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  • Use of a highly-sensitive rapid diagnostic test to screen for malaria in pregnancy in Indonesia
    Malaria J. (IF 2.798) Pub Date : 2020-01-16
    Vera T. Unwin; Rukhsana Ahmed; Rintis Noviyanti; Agatha M. Puspitasari; Retno A. S. Utami; Leily Trianty; Theda Lukito; Din Syafruddin; Jeanne R. Poespoprodjo; Maria A. Santana-Morales; Feiko O. Ter Kuile; Emily R. Adams

    The sensitivity of rapid diagnostic tests (RDTs) for malaria is inadequate for detecting low-density, often asymptomatic infections, such as those that can occur when screening pregnant women for malaria. The performance of the Alere™ Ultra-sensitive Malaria Ag Plasmodium falciparum RDT (uRDT) was assessed retrospectively in pregnant women in Indonesia. The diagnostic performance of the uRDT and the CareStart™ Malaria HRP2/pLDH VOM (Plasmodium vivax, Plasmodium ovale and Plasmodium malariae) Combo RDT (csRDT) were assessed using 270 stored red blood cell pellets and plasma samples from asymptomatic pregnant women. These included 112 P. falciparum negative and 158 P. falciparum positive samples detected by a composite test (qPCR, LAMP, nPCR) as reference standard. Diagnostic indicators: sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), diagnostic odds ratio (DOR) and the level of agreement (kappa) were calculated for comparison. Compared with the reference test, the uRDT had a sensitivity of 19.6% (95% CI 13.9–26.8) and specificity of 98.2% (93.1–99.7%). The csRDT was 22.8% (16.7–30.3) sensitive and 95.5% (89.4–98.3) specific for P. falciparum infections. Performance of the uRDT was non-significantly different to the csRDT (p = 0.169). RDT outcome was stratified by qPCR cycling threshold (Ct), and performance of the RDTs was found to be comparable across parasite loads. The uRDT performed similarly to the currently used csRDTs in detecting P. falciparum infections in asymptomatic pregnant women. In these settings, molecular diagnostics are currently the most sensitive for malaria.

    更新日期:2020-01-17
  • Molecular characteristics of odorant-binding protein 1 in Anopheles maculipennis
    Malaria J. (IF 2.798) Pub Date : 2020-01-17
    Mohammad Bagher Ghavami; Sakineh Khoeini; Navid Dinparast Djadid

    Anopheles maculipennis complex, the historic vector of malaria, causes serious medical problems worldwide and exhibits different behaviours. Studying the odorant-binding proteins (OBPs), which influence the chemosensory system and behavioural responses, is essential to understanding the population structure and developing effective control measures against this vector. The present study was designed to identify and analyse the obp1 gene in An. maculipennis. Adults of An. maculipennis sensu stricto were collected in Zanjan Province, northwest of Iran, and gDNAs of female mosquitoes were extracted. Fragments of An. maculipennis obp1 (Amacobp1) gene were amplified using degenerate and specific primers, and some of amplicons were selected for sequencing. Analysis of amplified products identified that the sequence of Amacobp1 gene was 1341 bp long. This gene contains three exons (5′, internal, and 3′of 160, 256, and 18 bp, respectively) and encodes 144 amino acids. The sizes of introns I and II in deduced gene are 268 and 358 nucleotides, respectively. The amino acid sequence in the C-terminal of AmacOBP1 is similar to that of major malaria vector Anopheles species. However, its N-terminal has a specific signal peptide with 19 amino acids. This peptide is conserved in different studied populations, and its sequence of amino acids shows the most variation among anopheline species. Degenerate primers in this study are suggested for studying obp1 gene in Anopheles species. Amacobp1 gene is proposed as a molecular marker for the detection of intraspecific ecotypes and diagnosis of different species within Maculipennis Group. Moreover, the N-terminal of AmacOBP1 peptide is recommended as a molecular marker to identify the Amacobp1 expression patterns in different chemosensory organs for assessing the molecular mechanisms and developing novel behavioural disturbance agents to control An. maculipennis.

    更新日期:2020-01-17
  • ‘We spray and walk away’: wall modifications decrease the impact of indoor residual spray campaigns through reductions in post-spray coverage
    Malaria J. (IF 2.798) Pub Date : 2020-01-17
    Mercy A. Opiyo; Krijn P. Paaijmans

    Malaria prevalence has significantly reduced since 2000, largely due to the scale-up of vector control interventions, mainly indoor residual spraying (IRS) and long-lasting insecticide-treated nets (LLINs). Given their success, these tools remain the frontline interventions in the fight against malaria. Their effectiveness relies on three key ingredients: the intervention, the mosquito vector and the end-user. Regarding the intervention, factors such as the insecticide active ingredient(s) used and the durability and/or bio-efficacy of the tool over time are critical. For the vectors, these factors include biting and resting behaviours and the susceptibility to insecticides. Finally, the end-users need to accept and properly use the intervention. Whilst human attitude and behaviour towards LLINs are well-documented both during and after distribution, only initial coverage is monitored for IRS and in a few geographic settings the residual efficacy of the used product. Here, the historical evidence on end-users modifying their wall surfaces post-spraying is presented, a behaviour that has the potential to reduce actual IRS coverage, effectiveness and impact, as fewer people are truly protected. Therefore, clear guidelines on how to monitor IRS acceptability and/or coverage, both before, during and after spraying, are urgently needed as part of the Monitoring and Evaluation of malaria programmes.

    更新日期:2020-01-17
  • A panel of recombinant proteins from human-infective Plasmodium species for serological surveillance
    Malaria J. (IF 2.798) Pub Date : 2020-01-17
    Nicole Müller-Sienerth; Jarrod Shilts; Khamisah Abdul Kadir; Victor Yman; Manijeh Vafa Homann; Muhammad Asghar; Billy Ngasala; Balbir Singh; Anna Färnert; Gavin J. Wright

    Malaria remains a global health problem and accurate surveillance of Plasmodium parasites that are responsible for this disease is required to guide the most effective distribution of control measures. Serological surveillance will be particularly important in areas of low or periodic transmission because patient antibody responses can provide a measure of historical exposure. While methods for detecting host antibody responses to Plasmodium falciparum and Plasmodium vivax are well established, development of serological assays for Plasmodium knowlesi, Plasmodium ovale and Plasmodium malariae have been inhibited by a lack of immunodiagnostic candidates due to the limited availability of genomic information. Using the recently completed genome sequences from P. malariae, P. ovale and P. knowlesi, a set of 33 candidate cell surface and secreted blood-stage antigens was selected and expressed in a recombinant form using a mammalian expression system. These proteins were added to an existing panel of antigens from P. falciparum and P. vivax and the immunoreactivity of IgG, IgM and IgA immunoglobulins from individuals diagnosed with infections to each of the five different Plasmodium species was evaluated by ELISA. Logistic regression modelling was used to quantify the ability of the responses to determine prior exposure to the different Plasmodium species. Using sera from European travellers with diagnosed Plasmodium infections, antigens showing species-specific immunoreactivity were identified to select a panel of 22 proteins from five Plasmodium species for serological profiling. The immunoreactivity to the antigens in the panel of sera taken from travellers and individuals living in malaria-endemic regions with diagnosed infections showed moderate power to predict infections by each species, including P. ovale, P. malariae and P. knowlesi. Using a larger set of patient samples and logistic regression modelling it was shown that exposure to P. knowlesi could be accurately detected (AUC = 91%) using an antigen panel consisting of the P. knowlesi orthologues of MSP10, P12 and P38. Using the recent availability of genome sequences to all human-infective Plasmodium spp. parasites and a method of expressing Plasmodium proteins in a secreted functional form, an antigen panel has been compiled that will be useful to determine exposure to these parasites.

    更新日期:2020-01-17
  • The use of spatial and genetic tools to assess Plasmodium falciparum transmission in Lusaka, Zambia between 2011 and 2015
    Malaria J. (IF 2.798) Pub Date : 2020-01-15
    Daniel J. Bridges; Sandra Chishimba; Mulenga Mwenda; Anna M. Winters; Erik Slawsky; Brenda Mambwe; Conceptor Mulube; Kelly M. Searle; Aves Hakalima; Roy Mwenechanya; David A. Larsen

    Zambia has set itself the ambitious target of eliminating malaria by 2021. To continue tracking transmission to zero, new interventions, tools and approaches are required. Urban reactive case detection (RCD) was performed in Lusaka city from 2011 to 2015 to better understand the location and drivers of malaria transmission. Briefly, index cases were followed to their home and all consenting individuals living in the index house and nine proximal houses were tested with a malaria rapid diagnostic test and treated if positive. A brief survey was performed and for certain responses, a dried blood spot sample collected for genetic analysis. Aggregate health facility data, individual RCD response data and genetic results were analysed spatially and against environmental correlates. Total number of malaria cases remained relatively constant, while the average age of incident cases and the proportion of incident cases reporting recent travel both increased. The estimated R0 in Lusaka was < 1 throughout the study period. RCD responses performed within 250 m of uninhabited/vacant land were associated with a higher probability of identifying additional infections. Evidence suggests that the majority of malaria infections are imported from outside Lusaka. However there remains some level of local transmission occurring on the periphery of urban settlements, namely in the wet season. Unfortunately, due to the higher-than-expected complexity of infections and the small number of samples tested, genetic analysis was unable to identify any meaningful trends in the data.

    更新日期:2020-01-15
  • Associations between red blood cell variants and malaria among children and adults from three areas of Uganda: a prospective cohort study
    Malaria J. (IF 2.798) Pub Date : 2020-01-15
    Elijah Kakande; Bryan Greenhouse; Francis Bajunirwe; Chris Drakeley; Joaniter I. Nankabirwa; Andrew Walakira; Samuel L. Nsobya; Agaba Katureebe; John Rek; Emmanuel Arinaitwe; Philip J. Rosenthal; Moses R. Kamya; Grant Dorsey; Isabel Rodriguez-Barraquer

    Multiple red blood cell (RBC) variants appear to offer protection against the most severe forms of Plasmodium falciparum malaria. Associations between these variants and uncomplicated malaria are less clear. Data from a longitudinal cohort study conducted in 3 sub-counties in Uganda was used to quantify associations between three red blood cell variants Hb [AA, AS, S (rs334)], alpha thalassaemia 3.7 kb deletion, and glucose-6-phosphate dehydrogenase deficiency A—(G6PD 202A genotype) and malaria incidence, parasite prevalence, parasite density (a measure of anti-parasite immunity) and body temperature adjusted for parasite density (a measure of anti-disease immunity). All analyses were adjusted for age, average household entomological inoculation rate, and study site. Results for all variants were compared to those for wild type genotypes. In children, HbAS was associated, compared to wild type, with a lower incidence of malaria (IRR = 0.78, 95% CI 0.66–0.92, p = 0.003), lower parasite density upon infection (PR = 0.66, 95% CI 0.51–0.85, p = 0.001), and lower body temperature for any given parasite density (− 0.13 ℃, 95% CI − 0.21, − 0.05, p = 0.002). In children, HbSS was associated with a lower incidence of malaria (IRR = 0.17, 95% CI 0.04–0.71, p = 0.02) and lower parasite density upon infection (PR = 0.31, 95% CI 0.18–0.54, p < 0.001). α−/αα thalassaemia, was associated with higher parasite prevalence in both children and adults (RR = 1.23, 95% CI 1.06–1.43, p = 0.008 and RR = 1.52, 95% CI 1.04–2.23, p = 0.03, respectively). G6PD deficiency was associated with lower body temperature for any given parasite density only among male hemizygote children (− 0.19 ℃, 95% CI − 0.31, − 0.06, p = 0.003). RBC variants were associated with non-severe malaria outcomes. Elucidation of the mechanisms by which they confer protection will improve understanding of genetic protection against malaria.

    更新日期:2020-01-15
  • Preferred resting surfaces of dominant malaria vectors inside different house types in rural south-eastern Tanzania
    Malaria J. (IF 2.798) Pub Date : 2020-01-15
    Betwel J. Msugupakulya; Emmanuel W. Kaindoa; Halfan S. Ngowo; Japhet M. Kihonda; Najat F. Kahamba; Dickson S. Msaky; Damaris Matoke-Muhia; Patrick K. Tungu; Fredros O. Okumu

    Malaria control in Africa relies extensively on indoor residual spraying (IRS) and insecticide-treated nets (ITNs). IRS typically targets mosquitoes resting on walls, and in few cases, roofs and ceilings, using contact insecticides. Unfortunately, little attention is paid to where malaria vectors actually rest indoors, and how such knowledge could be used to improve IRS. This study investigated preferred resting surfaces of two major malaria vectors, Anopheles funestus and Anopheles arabiensis, inside four common house types in rural south-eastern Tanzania. The assessment was done inside 80 houses including: 20 with thatched roofs and mud walls, 20 with thatched roofs and un-plastered brick walls, 20 with metal roofs and un-plastered brick walls, and 20 with metal roofs and plastered brick walls, across four villages. In each house, resting mosquitoes were sampled in mornings (6 a.m.–8 a.m.), evenings (6 p.m.–8 p.m.) and at night (11 p.m.–12.00 a.m.) using Prokopack aspirators from multiple surfaces (walls, undersides of roofs, floors, furniture, utensils, clothing, curtains and bed nets). Overall, only 26% of An. funestus and 18% of An. arabiensis were found on walls. In grass-thatched houses, 33–55% of An. funestus and 43–50% of An. arabiensis rested under roofs, while in metal-roofed houses, only 16–20% of An. funestus and 8–30% of An. arabiensis rested under roofs. Considering all data together, approximately 40% of mosquitoes rested on surfaces not typically targeted by IRS, i.e. floors, furniture, utensils, clothing and bed nets. These proportions were particularly high in metal-roofed houses (47–53% of An. funestus; 60–66% of An. arabiensis). While IRS typically uses contact insecticides to target adult mosquitoes on walls, and occasionally roofs and ceilings, significant proportions of vectors rest on surfaces not usually sprayed. This gap exceeds one-third of malaria mosquitoes in grass-thatched houses, and can reach two-thirds in metal-roofed houses. Where field operations exclude roofs during IRS, the gaps can be much greater. In conclusion, there is need for locally-obtained data on mosquito resting behaviours and how these influence the overall impact and costs of IRS. This study also emphasizes the need for alternative approaches, e.g. house screening, which broadly tackle mosquitoes beyond areas reachable by IRS and ITNs.

    更新日期:2020-01-15
  • RDL mutations in Guangxi Anopheles sinensis populations along the China–Vietnam border: distribution frequency and evolutionary origin of A296S resistance allele
    Malaria J. (IF 2.798) Pub Date : 2020-01-15
    Nian Liu; Xiangyang Feng; Xinghui Qiu

    Malaria is a deadly vector-borne disease in tropical and subtropical regions. Although indigenous malaria has been eliminated in Guangxi of China, 473 confirmed cases were reported in the Northern region of neighbouring Vietnam in 2014. Considering that frequent population movement occurs across the China–Vietnam border and insecticide resistance is a major obstacle in disease vector control, there is a need to know the genotype and frequency of insecticide resistance alleles in Anopheles sinensis populations along the China–Vietnam border and to take action to prevent the possible migration of insecticide resistance alleles across the border. Two hundred and eight adults of An. sinensis collected from seven locations in Guangxi along the China–Vietnam border were used in the investigation of individual genotypes of the AsRDL gene, which encodes the RDL gamma-aminobutyric acid (GABA) receptor subunit in An. sinensis. PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) analysis was deployed to genotype codon 345, while direct sequencing of PCR products was conducted to clarify the genotypes for codons 296 and 327 of the AsRDL gene. The genealogical relation of AsRDL haplotypes was analyzed using Network 5.0. Three putative insecticide resistance related mutations (A296S, V327I and T345S) were detected in all the seven populations of An. sinensis in Guangxi along the China–Vietnam border. The resistance-conferring A296S mutation was found to be widely distributed and present at notably high frequencies (78.8% to 100%). Relatively lower frequencies of mutations V327I (26.9% to 53.2%) and T345S (0% to 28.8%) were observed. The V327I or T345S always occurred in the presence of A296S. Evolutionary analysis of 21 AsRDL haplotypes indicated multiple origins of the A296S and V327I mutations. The resistance A296S allele was present at high frequencies in the An. sinensis populations along the China–Vietnam border, indicating a risk of resistance to insecticides targeting RDL. The double mutations (A296S + V327I) may have evolved from alleles carrying the A296S mutation by scaffolding the additional mutation V327I, and A296S allele may have multiple evolutionary origins. These findings will help inform strategies for vector control and malaria prevention.

    更新日期:2020-01-15
  • The effectiveness of older insecticide-treated bed nets (ITNs) to prevent malaria infection in an area of moderate pyrethroid resistance: results from a cohort study in Malawi
    Malaria J. (IF 2.798) Pub Date : 2020-01-15
    Monica P. Shah; Laura C. Steinhardt; Dyson Mwandama; Themba Mzilahowa; John E. Gimnig; Andy Bauleni; Jacklyn Wong; Ryan Wiegand; Don P. Mathanga; Kim A. Lindblade

    A previous cohort study in Malawi showed that users of new insecticide-treated bed nets (ITNs) were significantly protected against malaria compared to non-users, despite moderate levels of pyrethroid resistance among the primary mosquito vectors. The present study investigated whether ITNs that were 1–2 years old continued to protect users in the same area with moderate pyrethroid resistance. One year following a baseline cross-sectional malaria parasitaemia prevalence survey and universal distribution of deltamethrin ITNs (May 2012), a fixed cohort of 1223 children aged 6–59 months was enrolled (April 2013). Children were tested for parasitaemia at monthly scheduled visits and at unscheduled sick visits from May to December 2013 using rapid diagnostic tests. ITN use the prior night and the condition of ITNs (based on presence of holes) was assessed by caregiver self-report. The incidence rate ratio (RR) comparing malaria infection among users and non-users of ITNs was modelled using generalized estimating equations adjusting for potential confounders and accounting for repeated measures on each child. The protective efficacy (PE) of ITN use was calculated as 1 − RR. In this cohort, self-reported ITN use remained consistently high (> 95%) over the study period. Although users of ITNs were slightly more protected compared to non-users of ITNs, the difference in incidence of infection was not statistically significant (RR 0.83, 95% confidence interval [CI] 0.54–1.27). Among ITN users, malaria incidence was significantly lower in users of ITNs with no holes (of any size) compared to users of ITNs with ≥ 1 hole (RR 0.82, 95% CI 0.69–0.98). There was no significant PE of using 1–2 year-old ITNs on the incidence of malaria in children in an area of moderate pyrethroid resistance, but among ITN users, the authors found increased protection by ITNs with no holes compared to ITNs with holes. Given the moderate levels of pyrethroid resistance in the primary malaria vector and recent evidence of added benefits of ITNs with synergists or non-pyrethroid insecticides, next-generation ITNs may be a useful strategy to address pyrethroid resistance and should be further explored in Malawi.

    更新日期:2020-01-15
  • Exploring association between MBL2 gene polymorphisms and the occurrence of clinical blackwater fever through a case–control study in Congolese children
    Malaria J. (IF 2.798) Pub Date : 2020-01-15
    Joseph M. Bodi; Célestin N. Nsibu; Roland L. Longenge; Michel N. Aloni; Pierre Z. Akilimali; Patrick K. Kayembe; Ahmeddin H. Omar; Jan Verhaegen; Pierre M. Tshibassu; Prosper T. Lukusa; Aimé Lumaka; Kenji Hirayama

    Blackwater fever (BWF), one of the most severe and life-threatening forms of falciparum malaria, is characterized by acute massive intravascular haemolysis, often leading to acute renal failure. Thus far, the genetics of the underlying susceptibility to develop BWF is not fully elucidated. Deficiency in the MBL protein, an important component of the innate immune system, has previously been suggested to be a susceptibility factor for the development of severe malaria. This study aimed to evaluate the association between MBL2 gene polymorphisms, known to affect the MBL protein level/activity, and the occurrence of BWF among Congolese children. This is a case–control study. Cases were patients with BWF, whereas controls, matched for gender and age, had uncomplicated malaria (UM). Dried blood spot was collected for genotyping. A total of 129 children were screened, including 43 BWF and 86 UM. The common allele in BWF and UM was A, with a frequency of 76.7 and 61.0%, respectively (OR: 2.67 (0.87–829) and p = 0.079). The frequency of the C allele was 18.6 and 29.1% in BWF and UM groups, respectively, with p = 0.858. Not a single D allele was encountered. Genotype AA was at higher risk for BWF whereas genotypes A0 (AB and AC) were over-represented in UM group (OR: 0.21 (0.06–0.78)) with p = 0.019. Nine haplotypes were observed in this study: 3 high MBL expression haplotypes and 6 low MBL expression haplotype. One new haplotype HYPC was observed in this study. None of these haplotypes was significantly associated with BWF. This pilot study is a preliminary research on MBL2 gene and infectious diseases in DRC. The study results show a higher risk for BWF in AA. This suggests that future studies on BWF should further investigate the contribution of a strong immune response to the occurrence of BWF.

    更新日期:2020-01-15
  • Resistance status of Anopheles gambiae s.l. to insecticides following the 2011 mass distribution campaign of long-lasting insecticidal nets (LLINs) in the Plateau Department, south-eastern Benin
    Malaria J. (IF 2.798) Pub Date : 2020-01-15
    Arthur Sovi; Renaud Govoétchan; Razaki Ossé; Come Z. Koukpo; Albert S. Salako; Thomas Syme; Rodrigue Anagonou; Augustin Fongnikin; Udoka C. Nwangwu; Frédéric Oké-Agbo; Filémon Tokponnon; Gil Germain Padonou; Martin Codjo Akogbeto

    In 2011, Benin’s National Malaria Control Programme (NMCP) organized a nationwide mass distribution campaign of LLINs throughout the country. Following this intervention, it was important to assess whether the level of susceptibility of malaria vectors to insecticides had remained the same as compared to the pre-intervention period. The current study investigated this. Larval collections were conducted in Ifangni, Sakété, Pobè and Kétou districts located in Plateau department, Southeastern Benin before (2009) and after (2012–2013) LLIN distribution. Anopheles gambiae sensu lato (s.l.) larvae from the 4 study districts were reared to adulthood and WHO susceptibility tests were conducted. The insecticides tested were deltamethrin (0.05%), permethrin (0.75%), bendiocarb (0.1%) and DDT (4%). Molecular species identification as well as, the characterization of the kdr L1014F mutation were also performed in the An. gambiae s.l. complex using PCR method. Overall, a significant decrease in mortality rates of An. gambiae s.l. to deltamethrin (0.05%), permethrin (0.75%) and DDT (4%) was observed post-LLIN distribution, respectively: (100% vs 80.9%, p < 0.0001), (77.5% vs 70%, p = 0.01) and, (47.8% vs 4.4%, p < 0.0001). By contrast, susceptibility of vectors to bendiocarb (0.1%) remained the same (100% mortality in the WHO susceptibility tube tests) pre- and post-intervention. An increase in the kdr L1014F frequency was observed post-LLIN distribution [F(kdr) = 0.91)] compared to the pre-intervention period [F(kdr) = 0.56], p < 0.0001. Anopheles coluzzii and An. gambiae were the two molecular species identified in the study area. The decrease susceptibility to pyrethroids and DDT as well as, the increase in the frequency of the kdr L1014F mutation after the intervention stressed at the time, the need for the development and implementation of effective insecticide resistance management strategies. At present, an update of the vectors resistance status in the area is also necessary for decision-making.

    更新日期:2020-01-15
  • A survey of Anopheles species composition and insecticide resistance on the island of Bubaque, Bijagos Archipelago, Guinea-Bissau
    Malaria J. (IF 2.798) Pub Date : 2020-01-15
    Thomas Ant; Erin Foley; Scott Tytheridge; Colin Johnston; Adriana Goncalves; Sainey Ceesay; Mamadou Ousmane Ndiath; Muna Affara; Julien Martinez; Elizabeth Pretorius; Chris Grundy; Amabelia Rodrigues; Paulo Djata; Umberto d’Alessandro; Robin Bailey; David Mabey; Anna Last; James G. Logan

    Bubaque is the most populous island of the Bijagos archipelago, a group of malaria-endemic islands situated off the coast of Guinea-Bissau, West Africa. Malaria vector control on Bubaque relies almost exclusively on the use of long-lasting insecticidal nets (LLINs). However, there is little information on local vector bionomics and insecticide resistance. A survey of mosquito species composition was performed at the onset of the wet season (June/July) and the beginning of the dry season (November/December). Sampling was performed using indoor adult light-traps and larval dipping. Anopheles mosquitoes were identified to species level and assessed for kdr allele frequency by TaqMan PCR. Females were analysed for sporozoite positivity by CSP-ELISA. Resistance to permethrin and α-cypermethrin was measured using the CDC-bottle bioassay incorporating the synergist piperonyl-butoxide. Several Anopheles species were found on the island, all belonging to the Anopheles gambiae sensu lato (s.l.) complex, including An. gambiae sensu stricto, Anopheles coluzzii, Anopheles melas, and An. gambiae/An. coluzzii hybrids. Endophagic Anopheles species composition and abundance showed strong seasonal variation, with a majority of An. gambiae (50% of adults collected) caught in June/July, while An. melas was dominant in November/December (83.9% of adults collected). Anopheles gambiae had the highest sporozoite rate in both seasons, with infection rates of 13.9% and 20% in June/July and November/December, respectively. Moderate frequencies of the West African kdr allele were found in An. gambiae (36%), An. coluzzii (35%), An. gambiae/An. coluzzii hybrids (42%). Bioassays suggest moderate resistance to α-cypermethrin, but full susceptibility to permethrin. The island of Bubaque maintained an An. gambiae s.l. population in both June/July and November/December. Anopheles gambiae was the primary vector at the onset of the wet season, while An. melas is likely to be responsible for most dry season transmission. There was moderate kdr allele frequency and synergist assays suggest likely metabolic resistance, which could reduce the efficacy of LLINs. Future control of malaria on the islands should consider the seasonal shift in mosquito species, and should employ continuous monitoring for insecticide resistance.

    更新日期:2020-01-15
  • Evaluation of long-lasting indoor residual spraying of deltamethrin 62.5 SC-PE against malaria vectors in India
    Malaria J. (IF 2.798) Pub Date : 2020-01-14
    Sudhansu Sekhar Sahu; Sonia Thankachy; Smrutidhara Dash; Krishnamoorthy Nallan; Subramanian Swaminathan; Gunasekaran Kasinathan; Jambulingam Purushothaman

    Deltamethrin 62.5 polymer-enhanced suspension concentrate (SC-PE) is one of the World Health Organization-approved insecticides for indoor residual spraying and was recommended to evaluate its residual activity for determination of appropriate spray cycles in different eco-epidemiologic settings. In the current study, efficacy of deltamethrin 62.5 SC-PE was evaluated against vectors of malaria and its impact on malaria incidence in a Plasmodium falciparum hyper-endemic area in Koraput district, Odisha State, India. The trial had two comparable arms, arm 1 with residual spraying of deltamethrin 62.5 SC-PE and arm 2 with deltamethrin 2.5% WP (positive control). Comparative assessment of the impact of each intervention arm on entomological (density, parity, infection and human blood index), epidemiological (malaria incidence) parameters, residual efficacy and adverse effects were evaluated. Both the arms were comparable in terms of entomological and epidemiological parameters. While, deltamethrin 62.5 SC-PE was found to be effective for 150 days in mud and wood surfaces and 157 days in cement surfaces; deltamethrin 2.5% was effective only for 105 days on mud surfaces and 113 days on cement and wood surfaces. Deltamethrin 62.5 SC-PE had prolonged killing effectiveness up to 5 months. Hence, one round of IRS with deltamethrin 62.5 SC-PE would be sufficient to cover two existing malaria peak transmission seasons (July–August and October–November) in many parts of India.

    更新日期:2020-01-15
  • Testing possible causes of gametocyte reduction in temporally out-of-synch malaria infections
    Malaria J. (IF 2.798) Pub Date : 2020-01-14
    Mary L. Westwood; Aidan J. O’Donnell; Petra Schneider; Gregory F. Albery; Kimberley F. Prior; Sarah E. Reece

    The intraerythrocytic development cycle (IDC) of the rodent malaria Plasmodium chabaudi is coordinated with host circadian rhythms. When this coordination is disrupted, parasites suffer a 50% reduction in both asexual stages and sexual stage gametocytes over the acute phase of infection. Reduced gametocyte density may not simply follow from a loss of asexuals because investment into gametocytes (“conversion rate”) is a plastic trait; furthermore, the densities of both asexuals and gametocytes are highly dynamic during infection. Hence, the reasons for the reduction of gametocytes in infections that are out-of-synch with host circadian rhythms remain unclear. Here, two explanations are tested: first, whether out-of-synch parasites reduce their conversion rate to prioritize asexual replication via reproductive restraint; second, whether out-of-synch gametocytes experience elevated clearance by the host’s circadian immune responses. First, conversion rate data were analysed from a previous experiment comparing infections of P. chabaudi that were in-synch or 12 h out-of-synch with host circadian rhythms. Second, three new experiments examined whether the inflammatory cytokine TNF varies in its gametocytocidal efficacy according to host time-of-day and gametocyte age. There was no evidence that parasites reduce conversion or that their gametocytes become more vulnerable to TNF when out-of-synch with host circadian rhythms. The factors causing the reduction of gametocytes in out-of-synch infections remain mysterious. Candidates for future investigation include alternative rhythmic factors involved in innate immune responses and the rhythmicity in essential resources required for gametocyte development. Explaining why it matters for gametocytes to be synchronized to host circadian rhythms might suggest novel approaches to blocking transmission.

    更新日期:2020-01-14
  • Unlicensed medical practitioners in tribal dominated rural areas of central India: bottleneck in malaria elimination
    Malaria J. (IF 2.798) Pub Date : 2020-01-14
    Mrigendra Pal Singh; Sunil Kumar Chand; Kalyan Brata Saha; Neetiraj Singh; Ramesh C. Dhiman; Lora L. Sabin

    In India, Accredited Social Health Activists (ASHAs) deliver services for diagnosis and treatment of malaria, although unlicensed medical practitioners (UMPs) (informal health providers) are most preferred in communities. A cross sectional survey was conducted to: (i) assess knowledge and treatment-seeking practices in the community, and (ii) explore the diagnosis and treatment practices related to malaria of UMPs working in rural and tribal-dominated high malaria endemic areas of central India, and whether they adhere to the national guidelines. A multi-stage sampling method and survey technique was adopted. Heads of the households and UMPs were interviewed using a structured interview schedule to assess knowledge and malaria treatment practices. Knowledge regarding malaria symptoms was generally accurate, but misconceptions emerged related to malaria transmission and mosquito breeding places. Modern preventive measures were poorly accessed by the households. UMPs were the most preferred health providers (49%) and the first choice in households for seeking treatment. UMPs typically lacked knowledge of the names of malaria parasite species and species-specific diagnosis and treatment. Further, irrational use of anti-malarial drugs was common. UMPs were the most preferred type of health care providers in rural communities where health infrastructure is poor. The study suggests enhancing training of UMPs on national guidelines for malaria diagnosis and treatment to strengthen their ability to contribute to achievement of India’s malaria elimination goals.

    更新日期:2020-01-14
  • Analysis of anti-Plasmodium IgG profiles among Fulani nomadic pastoralists in northern Senegal to assess malaria exposure
    Malaria J. (IF 2.798) Pub Date : 2020-01-13
    Mame Cheikh Seck; Julie Thwing; Aida Sadikh Badiane; Eric Rogier; Fatou Ba Fall; Pape Ibrahima Ndiaye; Khadim Diongue; Moustapha Mbow; Mouhamadou Ndiaye; Mamadou Alpha Diallo; Jules François Gomis; Aminata Mbaye; Tolla Ndiaye; Aminata Gaye; Mohamad Sy; Awa Bineta Déme; Yaye Die Ndiaye; Daouda Ndiaye

    Northern Senegal is a zone of very low malaria transmission, with an annual incidence of < 5/1000 inhabitants. This area, where the Senegal National Malaria Control Programme has initiated elimination activities, hosts Fulani, nomadic, pastoralists that spend the dry season in the south where malaria incidence is higher (150–450/1000 inhabitants) and return to the north with the first rains. Previous research demonstrated parasite prevalence of < 1% in this Fulani population upon return from the south, similar to that documented in the north in cross-sectional surveys. A modified snowball sampling survey of nomadic pastoralists was conducted in five districts in northern Senegal during September and October 2014. Demographic information and dried blood spots were collected. Multiplex bead-based assays were used to assess antibody responses to merozoite surface protein (MSP-119) antigen of the four primary Plasmodium species, as well as circumsporozoite protein (CSP) and liver stage antigen (LSA-1) of Plasmodium falciparum. In the five study districts, 1472 individuals were enrolled, with a median age of 22 years (range 1 to 80 years). Thirty-two percent of subjects were under 14 years and 57% were male. The overall seroprevalence of P. falciparum MSP-119, CSP and LSA-1 antibodies were 45, 12 and 5%, respectively. Plasmodium falciparum MSP-119 antibody responses increased significantly with age in all study areas, and were significantly higher among males. The highest seroprevalence to P. falciparum antigens was observed in the Kanel district (63%) and the lowest observed in Podor (28%). Low seroprevalence was observed for non-falciparum species in all the study sites: 0.4, 0.7 and 1.8%, respectively, for Plasmodium ovale, Plasmodium vivax and Plasmodium malariae MSP-1. Antibody responses to P. vivax were observed in all study sites except Kanel. Prevalence of P. falciparum MSP-119 antibodies and increases by study participant age provided data for low levels of exposure among this transient nomadic population. In addition, antibody responses to P. falciparum short half-life markers (CSP and LSA-1) and non-falciparum species were low. Further investigations are needed to understand the exposure of the Fulani population to P. vivax.

    更新日期:2020-01-14
  • A systematic review of factors affecting adherence to malaria chemoprophylaxis amongst travellers from non-endemic countries
    Malaria J. (IF 2.798) Pub Date : 2020-01-13
    Julian Ahluwalia; Samantha K. Brooks; John Weinman; G. James Rubin

    The aim of this systematic review was to identify predictors of actual or intended adherence with malaria chemoprophylaxis amongst travellers from non-endemic countries visiting endemic countries. A systematic review of the literature was conducted using MEDLINE, Embase, PsycINFO and Global Health databases for studies published up to April 2019. Studies were included if they assessed reasons for adherence among people travelling from a country where malaria was not endemic to a country where it was. Thirty-two studies were included. Predictors of adherence were categorized as relating to either the nature of the travel or the traveller themselves. The three main predictors associated with nature of travel included: destination (e.g. country visited, urban vs rural areas), length of travel and type of travel (e.g. package vs backpacking holiday). The four main traveller-associated predictors were: age, reason for travel (e.g. business, leisure or visiting friends and relatives), perceived risk of catching malaria and experienced or expected medication effects. In order to improve adherence, clinicians should focus on travellers who are least likely to exhibit adherent behaviour. This includes travellers visiting destinations known to have lower adherence figures (such as rural areas), backpackers, business travellers, younger travellers and those travelling for longer periods of time. They should also check to ensure travellers’ perceptions of the risks of malaria are realistic. Where appropriate, misperceptions (such as believing that curing malaria is easier than taking prophylaxis or that travellers visiting relatives have some level of innate immunity) should be corrected. All travellers should be informed of the potential side-effects of medication and given guidance on why it is nonetheless beneficial to continue to take prophylaxis. Further research is required to test interventions to improve adherence.

    更新日期:2020-01-14
  • Willingness-to-pay for long-lasting insecticide-treated bed nets: a discrete choice experiment with real payment in Ghana
    Malaria J. (IF 2.798) Pub Date : 2020-01-13
    Y. Natalia Alfonso; Matthew Lynch; Elorm Mensah; Danielle Piccinini; David Bishai

    Expanding access to long-lasting insecticidal nets (LLINs) is difficult if one is limited to government and donor financial resources. Private commercial markets could play a larger role in the continuous distribution of LLINs by offering differentiated LLINs to middle-class Ghanaians. This population segment has disposable income and may be willing to pay for LLINs that meet their preferences. Measuring the willingness-to-pay (WTP) for LLINs with specialty features that appeal to middle-class Ghanaians could help malaria control programmes understand what is the potential for private markets to work alongside fully subsidized LLIN distribution channels to assist in spreading this commodity. This study conducted a discrete choice experiment (DCE) including a real payment choice among a representative sample of 628 middle-income households living in Ashanti, Greater Accra, and Western regions in Ghana. The DCE presented 18 paired combinations of LLIN features and various prices. Respondents indicated which LLIN of each pair they preferred and whether they would purchase it. To validate stated willingness-to-pay, each participant was given a cash payment of $14.30 (GHS 65) that they could either keep or immediately spend on one of the LLIN products. The households’ average probability of purchasing a LLIN with specialty features was 43.8% (S.D. 0.07) and WTP was $7.48 (GHS34.0). The preferred LLIN features were conical or rectangular one-point-hang shape, queen size, and zipper entry. The average WTP for a LLIN with all the preferred features was $18.48 (GHS 84). In a scenario with the private LLIN market, the public sector outlay could be reduced by 39% and private LLIN sales would generate $8.1 million ($311 per every 100 households) in revenue in the study area that would support jobs for Ghanaian retailers, distributors, and importers of LLINs. Results support a scenario in which commercial markets for LLINs could play a significant role in improving access to LLINs for middle-income Ghanaians. Manufacturers interested could offer LLIN designs with features that are most highly valued among middle-income households in Ghana and maintain a retail price that could yield sufficient economic returns.

    更新日期:2020-01-13
  • Quantification of malaria antigens PfHRP2 and pLDH by quantitative suspension array technology in whole blood, dried blood spot and plasma
    Malaria J. (IF 2.798) Pub Date : 2020-01-09
    Xavier Martiáñez-Vendrell; Alfons Jiménez; Ana Vásquez; Ana Campillo; Sandra Incardona; Raquel González; Dionicia Gamboa; Katherine Torres; Wellington Oyibo; Babacar Faye; Eusebio Macete; Clara Menéndez; Xavier C. Ding; Alfredo Mayor

    Malaria diagnostics by rapid diagnostic test (RDT) relies primarily on the qualitative detection of Plasmodium falciparum histidine-rich protein 2 (PfHRP2) and Plasmodium spp lactate dehydrogenase (pLDH). As novel RDTs with increased sensitivity are being developed and implemented as point of care diagnostics, highly sensitive laboratory-based assays are needed for evaluating RDT performance. Here, a quantitative suspension array technology (qSAT) was developed, validated and applied for the simultaneous detection of PfHRP2 and pLDH in a variety of biological samples (whole blood, plasma and dried blood spots) from individuals living in different endemic countries. The qSAT was specific for the target antigens, with analytical ranges of 6.8 to 762.8 pg/ml for PfHRP2 and 78.1 to 17076.6 pg/ml for P. falciparum LDH (Pf-LDH). The assay detected Plasmodium vivax LDH (Pv-LDH) at a lower sensitivity than Pf-LDH (analytical range of 1093.20 to 187288.5 pg/ml). Both PfHRP2 and pLDH levels determined using the qSAT showed to positively correlate with parasite densities determined by quantitative PCR (Spearman r = 0.59 and 0.75, respectively) as well as microscopy (Spearman r = 0.40 and 0.75, respectively), suggesting the assay to be a good predictor of parasite density. This immunoassay can be used as a reference test for the detection and quantification of PfHRP2 and pLDH, and could serve for external validation of RDT performance, to determine antigen persistence after parasite clearance, as well as a complementary tool to assess malaria burden in endemic settings.

    更新日期:2020-01-09
  • Update to: A stakeholder workshop about modelled maps of key malaria indicator survey indicators in Madagascar
    Malaria J. (IF 2.798) Pub Date : 2020-01-09
    Rosalind E. Howes; Kaleem Hawa; Voahangy Fanomezana Andriamamonjy; Thierry Franchard; Raharizo Miarimbola; Sedera Aurélien Mioramalala; Jean Florent Rafamatanantsoa; Mirana Ando Mbolatiana Rahantamalala; Solo Harimalala Rajaobary; Hariniaina David Gaël Rajaonera; Andrianiaina Parfait Rakotonindrainy; Clairaut Rakotoson Andrianjatonavalona; Dina Ny Aina Liantsoa Randriamiarinjatovo; Faratiana Michèle Randrianasolo; Rado Malalatiana Ramasy Razafindratovo; Masiarivony Ravaoarimanga; Maurice Ye; Peter W. Gething; Cameron A. Taylor

    Following publication of the original article [1], the authors expressed their wish to provide a French version of the article. To this end, please find a (French) translation of the article in the additional file included with this update (Additional file 1). By providing this translation, the authors hope to expand the readership of their article; for example, in French the article is more widely accessible to Malagasy people wanting to know more about the outcomes of the meeting detailed in the article. The authors thank you for reading this update. 1. Howes RE, Hawa K, Andriamamonjy VF, Franchard T, Miarimbola R, Mioramalala SA, Rafamatanantsoa JF, Rahantamalala MA, Rajaobary SH, Rajaonera HD, Rakotonindrainy AP. A stakeholder workshop about modelled maps of key malaria indicator survey indicators in Madagascar. Malaria J. 2019;18:90. https://doi.org/10.1186/s12936-019-2729-7. Article Google Scholar Download references Affiliations Malaria Atlas Project, Nuffield Department of Medicine, Big Data Institute, University of Oxford, Oxford, UK Rosalind E. Howes , Kaleem Hawa  & Peter W. Gething National Malaria Control Programme, Ministry of Health, Antananarivo, Madagascar Voahangy Fanomezana Andriamamonjy , Mirana Ando Mbolatiana Rahantamalala , Solo Harimalala Rajaobary , Hariniaina David Gaël Rajaonera  & Faratiana Michèle Randrianasolo Ministry of Health, Antananarivo, Madagascar Thierry Franchard , Raharizo Miarimbola , Sedera Aurélien Mioramalala  & Rado Malalatiana Ramasy Razafindratovo Faculty of Science, University of Antananarivo, Antananarivo, Madagascar Thierry Franchard Department of Public Health, Faculty of Medicine, University of Antananarivo, Antananarivo, Madagascar Raharizo Miarimbola , Sedera Aurélien Mioramalala , Mirana Ando Mbolatiana Rahantamalala  & Rado Malalatiana Ramasy Razafindratovo Direction des Études et de la Planification, Ministry of Health, Antananarivo, Madagascar Jean Florent Rafamatanantsoa  & Clairaut Rakotoson Andrianjatonavalona Direction du Système d’Information, Ministry of Health, Antananarivo, Madagascar Andrianiaina Parfait Rakotonindrainy Institut Pasteur de Madagascar, Antananarivo, Madagascar Dina Ny Aina Liantsoa Randriamiarinjatovo  & Masiarivony Ravaoarimanga MEASURE-Evaluation, ICF, Antananarivo, Madagascar Maurice Ye The DHS Program, ICF, Rockville, USA Cameron A. TaylorAuthors Search for Rosalind E. Howes in: PubMed • Google Scholar Search for Kaleem Hawa in: PubMed • Google Scholar Search for Voahangy Fanomezana Andriamamonjy in: PubMed • Google Scholar Search for Thierry Franchard in: PubMed • Google Scholar Search for Raharizo Miarimbola in: PubMed • Google Scholar Search for Sedera Aurélien Mioramalala in: PubMed • Google Scholar Search for Jean Florent Rafamatanantsoa in: PubMed • Google Scholar Search for Mirana Ando Mbolatiana Rahantamalala in: PubMed • Google Scholar Search for Solo Harimalala Rajaobary in: PubMed • Google Scholar Search for Hariniaina David Gaël Rajaonera in: PubMed • Google Scholar Search for Andrianiaina Parfait Rakotonindrainy in: PubMed • Google Scholar Search for Clairaut Rakotoson Andrianjatonavalona in: PubMed • Google Scholar Search for Dina Ny Aina Liantsoa Randriamiarinjatovo in: PubMed • Google Scholar Search for Faratiana Michèle Randrianasolo in: PubMed • Google Scholar Search for Rado Malalatiana Ramasy Razafindratovo in: PubMed • Google Scholar Search for Masiarivony Ravaoarimanga in: PubMed • Google Scholar Search for Maurice Ye in: PubMed • Google Scholar Search for Peter W. Gething in: PubMed • Google Scholar Search for Cameron A. Taylor in: PubMed • Google Scholar Corresponding authors Correspondence to Rosalind E. Howes or Cameron A. Taylor. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Additional file 1. French translation of meeting report. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Reprints and Permissions Cite this article Howes, R.E., Hawa, K., Andriamamonjy, V.F. et al. Update to: A stakeholder workshop about modelled maps of key malaria indicator survey indicators in Madagascar. Malar J 19, 13 (2020) doi:10.1186/s12936-019-3052-z Download citation Published 09 January 2020 DOI https://doi.org/10.1186/s12936-019-3052-z

    更新日期:2020-01-09
  • Childhood malaria case incidence in Malawi between 2004 and 2017: spatio-temporal modelling of climate and non-climate factors
    Malaria J. (IF 2.798) Pub Date : 2020-01-06
    James Chirombo; Pietro Ceccato; Rachel Lowe; Dianne J Terlouw; Madeleine C Thomson; Austin Gumbo; Peter J Diggle; Jonathan M Read

    Malaria transmission is influenced by a complex interplay of factors including climate, socio-economic, environmental factors and interventions. Malaria control efforts across Africa have shown a mixed impact. Climate driven factors may play an increasing role with climate change. Efforts to strengthen routine facility-based monthly malaria data collection across Africa create an increasingly valuable data source to interpret burden trends and monitor control programme progress. A better understanding of the association with other climatic and non-climatic drivers of malaria incidence over time and space may help guide and interpret the impact of interventions. Routine monthly paediatric outpatient clinical malaria case data were compiled from 27 districts in Malawi between 2004 and 2017, and analysed in combination with data on climatic, environmental, socio-economic and interventional factors and district level population estimates. A spatio-temporal generalized linear mixed model was fitted using Bayesian inference, in order to quantify the strength of association of the various risk factors with district-level variation in clinical malaria rates in Malawi, and visualized using maps. Between 2004 and 2017 reported childhood clinical malaria case rates showed a slight increase, from 50 to 53 cases per 1000 population, with considerable variation across the country between climatic zones. Climatic and environmental factors, including average monthly air temperature and rainfall anomalies, normalized difference vegetative index (NDVI) and RDT use for diagnosis showed a significant relationship with malaria incidence. Temperature in the current month and in each of the 3 months prior showed a significant relationship with the disease incidence unlike rainfall anomaly which was associated with malaria incidence at only three months prior. Estimated risk maps show relatively high risk along the lake and Shire valley regions of Malawi. The modelling approach can identify locations likely to have unusually high or low risk of malaria incidence across Malawi, and distinguishes between contributions to risk that can be explained by measured risk-factors and unexplained residual spatial variation. Also, spatial statistical methods applied to readily available routine data provides an alternative information source that can supplement survey data in policy development and implementation to direct surveillance and intervention efforts.

    更新日期:2020-01-07
  • Genetic polymorphisms in malaria vaccine candidate Plasmodium falciparum reticulocyte-binding protein homologue-5 among populations in Lagos, Nigeria
    Malaria J. (IF 2.798) Pub Date : 2020-01-06
    Olusola Ajibaye; Akinniyi A. Osuntoki; Emmanuel O. Balogun; Yetunde A. Olukosi; Bamidele A. Iwalokun; Kolapo M. Oyebola; Kenji Hikosaka; Yoh-ichi Watanabe; Godwin U. Ebiloma; Kiyoshi Kita; Alfred Amambua-Ngwa

    Vaccines are the most reliable alternative to elicit sterile immunity against malaria but their development has been hindered by polymorphisms and strain-specificity in previously studied antigens. New vaccine candidates are therefore urgently needed. Highly conserved Plasmodium falciparum reticulocyte-binding protein homologue-5 (PfRH5) has been identified as a potential candidate for anti-disease vaccine development. PfRH5 is essential for erythrocyte invasion by merozoites and crucial for parasite survival. However, there is paucity of data on the extent of genetic variations on PfRH5 in field isolates of Plasmodium falciparum. This study described genetic polymorphisms at the high affinity binding polypeptides (HABPs) 36718, 36727, 36728 of PfRH5 in Nigerian isolates of P. falciparum. This study tested the hypothesis that only specific conserved B and T cell epitopes on PfRH5 HABPs are crucial for vaccine development. One hundred and ninety-five microscopically confirmed P. falciparum samples collected in a prospective cross-sectional study of three different populations in Lagos, Nigeria. Genetic diversity and haplotype construct of Pfrh5 gene were determined using bi-directional sequencing approach. Tajima’s D and the ratio of nonsynonymous vs synonymous mutations were utilized to estimate the extent of balancing and directional selection in the pfrh5 gene. Sequence analysis revealed three haplotypes of PfRH5 with negative Tajima’s D and dN/dS value of − 1.717 and 0.011 ± 0.020, respectively. A single nucleotide polymorphism, SNP (G → A) at position 608 was observed, which resulted in a change of the amino acid cysteine at position 203 to tyrosine. Haplotype and nucleotide diversities were 0.318 ± 0.016 and 0.0046 ± 0.0001 while inter-population genetic differentiation ranged from 0.007 to 0.037. Five polypeptide variants were identified, the most frequent being KTKYH with a frequency of 51.3%. One B-cell epitope, 151 major histocompatibility complex (MHC) class II T-cell epitopes, four intrinsically unstructured regions (IURs) and six MHC class I T-cell epitopes were observed in the study. Phylogenetic analysis of the sequences showed clustering and evidence of evolutionary relationship with 3D7, PAS-2 and FCB-2 RH5 sequences. This study has revealed low level of genetic polymorphisms in PfRH5 antigen with B- and T-cell epitopes in intrinsically unstructured regions along the PfRH5 gene in Lagos, Nigeria. A broader investigation is however required in other parts of the country to support the possible inclusion of PfRH5 in a cross-protective multi-component vaccine.

    更新日期:2020-01-07
  • Utilization of insecticide-treated bed nets and care-seeking for fever and its associated socio-demographic and geographical factors among under-five children in different regions: evidence from the Myanmar Demographic and Health Survey, 2015–2016
    Malaria J. (IF 2.798) Pub Date : 2020-01-06
    Kyi Thar Min; Thae Maung Maung; Myo Minn Oo; Tin Oo; Zaw Lin; Aung Thi; Jaya Prasad Tripathy

    Malaria is one of the top-five contributors to under-5 deaths in Myanmar. Use of insecticide-treated nets (ITN) and receiving early appropriate care in case of fever are the core interventions to prevent malaria and its complications and thereby deaths. This study aimed to assess among the under-five children, (a) utilization of ITNs and its associated factors, (b) care-seeking behaviour among their caregivers and its associated factors and uptake of malaria testing among those with fever in the last 2 weeks. This was a cross sectional study using secondary analysis of Myanmar Demographic and Health Survey (MDHS) conducted in 2015–2016. Multivariable logistic regression was used to explore the factors associated with non-utilization of ITNs and not seeking care for fever. Effect sizes have been presented using odds ratios with 95% confidence intervals. Data analysis was done using svyset command in STATA to account for the multi-stage sampling design of the survey. Of 4597 alive under-five children, 80.5% did not sleep under an ITN last night. The factors significantly associated with non-utilization of ITNs were residing in malaria elimination regions (aOR = 2.0, 1.3–3.2), urban residence (aOR = 1.8, 1.2–2.9), staying in delta region (aOR = 8.7, 4.7–12.2), hilly region (aOR = 3.0, 2.0–4.6, and having highest wealth quintile (aOR = 1.8, 1.1–3.0). Around 16% had fever in the last 2 weeks, of whom 66.7% sought care for fever and 3% got tested for malaria. Nearly half (50.9%) of the caregivers sought care from a government health facility, followed by private hospital/doctor (27.8%), shop (8.0%), village health worker (4.4%) and pharmacy (3.1%). The factors associated with not seeking care for fever were residing in specific geographical locations (hilly, delta and central plains compared to coastal region) and having lowest wealth quintile (aOR = 2.3, 1.1–5.7). This study highlighted that ownership and utilization of ITNs was very poor among under-5children. Care-seeking behaviour of the caregivers of under-5 children in case of fever was dismal with two-thirds not seeking care. The programme should seriously consider addressing these barriers if Myanmar is to achieve zero malaria deaths by 2030.

    更新日期:2020-01-07
  • In vivo/ex vivo efficacy of artemether–lumefantrine and artesunate–amodiaquine as first-line treatment for uncomplicated falciparum malaria in children: an open label randomized controlled trial in Burkina Faso
    Malaria J. (IF 2.798) Pub Date : 2020-01-06
    Moussa Lingani; Léa Nadège Bonkian; Isidore Yerbanga; Adama Kazienga; Innocent Valéa; Hermann Sorgho; Jean Bosco Ouédraogo; Petronella Francisca Mens; Henk D. F. H. Schallig; Raffaella Ravinetto; Umberto d’Alessandro; Halidou Tinto

    Artemisinin-based combination therapy (ACT) is recommended to improve malaria treatment efficacy and limit drug-resistant parasites selection in malaria endemic areas. 5 years after they were adopted, the efficacy and safety of artemether–lumefantrine (AL) and artesunate–amodiaquine (ASAQ), the first-line treatments for uncomplicated malaria were assessed in Burkina Faso. In total, 440 children with uncomplicated Plasmodium falciparum malaria were randomized to receive either AL or ASAQ for 3 days and were followed up weekly for 42 days. Blood samples were collected to investigate the ex vivo susceptibility of P. falciparum isolates to lumefantrine, dihydroartemisinin (the active metabolite of artemisinin derivatives) and monodesethylamodiaquine (the active metabolite of amodiaquine). The modified isotopic micro test technique was used to determine the 50% inhibitory concentration (IC50) values. Primary endpoints were the risks of treatment failure at days 42. Out of the 440 patients enrolled, 420 (95.5%) completed the 42 days follow up. The results showed a significantly higher PCR unadjusted cure rate in ASAQ arm (71.0%) than that in the AL arm (49.8%) on day 42, and this trend was similar after correction by PCR, with ASAQ performing better (98.1%) than AL (91.1%). Overall adverse events incidence was low and not significantly different between the two treatment arms. Ex vivo results showed that 6.4% P. falciparum isolates were resistant to monodesthylamodiaquine. The coupled in vivo/ex vivo analysis showed increased IC50 values for lumefantrine and monodesethylamodiaquine at day of recurrent parasitaemia compared to baseline values while for artesunate, IC50 values remained stable at baseline and after treatment failure (p > 0.05). These findings provide substantial evidence that AL and ASAQ are highly efficacious for the treatment of uncomplicated malaria in children in Burkina Faso. However, the result of P. falciparum susceptibility to the partner drugs advocates the need to regularly replicate such surveillance studies. This would be particularly indicated when amodiaquine is associated in seasonal malaria chemoprophylaxis (SMC) mass drug administration in children under 5 years in Burkina Faso. Trial registration clinicaltrials, NCT00808951. Registered 05 December 2008,https://clinicaltrials.gov/ct2/show/NCT00808951?cond=NCT00808951&rank=1

    更新日期:2020-01-07
  • The impact of transfluthrin on the spatial repellency of the primary malaria mosquito vectors in Vietnam: Anopheles dirus and Anopheles minimus
    Malaria J. (IF 2.798) Pub Date : 2020-01-06
    Nicholas J. Martin; Vu S. Nam; Andrew A. Lover; Tran V. Phong; Tran C. Tu; Ian H. Mendenhall

    The complexity of mosquito-borne diseases poses a major challenge to global health efforts to mitigate their impact on people residing in sub-tropical and tropical regions, to travellers and deployed military personnel. To supplement drug- and vaccine-based disease control programmes, other strategies are urgently needed, including the direct control of disease vectors. Modern vector control research generally focuses on identifying novel active ingredients and/or innovative methods to reduce human-mosquito interactions. These efforts include the evaluation of spatial repellents, which are compounds capable of altering mosquito feeding behaviour without direct contact with the chemical source. This project examined the impact of airborne transfluthrin from impregnated textile materials on two important malaria vectors, Anopheles dirus and Anopheles minimus. Repellency was measured by movement within taxis cages within a semi-field environment at the National Institute of Hygiene and Epidemiology in Hanoi, Vietnam. Knockdown and mortality were measured in adult mosquito bioassay cages. Metered-volume air samples were collected at a sub-set of points in the mosquito exposure trial. Significant differences in knockdown/mortality were observed along a gradient from the exposure source with higher rates of knockdown/mortality at 2 m and 4 m when compared with the furthest distance (16 m). Knockdown/mortality was also greater at floor level and 1.5 m when compared to 3 m above the floor. Repellency was not significantly different except when comparing 2 m and 16 m taxis cages. Importantly, the two species reacted differently to transfluthrin, with An. minimus being more susceptible to knockdown and mortality. The measured concentrations of airborne transfluthrin ranged from below the limit of detection to 1.32 ng/L, however there were a limited number of evaluable samples complicating interpretation of these results. This study, measuring repellency, knockdown and mortality in two malaria vectors in Vietnam demonstrates that both species are sensitive to airborne transfluthrin. The differences in magnitude of response between the two species requires further study before use in large-scale vector control programmes to delineate how spatial repellency would impact the development of insecticide resistance and the disruption of biting behaviour.

    更新日期:2020-01-07
  • Identification of Plasmodium falciparum proteoforms from liver stage models
    Malaria J. (IF 2.798) Pub Date : 2020-01-07
    Benjamin Winer; Kimberly A. Edgel; Xiaoyan Zou; Julie Sellau; Sri Hadiwidjojo; Lindsey S. Garver; Christin E. McDonough; Neil L. Kelleher; Paul M. Thomas; Eileen Villasante; Alexander Ploss; Vincent R. Gerbasi

    Immunization with attenuated malaria sporozoites protects humans from experimental malaria challenge by mosquito bite. Protection in humans is strongly correlated with the production of T cells targeting a heterogeneous population of pre-erythrocyte antigen proteoforms, including liver stage antigens. Currently, few T cell epitopes derived from Plasmodium falciparum, the major aetiologic agent of malaria in humans are known. In this study both in vitro and in vivo malaria liver stage models were used to sequence host and pathogen proteoforms. Proteoforms from these diverse models were subjected to mild acid elution (of soluble forms), multi-dimensional fractionation, tandem mass spectrometry, and top-down bioinformatics analysis to identify proteoforms in their intact state. These results identify a group of host and malaria liver stage proteoforms that meet a 5% false discovery rate threshold. This work provides proof-of-concept for the validity of this mass spectrometry/bioinformatic approach for future studies seeking to reveal malaria liver stage antigens towards vaccine development.

    更新日期:2020-01-07
  • Indoor use of attractive toxic sugar bait in combination with long-lasting insecticidal net against pyrethroid-resistant Anopheles gambiae: an experimental hut trial in Mbé, central Côte d’Ivoire
    Malaria J. (IF 2.798) Pub Date : 2020-01-07
    Joanna E. C. Furnival-Adams; Soromane Camara; Mark Rowland; Alphonsine A. Koffi; Ludovic P. Ahoua Alou; Welbeck A. Oumbouke; Raphael N’Guessan

    Indoor attractive toxic sugar bait (ATSB) has potential as a supplementary vector-control and resistance-management tool, offering an alternative mode of insecticide delivery to current core vector-control interventions, with potential to deliver novel insecticides. Given the high long-lasting insecticidal bed net (LLIN) coverage across Africa, it is crucial that the efficacy of indoor ATSB in combination with LLINs is established before it is considered for wider use in public health. An experimental hut trial to evaluate the efficacy of indoor ATSB traps treated with 4% boric acid (BA ATSB) or 1% chlorfenapyr (CFP ATSB) in combination with untreated nets or LLINs (holed or intact), took place at the M’bé field station in central Côte d’Ivoire against pyrethroid resistant Anopheles gambiae sensu lato. The addition of ATSB to LLINs increased the mortality rates of wild pyrethroid-resistant An. gambiae from 19% with LLIN alone to 28% with added BA ATSB and to 39% with added CFP ATSB (p < 0.001). Anopheles gambiae mortality with combined ATSB and untreated net was similar to that of combined ATSB and LLIN regardless of which insecticide was used in the ATSB. The presence of holes in the LLIN did not significantly affect ATSB-induced An. gambiae mortality. Comparative tests against pyrethroid resistant and susceptible strains using oral application of ATSB treated with pyrethroid demonstrated 66% higher survival rate among pyrethroid-resistant mosquitoes. Indoor ATSB traps in combination with LLINs enhanced the control of pyrethroid-resistant An. gambiae. However, many host-seeking An. gambiae entering experimental huts with indoor ATSB exited into the verandah trap without sugar feeding when restricted from a host by a LLIN. Although ATSB has potential for making effective use of classes of insecticide otherwise unsuited to vector control, it does not exempt potential selection of resistance via this route.

    更新日期:2020-01-07
  • Upsurge of malaria transmission after indoor residual spraying withdrawal in Atacora region in Benin, West Africa
    Malaria J. (IF 2.798) Pub Date : 2020-01-03
    Rock Yves Aïkpon; Gil Padonou; Fortuné Dagnon; Razaki Ossè; Aurore Ogouyemi Hounto; Filémon Tokponon; Gorgias Aïkpon; Laurent Lyikirenga; Martin Akogbéto

    In Benin, malaria vector control mostly relies on long-lasting, insecticidal-treated bed nets (LLINs) and indoor residual spraying (IRS) operations. From 2011 to 2016, an IRS programme has been implemented in Atacora region. However, in 2017 the programme was withdrawn from two other regions in the northern part of the country, with hopes that gains would be relatively sustained because of the seasonality of malaria transmission. What would be the vulnerability of populations to malaria after the withdrawal of IRS? Monthly mosquito collections were performed through human landing captures (HLCs) for 24 months (from January to December 2016 during the last IRS campaign, and from January to December 2018, 2 years after the withdrawal of IRS). Vector mosquitoes biting density was sampled by HLC and was tested for presence of Plasmodium falciparum sporozoites. The carcass of these mosquitoes (abdomens, wing, legs) were subjected to molecular species identification using polymerase chain reaction (PCR) assays. It is noticed a drastic increase (~ 3 times higher) of vector abundance after the withdrawal of IRS. Mosquito biting rates in the 3 survey districts increased significantly after IRS was withdrawn. In 2018, after IRS cessation a significant increase of entomological inoculation rate was recorded, where each inhabitant received an average of 94.9 infected bites/year to 129.21 infected bites/year against an average of 17.15 infected bites/year to 24.82 infected bites/year in 2016. It is obvious that the withdrawal of IRS confers a vulnerability of the population with regard to the malaria transmission. Robust monitoring is needed to better understand when and where IRS should be most adequate, or can be safely withdrawn. In case of withdrawal, adapted accompanying measures should be proposed according to the context not only to maintain the gains capitalized with IRS, but also to avoid any rebound of transmission.

    更新日期:2020-01-04
  • The use of ultrasensitive quantitative-PCR to assess the impact of primaquine on asymptomatic relapse of Plasmodium vivax infections: a randomized, controlled trial in Lao PDR
    Malaria J. (IF 2.798) Pub Date : 2020-01-03
    Koukeo Phommasone; Frank van Leth; Mallika Imwong; Gisela Henriques; Tiengkham Pongvongsa; Bipin Adhikari; Thomas J. Peto; Cholrawee Promnarate; Mehul Dorda; Pasathorn Sirithiranont; Mavuto Mukaka; Pimnara Peerawaranun; Nicholas P. J. Day; Frank Cobelens; Arjen M. Dondorp; Paul N. Newton; Nicholas J. White; Lorenz von Seidlein; Mayfong Mayxay

    Trials to assess the efficacy of the radical cure of Plasmodium vivax malaria with 8-aminoquinolines require that most post-treatment relapses are identified, but there is no consensus on the optimal duration of follow-up in either symptomatic or asymptomatic vivax malaria. The efficacy of a 14-day course of primaquine on the cumulative incidence of recurrent asymptomatic P. vivax infections detected by ultrasensitive quantitative PCR (uPCR) as a primary endpoint was assessed. A randomized, placebo-controlled, single-blind trial was conducted in four villages of the Lao PDR during 2016–2018 nested in a larger project evaluating mass drug administrations (MDA) with dihydroartemisinin-piperaquine (DP) and a single low-dose primaquine to clear Plasmodium falciparum infections. In the nested sub-study, eligible participants with mono- or mixed P. vivax infections detected by uPCR were randomized to receive either 14 days of primaquine (0.5 mg/kg/day) or placebo during the last round of MDA (round 3) through directly observed therapy. Participants were checked monthly for 12 months for parasitaemia using uPCR. The primary outcome was cumulative incidence of participants with at least one recurrent episode of P. vivax infection. 20 G6PD-normal participants were randomized in each arm. 5 (29%) of 20 participants in the placebo arm experienced asymptomatic, recurrent P. vivax infections, resulting in a cumulative incidence at month 12 of 29%. None of the 20 participants in the intervention arm had recurrent infections (p = 0.047 Fisher’s exact test). Participants with recurrent P. vivax infections were found to be parasitaemic for between one and five sequential monthly tests. The median time to recurrence of P. vivax parasitaemia was 178 days (range 62–243 days). A 14-day course of primaquine in addition to a DP-MDA was safe, well-tolerated, and prevented recurrent asymptomatic P. vivax infections. Long follow-up for up to 12 months is required to capture all recurrences following the treatment of asymptomatic vivax infection. To eliminate all malarias in settings where P. vivax is endemic, a full-course of an 8-aminoquinolines should be added to MDA to eliminate all malarias. Trial registration This study was registered with ClinicalTrials.gov under NCT02802813 on 16th June 2016. https://clinicaltrials.gov/ct2/show/NCT02802813

    更新日期:2020-01-04
  • An in vitro toolbox to accelerate anti-malarial drug discovery and development
    Malaria J. (IF 2.798) Pub Date : 2020-01-02
    Susan A. Charman; Alice Andreu; Helena Barker; Scott Blundell; Anna Campbell; Michael Campbell; Gong Chen; Francis C. K. Chiu; Elly Crighton; Kasiram Katneni; Julia Morizzi; Rahul Patil; Thao Pham; Eileen Ryan; Jessica Saunders; David M. Shackleford; Karen L. White; Lisa Almond; Maurice Dickins; Dennis A. Smith; Joerg J. Moehrle; Jeremy N. Burrows; Nada Abla

    Modelling and simulation are being increasingly utilized to support the discovery and development of new anti-malarial drugs. These approaches require reliable in vitro data for physicochemical properties, permeability, binding, intrinsic clearance and cytochrome P450 inhibition. This work was conducted to generate an in vitro data toolbox using standardized methods for a set of 45 anti-malarial drugs and to assess changes in physicochemical properties in relation to changing target product and candidate profiles. Ionization constants were determined by potentiometric titration and partition coefficients were measured using a shake-flask method. Solubility was assessed in biorelevant media and permeability coefficients and efflux ratios were determined using Caco-2 cell monolayers. Binding to plasma and media proteins was measured using either ultracentrifugation or rapid equilibrium dialysis. Metabolic stability and cytochrome P450 inhibition were assessed using human liver microsomes. Sample analysis was conducted by LC–MS/MS. Both solubility and fraction unbound decreased, and permeability and unbound intrinsic clearance increased, with increasing Log D7.4. In general, development compounds were somewhat more lipophilic than legacy drugs. For many compounds, permeability and protein binding were challenging to assess and both required the use of experimental conditions that minimized the impact of non-specific binding. Intrinsic clearance in human liver microsomes was varied across the data set and several compounds exhibited no measurable substrate loss under the conditions used. Inhibition of cytochrome P450 enzymes was minimal for most compounds. This is the first data set to describe in vitro properties for 45 legacy and development anti-malarial drugs. The studies identified several practical methodological issues common to many of the more lipophilic compounds and highlighted areas which require more work to customize experimental conditions for compounds being designed to meet the new target product profiles. The dataset will be a valuable tool for malaria researchers aiming to develop PBPK models for the prediction of human PK properties and/or drug–drug interactions. Furthermore, generation of this comprehensive data set within a single laboratory allows direct comparison of properties across a large dataset and evaluation of changing property trends that have occurred over time with changing target product and candidate profiles.

    更新日期:2020-01-02
  • Adherence to malaria rapid diagnostic test result among healthcare workers in Sokoto metropolis, Nigeria
    Malaria J. (IF 2.798) Pub Date : 2020-01-02
    Aliyu Mamman Na’uzo; Dahiru Tukur; Mu’awiyyah Babale Sufiyan; Adebowale Ayo Stephen; IkeOluwapo Ajayi; Eniola Bamgboye; Abdulrazaq Abdullahi Gobir; Chukwuma David Umeokonkwo; Zainab Abdullahi; Olufemi Ajumobi

    Presumptive diagnosis and prescription of anti-malarial medicines to malaria rapid diagnostic test (RDT)-negative patients is a common practice among health care workers (HCWs) in Nigeria. There is paucity of data on HCWs adherence to RDT result in Sokoto metropolis, Nigeria. The study was conducted to determine HCWs adherence to malaria test result and the influencing factors. A cross-sectional study was conducted among 262 HCWs selected by multistage sampling technique from primary and secondary health facilities in Sokoto metropolis. Data on demographic characteristics, adherence to RDT result and its influencing factors were collected from the HCWs. Adherence was categorized into good if adherence score is ≥ 4 and poor if otherwise. Chi-squared test was used to test association between adherence to test results and patients’ fever presentation, expectation to be given anti-malarials, prior HCWs’ case management training, among others. Independent predictors of adherence to RDT results were ascertained. Respondents’ mean age was 33.5 ± 7.9 years, 190 (72.5%) worked in Primary Health Care facilities, 112 (42.8%) were Community Health Workers, 178 (67.9%) had National Diploma Certificate. The median years of practice was 5.0 (IQR: 3–10) years, while 118 (45.0%) had at most 4 years of practice. Overall, 211 (80.5%) had good adherence to RDT results. About 108 (89.3%) of HCWs who had training on malaria case management and 35 (89.7%) certificate holders had good adherence to RDT results. Predictors of adherence to test results were presence of fever in the patient [adjusted odds ratio (aOR): 2.53, 95% confidence interval (CI) 1.18–5.43], patients’ expectation to be given anti-malarial medicines by the HCW (aOR: 3.06, 95% CI 1.42–6.58) and having been trained on malaria case management (aOR: 2.63; 95% CI 1.26–5.44). High level of adherence to RDT results among HCWs in Sokoto metropolis could be attributed to prior malaria case management training and HCWs’ confidence in the national treatment guidelines. Continual training and supportive supervision of HCWs on malaria case management might optimize the current level of adherence to RDT results in Sokoto metropolis, Nigeria. Similarly, patients/caregivers’ health education could aid better understanding of the need for anti-malarials thus reducing unnecessary demand.

    更新日期:2020-01-02
  • Antiplasmodial profile of selected compounds from Malaria Box: in vitro evaluation, speed of action and drug combination studies
    Malaria J. (IF 2.798) Pub Date : 2019-12-30
    Guilherme Eduardo de Souza; Renata Vieira Bueno; Juliana Oliveira de Souza; Camila Lima Zanini; Fábio Cardoso Cruz; Glaucius Oliva; Rafael Victório Carvalho Guido; Anna Caroline Campos Aguiar

    Artemisinin-based combination therapy (ACT) is used as the first-line treatment of uncomplicated malaria caused by the Plasmodium falciparum parasite and chloroquine-resistant Plasmodium vivax parasites. Evidence of resistance to ACT has been reported in Cambodia, and without new and effective anti-malarial agents, malaria burden and mortality will rise. The used MolPrint 2D fingerprints and the Tanimoto similarity index were used to perform a structural similarity search within the Malaria Box collection to select diverse molecular scaffolds that are different from artesunate. Next, the inhibitory potency against the P. falciparum 3D7 strain (SYBR Green I inhibition assay) and the cytotoxicity against HepG2 cells (MTT and neutral red assays) were evaluated. Then, the speed of action, the combination profile of selected inhibitors with artesunate, and the P. berghei in vivo activity of the best compounds were assessed. A set of 11 structurally diverse compounds from the Malaria Box with a similarity threshold of less than 0.05 was selected and compared with artesunate. The in vitro inhibitory activity of each compound confirmed the reported potencies (IC50 values ranging from 0.005 to 1 µM). The cytotoxicity of each selected compound was evaluated and used to calculate the selectivity index (SI values ranging from 15.1 to 6100). Next, both the speed of action and the combination profile of each compound with artesunate was assessed. Acridine, thiazolopyrimidine, quinoxaline, benzimidazole, thiophene, benzodiazepine, isoxazole and pyrimidoindole derivatives showed fast in vitro inhibitory activity of parasite growth, whereas hydrazinobenzimidazole, indenopyridazinone and naphthalenone derivatives were slow-acting in vitro inhibitors. Combinatory profile evaluation indicated that thiazolopyrimidinone and benzodiazepine derivatives have an additive profile, suggesting that the combination of these inhibitors with artesunate is favourable for in vitro inhibitory activity. The remaining compounds showed an antagonistic combinatory profile with artesunate. The collected data indicated that the indenopyridazinone derivative, a bc1 complex inhibitor, had a similar association profile in combination with proguanil when compared to atovaquone combined with proguanil, thereby corroborating the correlation between the molecular target and the combination profile. Lastly, the in vivo activity of the thiazolopyrimidinone and benzodiazepine derivatives were assessed. Both compounds showed oral efficacy at 50 mg/kg in a mouse model of Plasmodium berghei malaria (64% and 40% reduction in parasitaemia on day 5 post-infection, respectively). The findings in this paper shed light on the relationship among the speed of action, molecular target and combinatory profile and identified new hits with in vivo activity as candidates for anti-malarial combination therapy.

    更新日期:2019-12-31
  • Intravenous artesunate plus oral dihydroartemisinin–piperaquine or intravenous quinine plus oral quinine for optimum treatment of severe malaria: lesson learnt from a field hospital in Timika, Papua, Indonesia
    Malaria J. (IF 2.798) Pub Date : 2019-12-30
    Silvester Alexandro Sikora; Jeanne Rini Poespoprodjo; Enny Kenangalem; Daniel A. Lampah; Paulus Sugiarto; Ida Safitri Laksono; Riris Andono Ahmad; E. Elsa Herdiana Murhandarwati

    Intravenous artesunate and its follow on full course dihydroartemisinin–piperaquine are the standard treatment for severe malaria in Indonesia. The current policy suggests that intravenous and oral quinine could be used when standard therapy is not available. Its pragmatic use of both treatment combinations in a field hospital is evaluated. A retrospective study among hospitalized malaria patients receiving intravenous anti-malarial treatments at Mitra Masyarakat Hospital, Timika from April 2004 to December 2013 was conducted. The length of hospital stay (LoS) and the risk of malaria recurrence within 28 days after hospital admission were compared between patients receiving intravenous artesunate and oral dihydroartemisinin–piperaquine (Iv Art + DHP) and those receiving intravenous and oral quinine (Iv + Oral Qu). Of 10,514 patients requiring intravenous therapy, 2759 received Iv + Oral Qu and 7755 received Iv Art + DHP. Plasmodium falciparum infection accounted for 65.8% (6915), while Plasmodium vivax, Mixed infections, Plasmodium malariae and Plasmodium ovale were accounted for 17.0% (1789), 16.4% (1729), 0.8% (79) and 0.01% (2) of the infections, respectively. The majority of severe malaria hospital admissions were highland Papuans (78.0%, 8201/10,501). In total 49% (5158) of patients were older than 15 years and 3463 (32.9%) were children under 5 years old. The median LoS was shorter in patients receiving intravenous artesunate compared to those treated with intravenous quinine (median = 2 [IQR 1–3] versus 3 days [IQR 2–4], p < 0.0001). Patients treated with intravenous quinine had higher risk of being hospitalized longer than 2 days (aOR of 1.70 [95% CI 1.54–1.88], p < 0.0001). The risk of recurrences within 28 days after hospital admission was 1.94 times higher (95% CI aHR 1.57–2.39, p < 0.0001) in patients receiving intravenous quinine with follow on oral quinine treatment than in patients treated with DHP after intravenous artesunate therapy. Intravenous artesunate reduced the LoS of malaria patients and in combination with DHP reduced the risk of malaria recurrence within 28 days after hospital admission compared to those with Iv + Oral Qu treatment. Thus, ensuring continuous supply of intravenous artesunate and artemisinin-based combination therapy (ACT) should be a priority.

    更新日期:2019-12-31
  • The probability of a sequential Plasmodium vivax infection following asymptomatic Plasmodium falciparum and P. vivax infections in Myanmar, Vietnam, Cambodia, and Laos
    Malaria J. (IF 2.798) Pub Date : 2019-12-30
    Lorenz von Seidlein; Pimnara Peerawaranun; Mavuto Mukaka; Francois H. Nosten; Thuy-Nhien Nguyen; Tran Tinh Hien; Rupam Tripura; Thomas J. Peto; Tiengkham Pongvongsa; Koukeo Phommasone; Mayfong Mayxay; Mallika Imwong; James Watson; Sasithon Pukrittayakamee; Nicholas P. J. Day; Arjen M. Dondorp

    Adding 8-aminoquinoline to the treatment of falciparum, in addition to vivax malaria, in locations where infections with both species are prevalent could prevent vivax reactivation. The potential risk of haemolysis under a universal radical cure policy using 8-aminoquinoline needs to be weighed against the benefit of preventing repeated vivax episodes. Estimating the frequency of sequential Plasmodium vivax infections following either falciparum or vivax malaria episodes is needed for such an assessment. Quarterly surveillance data collected during a mass drug administration trial in the Greater Mekong Subregion in 2013–17 was used to estimate the probability of asymptomatic sequential infections by the same and different Plasmodium species. Asymptomatic Plasmodium infections were detected by high-volume ultrasensitive qPCR. Quarterly surveys of asymptomatic Plasmodium prevalence were used to estimate the probability of a P. vivax infection following Plasmodium falciparum and P. vivax infections. 16,959 valid sequential paired test results were available for analysis. Of these, 534 (3%) had an initial P. falciparum monoinfection, 1169 (7%) a P. vivax monoinfection, 217 (1%) had mixed (P. falciparum + P. vivax) infections, and 15,039 (89%) had no Plasmodium detected in the initial survey. Participants who had no evidence of a Plasmodium infection had a 4% probability to be found infected with P. vivax during the subsequent survey. Following an asymptomatic P. falciparum monoinfection participants had a 9% probability of having a subsequent P. vivax infection (RR 2.4; 95% CI 1.8 to 3.2). Following an asymptomatic P. vivax monoinfection, the participants had a 45% probability of having a subsequent P. vivax infection. The radical cure of 12 asymptomatic P. falciparum monoinfections would have prevented one subsequent P. vivax infection, whereas treatment of 2 P. vivax monoinfections may suffice to prevent one P. vivax relapse. Universal radical cure could play a role in the elimination of vivax malaria. The decision whether to implement universal radical cure for P. falciparum as well as for P. vivax depends on the prevalence of P. falciparum and P. vivax infections, the prevalence and severity of G6PD deficiency in the population and the feasibility to administer 8-aminoquinoline regimens safely. Trial registration ClinicalTrials.gov Identifier: NCT01872702, first posted June 7th 2013, https://clinicaltrials.gov/ct2/show/NCT01872702. This study was registered with ClinicalTrials.gov under NCT02802813 on 16th June 2016. https://clinicaltrials.gov/ct2/show/NCT02802813

    更新日期:2019-12-31
  • Genetic polymorphism of histidine rich protein 2 in Plasmodium falciparum isolates from different infection sources in Yunnan Province, China
    Malaria J. (IF 2.798) Pub Date : 2019-12-30
    Ying Dong; Shuping Liu; Yan Deng; Yanchun Xu; Mengni Chen; Yan Liu; Jingpo Xue

    Failed diagnoses of some falciparum malaria cases by RDTs are constantly reported in recent years. Plasmodium falciparum histidine-rich protein 2 (pfhpr2) gene deficiency has been found to be the major reason of RDTs failure in many countries. This article analysed the deletion of pfhpr2 gene of falciparum malaria cases isolated in Yunnan Province, China. Blood samples from falciparum malaria cases diagnosed in Yunnan Province were collected. Plasmodium genomic DNA was extracted and the pfhrp2 gene exon2 region was amplified via nested PCR. The haplotype of the DNA sequence, the nucleic acid diversity index (PI) and expected heterozygosity (He) were analyzed. Count PfHRP2 amino acid peptide sequence repeat and its times, and predict the properties of PfHRP2 peptide chain reaction to RDTs testing. A total of 306 blood samples were collected, 84.9% (259/306) from which pfhrp2 PCR amplification products (gene exon2) were obtained, while the remaining 47 samples were false amplification. The length of the 250 DNA sequences ranged from 345 - 927 bp, with 151 haplotypes, with PI and He values of 0.169 and 0.983, respectively. The length of the PfHRP2 peptide chain translated from 250 DNA sequences ranged from 115 to 309 aa. All peptide chains had more than an amino acid codon deletion. All 250 PfHRP2 strands ended with a type 12 amino acid repeat, 98.0% (245/250) started with a type 1 repetition and 2.0% (5/250) with a type 2 repetition. The detection rate for type 2 duplicates was 100% (250/250). Prediction of RDT sensitivity of PfHRP2 peptide chains based on type 2 and type 7 repeats showed that 9.60% (24/250), 50.0% (125/250), 13.20% (33/250) and 27.20.5% (68/250) of the 250 peptide chains were very sensitive, sensitive, borderline and non-sensitive, respectively. The diversified polymorphism of the pfhrp2 gene deletion from different infection sources in the Yunnan province are extremely complex. The cause of the failure of pfhrp2 exon2 amplification is still to be investigated. The results of this study appeal to Yunnan Province for a timely evaluation of the effectiveness and applicability of RDTs in the diagnosis of malaria.

    更新日期:2019-12-30
  • Impact of vector control interventions on malaria transmission intensity, outdoor vector biting rates and Anopheles mosquito species composition in Tororo, Uganda
    Malaria J. (IF 2.798) Pub Date : 2019-12-27
    Alex K. Musiime; David L. Smith; Maxwell Kilama; John Rek; Emmanuel Arinaitwe; Joaniter I. Nankabirwa; Moses R. Kamya; Melissa D. Conrad; Grant Dorsey; Anne M. Akol; Sarah G. Staedke; Steve W. Lindsay; James P. Egonyu

    Long-lasting insecticidal nets (LLINs) and indoor residual spraying of insecticide (IRS) are widely recommended for the prevention of malaria in endemic regions. Data from human landing catches provide information on the impact of vector control on vector populations. Here, malaria transmission indoors and outdoors, before and after mass deployment of LLINs and IRS in Uganda was compared. The study took place in Tororo district, a historically high transmission area where universal LLIN distribution was conducted in November 2013 and May 2017 and 6 rounds of IRS implemented from December 2014 to July 2018. Human landing catches were performed in 8 houses monthly from October 2011 to September 2012 (pre-intervention period) and every 4 weeks from November 2017 to October 2018 (post-intervention period). Mosquitoes were collected outdoors from 18:00 to 22:00 h and indoors from 18:00 to 06:00 h. Female Anopheles were tested for the presence of Plasmodium falciparum sporozoites and species identification performed using gross dissection and polymerase chain reaction (PCR). The interventions were associated with a decline in human biting rate from 19.6 to 2.3 female Anopheles mosquitoes per house per night (p < 0.001) and annual entomological inoculation rate from 129 to 0 infective bites per person per year (p < 0.001). The proportion of mosquitoes collected outdoors increased from 11.6 to 49.4% (p < 0.001). Prior to the interventions the predominant species was Anopheles gambiae sensu stricto (s.s.), which comprised an estimated 76.7% of mosquitoes. Following the interventions, the predominant species was Anopheles arabiensis, which comprised 99.5% of mosquitoes, with almost complete elimination of An. gambiae s.s. (0.5%). Mass distribution of LLINs and 6 rounds of IRS dramatically decreased vector density and sporozoite rate resulting in a marked reduction in malaria transmission intensity in a historically high transmission site in Uganda. These changes were accompanied by a shift in vector species from An. gambiae s.s. to An. arabiensis and a relative increase in outdoor biting.

    更新日期:2019-12-27
  • Economic considerations support C-reactive protein testing alongside malaria rapid diagnostic tests to guide antimicrobial therapy for patients with febrile illness in settings with low malaria endemicity
    Malaria J. (IF 2.798) Pub Date : 2019-12-26
    Yoel Lubell; Arjun Chandna; Frank Smithuis; Lisa White; Heiman F. L. Wertheim; Maël Redard-Jacot; Zachary Katz; Arjen Dondorp; Nicholas Day; Nicholas White; Sabine Dittrich

    Malaria is no longer a common cause of febrile illness in many regions of the tropics. In part, this success is a result of improved access to accurate diagnosis and effective anti-malarial treatment, including in many hard-to-reach rural areas. However, in these settings, management of other causes of febrile illness remains challenging. Health systems are often weak and other than malaria rapid tests no other diagnostics are available. With millions of deaths occurring annually due to treatable bacterial infections and the ever increasing spread of antimicrobial resistance, improvement in the management of febrile illness is a global public health priority. Whilst numerous promising point-of-care diagnostics are in the pipeline, substantial progress can be made in the interim with existing tools: C-reactive protein (CRP) is a highly sensitive and moderately specific biomarker of bacterial infection and has been in clinical use for these purposes for decades, with dozens of low-cost devices commercially available. This paper takes a health-economics approach to consider the possible advantages of CRP point-of-care tests alongside rapid diagnostic tests for malaria, potentially in a single multiplex device, to guide antimicrobial therapy for patients with febrile illness. Three rudimentary assessments of the costs and benefits of this approach all indicate that this is likely to be cost-effective when considering the incremental costs of the CRP tests as compared with either (i) the improved health outcomes for patients with bacterial illnesses; (ii) the costs of antimicrobial resistance averted; or (iii) the economic benefits of better management of remaining malaria cases and shorter malaria elimination campaigns in areas of low transmission. While CRP-guided antibiotic therapy alone cannot resolve all challenges associated with management of febrile illness in remote tropical settings, in the short-term a multiplexed CRP and malaria RDT could be highly cost-effective and utilize the well-established funding and distribution systems already in place for malaria RDTs. These findings should spark further interest amongst industry, academics and policy-makers in the development and deployment of such diagnostics, and discussion on their geographically appropriate use.

    更新日期:2019-12-27
  • Clinical diagnostic evaluation of HRP2 and pLDH-based rapid diagnostic tests for malaria in an area receiving seasonal malaria chemoprevention in Niger
    Malaria J. (IF 2.798) Pub Date : 2019-12-26
    Matthew E. Coldiron; Bachir Assao; Céline Langendorf; Nathan Sayinzoga-Makombe; Iza Ciglenecki; Roberto de la Tour; Erwan Piriou; Mahaman Yarima Bako; Ann Mumina; Ousmane Guindo; Anne-Laure Page; Rebecca F. Grais

    Rapid diagnostic tests (RDT) for malaria are common, but their performance varies. Tests using histidine-rich protein 2 (HRP2) antigen are most common, and many have high sensitivity. HRP2 tests can remain positive for weeks after treatment, limiting their specificity and usefulness in high-transmission settings. Tests using Plasmodium lactate dehydrogenase (pLDH) have been less widely used but have higher specificity, mostly due to a much shorter time to become negative. A prospective, health centre-based, diagnostic evaluation of two malaria RDTs was performed in rural Niger during the high malaria transmission season (3–28 October, 2017) and during the low transmission season (28 January–31 March, 2018). All children under 5 years of age presenting with fever (axillary temperature > 37.5 °C) or history of fever in the previous 24 h were eligible. Capillary blood was collected by finger prick. The SD Bioline HRP2 (catalog: 05FK50) and the CareStart pLDH(pan) (catalog: RMNM-02571) were performed in parallel, and thick and thin smears were prepared. Microscopy was performed at Epicentre, Maradi, Niger, with external quality control. The target sample size was 279 children with microscopy-confirmed malaria during each transmission season. In the high season, the sensitivity of both tests was estimated at > 99%, but the specificity of both tests was lower: 58.0% (95% CI 52.1–63.8) for the pLDH test and 57.4% (95% CI 51.5–63.1) for the HRP2 test. The positive predictive value was 66.3% (95% CI 61.1–71.2) for both tests. In the low season, the sensitivity of both tests dropped: 91.0% (95% CI 85.3–95.0) for the pLDH test and 85.8% (95% CI 79.3–90.9) for the HRP2 test. The positive predictive value remained low for both tests in the low season: 60.5% (95% CI 53.9–66.8) for the pLDH test and 61.9% (55.0–68.4) for the HRP2 test. Performance was similar across different production lots, gender, age of the children, and, during the high season, time since the most recent distribution of seasonal malaria chemoprevention. The low specificity of the pLDH RDT in this setting was unexpected and is not easily explained. As the pLDH test continues to be introduced into new settings, the questions raised by this study will need to be addressed.

    更新日期:2019-12-27
  • Indigenously developed digital handheld Android-based Geographic Information System (GIS)-tagged tablets (TABs) in malaria elimination programme in Mangaluru city, Karnataka, India
    Malaria J. (IF 2.798) Pub Date : 2019-12-26
    B. Shantharam Baliga; Animesh Jain; Naren Koduvattat; B. G. Prakash Kumar; Manu Kumar; Arun Kumar; Susanta K. Ghosh

    Under-reporting, delayed diagnosis, incomplete treatment and inadequate vector management are few among many factors responsible for uninterrupted transmission of malaria in India. Information technology (IT) and mobile apps can be utilized effectively to overcome these hurdles. Indigenously developed digital handheld geographic information system (GIS)-tagged Android-based tablets (TABs) has been designed especially for implementation of digitization protocol. This has changed the effectiveness of malaria surveillance and intervention strategies in a malaria endemic area of Mangaluru city, Karnataka, India. A software was developed and implemented for control measures to create a digital database of each malaria case. Secondary data analyses were carried out to determine and compare differences in malariometric indices between pre- and post-digitization years. With the introduction of this software active surveillance, information education and communication (IEC), and anti-vector measures were made ‘incidence-centric’. This means that the entire control measures were carried out in the houses where the malaria cases (index cases) were reported and also in surrounding houses. Annual blood examination rate (ABER) increased from 13.82 to 32.8%. Prompt reporting of new cases had improved (36% within 24 h and 80% within 72 h). Complete treatment and parasite clearance time were documented in 98% of cases. In the second post-digitization year untraceable cases reduced from 11.3 to 2.7%; contact blood smears collection also increased significantly (p < 0.001); Slide Positivity Rate (SPR) decreased from 15.5 to 10.48%; malaria cases reduced by 30%. IT is very useful in translation of digitized surveillance to core interventions thereby effectively reduce incidence of malaria. This technology can be used effectively to translate smart surveillance to core interventions following the ‘1-3-7-14’ strategy.

    更新日期:2019-12-27
  • Characterising malaria connectivity using malaria indicator survey data
    Malaria J. (IF 2.798) Pub Date : 2019-12-23
    Carlos A. Guerra; Daniel T. Citron; Guillermo A. García; David L. Smith

    Malaria connectivity describes the flow of parasites among transmission sources and sinks within a given landscape. Because of the spatial and temporal scales at which parasites are transported by their hosts, malaria sub-populations are largely defined by mosquito movement and malaria connectivity among them is largely driven by human movement. Characterising malaria connectivity thus requires characterising human travel between areas with differing levels of exposure to malaria. Whilst understanding malaria connectivity is fundamental for optimising interventions, particularly in areas seeking or sustaining elimination, there is a dearth of human movement data required to achieve this goal. Malaria indicator surveys (MIS) are a generally under utilised but potentially rich source of travel data that provide a unique opportunity to study simple associations between malaria infection and human travel in large population samples. This paper shares the experience working with MIS data from Bioko Island that revealed programmatically useful information regarding malaria importation through human travel. Simple additions to MIS questionnaires greatly augmented the level of detail of the travel data, which can be used to characterise human travel patterns and malaria connectivity to assist targeting interventions. It is argued that MIS potentially represent very important and timely sources of travel data that need to be further exploited.

    更新日期:2019-12-23
  • The development and evaluation of a self-marking unit to estimate malaria vector survival and dispersal distance
    Malaria J. (IF 2.798) Pub Date : 2019-12-23
    Adam Saddler; Katharina S. Kreppel; Nakul Chitnis; Thomas A. Smith; Adrian Denz; Jason D. Moore; Mgeni M. Tambwe; Sarah J. Moore

    A clear understanding of mosquito biology is fundamental to the control efforts of mosquito-borne diseases such as malaria. Mosquito mark-release-recapture (MMRR) experiments are a popular method of measuring the survival and dispersal of disease vectors; however, examples with African malaria vectors are limited. Ethical and technical difficulties involved in carrying out MMRR studies may have held back research in this area and, therefore, a device that marks mosquitoes as they emerge from breeding sites was developed and evaluated to overcome the problems of MMRR. A modified self-marking unit that marks mosquitoes with fluorescent pigment as they emerge from their breeding site was developed based on a previous design for Culex mosquitoes. The self-marking unit was first evaluated under semi-field conditions with laboratory-reared Anopheles arabiensis to determine the marking success and impact on mosquito survival. Subsequently, a field evaluation of MMRR was conducted in Yombo village, Tanzania, to examine the feasibility of the system. During the semi-field evaluation the self-marking units successfully marked 86% of emerging mosquitoes and there was no effect of fluorescent marker on mosquito survival. The unit successfully marked wild male and female Anopheles gambiae sensu lato (s.l.) in sufficiently large numbers to justify its use in MMRR studies. The estimated daily survival probability of An. gambiae s.l. was 0.87 (95% CI 0.69–1.10) and mean dispersal distance was 579 m (95% CI 521–636 m). This study demonstrates the successful use of a self-marking device in an MMRR study with African malaria vectors. This method may be useful in investigating population structure and dispersal of mosquitoes for deployment and evaluation of future vector control tools, such as gene drive, and to better parameterize mathematical models.

    更新日期:2019-12-23
  • Effectiveness of plant-based repellents against different Anopheles species: a systematic review
    Malaria J. (IF 2.798) Pub Date : 2019-12-21
    Amin Asadollahi; Mehdi Khoobdel; Alireza Zahraei-Ramazani; Sahar Azarmi; Sayed Hussain Mosawi

    Plant-based repellents have been applied for generations in traditional practice as a personal protection approach against different species of Anopheles. Knowledge of traditional repellent plants is a significant resource for the development of new natural products as an alternative to chemical repellents. Many studies have reported evidence of repellant activities of plant extracts or essential oils against malaria vectors worldwide. This systematic review aimed to assess the effectiveness of plant-based repellents against Anopheles mosquitoes. All eligible studies on the repellency effects of plants against Anopheles mosquitoes published up to July 2018 were systematically searched through PubMed/Medline, Scopus and Google scholar databases. Outcomes measures were percentage repellency and protection time. A total of 62 trials met the inclusion criteria. The highest repellency effect was identified from Ligusticum sinense extract, followed by citronella, pine, Dalbergia sissoo, peppermint and Rhizophora mucronata oils with complete protection time ranging from 9.1 to 11.5 h. Furthermore, essential oils from plants such as lavender, camphor, catnip, geranium, jasmine, broad-leaved eucalyptus, lemongrass, lemon-scented eucalyptus, amyris, narrow-leaved eucalyptus, carotin, cedarwood, chamomile, cinnamon oil, juniper, cajeput, soya bean, rosemary, niaouli, olive, tagetes, violet, sandalwood, litsea, galbanum, and Curcuma longa also showed good repellency with 8 h complete repellency against different species of Anopheles. Essential oils and extracts of some plants could be formulated for the development of eco-friendly repellents against Anopheles species. Plant oils may serve as suitable alternatives to synthetic repellents in the future as they are relatively safe, inexpensive, and are readily available in many parts of the world.

    更新日期:2019-12-21
  • Understanding challenges to malaria elimination in Nepal: a qualitative study with an embedded capacity-building exercise
    Malaria J. (IF 2.798) Pub Date : 2019-12-21
    Shiva Raj Adhikari; Vishnu P. Sapkota; Arjun K. Thapa; Yubraj Acharya

    The Nepalese Government has made significant progress toward the elimination of malaria. However, given the surge in the prevalence of non-communicable diseases, such as diabetes and hypertension, and the localized nature of malaria prevalence, malaria elimination will remain a challenge. In the current study, the authors sought to understand local perceptions on threats to malaria elimination in three endemic districts. The authors conducted a capacity-building exercise embedded within a qualitative study. The study component aimed to understand how local policymakers and actors perceive challenges in malaria elimination. For them to be able to articulate the challenges, however, an understanding of malaria elimination in the context of a broader health system in Nepal would be required. The capacity-building component, thus, involved providing that knowledge. Although the prevalence of malaria is high in the three districts where the study was conducted, there are significant gaps in human resources, diagnosis and treatment, and the provision of indoor residual spraying and long-lasting insecticide treated nets. More importantly, the authors’ experience suggests that it may be possible to capitalize on local expertise in order to identify gaps in malaria elimination at a sub-national level by building in a capacity-building exercise within a study. Locals in three malaria-endemic districts of Nepal perceive that there are significant gaps in human resources, diagnosis and treatment, the provision of insecticide treated nets, and indoor residual spraying.

    更新日期:2019-12-21
  • Adherence to the referral advice after introduction of rectal artesunate for pre-referral treatment of severe malaria at the community level: a noninferiority trial in the Democratic Republic of the Congo
    Malaria J. (IF 2.798) Pub Date : 2019-12-21
    Patrick M. Mvumbi; Jeanine Musau; Ousmane Faye; Hyppolite Situakibanza; Emile Okitolonda

    The Democratic Republic of the Congo adopted the strategy of using, at the community level, a dose of rectal artesunate as a pre-referral treatment for severe malaria amongst children under 5 years who could not quickly reach a health care facility and take oral medication. However, the adherence to referral advice after the integration of this strategy and the acceptability of the strategy were unknown. To assess adherence by the mothers/caretakers of children under 5 years to referral advice provided by the community health workers after pre-referral treatment of severe malaria with rectal artesunate, the authors conducted a noninferiority community trial with a pre- and post-intervention design in 63 (pre-intervention) and 51 (post-intervention) community care sites in 4 provinces (Kasaï-Oriental, Kasaï-Central, Lomami, Lualaba) from August 2014 through June 2016. The pre- and post-intervention surveys targets 387 mothers of children under 5 years and 63 community health workers and 346 mothers and 41 community health workers, respectively. A 15% margin was considered for noninferiority analyses due to the expected decrease in adherence to referral advice after the introduction of the new intervention. The mothers acknowledged that the rectal route was often used (60.7%), and medicines given rectally were considered more effective (63.6%) and easy to administer (69.7%). The acceptability of pre-referral rectal artesunate was relatively high: 79.4% (95% CI 75.4–83.3) among mothers, 90.3% (95% CI 82.3–96.8) among community health workers, and 97.8% (95% CI 93.3–100) among nurses. Adherence to referral advice at post-intervention [84.3% (95% CI 80.6–88.1)] was non-inferior to pre-intervention adherence [94.1% (95% CI 91.7–96.4)]. The integration of pre-referral rectal artesunate for severe malaria into the community care site in the DR Congo is feasible and acceptable. It positively affected adherence to referral advice. However, more health education is needed for parents of children under 5 years and community health workers.

    更新日期:2019-12-21
  • Doses of chloroquine in the treatment of malaria by Plasmodium vivax in patients between 2 and 14 years of age from the Brazilian Amazon basin
    Malaria J. (IF 2.798) Pub Date : 2019-12-21
    Luann Wendel Pereira de Sena; Amanda Gabryelle Nunes Cardoso Mello; Michelle Valéria Dias Ferreira; Marcieni Andrade de Ataide; Rosa Maria Dias; José Luiz Fernandes Vieira

    A total dose of chloroquine of 25 mg/kg is recommended by the World Health Organization (WHO) to treat malaria by Plasmodium vivax. In several endemic areas, including the Brazilian Amazon basin, anti-malarial drugs are dispensed in small plastic bags at a dosing regimen based on age. This practice can lead to suboptimal dosing of the drug, which can impact treatment outcomes. The aim of the present study was to estimate the extent of sub-dosing of chloroquine in children and adolescents with vivax malaria using an age-based dose regimen, in addition to investigating the influence of age on the plasma concentrations of chloroquine and desethylchloroquine. A study of cases was conducted with male patients with a confirmed infection by P. vivax, ages 2 to 14 years, using a combined regimen of chloroquine and primaquine. Height, weight and body surface area were determined at admission on the study. The total dose of chloroquine administered was estimated based on the weight and on the body surface area of the study patients. Chloroquine and desethylchloroquine were measured on Day 7 in each patient included in the study by a high-performance liquid chromatographic method with fluorescence detection. A total of 81 patients were enrolled and completed the study. The median age was 9 years (2–14 years). All patients presented negative blood smears at 42 days follow-up. The total dose of chloroquine ranged from 13.1 to 38.1 mg/kg. The percentage of patients with a total dose of the drug below 25 mg/kg ranged from 29.4 to 63.6%. The total dose of chloroquine administered based on BSA ranged from 387 to 1079 mg/m2, increasing with age. Plasma chloroquine concentrations ranged from 107 to 420 ng/ml, increasing with age. For desethylchloroquine, the plasma concentrations ranged from 167 to 390 ng/ml, with similar values among age-groups. The data demonstrated the widespread exposure of children and adolescents to suboptimal doses of chloroquine in the endemic area investigated.

    更新日期:2019-12-21
  • High cases of submicroscopic Plasmodium falciparum infections in a suburban population of Lagos, Nigeria
    Malaria J. (IF 2.798) Pub Date : 2019-12-19
    Florence A. Umunnakwe; Emmanuel T. Idowu; Olusola Ajibaye; Blessed Etoketim; Samuel Akindele; Aminat O. Shokunbi; Olubunmi A. Otubanjo; Gordon A. Awandare; Alfred Amambua-Ngwa; Kolapo M. Oyebola

    Asymptomatic malaria parasites are significant sources of infections for onward malaria transmission. Conventional tools for malaria diagnosis such as microscopy and rapid diagnostic test kits (RDT) have relatively low sensitivity, hence the need for alternative tools for active screening of such low-density infections. This study tested var acidic terminal sequence-based (varATS) quantitative polymerase chain reaction (qPCR) for screening asymptomatic Plasmodium falciparum infections among dwellers of a sub-urban community in Lagos, Nigeria. Clinically healthy participants were screened for malaria using microscopy, RDT and varATS qPCR techniques. Participants were stratified into three age groups: 1–5, 6–14 and > 14 years old. Of the 316 participants screened for asymptomatic malaria infection, 78 (24.68%) were positive by microscopy, 99 (31.33%) were positive by RDT and 112 (35.44%) by varATS qPCR. Participants aged 6–14 years had the highest prevalence of asymptomatic malaria, with geometric means of ~ 116 parasites/µL and ~ 6689 parasites/µL as detected by microscopy and varATS, respectively. This study has revealed high prevalence of asymptomatic malaria in the study population, with varATS detecting additional sub-microscopic infections. The highest concentration of asymptomatic malaria was observed among school-age children between 6 and 14 years old. A large-scale screening to identify other potential hotspots of asymptomatic parasites in the country is recommended.

    更新日期:2019-12-20
  • IL35 modulation altered survival, cytokine environment and histopathological consequences during malaria infection in mice
    Malaria J. (IF 2.798) Pub Date : 2019-12-19
    Ramatu Omenesa Bello; Maizaton Atmadini Abdullah; Roslaini Abd Majid; Voon Kin Chin; Mohammed Faruq Abd Rachman Isnadi; Zaid Osama Ibraheem; Mohd Khairi Hussain; Mohammed Garba Magaji; Rusliza Basir

    The immune modulating potential of IL-35 in multiple human disorders has been reported. Consequent upon the recognition of inflammatory cytokine activation and its preponderance for mediating pathology during malaria infection, the study aimed to characterize the expression and functional contribution(s) of IL-35 in Plasmodium berghei (strain ANKA) infected mice. Plasmodium berghei infection in male ICR mice was used as the rodent model of choice. The time course of IL-35 expression in the systemic circulation and tissues of P. berghei infected mice as well as their healthy control counterparts was assessed by enzyme linked immunosorbent assay and immunohistochemistry respectively. The effect of modulating IL-35 by recombinant IL-35 protein or neutralizing anti-Epstein-Barr virus-induced gene 3 antibody on the cytokine environment during P. berghei infection was assessed by flow cytometry. Furthermore, the influence of modulating IL-35 on histopathological hallmarks of malaria and disease progression was evaluated. Interleukin-35 was significantly up regulated in serum and tissues of P. berghei infected mice and correlated with parasitaemia. Neutralization of IL-35 significantly enhanced the release of IFN-γ, decreased the expression of IL-6 and decreased parasitaemia patency. Neutralization of IL-35 was also associated with a tendency towards increased survival as well as the absence of pathological features associated with malaria infection unlike recombinant IL-35 protein administration which sustained a normal course of infection and unfavourable malaria associated histological outcomes in P. berghei infected mice. These results indicate the involvement of IL-35 in P. berghei induced malaria infection. IL-35 neutralization strategies may represent viable therapeutic modalities beneficial for the resolution of malaria infection.

    更新日期:2019-12-20
  • Risk factor assessment for clinical malaria among forest-goers in a pre-elimination setting in Phu Yen Province, Vietnam
    Malaria J. (IF 2.798) Pub Date : 2019-12-20
    Sara E. Canavati; Gerard C. Kelly; Cesia E. Quintero; Thuan Huu Vo; Long Khanh Tran; Colin Ohrt; Thang Duc Ngo; Duong Thanh Tran; Nicholas J. Martin

    The transition from malaria control to elimination requires understanding and targeting interventions among high-risk populations. In Vietnam, forest-goers are often difficult to test, treat and follow-up for malaria because they are highly mobile. If undiagnosed, forest-goers can maintain parasite reservoirs and contribute to ongoing malaria transmission. A case–control study was conducted to identify malaria risk factors associated with forest-goers in three communes in Phu Yen Province, Vietnam. Cases (n = 81) were residents from the study area diagnosed with malaria and known to frequent forest areas. Controls (n = 94) were randomly selected forest-going residents from within the study area with no identified malaria infection. Participants were interviewed face-to-face using a standard questionnaire to identify malaria risk factors. Logistic regression was used to calculate odds ratios (ORs) and 95% CI for risk factors after adjusting for socio-demographic characteristics. Among the cases, malaria infection varied by species: 66.7% were positive for Plasmodium falciparum, 29.6% for Plasmodium vivax, and 3.7% were diagnosed as mixed infection. Cases were less likely than controls to use treated nets (aOR = 0.31; 95% CI 0.12–0.80), work after dark (aOR = 2.93; 95% CI 1.35, 6.34), bath in a stream after dark (aOR = 2.44; 95% CI 1.02–5.88), and collect water after dark (aOR = 1.99; 95% CI 1.02–3.90). As Vietnam moves toward malaria elimination, these findings can inform behaviour change communication and malaria prevention strategies, incorporating the risk of after-dark and water-related activities, in this priority and difficult-to-access population group.

    更新日期:2019-12-20
  • The 2019 Isdell:Flowers Cross Border Malaria Initiative Round Table: community engagement in the context of malaria elimination
    Malaria J. (IF 2.798) Pub Date : 2019-12-19
    Alexandra Gordon; Rebecca J. Vander Meulen; Alysse Maglior

    Government officials, representatives from malaria endemic communities, and nonprofit, academic, and private sector partners convened at the 2019 Isdell:Flowers Cross Border Malaria Initiative Round Table in Livingstone, Zambia from February 28–March 1, 2019 to discuss the necessity of community engagement and the involvement of those directly affected by malaria in malaria elimination efforts. Participants shared practical examples and principles of successful community engagement over the course of the Round Table. Three core principles of effective community engagement emerged: (1) there is no “one size fits all” community engagement strategy, (2) community engagement must be a bidirectional activity, and (3) community members must be at the heart of malaria elimination efforts.

    更新日期:2019-12-19
  • Optimization of an in vivo model to study immunity to Plasmodium falciparum pre-erythrocytic stages
    Malaria J. (IF 2.798) Pub Date : 2019-12-18
    Yevel Flores-Garcia; Sonia M. Herrera; Hugo Jhun; Daniel W. Pérez-Ramos; C. Richter King; Emily Locke; Ramadevi Raghunandan; Fidel Zavala

    The circumsporozoite protein (CSP) of Plasmodium is a key surface antigen that induces antibodies and T-cells, conferring immune protection in animal models and humans. However, much of the work on CSP and immunity has been developed based on studies using rodent or non-human primate CSP antigens, which may not be entirely translatable to CSP expressed by human malaria parasites, especially considering the host specificity of the different species. Using a genetically engineered strain of Plasmodium berghei that expresses luciferase, GFP and the Plasmodium falciparum orthologue of CSP, the effect of laboratory preparation, mosquito treatment and mouse factors on sporozoite infectivity was assessed using an in vivo bioluminescence assay on mice. This assay was compared with a PCR-based protection assay using an already described monoclonal antibody that can provide sterile protection against sporozoite challenge. Bioluminescence assay demonstrated similar detection levels of the quantity and kinetics of liver-stage infection, compared to PCR-based detection. This assay was used to evaluate treatment of sporozoite and delivery method on mouse infectivity, as well as the effects of age, sex and strain of mice. Finally, this assay was used to test the protective capacity of monoclonal antibody AB317; results strongly recapitulate the findings of previous work on this antibody. The PbGFP-Luc line and in vivo bioluminescence imaging provide highly sensitive read-outs of liver-stage infection in mice, and this method can be useful to reliably evaluate potency of pre-erythrocytic interventions.

    更新日期:2019-12-19
  • Anti-malarial ozonides OZ439 and OZ609 tested at clinically relevant compound exposure parameters in a novel ring-stage survival assay
    Malaria J. (IF 2.798) Pub Date : 2019-12-18
    Annabelle Walz; Didier Leroy; Nicole Andenmatten; Pascal Mäser; Sergio Wittlin

    Drug efficacy against kelch 13 mutant malaria parasites can be determined in vitro with the ring-stage survival assay (RSA). The conventional assay protocol reflects the exposure profile of dihydroartemisinin. Taking into account that other anti-malarial peroxides, such as the synthetic ozonides OZ439 (artefenomel) and OZ609, have different pharmacokinetics, the RSA was adjusted to the concentration–time profile of these ozonides in humans and a novel, semi-automated readout was introduced. When tested at clinically relevant parameters, it was shown that OZ439 and OZ609 are active against the Plasmodium falciparum clinical isolate Cam3.IR539T. If the in vitro RSA does indeed predict the potency of compounds against parasites with increased tolerance to artemisinin and its derivatives, then the herein presented data suggest that following drug-pulses of at least 48 h, OZ439 and OZ609 will be highly potent against kelch 13 mutant isolates, such as P. falciparum Cam3.IR539T.

    更新日期:2019-12-19
  • Intracluster correlation coefficients in the Greater Mekong Subregion for sample size calculations of cluster randomized malaria trials
    Malaria J. (IF 2.798) Pub Date : 2019-12-18
    Pimnara Peerawaranun; Jordi Landier; Francois H. Nosten; Thuy-Nhien Nguyen; Tran Tinh Hien; Rupam Tripura; Thomas J. Peto; Koukeo Phommasone; Mayfong Mayxay; Nicholas P. J. Day; Arjen Dondorp; Nick White; Lorenz von Seidlein; Mavuto Mukaka

    Sample size calculations for cluster randomized trials are a recognized methodological challenge for malaria research in pre-elimination settings. Positively correlated responses from the participants in the same cluster are a key feature in the estimated sample size required for a cluster randomized trial. The degree of correlation is measured by the intracluster correlation coefficient (ICC) where a higher coefficient suggests a closer correlation hence less heterogeneity within clusters but more heterogeneity between clusters. Data on uPCR-detected Plasmodium falciparum and Plasmodium vivax infections from a recent cluster randomized trial which aimed at interrupting malaria transmission through mass drug administrations were used to calculate the ICCs for prevalence and incidence of Plasmodium infections. The trial was conducted in four countries in the Greater Mekong Subregion, Laos, Myanmar, Vietnam and Cambodia. Exact and simulation approaches were used to estimate ICC values for both the prevalence and the incidence of parasitaemia. In addition, the latent variable approach to estimate ICCs for the prevalence was utilized. The ICCs for prevalence ranged between 0.001 and 0.082 for all countries. The ICC from the combined 16 villages in the Greater Mekong Subregion were 0.26 and 0.21 for P. falciparum and P. vivax respectively. The ICCs for incidence of parasitaemia ranged between 0.002 and 0.075 for Myanmar, Cambodia and Vietnam. There were very high ICCs for incidence in the range of 0.701 to 0.806 in Laos during follow-up. ICC estimates can help researchers when designing malaria cluster randomized trials. A high variability in ICCs and hence sample size requirements between study sites was observed. Realistic sample size estimates for cluster randomized malaria trials in the Greater Mekong Subregion have to assume high between cluster heterogeneity and ICCs. This work focused on uPCR-detected infections; there remains a need to develop more ICC references for trials designed around prevalence and incidence of clinical outcomes. Adequately powered trials are critical to estimate the benefit of interventions to malaria in a reliable and reproducible fashion. Trial registration: ClinicalTrials.govNCT01872702. Registered 7 June 2013. Retrospectively registered. https://clinicaltrials.gov/ct2/show/NCT01872702

    更新日期:2019-12-19
  • Management of imported malaria cases and healthcare institutions in central China, 2012–2017: application of decision tree analysis
    Malaria J. (IF 2.798) Pub Date : 2019-12-18
    Xi-Liang Wang; Jie-Bin Cao; Dan-Dan Li; Dong-Xiao Guo; Cheng-Da Zhang; Xiao Wang; Dan-Kang Li; Qing-Lin Zhao; Xiao-Wen Huang; Wei-Dong Zhang

    Imported malaria has been an important challenge for China. Fatality rates from malaria increased in China, particularly in Henan Province, primarily due to malpractice and misdiagnoses in healthcare institutions, and the level of imported malaria. This study aims to investigate the relationship between the state of diagnosis and subsequent complications among imported malaria cases at healthcare institutions, based on malaria surveillance data in Henan Province from 2012 to 2017. A retrospective descriptive analysis was performed using data from the Centre for Disease Control and Prevention, Zhengzhou City, the capital of Henan Province. A decision tree method was exploited to provide valuable insight into the correlation between imported malaria cases and healthcare institutions. From 2012 to 2017, there were 371 imported malaria cases, mostly in males aged between 20 and 50 years, including 319 Plasmodium falciparum cases. First visits of 32.3%, 19.9% and 15.9% malaria cases for treatment were to provincial, municipal and county healthcare institutions, respectively. The time interval between onset and initial diagnosis of 284 cases (76.5%) and the time interval between initial diagnosis and final diagnosis of 197 cases (53.1%) was no more than 72 h. An apparent trend was found that there were notably fewer patients misdiagnosed at first visit to healthcare institutions of a higher administrative level; 12.5% of cases were misdiagnosed in provincial healthcare institutions compared to 98.2% in private clinics, leading to fewer complications at healthcare institutions of higher administrative level due to correct initial diagnosis. In the tree model, the rank of healthcare facilities for initial diagnosis, and number of days between onset and initial diagnosis, made a major contribution to the classification of initial diagnosis, which subsequently became the most significant factor influencing complications developed in the second tree model. The classification accuracy were 82.2 and 74.1%, respectively for the tree models of initial diagnosis and complications developed. Inadequate seeking medical care by imported malaria patients, and insufficient capacity to diagnose malaria by healthcare institutions of lower administrative level were identified as major factors influencing complications of imported malaria cases in Henan Province. The lack of connection between uncommon imported malaria cases and superior medical resources was found to be the crucial challenge. A web-based system combined with WeChat to target imported malaria cases was proposed to cope with the challenge.

    更新日期:2019-12-19
  • Markers of sulfadoxine–pyrimethamine resistance in Eastern Democratic Republic of Congo; implications for malaria chemoprevention
    Malaria J. (IF 2.798) Pub Date : 2019-12-18
    Marit van Lenthe; Renske van der Meulen; Maryvonne Lassovski; Adelaide Ouabo; Edwige Bakula; Colette Badio; Deogratias Cibenda; Lucy Okell; Erwan Piriou; Lynn Grignard; Kjerstin Lanke; Bhargavi Rao; Teun Bousema; Cally Roper

    Sulfadoxine–pyrimethamine (SP) is a cornerstone of malaria chemoprophylaxis and is considered for programmes in the Democratic Republic of Congo (DRC). However, SP efficacy is threatened by drug resistance, that is conferred by mutations in the dhfr and dhps genes. The World Health Organization has specified that intermittent preventive treatment for infants (IPTi) with SP should be implemented only if the prevalence of the dhps K540E mutation is under 50%. There are limited current data on the prevalence of resistance-conferring mutations available from Eastern DRC. The current study aimed to address this knowledge gap. Dried blood-spot samples were collected from clinically suspected malaria patients [outpatient department (OPD)] and pregnant women attending antenatal care (ANC) in four sites in North and South Kivu, DRC. Quantitative PCR (qPCR) was performed on samples from individuals with positive and with negative rapid diagnostic test (RDT) results. Dhps K450E and A581G and dhfr I164L were assessed by nested PCR followed by allele-specific primer extension and detection by multiplex bead-based assays. Across populations, Plasmodium falciparum parasite prevalence was 47.9% (1160/2421) by RDT and 71.7 (1763/2421) by qPCR. Median parasite density measured by qPCR in RDT-negative qPCR-positive samples was very low with a median of 2.3 parasites/µL (IQR 0.5–25.2). Resistance genotyping was successfully performed in RDT-positive samples and RDT-negative/qPCR-positive samples with success rates of 86.2% (937/1086) and 55.5% (361/651), respectively. The presence of dhps K540E was high across sites (50.3–87.9%), with strong evidence for differences between sites (p < 0.001). Dhps A581G mutants were less prevalent (12.7–47.2%). The dhfr I164L mutation was found in one sample. The prevalence of the SP resistance marker dhps K540E exceeds 50% in all four study sites in North and South Kivu, DRC. K540E mutations regularly co-occurred with mutations in dhps A581G but not with the dhfr I164L mutation. The current results do not support implementation of IPTi with SP in the study area.

    更新日期:2019-12-19
  • Terminalia albida treatment improves survival in experimental cerebral malaria through reactive oxygen species scavenging and anti-inflammatory properties
    Malaria J. (IF 2.798) Pub Date : 2019-12-18
    Aissata Camara; Mohamed Haddad; Karine Reybier; Mohamed Sahar Traoré; Mamadou Aliou Baldé; Jade Royo; Alpha Omar Baldé; Philippe Batigne; Mahamane Haidara; Elhadj Saidou Baldé; Agnès Coste; Aliou Mamadou Baldé; Agnès Aubouy

    The development of Plasmodium resistance to the last effective anti-malarial drugs necessitates the urgent development of new anti-malarial therapeutic strategies. To this end, plants are an important source of new molecules. The objective of this study was to evaluate the anti-malarial effects of Terminalia albida, a plant used in Guinean traditional medicine, as well as its anti-inflammatory and antioxidant properties, which may be useful in treating cases of severe malaria. In vitro antiplasmodial activity was evaluated on a chloroquine-resistant strain of Plasmodium falciparum (K-1). In vivo efficacy of the plant extract was measured in the experimental cerebral malaria model based on Plasmodium berghei (strain ANKA) infection. Mice brains were harvested on Day 7–8 post-infection, and T cells recruitment to the brain, expression levels of pro- and anti-inflammatory markers were measured by flow cytometry, RT-qPCR and ELISA. Non-malarial in vitro models of inflammation and oxidative response were used to confirm Terminalia albida effects. Constituents of Terminalia albida extract were characterized by ultra‐high performance liquid chromatography coupled with high resolution mass spectrometry. Top ranked compounds were putatively identified using plant databases and in silico fragmentation patterns. In vitro antiplasmodial activity of Terminalia albida was confirmed with an IC50 of 1.5 μg/mL. In vivo, Terminalia albida treatment greatly increased survival rates in P. berghei-infected mice. Treated mice were all alive until Day 12, and the survival rate was 50% on Day 20. Terminalia albida treatment also significantly decreased parasitaemia by 100% on Day 4 and 89% on Day 7 post-infection. In vivo anti-malarial activity was related to anti-inflammatory properties, as Terminalia albida treatment decreased T lymphocyte recruitment and expression of pro-inflammatory markers in brains of treated mice. These properties were confirmed in vitro in the non-malarial model. In vitro, Terminalia albida also demonstrated a remarkable dose-dependent neutralization activity of reactive oxygen species. Twelve compounds were putatively identified in Terminalia albida stem bark. Among them, several molecules already identified may be responsible for the different biological activities observed, especially tannins and triterpenoids. The traditional use of Terminalia albida in the treatment of malaria was validated through the combination of in vitro and in vivo studies.

    更新日期:2019-12-19
  • Use of gene expression studies to investigate the human immunological response to malaria infection
    Malaria J. (IF 2.798) Pub Date : 2019-12-13
    Susanne H. Hodgson; Julius Muller; Helen E. Lockstone; Adrian V. S. Hill; Kevin Marsh; Simon J. Draper; Julian C. Knight

    Transcriptional profiling of the human immune response to malaria has been used to identify diagnostic markers, understand the pathogenicity of severe disease and dissect the mechanisms of naturally acquired immunity (NAI). However, interpreting this body of work is difficult given considerable variation in study design, definition of disease, patient selection and methodology employed. This work details a comprehensive review of gene expression profiling (GEP) of the human immune response to malaria to determine how this technology has been applied to date, instances where this has advanced understanding of NAI and the extent of variability in methodology between studies to allow informed comparison of data and interpretation of results. Datasets from the gene expression omnibus (GEO) including the search terms; ‘plasmodium’ or ‘malaria’ or ‘sporozoite’ or ‘merozoite’ or ‘gametocyte’ and ‘Homo sapiens’ were identified and publications analysed. Datasets of gene expression changes in relation to malaria vaccines were excluded. Twenty-three GEO datasets and 25 related publications were included in the final review. All datasets related to Plasmodium falciparum infection, except two that related to Plasmodium vivax infection. The majority of datasets included samples from individuals infected with malaria ‘naturally’ in the field (n = 13, 57%), however some related to controlled human malaria infection (CHMI) studies (n = 6, 26%), or cells stimulated with Plasmodium in vitro (n = 6, 26%). The majority of studies examined gene expression changes relating to the blood stage of the parasite. Significant heterogeneity between datasets was identified in terms of study design, sample type, platform used and method of analysis. Seven datasets specifically investigated transcriptional changes associated with NAI to malaria, with evidence supporting suppression of the innate pro-inflammatory response as an important mechanism for this in the majority of these studies. However, further interpretation of this body of work was limited by heterogeneity between studies and small sample sizes. GEP in malaria is a potentially powerful tool, but to date studies have been hypothesis generating with small sample sizes and widely varying methodology. As CHMI studies are increasingly performed in endemic settings, there will be growing opportunity to use GEP to understand detailed time-course changes in host response and understand in greater detail the mechanisms of NAI.

    更新日期:2019-12-17
  • Artenimol–piperaquine in children with uncomplicated imported falciparum malaria: experience from a prospective cohort
    Malaria J. (IF 2.798) Pub Date : 2019-12-16
    Lauren Pull; Jean-Marc Lupoglazoff; Matthew Beardmore; Jean-François Michel; Pierre Buffet; Olivier Bouchaud; Jean-Yves Siriez

    Although malaria remains one of the major public health threats in inter-tropical areas, there is limited understanding of imported malaria in children by paediatricians and emergency practitioners in non-endemic countries, often resulting in misdiagnosis and inadequate treatment. Moreover, classical treatments (atovaquone-proguanil, quinine, mefloquine) are limited either by lengthy treatment courses or by side effects. Since 2010, the World Health Organization (WHO) has recommended the use of oral artemisinin-based combination therapy for the treatment of uncomplicated Plasmodium falciparum malaria worldwide. The benefits of artenimol–piperaquine in children have been validated in endemic countries but experience remains limited in cases of imported malaria. This prospective observational study in routine paediatric care took place at the Emergency Department, Robert-Debré Hospital (Paris, France) from September 2012 to December 2014. Tolerance and efficacy of artenimol–piperaquine in children presenting with the following inclusion criteria were assessed: P. falciparum positive on thin or thick blood smear; and the absence of WHO-defined features of severity. Among 83 children included in this study, treatment with artenimol–piperaquine was successful in 82 children (98.8%). None of the adverse events were severe and all were considered mild with no significant clinical impact. This also applied to cardiological adverse events despite a significant increase of the mean post-treatment QTc interval. Artenimol–piperaquine displays a satisfying efficacy and tolerance profile as a first-line treatment for children with imported uncomplicated falciparum malaria and only necessitates three once-daily oral intakes of the medication. Comparative studies versus artemether-lumefantrine or atovaquone-proguanil would be useful to confirm the results of this study.

    更新日期:2019-12-17
  • Producing routine malaria data: an exploration of the micro-practices and processes shaping routine malaria data quality in frontline health facilities in Kenya
    Malaria J. (IF 2.798) Pub Date : 2019-12-16
    George Okello; Sassy Molyneux; Scholastica Zakayo; Rene Gerrets; Caroline Jones

    Routine health information systems can provide near real-time data for malaria programme management, monitoring and evaluation, and surveillance. There are widespread concerns about the quality of the malaria data generated through routine information systems in many low-income countries. However, there has been little careful examination of micro-level practices of data collection which are central to the production of routine malaria data. Drawing on fieldwork conducted in two malaria endemic sub-counties in Kenya, this study examined the processes and practices that shape routine malaria data generation at frontline health facilities. The study employed ethnographic methods—including observations, records review, and interviews—over 18-months in four frontline health facilities and two sub-county health records offices. Data were analysed using a thematic analysis approach. Malaria data generation was influenced by a range of factors including human resource shortages, tool design, and stock-out of data collection tools. Most of the challenges encountered by health workers in routine malaria data generation had their roots in wider system issues and at the national level where the framing of indicators and development of data collection tools takes place. In response to these challenges, health workers adopted various coping mechanisms such as informal task shifting and use of improvised tools. While these initiatives sustained the data collection process, they also had considerable implications for the data recorded and led to discrepancies in data that were recorded in primary registers. These discrepancies were concealed in aggregated monthly reports that were subsequently entered into the District Health Information Software 2. Challenges to routine malaria data generation at frontline health facilities are not malaria or health information systems specific; they reflect wider health system weaknesses. Any interventions seeking to improve routine malaria data generation must look beyond just malaria or health information system initiatives and include consideration of the broader contextual factors that shape malaria data generation.

    更新日期:2019-12-17
  • In vitro anti-malarial efficacy of chalcones: cytotoxicity profile, mechanism of action and their effect on erythrocytes
    Malaria J. (IF 2.798) Pub Date : 2019-12-16
    Shweta Sinha; Daniela I. Batovska; Bikash Medhi; B. D. Radotra; Ashish Bhalla; Nadezhda Markova; Rakesh Sehgal

    Malaria extensively leads to mortality and morbidity in endemic regions, and the emergence of drug resistant parasites is alarming. Plant derived synthetic pharmaceutical compounds are found to be a foremost research to obtain diverse range of potent leads. Amongst them, the chalcone scaffold is a functional template for drug discovery. The present study involves synthesis of ten chalcones with various substitution pattern in rings A and B and assessment of their anti-malarial efficacy against chloroquine sensitive and chloroquine resistant strains as well as of their cytotoxicity and effect on haemozoin production. The chalcones were synthesized by Claisen-Schmidt condensation between equimolar quantities of substituted acetophenones and aryl benzaldehydes (or indole-3-carboxaldehyde) and were screened for anti-malarial activity by WHO Mark III schizont maturation inhibition assay. The cytotoxicity profile of a HeLa cell line was evaluated through MTT viability assay and the selectivity index (SI) was calculated. Haemozoin inhibition assay was performed to illustrate mode of action on a Plasmodium falciparum strain. The IC50 values of all compounds were in the range 0.10–0.40 μg/mL for MRC-2 (a chloroquine sensitive strain) and 0.14–0.55 μg/mL for RKL-9 (a chloroquine resistant strain) of P. falciparum. All the chalcones showed low cellular toxicity with minimal haemolysis. The statistically significant reduction (p < 0.05) in the haemozoin production suggests a similar mechanism than that of chloroquine. Out of ten chalcones, number 7 was found to be a lead compound with the highest potency (IC50 = 0.11 µg/mL), as compared to licochalcone (IC50 = 1.43 µg/mL) and with high selectivity index of 85.05.

    更新日期:2019-12-17
  • Plasmodium vivax severe imported malaria in two migrants in France
    Malaria J. (IF 2.798) Pub Date : 2019-12-16
    Arezki Izri; Sandrine Cojean; Claire Leblanc; Yves Cohen; Olivier Bouchaud; Rémy Durand

    With less than one severe case per year in average, Plasmodium vivax is very rarely associated with severe imported malaria in France. Two cases of P. vivax severe malaria occurred in patients with no evident co-morbidity. Interestingly, both cases did not occur at the primary infection but during relapses. Patient 1: A 27-year old male, born in Afghanistan and living in France since 2012, was admitted on August 2015 to the Avicenne hospital because of abdominal pain, intense headache, fever and hypotension. The patient was haemodynamically unstable despite 5 L of filling solution. A thin blood film showed P. vivax trophozoites within the red blood cells. To take care of the septic shock, the patient was given rapid fluid resuscitation, norepinephrine (0.5 mg/h), and intravenous artesunate. Nested polymerase chain reactions of the SSUrRNA gene were negative for Plasmodium falciparum but positive for P. vivax. The patient became apyretic in less than 24H and the parasitaemia was negative at the same time. Patient 2: A 24-year old male, born in Pakistan and living in France, was admitted on August 2016 because of fever, abdominal pain, headache, myalgia, and nausea. The last travel of the patient in a malaria endemic area occurred in 2013. A thin blood film showed P. vivax trophozoites within the red blood cells. The patient was treated orally by dihydroartemisinin-piperaquine and recovered rapidly. Nine months later, the patient returned to the hospital with a relapse of P. vivax malaria. The malaria episode was uncomplicated and the patient recovered rapidly. Three months later, the patient came back again with a third episode of P. vivax malaria. Following a rapid haemodynamic deterioration, the patient was transferred to the intensive care unit of the hospital. In all the patient received 10 L of filling solution to manage the septic shock. After 5 days of hospitalization and a specific treatment, the patient was discharged in good clinical conditions. Clinicians should be aware of the potential severe complications associated with P. vivax in imported malaria, even though the primary infection is uncomplicated.

    更新日期:2019-12-17
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