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Demining can help a community access agricultural land, markets and food supply, schools, hospitals and other essential services, through the clearing of transportation links and routes. By clearing anti-personnel (AP) and anti-vehicle mines (AVMs) from roads and fields, people and communities are reconnected, and this can bring huge socio-economic benefits to developing countries where these are most needed. Clearing AVMs from roads can also be a prerequisite for other aid agencies and government services to access remote communities. It restores freedom of movement and fosters freedom from fear. However, efforts to clear roads and fields from the threat of landmines are complicated by two issues: 1) the slow speed of current demining approaches particularly for certain classes of landmine; and 2) the need to prioritise the order in which different areas and land types are cleared for maximum benefit in the shortest possible timeframe. We propose a project to tackle both of these issues, creating a new technological tool for detecting landmines alongside a methodology for examining cultural, political, and socio-economic factors at the national, district, and even community levels. This approach can guarantee the deployment of the technology for the greatest possible benefit in the shortest possible time. To the best of our knowledge this is the first time that a combined strategy of this kind has been attempted. The particular target of the project is minimum-metal AVMs laid in roads and fields, which is a class of landmines that is very difficult to detect by other methods, and thus very slow and costly to clear. Beyond this synergistic approach, the project will benefit from the unique advantages of our proposed technology for the clearance of AVMs. This is because our sensor relies on a frequency-sensitive detection of the explosive material, which is contained in large quantities in anti-vehicle mines. The sensor's underlying technology is based on a quadrupole resonance (QR) approach, which relies on a simple detection mechanism: a pulse or series of radiofrequency (RF) pulses is applied at a particular frequency for the explosives of interest, and the presence (or absence) of a return signal is sought. As with metal detectors, a specially-designed planar RF antenna is placed close to ground level and fed with a sequence of RF pulses at or close to the QR frequency of the explosive to be detected. The same antenna is then used to detect the weak signals emitted by the explosive following the excitation. The important difference from metal detection is that it is the actual explosive contained within the mine that is detected and not any feature of the mine (such as the casing or the trigger), so the false alarm rate is low. This is particularly important for humanitarian demining, which aims to clear most, if not all, of the landmines in the interrogated terrain.","The Global Challenges Research Fund (GCRF) supports cutting-edge research to address challenges faced by developing countries. The fund addresses the UN sustainable development goals. 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Without radical cure more than half of all patients with vivax malaria suffer one or often many repeated relapses. Not only does relapse cause suffering, loss of income and misery, people with relapsing malaria are also infectious and contribute to the continued transmission of vivax malaria. Vivax malaria relapse can be prevented by the administration of drug regimens which include primaquine. These drug regimens are underused because they can potentially trigger hemolysis (rupturing of red blood cells) in people with an inborn error in an enzyme (G6PD), which can be severe enough to require blood transfusions. Two important developments make it now easier to administer radical cure for vivax malaria. First, several companies have developed point-of-care sophisticated devices (biosensors) to measure G6PD enzyme activity. Using biosensors health care providers can detect patients with an enzyme deficiency and exclude them from treatment with primaquine. Second, a recent study has shown that a 7-day primaquine regimen is as safe and as good at clearing vivax malaria as the traditional 14-day drug regimen. We think that patients are more likely to complete a 7-day course than a 14-day course. These two developments, biosensors and 7-day primaquine regimens, should lead to the widespread uptake of radical cure with primaquine. However, many health care providers and the policymakers (who make the guidelines health care providers follow) are not aware of these recent developments. Furthermore, the currently available evidence may not convince them. One way to convince them may be to start discussions on the preparation and eventual results from large demonstration trials. We are planning a large trial in which all vivax patients in selected villages receive a primaquine regimen. 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In 2015, WHO estimated there were 9.6 million TB cases and 1.5 TB deaths. Nearly 500,000 of these cases were resistant to two or more of the main drugs used to treat TB. New drugs, and combinations of drugs, are being developed to treat tuberculosis, as are new vaccines that may protect against disease in adults. Quantifying the burden of TB is fundamental to understanding its global epidemiology and for making appropriate resource allocation decisions. Most estimates of new TB case numbers each year rely strongly on the number of cases reported by countries in that year to WHO. Unfortunately, one in three TB cases are thought to go either undetected or unreported, so the number of cases reported underestimates the number of new cases. While one can correct for this, it is hard to know exactly how much to adjust the reported numbers. Some countries have good systems for recording causes of deaths, which can be used to estimate the number of deaths caused by TB. Increasingly, large and expensive prevalence surveys are being used to estimate the number of people with active disease in a population. These estimates are less subject to bias, but measure a different quantity. Little work has explored the best way of combining these three data sources. A major goal of this work is to use mathematical transmission models for burden estimation and provide a unified framework for all data. These models yield the number of new cases, deaths, and also the prevalence of disease. They explicitly represent disease transmission and so introduce a dependence between the number of new cases in different years. These models involve parameters evidenced from previous epidemiological work, but must be calibrated to learn from data on TB reports, deaths and prevalence. Calibration means adjusting imperfectly known model parameters in order to match observed model outputs to the data. 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I will explore these techniques for the transmission model, and also in statistical modelling aiming to account for the observed patterns of drug-resistance. The transmission model will ultimately be extended to include different types of drug resistance. As new treatments and vaccines emerge, those with responsibility for public health will want to understand the potential impact these new technologies can have in terms of gains in health, and changes in spending. Producing cost-effectiveness and budget impact evidence requires a model that includes transmission, in order to account for indirect benefits accrued by avoiding secondary cases. We will use our model to provide guidance to decision-makers seeking to maximise health gain with limited resources. 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modulating susceptibility of African malaria parasites to artemisinin"], "description_narrative":["Combination drugs for treatment of malaria deployed globally since the start of the 21st century have provided a substantial public health benefit. Malaria deaths across Africa in particular have plummeted since a peak in the 1990s, when failure of the drugs chloroquine and sulphadoxine-pyrimethamine precipitated a rise in infant and child deaths. A key component in all the currently effective drug combinations is the plant-derived chemical called artemisinin. The parasite-killing ability of artemisinin has recently been threatened by the emergence of reduced susceptibility in the Mekong region: this is manifest as a slowing of artemisinin clearance of P. falciparum from the blood of treated malaria patients. Although under combination treatments these patients should eventually experience a full cure in most cases, in this region the combination partner drugs are also failing in some patients. Careful monitoring and vigilance of malaria drug resistance is therefore needed. A parasite gene has been identified in Cambodia and the surrounding region which contributes to the loss of effectiveness of the artemisinin drug - this gene, which encodes a kelch-domain protein and is called K13, has accumulated a variety of mutations. These are strongly associated with the loss of effectiveness of artemisinin against these parasites. However, this same phenomenon has not yet been observed in African malaria parasites - in the small number of cases where drug treatment does not work, K13 mutations are not implicated as the cause. In the past 2 years, gene-editing studies by ourselves and others have successfully demonstrated a direct effect of 3 genes in reducing susceptibility to artemisinin : pfap2mu, pfubp1 and pfcoronin. Variants of these genes elicit increased parasite survival in vitro in the ring-stage artemisinin survival assay (RSA). In the case of trafficking adaptor potein subunit AP-2mu, we have shown that the role of this protein in P. falciparum is unlike in other organisms as it does not interact with clathrin, but is associated with an as yet unknown compartment in the cell that appears to also contain K13, although we found no evidence of direct interaction between AP-2mu and the K13 protein. There is, however, good evidence of direct interaction of AP-2mu with a different kelch protein , K10. Polymorphisms in the gene encoding the K10 protein have been previously identified as a genetic component of parasites from the Mekong region in which the K13-dependent reduced artemisinin susceptibility originally arose. This work was carried out by PhD student Ryan Henrici, who completed his doctoral studies in 2018 and has moved on. We now request support to extend this work, using gene editing to test the effect of new mutations. In preliminary studies of both field samples and UK isolates, we have already identified a number of such new mutations in our current five genes of interest - pfk13, pfap2mu, pfubp1, pfcoronin and pfk10 (see Case for Support). For each new isolate (either from the UK or from our collaborator Dr Bismarck Dinko in Ho, Ghana) that is adapted to culture, we will fully test drug susceptibility, and genetically characterise them using genome sequencing. In gene-editing experiments we will then directly measure the impact of each candidate gene variant in both established laboratory lines and in our new cultures from UK and Ghanaian patients; any variant proven to generate a drug susceptibility phenotype may therefore be contributing to changing patterns of drug susceptibility, and could be developed as a surveillance marker for use in malaria endemic areas. Our work will thus assist our understanding of resistance to our current combination drugs, and help us to devise strategies for deploying these drugs carefully in both the UK and Africa, to maximise their useful life in curing malaria patients.","The Global Challenges Research Fund (GCRF) supports cutting-edge research to address challenges faced by developing countries. The fund addresses the UN sustainable development goals. 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