Antimalarial Treatment Research Articles

Severe imported malaria involving hyperparasitemia (≥ 10%) in non-immune children: Assessment of French practices

BackgroundPlasmodium falciparum hyperparasitemia (over or equal to 10%), isolated or associated with other severity criteria, should be managed in a pediatric intensive care unit according to the French pediatric guidelines. The main objective of our study was to describe the management and course of these special cases. Population and methodsWe conducted a retrospective study in eight French hospital facilities from January 2007 to December 2014. We reviewed the management of non-immune children aged 0–15 years, assessing the following: clinical and paraclinical data, type of care unit, treatment initiated, initial and long-term course. Data were analyzed for the whole population and for two groups according to the place of first-line management: group A (in pediatric intensive care unit), and group B (other places). ResultsA total of 61 children were included, 14 (23%) of whom were initially admitted to the intensive care unit (group A), all with neurological or hemodynamic disorders. Only 23 children (38%) overall received intravenous antimalarial treatment and the other patients received exclusively oral treatment. No deaths were reported. Median parasitemia was comparable in the two groups. In group B (n = 47/61, 77%), isolated hyperparasitemia, jaundice, and renal failure were predominant. The children who underwent initial intravenous treatment (n = 5/47, 11%) all progressed favorably, as did 92% of the children who received oral treatment (n = 42/47, 89%). ConclusionA majority of children with Plasmodium falciparum hyperparasitemia were managed outside the pediatric intensive care unit via the oral route, against the French pediatric guidelines except when neurologic or hemodynamic disorders were present. Initial clinical evaluation and hospital supervision are essential for the best management of these patients.

Factors influencing health workers\u2019 compliance with outpatient malaria \u2018test and treat\u2019 guidelines during the plateauing performance phase in Kenya, 2014\u20132016

BackgroundHealth workers’ compliance with outpatient malaria ‘test and treat’ guidelines has improved since 2010 but plateaued from 2014 at suboptimal levels in Kenya. This study examined the factors associated with high but suboptimal compliance levels at facilities with available malaria tests and drugs.MethodsData from four national, cross-sectional health facility surveys undertaken between 2014 and 2016 in Kenya were analysed. Association between 31 factors and compliance with malaria testing (survey range (SR): 65–69%) and no anti-malarial treatment for test negative patients (SR: 90–92%) were examined using multilevel logistic regression models.ResultsA total of 2,752 febrile patients seen by 594 health workers at 486 health facilities were analysed. Higher odds of malaria testing were associated with lake endemic (aOR = 12.12; 95% CI: 5.3–27.6), highland epidemic (aOR = 5.06; 95% CI: 2.7–9.5) and semi-arid seasonal (aOR = 2.07; 95% CI: 1.2–3.6) compared to low risk areas; faith-based (FBO)/ non-governmental organization (NGO)-owned compared to government-owned facilities (aOR = 5.80; 95% CI: 3.2–10.6); health workers’ perception of malaria endemicity as high-risk (aOR = 3.05; 95% CI: 1.8–5.2); supervision with feedback (aOR = 1.84; 95% CI: 1.2–2.9); access to guidelines (aOR = 1.96; 95% CI: 1.1–3.4); older patients compared to infants, higher temperature measurements and main complaints of fever, diarrhoea, headache, vomiting and chills. Lower odds of testing were associated with febrile patients having main complaints of a cough (aOR = 0.65; 95% CI: 0.5–0.9), a rash (aOR = 0.32; 95% CI: 0.2–0.7) or a running nose (aOR = 0.59; 95% CI: 0.4–0.9). Other factors associated with compliance with test negative results included the type of diagnostic test available at the facility, in-service training, health workers’ age, and correct knowledge of the targeted treatment policy.ConclusionsTo optimize outpatient malaria case-management, reduce testing compliance gaps and eliminate overtreatment of test negative patients, there is a need to focus on compliance within low malaria risk areas in addition to ensuring the universal and continuous availability of ‘test and treat’ commodities. Targeting of older and government health workers; dissemination of updated guidelines; and continuing with in-service training and supportive supervision with feedback is essential. Lastly, there is a need to improve health workers’ knowledge about malaria testing criteria considering their perceptions of endemicity.

Liver Enzymes and Lipid Profile of Malaria Patients Before and After Antimalarial Drug Treatment at Dembia Primary Hospital and Teda Health Center, Northwest, Ethiopia.

BackgroundInfection with malaria in humans involves liver cell destruction, which alters the levels of liver enzymes and lipid profiles. A number of studies have been conducted to address the impact of malaria on liver enzymes and lipid profiles but no studies were addressed after antimalarial treatment in Ethiopia. This study is intended to fill this gap.MethodsAn observational cohort study was conducted at Dembia Primary Hospital and Teda Health Center, from June to August 2020. Eighty eight malaria infected study participants were recruited using random sampling techniques. Socio-demographic data, capillary and venous blood samples were collected. Assessment of liver enzymes and lipid profiles was done using Beckman Coulter DC-700 clinical chemistry analyzer. Data were entered using Epi-data and exported to SPSS version 20 for analysis. One way ANOVA, independent t-test, and paired t-test were used to compare the mean liver enzymes and lipid profile. p-value<0.05 was considered statistically significant.ResultsBefore anti-malaria treatment, among 88 study participants, elevated AST (87.5%), ALT (12.5%), ALP (43.2%), and TG (17.2%) and lower HDL (87.5%) and normal LDL and TC were observed. After treatment, 100% AST, ALT, HDL, and LDL and 92% ALP, 94.3% TC, and 86.4% TG levels were in the normal range. The mean level of AST and ALT increased while HDL decreased from low to higher density parasitaemia. Mean level of AST was significantly lower while ALT did not alter. HDL, LDL, and TC level were increased but statistically were insignificant (P>0.05).ConclusionMalaria could be responsible for increased liver enzymes and certain lipids while decreasing some lipid profiles. After anti-malaria treatment, these parameters were reversed to normal from 86.4% to 100%. Hence, prompt treatment is important to improve liver enzymes and lipid profile impairment during malaria infection.

Delayed presentation to hospital care is associated with sequelae but not mortality in children with cerebral malaria in Malawi

BackgroundCerebral malaria is still a major cause of death in children in sub-Saharan Africa. Among survivors, debilitating neurological sequelae can leave children with permanent cognitive impairments and societal stigma, resulting in taxing repercussions for their families. This study investigated the effect of delay in presentation to medical care on outcome in children with cerebral malaria in Malawi.MethodsThis retrospective study included participants enrolled in a longstanding study of cerebral malaria between 2001 and 2021 and considered coma duration prior to arrival at hospital (with or without anti-malarial treatment), HIV status, blood lactate levels at admission and age as factors that could affect clinical outcome. Outcomes were categorized as full recovery, sequelae at the time of discharge, or death. A multinomial regression was fit and run controlling for coma duration, HIV status, lactate levels and age, to determine the association between each explanatory variable and outcome.ResultsA total of 1663 children with cerebral malaria, aged 6 months to 14 years were included. Longer coma duration (in hours) was associated with greater odds of developing sequelae (OR = 1.023, 95% CI 1.007–1.039, p = 0.006) but not death (OR = 1.00, 95% CI 0.986–1.015, p = 0.961). Younger age (in months) was also correlated with higher rates of sequelae, (OR = 0.990, 95% CI 0.983–0.997, p = 0.004) but not with increased mortality (OR = 0.998, 95% CI 0.993–1.003, p = 0.335). Blood lactate levels on admission were correlated with mortality (OR = 1.125, 95% CI 1.090–1.161, p < 0.001) but not associated with increased rates of sequelae (OR = 1.016, 95% CI 0.973–1.060, p = 0.475). Positive HIV status and treatment with an anti-malarial (artemisinin or non-artemisinin-based) prior to arrival at the hospital were not significantly associated with either adverse outcome.ConclusionsIn Malawian children with cerebral malaria, higher rates of sequelae were significantly associated with extended coma duration prior to admission and younger age. Mortality rates were correlated with increased lactate levels on admission. The differential effects of variables on clinical outcomes suggest that there may be different pathogenic pathways leading to sequelae and death. Actions taken by parents and health care professionals are critical in defining when patients arrive at hospital and determining their ultimate outcome.

Effectiveness and safety of artesunate\u2013amodiaquine versus artemether\u2013lumefantrine for home-based treatment of uncomplicated Plasmodium falciparum malaria among children 6\u2013120\xa0months in Yaound\xe9, Cameroon: a randomized trial

BackgroundMany studies have reported high efficacy and safety of artesunate-amodiaquine (AS-AQ) and artemether-lumefantrine (AL) when administered under direct observation in Cameroon. There is paucity of data to support their continuous use in home-based treatment of uncomplicated Plasmodium falciparum malaria in Cameroon. Hence, this study aimed to assess the effectiveness and safety of AS-AQ versus AL for home-based treatment of uncomplicated P. falciparum malaria among children 6–120 months in Yaoundé, Cameroon.MethodsA two-arm, open-label, randomized, controlled trial comparing the equivalence of AS-AQ (experimental group) and AL (control group) was carried out from May 2019 to April 2020 at two secondary hospitals in Yaoundé. Participants were randomized to receive either AS-AQ or AL. After the first dose, antimalarial drugs were given at home, rather than under direct observation by a study staff. The conventional on-treatment and post-treatment laboratory and clinical evaluations were not done until day 3 of the full antimalarial treatment course. The evaluation of effectiveness was mainly based on per protocol polymerase chain reaction adjusted adequate clinical and parasitological response (PP PCR adjusted ACPR) on day 28 post-treatment. Safety was based on assessment of adverse events (AEs) and severe adverse events (SAEs) from day 1 to day 28.ResultsA total of 242 children were randomized to receive AS-AQ (n = 114) and AL (n = 128). The PP PCR adjusted day 28 cure rates were [AS-AQ = 96.9% (95% CI, 91.2–99.4) versus AL = 95.5% (95% CI, 89.9–98.5), P = 0.797]. Expected mild to moderate adverse events were reported in both arms [AS-AQ = 83 (84.7%) versus AL = 99 (86.1%), P = 0.774]. The most common adverse events included: transient changes of hematologic indices and fever.ConclusionsThis study demonstrated that AS-AQ and AL are effective and safe for home management of malaria in Yaoundé. The evidence from this study supports the parallel use of the two drugs in routine practice. However, the findings from this study do not describe the likely duration of antimalarial effectiveness in holoendemic areas where multiple courses of treatment might be required.Trial registration: This study is a randomized controlled trial and it was retrospectively registered on 23/09/2020 at ClinicalTrials.gov with registration number NCT04565184.

Interaction of Antimalarial Drug, Pyrimethamine and Sulphadoxine with Sickle Haemoglobin at pH 5.0 and pH 7.2: A Fourier Transform Infrared (FTIR) Study

Aggregation of sickle haemoglobin (HbS), upon deoxygenation, is responsible for an inherited genetic disorder in the human red blood cells (RBCs) known as Sickle cell disease (SCD). On the suggestion that this phenomenon could arise from some form of conformational changes in the structure of HbS arising from a pH-induced rearrangement of secondary structural elements of the haemoglobin, Fourier Transform Infrared (FTIR) spectroscopy (in the mid-infrared region) was used to measure the amino acid side chain absorbance and also, the secondary structural transitions in the protein. A comparative study between the interaction of HbS with Pyrimethamine and sulphadoxine at pH 5.0, (the acidic pH of malarial parasites’ digestive vacuole during the intra-erythrocytic development and proliferation), and the body’s physiological pH of 7.2 was carried out. The amide I region (1700 – 1600 cm-1) comprising the amino acids side-chains absorbance and the proteins secondary structural components (α-helix, β-sheets, random and turn structures) showed that at pH 5.0 for Pyrimethamine-sulphadoxine combination therapy, there were significant changes in absorbance for HbS while at pH 7.2, little or no significant absorbance changes were observed. The results suggest that HbS is easily destabilized at pH 5.0 than pH 7.2 on interaction with Pyrimethamine and sulphadoxine. These interactions may hinder the development of the Plasmodium falciparum at the intra-erythrocytic stage and may account for the novel strategies of monitoring HbS aggregation during malarial infection as well as improvements in administering effective antimalarial treatment.

Quantitative standardization of pharmacologically active components from antiplasmodial plant Solanum nudum Dunal (wild and in vitro)

Solanum nudum Dunal (Solanaceae) is most commonly known and used by the population of the colombian Pacific coast as an antimalarial treatment. This article study into optimization and quantitative analysis of compounds steroidal over time of development of this species when grown in vitro and wild. A new steroidal compound named SN6 was elucidated by NMR and a new method of quantification of seven steroidal compounds (Diosgenone DONA and six steroids SNs) using HPLC-DAD-MS in extracts of cultures in vitro and wild was investigated. Biology activity of extracts was found to a range of antiplasmodial activity in FCB2 and NF-54 with inhibitory concentration (IC50) between (17.04 -100 μg/mL) and cytotoxicity in U-937 of CC50 (7.18 -104.7 μg/mL). This method creates the basis for the detection of seven sterols antiplasmodial present in extracts from S. nudum plant as a quality parameter in the control and expression of phytochemicals.

Strengthening therapeutic adherence and pharmacovigilance to antimalarial treatment in Manaus, Brazil: a multicomponent strategy using mHealth

BackgroundPublic health initiatives for improving adherence to primaquine based regimens and enhancing effective pharmacovigilance are needed to support the efforts for malaria elimination in real world conditions.MethodsA multicomponent patient-oriented strategy using a Smart Safety Surveillance (3S) approach including: (1) educational materials for treatment counselling and identification of warning symptoms of haemolytic anaemia; (2) an mHealth component using Short Message Service (SMS) treatment reminders and (3) development and implementation of follow-up phone surveys three days after treatment completion, using a web-based platform linked to the local information system of malaria. Adherence was measured using the Morisky Medication Adherence Scale. Self-reported events were registered using a structured questionnaire and communicated to the Brazilian Health Regulatory Agency.ResultsEducational materials were disseminated to 5594 patients, of whom 1512 voluntarily entered the mHealth component through the local information system; 7323 SMS were sent, and 1062 participants completed a follow-up survey after treatment. The mean age of patients was 37.36 years (SD 13.65), 61.24% were male, 98.54% were infected with. Plasmodium vivax and 95.90% received a short regimen of chloroquine plus primaquine (CQ + PQ 7 days), as per malaria case management guidelines in Brazil. From the 1062 surveyed participants 93.31% were considered adherent to the treatment. Most of the patients (95.20%) reported at least one adverse event. Headache, lack of appetite and nausea/vomiting were the most frequently reported adverse events by 77.31%, 70.90% and 56.78% of the patients respectively. A quarter of the patients reported anxiety or depression symptoms; 57 (5.37%) patients reported 5 to 6 warning symptoms of haemolytic anaemia including jaundice and dark urine in 44 (4.14%). Overall, three patients presenting symptoms of haemolytic anaemia attended a hospital and were diagnosed with G6PD deficiency, and one had haemolysis. All of them recovered.ConclusionsUnder real world conditions, a multicomponent patient-oriented strategy using information and communication technologies allowed health care providers to reinforce treatment adherence and enhance safety surveillance of adverse events associated with regimens using primaquine. Active monitoring through phone surveys also reduced under-reporting of ADRs. This approach is low-cost, scalable and able to support prioritized activities of the national malaria programme.

Association between oral antimalarial medication administration and mortality among patients with Ebola virus disease: a multisite cohort study

BackgroundEmpiric antimalarial treatment is a component of protocol-based management of Ebola virus disease (EVD), yet this approach has limited clinical evidence for patient-centered benefits.MethodsThis retrospective cohort study evaluated the association between antimalarial treatment and mortality among patients with confirmed EVD. The data was collected from five International Medical Corps operated Ebola Treatment Units (ETUs) in Sierra Leone and Liberia from 2014 through 2015. The standardized protocol used for patient care included empiric oral treatment with combination artemether and lumefantrine, twice daily for three days; however, only a subset of patients received treatment due to resource variability. The outcome of interest was mortality, comparing patients treated with oral antimalarials within 48-h of admission to those not treated. Analysis was conducted with logistic regression to generate adjusted odds ratios (aORs). Multivariable analyses controlled for ETU country, malaria rapid diagnostic test result, age, EVD cycle threshold value, symptoms of bleeding, diarrhea, dysphagia and dyspnea, and additional standard clinical treatments.ResultsAmong the 424 cases analyzed, 376 (88.7%) received early oral antimalarials. Across all cases, mortality occurred in 57.5% (244). In comparing unadjusted mortality prevalence, early antimalarial treated cases yielded 55.1% mortality versus 77.1% mortality for those untreated (p = 0.005). Multivariable analysis demonstrated evidence of reduced aOR for mortality with early oral antimalarial treatment versus non-treatment (aOR = 0.34, 95% Confidence Interval: 0.12, 0.92, p = 0.039).ConclusionEarly oral antimalarial treatment in an EVD outbreak was associated with reduced mortality. Further study is warranted to investigate this association between early oral antimalarial treatment and mortality in EVD patients.

FIT-PNAs as RNA-Sensing Probes for Drug-Resistant Plasmodium falciparum.

Detecting RNA at single-nucleotide resolution is a formidable task. Plasmodium falciparum is the deadliest form of malaria in humans and has shown to gain resistance to essentially all antimalarial drugs including artemisinin and chloroquine. Some of these drug resistances are associated with single-nucleotide polymorphisms (SNPs). Forced-intercalation peptide nucleic acids (FIT-PNAs) are DNA mimics that are designed as RNA-sensing molecules that fluoresce upon hybridization to their complementary (RNA) targets. We have previously designed and synthesized FIT-PNAs that target the C580Y SNP in the K13 gene of P. falciparum. In addition, we have now prepared FIT-PNAs that target the K76T SNP in the CRT gene of P. falciparum. Both SNPs are common ones associated with artemisinin and chloroquine drug resistance, respectively. Our FIT-PNAs are conjugated to a simple cell-penetrating peptide (CPP) that consists of eight d-lysines (dK8), which renders these FIT-PNAs cell-permeable to infected red blood cells (iRBCs). Herein, we demonstrate that FIT-PNAs clearly discriminate between wild-type (WT) strains (NF54-WT: artemisinin-sensitive or chloroquine-sensitive) and mutant strains (NF54-C580Y: artemisinin-resistant or Dd2: chloroquine-resistant) of P. falciparum parasites. Simple incubation of FIT-PNAs with live blood-stage parasites results in a substantial difference in fluorescence as corroborated by FACS analysis and confocal microscopy. We foresee FIT-PNAs as molecular probes that will provide a fast, simple, and cheap means for the assessment of drug resistance in malaria─a tool that would be highly desirable for the optimal choice of antimalarial treatment in endemic countries.

The Changing Global Landscape in the Development of Artemisinin-Based Treatments: A Clinical Trial Perspective.

Artemisinin and its derivatives (ARTs), due to their potent antimalarial activities, are widely used as frontline antimalarials across the world. Although the large-scale deployment of ARTs has significantly contributed to a substantial decline in malaria deaths, the global malaria burden is still high. New antimalarial treatments need to be developed to manage the growing artemisinin resistance. Understanding the status of ART development is crucial for developing strategies for new alternatives and identifying opportunities to develop ART-based treatments. This study sampled ART clinical trials from the past two decades to gain an overview of the global ART-development landscape. A total of 768 trials were collected to analyze the disease focuses, activity trends, development status, geographic distribution, and combination treatment profiles of ART trials. The findings highlighted the constant focus of ARTs on malaria, the evolving combination research focus, the distinctions between ART development preferences across global regions, the urgent demands for treatments for artemisinin-resistant malaria, and the unavoidable need to consider ART combinations in the development of new antimalarials.

Controlled Human Malaria Infection Studies in Africa-Past, Present, and Future.

Controlled human infection studies have contributed significantly to the understanding of pathogeneses and treatment of infectious diseases. In malaria, deliberately infecting humans with malaria parasites was used as a treatment for neurosyphilis in the early 1920s. More recently, controlled human malaria infection (CHMI) has become a valuable, cost-effective tool to fast-track the development and evaluation of new anti-malarial drugs and/or vaccines. CHMI studies have also been used to define host/parasite interactions and immunological correlates of protection. CHMI involves infecting a small number of healthy volunteers with malaria parasites, monitoring their parasitemia and providing anti-malarial treatment when a set threshold is reached. In this review we discuss the introduction, development, and challenges of modern-day Plasmodium falciparum CHMI studies conducted in Africa, and the impact of naturally acquired immunity on infectivity and vaccine efficacy. CHMIs have shown to be an invaluable tool particularly in accelerating malaria vaccine research. Although there are limitations of CHMI studies for estimating public health impacts and for regulatory purposes, their strength lies in proof-of-concept efficacy data at an early stage of development, providing a faster way to select vaccines for further development and providing valuable insights in understanding the mechanisms of immunity to malarial infection.

Computational identification of Plasmodium falciparum RNA pseudouridylate synthase as a viable drug target, its physicochemical properties, 3D structure prediction and prediction of potential inhibitors.

The increased resistance to the currently effective antimalarial drugs against Plasmodium falciparum has necessitated the development of new drugs for malaria treatment. Many proteins have been predicted using various means as potential drug targets for the treatment of the P. falciparum malaria infection. Meanwhile, only a few studies went on to predict the 3-dimensional (3D) structure of potential target. Therefore, this study aimed to predict potential antimalarial drug targets against the deadliest malaria parasite P. falciparum as well as to determine the 3D structure and possible inhibitors of one of the targets. We employed machine learning approach to predict suitable drug targets in P. falciparum. Five of the predicted protein targets were considered as potential drug targets as they were non-homologous to their human counterparts. Out of these, we determined the physicochemical properties, predicted the 3D structure and carried out docking-based virtual screening of P. falciparum RNA pseudouridylate synthase, putative (PfRPuSP). The PfRPuSP was one of the potential five target proteins. Homology modelling and the ab initio methods were used to predict the 3D structure of PfRPuSP. Then, a compound library of 5621 molecules was constructed from PubChem and ChEMBL databases using 5-fluorouridine as the control inhibitor. Docking-based virtual screening was performed using Autodock 4.2 and Autodock Vina to select compounds with high binding affinity. A total of 11 compounds were selected based on their binding energies from 881 compounds which were manually examined after docking. Seven of the 11 compounds that exhibited remarkable interactions with the residues in the active sites of PfRPuSP were analysed. These compounds performed favourably when compared to the control inhibitor and predicted to bind better than 5-fluorouridine. These seven compounds are suggested as new potential lead structures for antimalarial treatment.

Overview of Epidemiology of Malaria Associated with Pregnancy in Northwestern Colombia, 1985-2020

Background: Knowledge about malaria associated with pregnancy (MAP) is scarce in Latin America and Colombia. Methodology: This paper presents an overview of studies captained in Pubmed, Lilacs, GoogleScholar and thesis repositories from six Colombian universities and bibliographic references of manuscripts. Results: The following topics have been described: study sites, infectious agents, genetic variation of Plasmodium in MAP, vector resistance to insecticides, incubation period, natural susceptibility and resistance to infection, immunity in MAP, frequency, coexistence of gestational (GM) and placental (PM) malaria, associated factors, efficacy of antimalarial treatment, material living conditions in MAP. The MAP has a high prevalence, with a high frequency of submicroscopic infections. There are cases of MAP due to P. falciparum, P. vivax, or both. Monotherapy with chloroquine or amodiaquine for MAP for P. vivax has efficacy greater than 95% and artemether-lumefantrine or artesunate-mefloquine 100% for P. falciparum. There are high rates of anemia in pregnancies (30-70%). In “The Region,” there is no problem of resistance of vectors to insecticides. MAP occurs in poor territories, with interaction of food insecurity, chronic malnutrition, dissatisfaction of basic needs, intestinal parasites, violence and abuse of human rights. Conclusions: MAP study is just beginning in Colombia; there are no programmes that effectively operate to detect and solve this problem; Government agencies, international health organizations, and private companies should finance the multidisciplinary and comprehensive research (natural and social) of the MAP, in order to know its main characteristics throughout the country and use that knowledge as a basis to seek solutions.

Mass drug administration of ivermectin and dihydroartemisinin–piperaquine against malaria in settings with high coverage of standard control interventions: a cluster-randomised controlled trial in The Gambia

Although the malaria burden has substantially decreased in sub-Saharan Africa, progress has stalled. We assessed whether mass administration of ivermectin (a mosquitocidal drug) and dihydroartemisinin-piperaquine (an antimalarial treatment) reduces malaria in The Gambia, an area with high coverage of standard control interventions. This open-label, cluster-randomised controlled trial was done in the Upper River region of eastern Gambia. Villages with a baseline Plasmodium falciparum prevalence of 7-46% (all ages) and separated from each other by at least 3 km to reduce vector spillover were selected. Inclusion criteria were age and anthropometry (for ivermectin, weight of ≥15 kg; for dihydroartemisinin-piperaquine, participants older than 6 months); willingness to comply with trial procedures; and written informed consent. Villages were randomised (1:1) to either the intervention (ivermectin [orally at 300-400 μg/kg per day for 3 consecutive days] and dihydroartemisinin-piperaquine [orally depending on bodyweight] plus standard control interventions) or the control group (standard control interventions) using computer-based randomisation. Laboratory staff were masked to the origin of samples. In the intervention group, three rounds of mass drug administration once per month with ivermectin and dihydroartemisinin-piperaquine were given during two malaria transmission seasons from Aug 27 to Oct 31, 2018, and from July 15 to Sept 30, 2019. Primary outcomes were malaria prevalence by qPCR at the end of the second intervention year in November 2019, and Anopheles gambiae (s l) parous rate, analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03576313. Between Nov 20 and Dec 7, 2017, 47 villages were screened for eligibility in the study. 15 were excluded because the baseline malaria prevalence was less than 7% (figure 1). 32 villages were enrolled and randomised to either the intervention or control group (n=16 in each group). The study population was 10 638, of which 4939 (46%) participants were in intervention villages. Coverage for dihydroartemisinin-piperaquine was between 49·0% and 58·4% in 2018, and between 76·1% and 86·0% in 2019; for ivermectin, coverage was between 46·9% and 52·2% in 2018, and between 71·7% and 82·9% in 2019. In November 2019, malaria prevalence was 12·8% (324 of 2529) in the control group and 5·1% (140 of 2722) in the intervention group (odds ratio [OR] 0·30, 95% CI 0·16-0·59; p<0·001). A gambiae (s l) parous rate was 83·1% (552 of 664) in the control group and 81·7% (441 of 540) in the intervention group (0·90, 0·66-1·25; p=0·537). In 2019, adverse events were recorded in 386 (9·7%) of 3991 participants in round one, 201 (5·4%) of 3750 in round two, and 168 (4·5%) of 3752 in round three. None of the 11 serious adverse events were related to the intervention. The intervention was safe and well tolerated. In an area with high coverage of standard control interventions, mass drug administration of ivermectin and dihydroartemisinin-piperaquine significantly reduced malaria prevalence; however, no effect of ivermectin on vector parous rate was observed. Joint Global Health Trials Scheme. For the French translation of the abstract see Supplementary Materials section.

Frequency of Electrocardiographic Alterations and Pericardial Effusion in Patients With Uncomplicated Malaria

Studies have proposed that malaria may lead to electrocardiographic (ECG) changes and pericardial inflammation. We aimed to investigate the frequency of ECG alterations, determined by ECG and Holter monitoring, and pericardial effusion in patients with malaria infection. We performed a prospective observational study of adult patients with uncomplicated malaria in Amazonas, Brazil. Peripheral blood smears, ECG, and bedside echocardiography were conducted before antimalarial treatment and repeated at follow-up after completed treatment. We evaluated the diagnostic value of PR-segment depression, PR-segment elevation, and Spodick's sign for detecting pericardial effusion. A subset of patients underwent Holter monitoring at baseline. Among 98 cases of uncomplicated malaria (55% men; mean age 40 years; median parasite density 1,774/µl), 75 had Plasmodium vivax, 22 Plasmodium falciparum, and 1 had mixed infection. At baseline, 17% (n=17) had PR-segment depression, 12% (n=12) PR-segment elevation, 3% (n=2) Spodick's sign, and the prevalence of pericardial effusion was 9% (n=9). ECG alterations had sensitivities of 22% to 89% and specificities of 88% to 100% for detecting pericardial effusion at baseline. PR-segment depression had the best accuracy (sensitivity 89%, specificity 90%). Of the 25 patients, 4 patients who did not have pericardial effusion, displayed nonsustained ventricular tachycardia, determined by Holter monitoring (median duration 43 hours). Follow-up examination data were obtained for 71 patients (median 31 days), for whom PR-segment depression, elevation, and pericardial effusion had reduced significantly (p <0.05). In conclusion, our findings suggest that ECG alterations may be useful to detect pericardial effusion in malaria and that these findings decrease after completed antimalarial treatment.

Discovery of Novel Cyclic Ethers with Synergistic Antiplasmodial Activity in Combination with Valinomycin.

With drug resistance threatening our first line antimalarial treatments, novel chemotherapeutics need to be developed. Ionophores have garnered interest as novel antimalarials due to their theorized ability to target unique systems found in the Plasmodium-infected erythrocyte. In this study, during the bioassay-guided fractionation of the crude extract of Streptomyces strain PR3, a group of cyclodepsipeptides, including valinomycin, and a novel class of cyclic ethers were identified and elucidated. Further study revealed that the ethers were cyclic polypropylene glycol (cPPG) oligomers that had leached into the bacterial culture from an extraction resin. Molecular dynamics analysis suggests that these ethers are able to bind cations such as K+, NH4+ and Na+. Combination studies using the fixed ratio isobologram method revealed that the cPPGs synergistically improved the antiplasmodial activity of valinomycin and reduced its cytotoxicity in vitro. The IC50 of valinomycin against P. falciparum NF54 improved by 4–5-fold when valinomycin was combined with the cPPGs. Precisely, it was improved from 3.75 ± 0.77 ng/mL to 0.90 ± 0.2 ng/mL and 0.75 ± 0.08 ng/mL when dosed in the fixed ratios of 3:2 and 2:3 of valinomycin to cPPGs, respectively. Each fixed ratio combination displayed cytotoxicity (IC50) against the Chinese Hamster Ovary cell line of 57–65 µg/mL, which was lower than that of valinomycin (12.4 µg/mL). These results indicate that combinations with these novel ethers may be useful in repurposing valinomycin into a suitable and effective antimalarial.

The cognitive burden of severe malaria in the Ugandan classroom and the effects of a computerized intervention

IntroductionDue to the increased availability of anti-malarial treatments and the prevalence of malarial infection among vulnerable populations leading to cognitive impairment, malaria has become a leading cause of pediatric cognitive impairment in sub-Saharan Africa. ObjectivesTo examine the effects of malaria-induced cognitive impairment on school performance as an indicator of health and effects of a computerized intervention on school performance over time. DesignSecondary analysis. Sample216 school reports were collected from three hundred Ugandan children, aged five to twelve, enrolled in a randomized controlled trial. MeasurementsAcademic subjects (English, reading, writing, arithmetic, and Luganda); scores were standardized on an ordinal scale from one to five. ResultsAt baseline, malaria had no effect on academic performance, but age and socio-economic status had some effect. At one-year, there was no effect of the intervention on academic change over time; however, factors such as sex and home environment did demonstrate some effect on performance. ConclusionsThe results were unable to support the hypotheses that survivors of SM would demonstrate lower school performance than healthy comparisons and that the cognitive intervention would improve the performance of survivors. This suggests that future interventions ought to consider the influence of age, sex, and socio-economic status when caring for the cognitive needs of children in order to facilitate their ability to achieve academic success and, thus, improved quality of life.

Optimal control analysis of hepatocytic-erythrocytic dynamics of Plasmodium falciparum malaria.

This paper presents an in-host malaria model subject to anti-malarial drug treatment and malaria vaccine antigens combinations. Pontryagin's Maximum Principle is applied to establish optimal control strategies against infected erythrocytes, infected hepatocytes and malaria parasites. Results from numerical simulation reveal that a combination of pre-erythrocytic vaccine antigen, blood schizontocide and gametocytocide drugs would offer the best strategy to eradicate clinical P. falciparum malaria. Sensitivity analysis, further reveal that the efficacy of blood schizontocides and blood stage vaccines are crucial in the control of clinical malaria infection. Futhermore, we found that an effective blood schizontocide should be used alongside efficacious blood stage vaccine for rapid eradication of infective malaria parasites. The authors hope that the results of this study will help accelerate malaria elimination efforts by combining malaria vaccines and anti-malarial drugs against the deadly P. falciparum malaria.

Assessment of Vitamin D Status in Patients Suffering from Uncomplicated Malaria in a Health Center in the District of Abidjan (Côte d’Ivoire)

Aims: The pathophysiology of Plasmodium falciparum infection is most often associated with anemia and immune deficiency. Given the important role of vitamin D in the synthesis of hemoglobin and in the stimulation of the immune system, it would be essential to assess the vitamin D status of patients with malaria in order to improve the quality of treatment management.&#x0D; Methodology: A thick drop and a blood smear were used to determine parasite density and parasite species respectively. The complete blood count was performed using an automated analyzer labelled Sysmex XN 1000i. Biochemical parameters such as calcium and phosphorus were determined using the Cobas C311 Hitachi. The Vidas was used to determine the concentrations of 25 (OH) -vitamin D.&#x0D; Results: The results showed a decrease in 25 (OH) -vitamin D concentrations in relation to the parasite density and anemia observed in patients with uncomplicated malaria.&#x0D; Conclusion: Vitamin D status in patients with uncomplicated malaria could represent an essential biomarker in the monitoring of antimalarial treatment.