -0.9 to 88.1%) carried resistant genotypes versus 23.0% (1477/6468; 95%CI: 15.7-30.2%) while for 4698 samples analyzed for Pfmdr1 N86Y, 52.4% (592/1090; 95%CI: 42.3-62.5%) had resistant genotypes versus 25.9% (1314/3608; 95%CI: 5.8-46.0%), before and after chloroquine withdrawal, respectively. The median time since chloroquine withdrawal to data collection was 7.0 (interquartile range: 4.5-13.5) years. Low prevalence of resistant genotypes (Pfcrt K76T) was reported in Zambia (0%) in 2013, Malawi (0.1%) in 2009, Tanzania (0.2%) in 2018 and Madagascar (0.3%) in 2007 with significant variations in the included studies.
CONCLUSIONS
Chloroquine-resistant P. falciparum continues to disappear in countries with withdrawal of chloroquine. Areas with significant susceptible parasites, reintroduction of chloroquine can be considered, preferably in combination with other safe and affordable antimalarials.
Topics: Africa South of the Sahara; Antimalarials; Chloroquine; Drug Resistance; Humans; Malaria; Malaria, Falciparum; Membrane Transport Proteins; Plasmodium falciparum; Protozoan Proteins
PubMed: 35447389
DOI: 10.1016/j.jiph.2022.03.015 -
The Cochrane Database of Systematic... Aug 2023Insecticide-based interventions, such as long-lasting insecticide-treated nets (LLINs) and indoor residual spraying (IRS), remain the backbone of malaria vector control.... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Insecticide-based interventions, such as long-lasting insecticide-treated nets (LLINs) and indoor residual spraying (IRS), remain the backbone of malaria vector control. These interventions target mosquitoes that prefer to feed and rest indoors, but have limited capacity to prevent transmission that occurs outdoors or outside regular sleeping hours. In low-endemicity areas, malaria elimination will require that these control gaps are addressed, and complementary tools are found. The use of topical repellents may be particularly useful for populations who may not benefit from programmatic malaria control measures, such as refugees, the military, or forest goers. This Cochrane Review aims to measure the effectiveness of topical repellents to prevent malaria infection among high- and non-high-risk populations living in malaria-endemic regions.
OBJECTIVES
To assess the effect of topical repellents alone or in combination with other background interventions (long-lasting insecticide-treated nets, or indoor residual spraying, or both) for reducing the incidence of malaria in high- and non-high-risk populations living in endemic areas.
SEARCH METHODS
We searched the following databases up to 11 January 2023: the Cochrane Infectious Diseases Group Specialised Register; CENTRAL (in the Cochrane Library); MEDLINE; Embase; CAB Abstracts; and LILACS. We also searched trial registration platforms and conference proceedings; and contacted organizations and companies for ongoing and unpublished trials.
SELECTION CRITERIA
We included randomized controlled trials (RCTs) and cluster-randomized controlled trials (cRCTs) of topical repellents proven to repel mosquitoes. We also included non-randomized studies that complied with pre-specified inclusion criteria: controlled before-after studies (CBA), controlled interrupted time series (ITS), and controlled cross-over trials.
DATA COLLECTION AND ANALYSIS
Four review authors independently assessed trials for inclusion, and extracted the data. Two authors independently assessed the risk of bias (RoB) using the Cochrane RoB 2 tool. A fifth review author resolved any disagreements. We analysed data by conducting a meta-analysis, stratified by whether studies included populations considered to be at high-risk of developing malaria infection (for example, refugees, forest goers, or deployed military troops). We combined results from cRCTs with RCTs by adjusting for clustering and presented results using forest plots. We used the GRADE framework to assess the certainty of the evidence. We only included data on Plasmodium falciparum infections in the meta-analysis.
MAIN RESULTS
Thirteen articles relating to eight trials met the inclusion criteria and were qualitatively described. We included six trials in the meta-analysis (five cRCTs and one RCT). Effect on malaria incidence Topical repellents may slightly reduce P falciparum infection and clinical incidence when both outcomes are considered together (incidence rate ratio (IRR) 0.74, 95% confidence interval (CI) 0.56 to 0.98; 3 cRCTs and 1 RCT, 61,651 participants; low-certainty evidence); but not when these two outcomes were considered independently. Two cRCTs and one RCT (12,813 participants) evaluated the effect of topical repellents on infection incidence (IRR 0.76, 95% CI 0.56 to 1.02; low-certainty evidence). One cRCT (48,838 participants) evaluated their effect on clinical case incidence (IRR 0.66, 95% CI 0.32 to 1.36; low-certainty evidence). Three studies (2 cRCTs and 1 RCT) included participants belonging to groups considered at high-risk of being infected, while only one cRCT did not include participants at high risk. Adverse events Topical repellents are considered safe. The prevalence of adverse events among participants who used topical repellents was very low (0.6%, 283/47,515) and limited to mild skin reactions. Effect on malaria prevalence Topical repellents may slightly reduce P falciparum prevalence (odds ratio (OR) 0.81, 95% CI 0.67 to 0.97; 3 cRCTs and 1 RCT; 55,366 participants; low-certainty evidence). Two of these studies (1 cRCT and 1 RCT) were carried out in refugee camps, and included exclusively high-risk populations that were not receiving any other background vector control intervention.
AUTHORS' CONCLUSIONS
There is insufficient evidence to conclude that topical repellents can prevent malaria in settings where other vector control interventions are in place. We found the certainty of evidence for all outcomes to be low, primarily due to the risk of bias. A protective effect was suggested among high-risk populations, specially refugees, who might not have access to other standard vector control measures. More adequately powered clinical trials carried out in refugee camps could provide further information on the potential benefit of topical repellents in this setting. Individually randomized studies are also likely necessary to understand whether topical repellents have an effect on personal protection, and the degree to which diversion to non-protected participants affects overall transmission dynamics. Despite this, the potential additional benefits of topical repellents are most likely limited in contexts where other interventions are available.
Topics: Animals; Humans; Insecticides; Mosquito Vectors; Malaria, Falciparum; Controlled Before-After Studies; Culicidae
PubMed: 37602418
DOI: 10.1002/14651858.CD015422.pub2 -
Malaria Journal Sep 2012Confirmation of artemisinin-delayed parasite clearance in Plasmodium falciparum along the Thai-Myanmar border has inspired a global response to contain and monitor drug...
Molecular surveillance for drug-resistant Plasmodium falciparum in clinical and subclinical populations from three border regions of Burma/Myanmar: cross-sectional data and a systematic review of resistance studies.
BACKGROUND
Confirmation of artemisinin-delayed parasite clearance in Plasmodium falciparum along the Thai-Myanmar border has inspired a global response to contain and monitor drug resistance to avert the disastrous consequences of a potential spread to Africa. However, resistance data from Myanmar are sparse, particularly from high-risk areas where limited health services and decades of displacement create conditions for resistance to spread. Subclinical infections may represent an important reservoir for resistance genes that confer a fitness disadvantage relative to wild-type alleles. This study estimates the prevalence of resistance genotypes in three previously unstudied remote populations in Myanmar and tests the a priori hypothesis that resistance gene prevalence would be higher among isolates collected from subclinical infections than isolates collected from febrile clinical patients. A systematic review of resistance studies is provided for context.
METHODS
Community health workers in Karen and Kachin States and an area spanning the Indo-Myanmar border collected dried blood spots from 988 febrile clinical patients and 4,591 villagers with subclinical infection participating in routine prevalence surveys. Samples positive for P. falciparum 18 s ribosomal RNA by real-time PCR were genotyped for P. falciparum multidrug resistance protein (pfmdr1) copy number and the pfcrt K76T polymorphism using multiplex real-time PCR.
RESULTS
Pfmdr1 copy number increase and the pfcrt K76 polymorphism were determined for 173 and 269 isolates, respectively. Mean pfmdr1 copy number was 1.2 (range: 0.7 to 3.7). Pfmdr1 copy number increase was present in 17.5%, 9.6% and 11.1% of isolates from Karen and Kachin States and the Indo-Myanmar border, respectively. Pfmdr1 amplification was more prevalent in subclinical isolates (20.3%) than clinical isolates (6.4%, odds ratio 3.7, 95% confidence interval 1.1 - 12.5). Pfcrt K76T prevalence ranged from 90-100%.
CONCLUSIONS
Community health workers can contribute to molecular surveillance of drug resistance in remote areas of Myanmar. Marginal and displaced populations under-represented among previous resistance investigations can and should be included in resistance surveillance efforts, particularly once genetic markers of artemisinin-delayed parasite clearance are identified. Subclinical infections may contribute to the epidemiology of drug resistance, but determination of gene amplification from desiccated filter samples requires further validation when DNA concentration is low.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antimalarials; Asymptomatic Diseases; Child; Child, Preschool; DNA, Protozoan; Drug Resistance; Female; Genetic Variation; Genotype; Humans; Infant; Infant, Newborn; Malaria, Falciparum; Male; Membrane Transport Proteins; Middle Aged; Multidrug Resistance-Associated Proteins; Myanmar; Plasmodium falciparum; Polymerase Chain Reaction; Protozoan Proteins; Young Adult
PubMed: 22992214
DOI: 10.1186/1475-2875-11-333 -
Medical Science Monitor : International... Jul 2004The Parasight-F test is a device for the rapid diagnosis of Plasmodium falciparum malaria. In a number of field studies rather wide disparities in the performance of the... (Comparative Study)
Comparative Study Meta-Analysis Review
BACKGROUND
The Parasight-F test is a device for the rapid diagnosis of Plasmodium falciparum malaria. In a number of field studies rather wide disparities in the performance of the test have been reported. To provide an evaluation of the quality of available reports and an overall summary of diagnostic accuracy of the Parasight-F test, we have performed a systematic review.
MATERIAL/METHODS
Systematic review and meta-analysis of controlled studies evaluating the diagnostic accuracy of Parasight-F test in comparison with light microscopy.
DATA SOURCES
15,359 subjects (4,119 with falciparum malaria) studied with the Parasight-F test as reported in 32 studies from 29 publications.
MAIN OUTCOME MEASURES
Summary receiving operator characteristic (SROC) curve as well as odds ratio calculated by the fixed effect model and the random effect model. Based on pooled data, the predictive values were calculated for a range of P. falciparum prevalence through a Bayesian approach.
RESULTS
Overall, the Parasight-F test demonstrated 0.90 (95%, confidence intervals 0.88-0.93) sensitivity and 0.94 (0.92-0.96) specificity. Both sensitivity and specificity were significantly higher in the non-resident than in the resident population. The post-test probability indicates that in settings of low malaria prevalence, a negative test almost absolutely excludes infection, while in settings of high prevalence, the same result still gives a substantial chance of infection being present.
CONCLUSIONS
The Parasight-F test is a simple and accurate test for the diagnosis of P. falciparum infection. The test could be of particular value in the diagnosis of malaria in travelers returning from endemic areas.
Topics: Animals; Antigens, Protozoan; Confidence Intervals; Humans; Malaria, Falciparum; Microscopy; Odds Ratio; Plasmodium falciparum; Predictive Value of Tests; Prevalence; Reagent Kits, Diagnostic; Sensitivity and Specificity
PubMed: 15232515
DOI: No ID Found -
SAGE Open Medicine 2022Active detection of asymptomatic malaria cases and resolution of associated factors are essential for malaria elimination. There are no nationwide estimates for... (Review)
Review
Active detection of asymptomatic malaria cases and resolution of associated factors are essential for malaria elimination. There are no nationwide estimates for asymptomatic malaria and associated factors in Ethiopia. Therefore, this study aims to generate comprehensive and conclusive evidence from various studies conducted in Ethiopia. Published articles from various electronic databases such as PubMed, Google Scholar, CINAHL, Scopes, Cochrane Library, the Web of Science, and African Journals Online were accessed. Also, unpublished studies from Addis Ababa digital library were identified. All observational study designs were included in the search. Data were extracted on the Microsoft Excel spreadsheet and analyzed using STATA version 14.1. A random-effects model was fitted to estimate the pooled prevalence of asymptomatic malaria. A meta-regression and subgroup analysis was computed to see heterogeneity. The publication bias was assessed by the funnel plots and Egger's statistical tests. The analysis found that the pooled burden of asymptomatic malaria was 6.7 (95% confidence interval = 4.60, 8.79). The pooled prevalence of Plasmodium falciparum was 3.75 (95% confidence interval = 2.25, 5.18), and that of Plasmodium vivax was 2.22 (95% confidence interval = 1.46, 2.99). Factors such indoor residual spray service (odds ratio = 0.46; 95% confidence interval = 0.26, 0.81), never used insecticide-treated nets (odds ratio = 6.36; 95% confidence interval = 4.01, 10.09), and presence of stagnant water in the vicinity (odds ratio = 3.24; 95% confidence interval = 1.20, 8.71) were found to have a significant association with asymptomatic malaria. This study highlighted that pooled prevalence of asymptomatic malaria is high and varied by population groups. Prevalence of asymptomatic malaria was increased among those who never used insecticide-treated nets and were living near stagnant water by six and three times, respectively. The use of more sensitive diagnostic methods could yield a higher burden of the disease. Furthermore, active case detection is recommended for effective intervention toward elimination.
PubMed: 35433001
DOI: 10.1177/20503121221088085