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Background: Malaria remains a major public health threat and in low malaria transmission areas new tools are needed to detect infections for prompt treatment and to progress elimination efforts. Pregnant women are particularly vulnerable to malaria infections and access routine antenatal care, presenting a unique sentinel population to apply novel sero-surveillance tools to measure malaria transmission. The aim of this study was to quantify the dynamic antibody responses to multiple antigens during pregnancy to identify a single or multiple antibody response of exposure to malaria in pregnancy. Methods: Antibody-mediated immunity responses to six parasite antigens (five commonly studied merozoite antigens and the variant surface antigen 2-chondroitin sulphate A (VAR2CSA), a pregnancy-specific erythrocytic antigen) were measured over the gestation period until delivery (median of 7 measurements/woman) in 250 pregnant women who attended antenatal clinics located at the Thai-Myanmar border. A multivariate mixture linear mixed model was used to cluster the pregnant women into groups that have similar longitudinal antibody responses to all six antigens over the gestational period using a Bayesian approach. The variable-specific entropy was calculated to identify the antibody responses that have the highest influence on the classification of the women into clusters, and subsequent agreement with grouping of women based on exposure to malaria during pregnancy. Results: Of the 250 pregnant women, 135 had a Plasmodium infection detected by light microscopy during pregnancy, defined as cases. The antibody responses to all six antigens accurately identified the women who did not have a malaria infection detected during pregnancy (93%, 107/115 controls). Antibody responses to P. falciparum merozoite surface protein 3 (PfMSP3) and P. vivax apical membrane antigen 1 (PvAMA1) were the least dynamic. Antibody responses to the antigens P. falciparum apical membrane antigen 1 (PfAMA1) and PfVAR2CSA were able to identify the majority of the cases more accurately (63%, 85/135). Conclusion: These findings suggest that the combination of antibodies, PfAMA1 and PfVAR2CSA, may be useful for sero-surveillance of malaria infections in pregnant women, particularly in low malaria transmission settings, leading to the early detection and treatment of malaria infections in pregnant women.

Background The efficacy of artemisinin-based combination therapies (ACTs), currently the first-line antimalarial treatments, is declining due to the emergence of resistance of malaria parasites to these drugs. This has led drug development initiatives to search for novel combination therapies to replace the failing ACTs. We developed a biologically informed within-host model, validated against data from volunteer infection studies, to guide critical drug development decisions. Methods A within-host model was developed, linking drug concentrations of two novel antimalarial drugs, OZ439 and DSM265, to their combined killing action and accounting for differential killing of these compounds against stages of the parasite’s lifecycle. Data collected from malaria-infected volunteers treated with OZ439–DSM265 were used to estimate the model parameters in a hierarchical Bayesian framework. Posterior-predictive simulations of the model were used to determine the dosing regimen required to cure >90% patients. Results The results showed that 800 mg of OZ439 combined with 450 mg of DSM265, which are within the safe and tolerable dose range, can provide day 42 cure rates >90%, despite the estimated antagonistic interaction between the drugs. The importance of accommodating parasite age specificity of drug action was demonstrated. Conclusions The dosing regimens for the combination of OZ439-DSM265 determined from our data-informed in silico model suggest this compound may be a suitable candidate to replace failing ACTs. Key messages Assessing various scenarios within a simulation framework allows discovery of robust dosing regimens, accelerating the drug development process and ensuring efficient allocation of resources for phase 2 and 3 clinical trials.

Focus and outcomes for participants Presented by researchers from the Australian Centre of Research Excellence in Malaria Elimination (ACREME, www.acreme.org.au), the focus of the symposium will be the application of multi-disciplinary epidemiological and statistical approaches to inform the control and elimination of malaria in the Asia-Pacific region. The epidemiology of malaria is complex as it involves multiple mosquito vectors, different malarial species (that require species-specific treatments) and emerging insecticide and antimalarial drug resistance. The symposium will provide an overview of the significance of the changing epidemiological landscape of malaria globally, and how modern epidemiological methods, such as stepped-wedge designs, multi-state modelling, within-host mechanistic mathematical models, geospatial methods and cost-effectiveness modelling applied to clinical effectiveness trials, prospective cohort studies, volunteer infection studies and national and regional data have contributed to answering the key challenges in malaria research. Specifically we will discuss evidence for effective interventions to reduce the risk of malaria transmission, the effect of recurrent episodes of malaria on risk of hospitalisation and mortality, the selection of antimalarial drug combination therapies to fast track new drugs, understanding geospatial heterogeneity of malaria transmission, and the cost-effectiveness of scenarios using different treatment regimens. Discussion of the importance of these methodologies and their findings will be contextualised in the current global malaria elimination goals. As similar transformations in epidemiological environment have occurred in other disease elimination settings, we believe this symposium will have broad appeal and that the challenges faced and the methodological solutions proposed to accelerate progress in malaria elimination will have a high degree of relevance and be useful to researchers working in global health or infectious diseases. Rationale for the symposium, including for its inclusion in the Congress Following a two-decade period of declining malaria burden due to intensified control efforts, global progress against the disease has stalled, and in some countries, malaria has resurged. Emerging parasite resistance to insecticides and antimalarial drugs has reduced the effectiveness of cornerstone malaria control interventions. Malaria endemic areas of the Greater Mekong Sub region (GMS) have set the target to eliminate malaria by 2030, however, the failure of these established interventions and transition to low-transmission endemic environments has necessitated fundamental re-evaluation of the epidemiological landscape of the disease and emphasised timely development of robust evidence for novel interventions. In order to provide evidence, a wide range of advanced multi-disciplinary methodologies have been developed and applied in many malaria epidemiology areas and we believe discussion of these in the symposium will be highly relevant given the principal theme of the 2020 WCE (Methodological Innovations in Epidemiology). Additionally, the symposium will feature research where findings have been effectively translated to national and regional policy and practice, an important theme of the 2020 WCE. Presentation program Names of presenters

Background Inadequate prevention and treatment of malaria can lead to reinfections and recurrent episodes, and for vivax malaria, further recurrences from the dormant liver stage. This study quantified the impact of recurrent malaria episodes on morbidity and mortality. Methods Routinely collected data were available from 68,381 malaria patients presenting to the primary referral hospital in Papua, Indonesia. A multi-state modelling framework, with Cox regression for transition rates, was employed to determine the risks of re-presentation to hospital, receiving in-patient treatment, and early (≤14 days post treatment)/late death following multiple malaria episodes. Results The risk of re-presentation to hospital increased from 34.7% (95%CI: 34.4%–35.1%) at first episode to 58.6% (57.5%–59.6%) following the third episode. Infection with vivax malaria increased the rate of re-presentation to hospital by 1.48-fold (Hazard Ratio 1.48; 95%CI 1.44–1.51) and late hospital in-patient admission by 1.17-fold (1.11–1.22), compared to falciparum. Falciparum malaria caused a higher overall rate of early death (1.54 (1.25–1.92)), however, after multiple episodes, there was a trend towards a greater rate of early death for vivax infection (1.91 (0.73–4.97)). Conclusions Recurrent episodes of malaria can cause substantial morbidity and mortality, highlighting the importance of prevention and effective treatments for both falciparum and vivax malaria. Key messages To achieve elimination of malaria in South-East Asia, where prevalence of vivax malaria is high, we must prioritise the radical cure of vivax to eliminate the liver-stage of this species that causes relapses of infection.

Most deaths from severe falciparum malaria occur within 24 hours of presentation to hospital. Intravenous (i.v.) artesunate is the first-line treatment for severe falciparum malaria, but its efficacy may be compromised by delayed parasitological responses. In patients with severe malaria the life-saving benefit of the artemisinin derivatives is their ability to clear circulating parasites rapidly, before they can sequester and obstruct the microcirculation. To evaluate the dosing of i.v. artesunate for the treatment of artemisinin-sensitive and reduced ring stage sensitivity to artemisinin severe falciparum malaria infections Bayesian pharmacokinetic-pharmacodynamic modelling of data from 94 patients with severe malaria (80 children from Africa and 14 adults from Southeast Asia) was performed. Assuming delayed parasite clearance reflects a loss of ring stage sensitivity to artemisinin derivatives, the median (95% credible interval) percentage of patients clearing ≥99% parasites within 24 hours (PC24≥99%) for standard (2.4 mg/kg i.v. artesunate at 0 and 12 hours) and simplified (4 mg/kg i.v. artesunate at 0 hours) regimens were 65% (52.5%-74.5%) versus 44% (25%-61.5%) for adults, 62% (51.5%-74.5%) versus 39% (20.5%-58.5%) for larger children (≥20 kg) and 60% (48.5%-70%) versus 36% (20%-53.5%) for smaller children (

Background:Plasmodium falciparum causes placental malaria, which results in adverse outcomes for mother and child. P. falciparum-infected erythrocytes that express the parasite protein VAR2CSA on their surface can bind to placental chondroitin sulfate A. It has been hypothesized that naturally acquired antibodies towards VAR2CSA protect against placental infection, but it has proven difficult to identify robust antibody correlates of protection from disease. The objective of this study was to develop a prediction model using antibody features that could identify women protected from placental malaria.Methods:We used a systems serology approach with elastic net-regularized logistic regression, partial least squares discriminant analysis, and a case-control study design to identify naturally acquired antibody features mid-pregnancy that were associated with protection from placental malaria at delivery in a cohort of 77 pregnant women from Madang, Papua New Guinea.Results:The machine learning techniques selected 6 out of 169 measured antibody features towards VAR2CSA that could predict (with 86% accuracy) whether a woman would subsequently have active placental malaria infection at delivery. Selected features included previously described associations with inhibition of placental binding and/or opsonic phagocytosis of infected erythrocytes, and network analysis indicated that there are not one but multiple pathways to protection from placental malaria.Conclusions:We have identified candidate antibody features that could accurately identify malaria-infected women as protected from placental infection. It is likely that there are multiple pathways to protection against placental malaria.Funding:This study was supported by the National Health and Medical Research Council (Nos. APP1143946, GNT1145303, APP1092789, APP1140509, and APP1104975).

Background The efficacy of artemisinin-based combination therapies (ACTs), the first-line treatments for uncomplicated falciparum malaria, has been declining in malaria-endemic countries due to the emergence of malaria parasites resistant to these compounds. Novel alternative therapies are needed urgently to prevent the likely surge in morbidity and mortality due to failing ACTs. Objectives This study investigates the efficacy of the combination of two novel drugs, OZ439 and DSM265, using a biologically informed within-host mathematical model. Methods A within-host model was developed, which accounts for the differential killing of these compounds against different stages of the parasite’s life cycle and accommodates the pharmacodynamic interaction between the drugs. Data of healthy volunteers infected with falciparum malaria collected from four trials (three that administered OZ439 and DSM265 alone, and the fourth a combination of OZ439 and DSM265) were analysed. Model parameters were estimated in a hierarchical Bayesian framework. Results The posterior predictive simulations of our model predicted that 800 mg of OZ439 combined with 450 mg of DSM265, which are within the safe and tolerable dose range, can provide above 90% cure rates 42 days after drug administration. Conclusions Our results show that the combination of OZ439 and DSM265 can be a promising alternative to replace ACTs. Our model can be used to inform future Phase 2 and 3 clinical trials of OZ439/DSM265, fast-tracking the deployment of this combination therapy in the regions where ACTs are failing. The dosing regimens that are shown to be efficacious and within safe and tolerable limits are suggested for future investigations.

Ensuring continued success against malaria depends on a pipeline of new antimalarials. Antimalarial drug development utilizes preclinical murine and experimental human malaria infection studies to evaluate drug efficacy., Ensuring continued success against malaria depends on a pipeline of new antimalarials. Antimalarial drug development utilizes preclinical murine and experimental human malaria infection studies to evaluate drug efficacy. A sequential approach is typically adapted, with results from each stage informing the design of the next stage of development. The validity of this approach depends on confidence that results from murine malarial studies predict the outcome of clinical trials in humans. Parasite clearance rates following treatment are key parameters of drug efficacy. To investigate the validity of forward predictions, we developed a suite of mathematical models to capture parasite growth and drug clearance along the drug development pathway and estimated parasite clearance rates. When comparing the three infection experiments, we identified different relationships of parasite clearance with dose and different maximum parasite clearance rates. In Plasmodium berghei-NMRI mouse infections, we estimated a maximum parasite clearance rate of 0.2 (1/h); in Plasmodium falciparum-SCID mouse infections, 0.05 (1/h); and in human volunteer infection studies with P. falciparum, we found a maximum parasite clearance rate of 0.12 (1/h) and 0.18 (1/h) after treatment with OZ439 and MMV048, respectively. Sensitivity analysis revealed that host-parasite driven processes account for up to 25% of variance in parasite clearance for medium-high doses of antimalarials. Although there are limitations in translating parasite clearance rates across these experiments, they provide insight into characterizing key parameters of drug action and dose response and assist in decision-making regarding dosage for further drug development.

Most deaths from severe falciparum malaria occur within 24 h of presentation to a hospital. Intravenous (i.v.) artesunate is the first-line treatment for severe falciparum malaria, but its efficacy may be compromised by delayed parasitological responses. In patients with severe malaria, the life-saving benefit of the artemisinin derivatives is their ability to clear circulating parasites rapidly, before they can sequester and obstruct the microcirculation. To evaluate the dosing of i.v. artesunate for the treatment of artemisinin-sensitive and reduced ring stage sensitivity to artemisinin severe falciparum malaria infections, Bayesian pharmacokinetic-pharmacodynamic modeling of data from 94 patients with severe malaria (80 children from Africa and 14 adults from Southeast Asia) was performed. Assuming that delayed parasite clearance reflects a loss of ring stage sensitivity to artemisinin derivatives, the median (95% credible interval) percentage of patients clearing ≥99% of parasites within 24 h (PC24≥99%) for standard (2.4 mg/kg body weight i.v. artesunate at 0 and 12 h) and simplified (4 mg/kg i.v. artesunate at 0 h) regimens was 65% (52.5% to 74.5%) versus 44% (25% to 61.5%) for adults, 62% (51.5% to 74.5%) versus 39% (20.5% to 58.5%) for larger children (≥20 kg), and 60% (48.5% to 70%) versus 36% (20% to 53.5%) for smaller children (

The efficacy of Artemisinin-based Combination Therapies (ACTs), the first- line treatments of uncomplicated falciparum malaria, has been declining in malaria endemic countries due to the emergence of malaria parasites resistant to these com- pounds. Novel alternative therapies are needed urgently to prevent the likely surge in morbidity and mortality due to failing ACTs. This study investigates the efficacy of the combination of two novel drugs, OZ439 and DSM265, using a biologically informed within-host mathematical model that accounts for the pharmacodynamic interaction between the two drugs. Model parameters were estimated using data from healthy volunteers infected with falciparum malaria collected from four trials: three that administered OZ439 and DSM265 alone, and the fourth a combination of OZ439-DSM265. Posterior predictive simulations of the model were performed to determine efficacious dosing regimens. One such regimen that predicted at least 90% of infected individuals cured 42 days after the administration of the drugs, while within the tolerable dose range, is 800 mg of OZ439 and 450 mg of DSM265. Our model can be used to inform future phase 2 and 3 clinical trials of OZ439-DSM265, fast-tracking the deployment of this combination therapy in the regions where ACTs are failing.

Understanding the underlying mechanisms that produce the huge variety of swarming and aggregation patterns in animals and cells is fundamental in ecology, developmental biology, and regenerative medicine, to name but a few examples. Depending upon the nature of the interactions between individuals (cells or animals), a variety of different large-scale spatial patterns can be observed in their distribution; examples include cell aggregates, stripes of different coloured skin cells, etc. For the case where all individuals are of the same type (i.e., all interactions are alike), a considerable literature already exists on how the collective organisation depends on the inter-individual interactions. Here, we focus on the less studied case where there are two different types of individuals present. Whilst a number of continuum models of this scenario exist, it can be difficult to compare these models to experimental data, since real cells and animals are discrete. In order to overcome this problem, we develop an agent-based model to simulate some archetypal mechanisms involving attraction and repulsion. However, with this approach (as with experiments), each realisation of the model is different, due to stochastic effects. In order to make useful comparisons between simulations and experimental data, we need to identify the robust features of the spatial distributions of the two species which persist over many realisations of the model (for example, the size of aggregates, degree of segregation or intermixing of the two species). In some cases, it is possible to do this by simple visual inspection. In others, the features of the pattern are not so clear to the unaided eye. In this paper, we introduce a pair correlation function (PCF), which allows us to analyse multi-species spatial distributions quantitatively. We show how the differing strengths of inter-individual attraction and repulsion between species give rise to different spatial patterns, and how the PCF can be used to quantify these differences, even when it might be impossible to recognise them visually.

Background In 2017, an estimated 14 million cases of Plasmodium vivax malaria were reported from Asia, Central and South America, and the Horn of Africa. The clinical burden of vivax malaria is largely driven by its ability to form dormant liver stages (hypnozoites) that can reactivate to cause recurrent episodes of malaria. Elimination of both the blood and liver stages of the parasites (“radical cure”) is required to achieve a sustained clinical response and prevent ongoing transmission of the parasite. Novel treatment options and point-of-care diagnostics are now available to ensure that radical cure can be administered safely and effectively. We quantified the global economic cost of vivax malaria and estimated the potential cost benefit of a policy of radical cure after testing patients for glucose-6-phosphate dehydrogenase (G6PD) deficiency. Methods and findings Estimates of the healthcare provider and household costs due to vivax malaria were collated and combined with national case estimates for 44 endemic countries in 2017. These provider and household costs were compared with those that would be incurred under 2 scenarios for radical cure following G6PD screening: (1) complete adherence following daily supervised primaquine therapy and (2) unsupervised treatment with an assumed 40% effectiveness. A probabilistic sensitivity analysis generated credible intervals (CrIs) for the estimates. Globally, the annual cost of vivax malaria was US$359 million (95% CrI: US$222 to 563 million), attributable to 14.2 million cases of vivax malaria in 2017. From a societal perspective, adopting a policy of G6PD deficiency screening and supervision of primaquine to all eligible patients would prevent 6.1 million cases and reduce the global cost of vivax malaria to US$266 million (95% CrI: US$161 to 415 million), although healthcare provider costs would increase by US$39 million. If perfect adherence could be achieved with a single visit, then the global cost would fall further to US$225 million, equivalent to $135 million in cost savings from the baseline global costs. A policy of unsupervised primaquine reduced the cost to US$342 million (95% CrI: US$209 to 532 million) while preventing 2.1 million cases. Limitations of the study include partial availability of country-level cost data and parameter uncertainty for the proportion of patients prescribed primaquine, patient adherence to a full course of primaquine, and effectiveness of primaquine when unsupervised. Conclusions Our modelling study highlights a substantial global economic burden of vivax malaria that could be reduced through investment in safe and effective radical cure achieved by routine screening for G6PD deficiency and supervision of treatment. Novel, low-cost interventions for improving adherence to primaquine to ensure effective radical cure and widespread access to screening for G6PD deficiency will be critical to achieving the timely global elimination of P. vivax., Dr. Devine and co-authors highlight the global economic burden of vivax malaria that could be reduced through investment in radical cure. Safe and effective cure could be achieved by routine screening for G6PD deficiency and treatment supervision., Author summary Why was this study done? Vivax malaria is a mosquito-borne febrile illness common in Asia, Latin America, and the Horn of Africa. Although a cause of significant morbidity, its global cost burden has not previously been estimated using country-level data. The timely elimination of vivax malaria will require widespread access to safe and effective radical cure. What did the researchers do and find? Data on the epidemiology and costs of vivax malaria to healthcare providers and households were collated to derive the annual global cost burden of vivax malaria. The potential impact of widespread provision of primaquine radical cure was quantified in terms of case incidence and costs for 44 endemic countries. The global cost of vivax malaria in 2017 was US$359 million, but this could be reduced by US$93.6 million by screening for G6PD deficiency and provision of supervised high-dose primaquine. What do these findings mean? Supervised primaquine can lead to a substantial reduction in household and global costs of vivax malaria, although the costs to healthcare providers will be higher. Novel, low-cost methods for improving adherence are needed to ensure the affordability and scale-up of radical cure.

Background An acute episode of malaria can be followed by multiple recurrent episodes either due to re-infection, recrudescence of a partially treated parasite or, in the case of Plasmodium vivax or P. ovale, relapse from the dormant liver stage of the parasite. The aim of this study was to quantify the impact of recurrent malaria episodes on morbidity and mortality in Papua, Indonesia. Methods We undertook a retrospective analysis of routinely collected data from malaria patients attending the primary referral hospital in Papua, Indonesia, between April 2004 and December 2013. Multi-state modelling was used to estimate the effect of recurring malaria episodes on re-presentation and admission to hospital and death. The risks of early (≤ 14 days) and late (15 to 365 days) hospital admission and death were estimated separately in our study to distinguish between the direct and indirect effects of malaria recurrence on adverse outcomes. Results A total of 68,361 patients were included in the analysis, of whom 37,168 (54.4%) presented initially with P. falciparum, 22,209 (32.5%) with P. vivax, and 8984 (13.1%) with other species. During 12 months of follow-up after each of the first four malaria episodes, 10,868 (15.9%) patients were admitted to hospital and 897 (1.3%) died. The risk of re-presenting to the hospital with malaria increased from 34.7% (95% CI 34.4%, 35.1%) at first episode to 58.6% (57.5%, 59.6%) following the third episode of malaria. After adjusting for co-factors, infection with P. vivax was a significant risk factor for re-presentation (hazard ratio (HR) = 1.48 (95% CI 1.44, 1.51)) and late admission to hospital (HR = 1.17 (1.11, 1.22)). Patients infected with P. falciparum had a greater overall rate of mortality within 14 days (HR = 1.54 (1.25, 1.92)), but after multiple episodes of malaria, there was a trend towards a higher rate of early death in patients infected with P. vivax compared to P. falciparum (HR = 1.91 (0.73, 4.97)). Conclusions Compared to patients initially infected with P. falciparum, those infected with P. vivax had significantly more re-presentations to hospital with malaria, and this contributed to a high risk of inpatient admission and death. These findings highlight the importance of radical cure of P. vivax to eliminate the dormant liver stages that trigger relapses.

A tumour is a complex, growing tissue with a dynamic microenvironment. Its shape and size affect mass transport and thus the ability of drugs to penetrate into the tumour. Three-dimensional (3D) tumour spheroid culture has thus been recognised as an advanced tool for anti-cancer drug screening. However, the use of tumour spheroids has been hampered by the large variations in spheroid size, their irregular shape and the labour-intensive culture process. We explore thermosensitive hydrogels, P(NIPAM-AA), for culturing tumour spheroids and compare our approach with a traditional suspension culture method (non-adhesive surface) in terms of cell proliferation, tumour spheroid size distribution and spheroid morphology. Spheroids cultured in the microgel network show a narrower size distribution and a more spherical shape. We hypothesised that these observations could be explained by the fact that cells are homogeneously retained inside the hydrogels, cell aggregate formation is much slower due to network resistance and the cell death rate is smaller in comparison with the suspension culture. We developed a cellular automata (CA) model to validate these hypotheses. Spheroid formation with different parameter values, representing culture in suspension and in microgels, is simulated. Our results are consistent with the hypothesis that the microgel culture produces a more uniform size distribution of spheroids as a result of reduced cell death and the gel network resistance.

The first line treatment for uncomplicated falciparum malaria is artemisinin-based combination therapy (ACT), which consists of an artemisinin derivative co-administered with a longer acting partner drug. However, the spread ofPlasmodium falciparumresistant to both artemisinin and its partner drugs poses a major global threat to malaria control activities. Novel strategies are needed to retard and reverse the spread of these resistant parasites. One such strategy is triple artemisinin-based combination therapy (TACT). We developed a mechanistic within-host mathematical model to investigate the efficacy of a TACT (dihydroartemisinin-piperaquine-mefloquine - DHA-PQ-MQ), for use in South-East Asia, where DHA and PQ resistance are now increasingly prevalent. Comprehensive model simulations were used to explore the degree to which the underlying resistance influences the parasitological outcomes. The effect of MQ dosing on the efficacy of TACT was quantified at varying degrees of DHA and PQ resistance. To incorporate interactions between drugs, a novel model is presented for the combined effect of DHA-PQ-MQ, which illustrates how the interactions can influence treatment efficacy. When combined with a standard regimen of DHA and PQ, the administration of three 8.3 mg/kg doses of MQ was sufficient to achieve parasitological efficacy greater than that currently recommended by WHO guidelines.

Background In southern Papua, Indonesia, malaria is highly prevalent in young children and is a significant cause of morbidity and early mortality. The association between malaria and delayed mortality is unknown. Methods Routinely-collected hospital surveillance data from southern Papua, Indonesia, were used to assess the risk of recurrent malaria and mortality within 12 months of an initial presentation with malaria in all children younger than 5 years old attending the local hospital. Analysis was primarily by Kaplan Meier and Cox regression methods. Results In total 15,716 children presenting with malaria between April 2004 and December 2013 were included in the analysis; 6184 (39.3%) with Plasmodium falciparum, 7499 (47.7%) with P. vivax, 203 (1.3%) with P. malariae, 3 with P. ovale and 1827 (11.6%) with mixed infections. Within 1 year, 48.4% (7620/15,716) of children represented a total of 16,957 times with malaria (range 1 to 11 episodes), with the incidence of malaria being greater in patients initially presenting with P. vivax infection (1334 [95%CI 1307–1361] per 1000 patient years) compared to those with P. falciparum infection (920 [896–944]). In total 266 (1.7%) children died within 1 year of their initial presentation, 129 (48.5%) within 30 days and 137 (51.5%) between 31 and 365 days. There was no significant difference in the mortality risk in patients infected with P. vivax versus P. falciparum either before 30 days (Hazard Ratio (HR) 1.02 [0.69,1.49]) or between 31 and 365 days (HR = 1.30 [0.90,1.88]). Children who died had a greater incidence of malaria, 2280 [95%CI 1946–2671] per 1000 patient years preceding their death, compared to 1141 [95%CI 1124–1158] per 1000 patient years in those surviving. Conclusions Children under-5 years old with P. vivax malaria, are at significant risk of multiple representations with malaria and of dying within 1 year of their initial presentation. Preventing recurrent malaria must be a public health priority in this vulnerable population.

Astrocytesplay an important role in remyelination. Normally, they mediate an appropriate environment for oligodendrocyte progenitor cells (OPC) to migrate to the damaged region and differentiate into new myelin sheaths. However, it is reported that they can be harmful in some conditions.Astrocytessecrete pro-inflammatory cytokines and growth factors which are essential for recruiting OPCs to the damaged oligodendrocytes. However theiraccumulation around the lesion and creatingglialscarcan impede recruitment of OPCs by obstructing thepath. In this work we investigatethe role ofastrocytesin recruitment phase of remyelination using a new mathematical model.We introduce a new technique torelatecell concentrations in thepartial differential equations (PDE)to concrete objects in the model usingcircles ofNeumann boundary conditions. The positions of these circles are obtained by solving five PDEs describingphysiological processes .The novelty of this model isinrelating continuous variables for cell concentrationin PDEs to discrete objects. This approach is useful when objective characteristics of the cellsare important to us. In contrast to agent based models, in this modelling process no extended rules w ereassigned to discrete cells .

Automatic identification of the necrotic zone boundary is important in the assessment of treatments on in vitro tumour spheroids. This has been difficult especially when the difference in cell density between the necrotic and viable zones of a tumour spheroid is small. To help overcome this problem, we developed novel one-dimensional pair-correlation functions (PCFs) to provide quantitative estimates of the radial distance of the necrotic zone boundary from the centre of a tumour spheroid. We validate our approach on synthetic tumour spheroids in which the position of the necrotic zone boundary is known a priori . It is then applied to nine real tumour spheroids imaged with light sheet-based fluorescence microscopy. PCF estimates of the necrotic zone boundary are compared with those of a human expert and an existing standard computational method.