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It is uncertain to what extent oral supplementation with zinc can reduce episodes of malaria in endemic areas. Protection may depend on other nutrients. We measured the effect of supplementation with zinc and other nutrients on malaria rates. In a 2×2 factorial trial, 612 rural Tanzanian children aged 6-60 months in an area with intense malaria transmission and with height-for-age z-score≤-1.5 SD were randomized to receive daily oral supplementation with either zinc alone (10 mg), multi-nutrients without zinc, multi-nutrients with zinc, or placebo. Intervention group was indicated by colour code, but neither participants, researchers, nor field staff knew who received what intervention. Those with Plasmodium infection at baseline were treated with artemether-lumefantrine. The primary outcome, an episode of malaria, was assessed among children reported sick at a primary care clinic, and pre-defined as current Plasmodium infection with an inflammatory response, shown by axillary temperature ≥37.5°C or whole blood C-reactive protein concentration ≥ 8 mg/L. Nutritional indicators were assessed at baseline and at 251 days (median; 95% reference range: 191-296 days). In the primary intention-to-treat analysis, we adjusted for pre-specified baseline factors, using Cox regression models that accounted for multiple episodes per child. 592 children completed the study. The primary analysis included 1,572 malaria episodes during 526 child-years of observation (median follow-up: 331 days). Malaria incidence in groups receiving zinc, multi-nutrients without zinc, multi-nutrients with zinc and placebo was 2.89/child-year, 2.95/child-year, 3.26/child-year, and 2.87/child-year, respectively. There was no evidence that multi-nutrients influenced the effect of zinc (or vice versa). Neither zinc nor multi-nutrients influenced malaria rates (marginal analysis; adjusted HR, 95% CI: 1.04, 0.93-1.18 and 1.10, 0.97-1.24 respectively). The prevalence of zinc deficiency (plasma zinc concentration <9.9 µmol/L) was high at baseline (67% overall; 60% in those without inflammation) and strongly reduced by zinc supplementation. We found no evidence from this trial that zinc supplementation protected against malaria. ClinicalTrials.gov NCT00623857

Background Complex malaria infections are defined as those containing more than one genetically distinct lineage of Plasmodium parasite. Complexity of infection (COI) is a useful parameter to estimate from patient blood samples because it is associated with clinical outcome, epidemiology and disease transmission rate. This manuscript describes a method for estimating COI using likelihood, called COIL, from a panel of bi-allelic genotyping assays. Methods COIL assumes that distinct parasite lineages in complex infections are unrelated and that genotyped loci do not exhibit significant linkage disequilibrium. Using the population minor allele frequency (MAF) of the genotyped loci, COIL uses the binomial distribution to estimate the likelihood of a COI level given the prevalence of observed monomorphic or polymorphic genotypes within each sample. Results COIL reliably estimates COI up to a level of three or five with at least 24 or 96 unlinked genotyped loci, respectively, as determined by in silico simulation and empirical validation. Evaluation of COI levels greater than five in patient samples may require a very large collection of genotype data, making sequencing a more cost-effective approach for evaluating COI under conditions when disease transmission is extremely high. Performance of the method is positively correlated with the MAF of the genotyped loci. COI estimates from existing SNP genotype datasets create a more detailed portrait of disease than analyses based simply on the number of polymorphic genotypes observed within samples. Conclusions The capacity to reliably estimate COI from a genome-wide panel of SNP genotypes provides a potentially more accurate alternative to methods relying on PCR amplification of a small number of loci for estimating COI. This approach will also increase the number of applications of SNP genotype data, providing additional motivation to employ SNP barcodes for studies of disease epidemiology or control measure efficacy. The COIL program is available for download from GitHub, and users may also upload their SNP genotype data to a web interface for simple and efficient determination of sample COI.

Background Current World Health Organization recommendations for the management of malaria include the need for a parasitological confirmation prior to triggering appropriate treatment. The use of rapid diagnostic tests (RDTs) for malaria has contributed to a better infection recognition and a more targeted treatment. Nevertheless, low-density infections and parasites that fail to produce HRP2 can cause false-negative RDT results. Microscopy has traditionally been the methodology most commonly used to quantify malaria and characterize the infecting species, but the wider use of this technique remains challenging, as it requires trained personnel and processing capacity. Objective In this study, the feasibility of an on-line system for remote malaria species identification and differentiation has been investigated by crowdsourcing the analysis of digitalized infected thin blood smears by non-expert observers using a mobile app. Methods An on-line videogame in which players learned how to differentiate the young trophozoite stage of the five Plasmodium species has been designed. Images were digitalized with a smartphone camera adapted to the ocular of a conventional light microscope. Images from infected red blood cells were cropped and puzzled into an on-line game. During the game, players had to decide the malaria species ( Plasmodium falciparum , Plasmodium malariae, Plasmodium vivax , Plasmodium ovale , Plasmodium knowlesi ) of the infected cells that were shown in the screen. After 2 months, each player’s decisions were analysed individually and collectively. Results On-line volunteers playing the game made more than 500,000 assessments for species differentiation. Statistically, when the choice of several players was combined (n > 25), they were able to significantly discriminate Plasmodium species, reaching a level of accuracy of 99% for all species combinations, except for P. knowlesi (80%). Non-expert decisions on which Plasmodium species was shown in the screen were made in less than 3 s. Conclusion These findings show that it is possible to train malaria-naïve non-experts to identify and differentiate malaria species in digitalized thin blood samples. Although the accuracy of a single player is not perfect, the combination of the responses of multiple casual gamers can achieve an accuracy that is within the range of the diagnostic accuracy made by a trained microscopist.

RTS,S/AS02A is a pre-erythrocytic stage malaria vaccine that provides partial protection against infection in malaria-naive adult volunteers and hyperimmune adults. A previous report showed that this vaccine reduced risk of clinical malaria, delayed time to new infection, and reduced episodes of severe malaria over 6 months in African children. An important remaining issue is the durability of protection against clinical disease in these children. We did a randomised, controlled, phase IIb trial of RTS,S/AS02A given at 0, 1, and 2 months in 2022 Mozambican children aged 1–4 years. We previously determined vaccine efficacy (VE) against clinical malaria in a double-blind phase that included study months 2·5–8·5 (VE 2·5–8·5). We now report VE in a single-blind phase up to month 21 (VE 8·5–21). The primary endpoint was time to first or only clinical episode of Plasmodium falciparum malaria (axillary temperature ⩾37·5°C and P falciparum asexual parasitaemia >2500 per μL) detected through a passive case detection system. We also determined VE for other case definitions and for episodes of severe malaria. This study is registered with the ClinicalTrials.gov identifier NCT00197041. During the single-blind phase, VE (8·5–21) was 28·9% (95% CI 8·4–44·8; p=0·008). At month 21, prevalence of P falciparum infection was 29% lower in the RTS,S/AS02A group than in the control (p=0·017). Considering the entire study period, VE (2·5–21) was 35·3% (95% CI 21·6–46·6; p<0·0001) and VE (2·5–21) for severe malaria was 48·6% (95% CI 12·3–71·0; p=0·02). These results show that RTS,S/AS02A confers partial protection in African children aged 1–4 years living in rural endemic areas against a range of clinical disease caused by P falciparum for at least 18 months, and confirm the potential of malaria vaccines to become credible control tools for public-health use.

Pregnant women have an increased severity of infections with some organisms, including influenza virus, hepatitis E virus, herpes simplex virus, and malaria parasites. This review includes an update on immunologic alterations during pregnancy. Before the advent of antibiotic agents, pregnancy was a recognized risk factor for severe complications of pneumococcal pneumonia, including death. 1 The influenza pandemic of 2009 provided a more recent reminder that certain infections may disproportionately affect pregnant women. Are pregnant women at increased risk for acquiring infections? Are pregnant women with infection at increased risk for severe disease? During pregnancy, several mechanical and pathophysiological changes occur (e.g., a decrease in respiratory volumes and urinary stasis due to an enlarging uterus), and immune adaptations are required to accommodate the fetus. In this article, we review and synthesize new knowledge about the . . .

In malaria elimination areas, malaria cases are sporadic and consist predominantly of imported cases. Plasmodium knowlesi cases have been reported throughout Southeast Asia where long-tailed and pig-tailed macaques and Anopheles leucosphyrus group mosquitoes are sympatric. The limitation of microscopic examination to diagnose P. knowlesi is well known. In consequence, no P. knowlesi case has previously been reported from routine health facility-based case finding activities in Indonesia. This report describes two clusters of unexpected locally acquired P. knowlesi cases found in an area where Plasmodium falciparum and Plasmodium vivax infection had been eliminated in Sabang Municipality, Aceh, Indonesia. The difficulties in diagnosis and response illustrate challenges that Southeast Asian countries will increasingly face as the formerly common malaria parasites P. falciparum and P. vivax are gradually eliminated from the region.

Background Plasmodium falciparum infection is associated with the human ABO blood group. However, there is a paucity of data on the role that ABO and Rhesus blood groups play in malaria clinical presentations. Therefore, the objective of this study was to assess the association of human ABO blood groups and the Rhesus blood (Rh) types with the severity of malaria. Methods This cross-sectional study was carried out at the Suhum Government Hospital in the Eastern region of Ghana. Conveniently, study participants with malaria, diagnosed by microscopy, were selected into the study. Subsequently, their ABO and Rh blood groups were determined (Accucare ABO/Rh monoclonal antibodies, Chennai, India). Malaria severity was assessed using the criteria for assessing severe malarial anaemia published by the World Health Organization. According to the criteria, severe malarial anaemia was classified as having haemoglobin (Hb) < 5 g/dL for children < 12 years and in patients ≥ 12 years, Hb level < 7 g/dL, with parasitaemia > 10,000/µL in both cases. Severe malarial anaemia was also classified as having plasma bilirubin > 50 µmol/L with parasitaemia ≥ 100,000/µL, for all ages. Chi square statistical analysis was used to test the association between the blood groups and the clinical or laboratory findings, while multivariate analysis was performed to identify which blood groups were more vulnerable to develop severe malarial anaemia. Results Of the total number of the study participants (n = 328), most of the patients had blood group O Rh positive (35.7%) while few of them had blood group AB Rh negative (2.1%). The types of Rhesus did not associate with malaria. However, compared to blood group O, the odds of developing severe malarial anaemia, in children < 12 years and in patients ≥ 12 years, were 16 times and 17.8 times higher among patients with blood group A, respectively. Furthermore, the odds of having bilirubin level > 50 µmol/L with parasitaemia ≥ 100,000 /µL was 10 times higher among patients with blood groups A and 2.6 times higher in patients with blood group B, compared to blood group O. Finally, in patients with blood group A majority (71.6%) of them developed high temperature (> 37.5 °C) while 43.3% of them vomited and had diarrhoea. However, pallor (group B = 46.2% vs group A = 37.3%), fever (group B = 84.6% vs group A = 79.1%) and nausea (group B = 46.2% vs group A = 25.4%) were more frequent in patients with blood group B than A. Conclusions This study found that people with blood groups A and B were severely affected by malaria, with group A being the most vulnerable. It is recommended that blood group assessment be performed for all patients with malaria. Patients found to have blood group A or B must be promptly and efficiently managed to avoid the development of severe malaria anaemia.

Background Artisanal mining creates enabling breeding ground for the vector of malaria parasites. There is paucity of data on the effects of artisanal mining on malaria. This study assessed burden of malaria and caregivers’ health-seeking behaviour for children under five in artisanal mining communities in East Akim District in Ghana. Methods A cross-sectional study involving caregivers and their children under five was conducted in three artisanal mining communities in the East Akim District in Ghana. Caregivers were interviewed using a structured questionnaire. Finger prick blood samples were collected and analysed for haemoglobin concentration using a rapid diagnostic test, and thick and thin blood smears were analysed to confirm the presence of malaria parasites. Results Of the 372 children under 5 years included in the study, 197 (53.1%) were male, with a mean age (± SD) of 23.0 ± 12.7 months. The proportion of children with malaria ( Plasmodium falciparum and P. malariae ) was 98.1% and 1.9%, respectively, whilst the proportion with anaemia (Hb < 11.0 g/dl) was 39.5% ( n  = 147). Almost all caregivers were female (98.9%), and 28.6% ( n  = 106) did not have access to any malaria control information. Caregivers associated malaria infection with mosquito bites (68.3%, n  = 254) and poor sanitation (21.2%, n  = 79). Malaria in children under five was significantly associated with anaemia (OR 11.07, 95% CI 6.59–18.68, n  = 111/160, 69.4%; P  < 0.0001), residing close to stagnant water (≤ 25 m) from an artisanal mining site (AOR 2.91, 95% CI 1.47–5.76, P  = 0.002) and caregiver age younger than 30 years (OR 0.44, 95% CI 0.208–0.917, n  = 162, 43.55%, P  = 0.001). Conclusions There is a high burden of malaria and anaemia among children under five in artisanal mining communities of the East Akim District, and far higher than in non-artisanal mining sites. Interventions are needed to effectively regulate mining activities in these communities, and strengthen malaria control and health education campaigns to curtail the high malaria burden and improve health-seeking behaviour. Graphical abstract

Recent initiatives to improve translation of findings from animal models to human disease have focussed on reproducibility but quantifying the relevance of animal models remains a challenge. Here, we use comparative transcriptomics of blood to evaluate the systemic host response and its concordance between humans with different clinical manifestations of malaria and five commonly used mouse models. Plasmodium yoelii 17XL infection of mice most closely reproduces the profile of gene expression changes seen in the major human severe malaria syndromes, accompanied by high parasite biomass, severe anemia, hyperlactatemia, and cerebral microvascular pathology. However, there is also considerable discordance of changes in gene expression between the different host species and across all models, indicating that the relevance of biological mechanisms of interest in each model should be assessed before conducting experiments. These data will aid the selection of appropriate models for translational malaria research, and the approach is generalizable to other disease models.

Background and Objectives: Malaria is a disease that can result in a variety of complications. Diagnosis is carried out by an optical microscope and depends on operator experience. The use of artificial intelligence to identify morphological patterns in erythrocytes would improve our diagnostic capability. The object of this study was therefore to establish computer viewing models able to classify blood cells infected with Plasmodium spp. to support malaria diagnosis by optical microscope. Materials and Methods: A total of 27,558 images of human blood sample extensions were obtained from a public data bank for analysis; half were of parasite-infected red cells (n = 13,779), and the other half were of uninfected erythrocytes (n = 13,779). Six models (five machine learning algorithms and one pre-trained for a convolutional neural network) were assessed, and the performance of each was measured using metrics like accuracy (A), precision (P), recall, F1 score, and area under the curve (AUC). Results: The model with the best performance was VGG-19, with an AUC of 98%, accuracy of 93%, precision of 92%, recall of 94%, and F1 score of 93%. Conclusions: Based on the results, we propose a convolutional neural network model (VGG-19) for malaria diagnosis that can be applied in low-complexity laboratories thanks to its ease of implementation and high predictive performance.