 So I'm just really giving an overview of the AMR problem and some of the strategies that are being used or could be used to address it. Okay, next slide. Okay, so there've been a number of sort of high profile reports aimed at policymakers as well as book same to the public that really sort of highlights the kind of extreme sort of nature of this problem. Just some examples there. The middle one has probably been one of the most influential reports, the O'Neill reports from 2016. And it's not necessarily the most sort of scientifically rigorous, but it sort of came up with estimates of the burden of AMR currently and projections of what the burden might be by 2050 if we don't do something about it. And even though they're sort of back of the envelope calculations and no one takes them too seriously, I think most people think they're broadly in the right ballpark, they're certainly plausible. And in fact, so that sort of comes up with an estimate now of about 700,000 deaths per year due to AMR. And this is certainly, I mean, sort of current thinking the sort of smart money is that this is really quite on the low side. Probably if we just consider bacterial infections, excluding TB, sort of the best guess is a more like double that per year. So instead of COVID units, we're looking at the equivalent of a sort of pandemic worth of deaths every five years or so. And that's currently that's that's if the situation doesn't get worse. So so it's clearly a very serious problem. And the overwhelming burden of that problem, both now and projected into the future is in low and middle income countries. So this is again a graphic from the O'Neill report just highlighting that Africa and Asia. They both currently are thought to to experience the greatest burden and projected to experience the greatest burden as well. So so what's causing this problem, what's causing resistance. So you sometimes read that the problem is caused by overuse of antibiotics. But I think it's fair to say the problem is just caused by use of antibiotics because the bacteria don't care whether the antibiotics are used appropriately or not. So really here we're thinking about I'm just thinking about bacterial pathogens and and not so much about TB, which is a kind of slightly separate issue, but about pathogens which are normally carried asymptomatically. But in a small proportion of cases can go on to develop infections. So so so how does how does antibiotics select for resistance in these? Well, it's kind of three sort of key pathways, I guess. There's one that's within host processes shown in the shown in the sort of top figure where someone takes antibiotics. They have a small proportion of resistant bugs, say in their gut flores. These circles are my illustration of bacteria. The are shows resistance bacteria and the antibiotics give those resistance bugs an advantage and they grow and sort of take over. And that means they can spread more easily between people and the patient, the person will become colonised for longer. Antibiotics can also select for resistance with someone who's susceptible, who's not carrying resistant bugs, takes antibiotics that can increase their susceptibility to becoming infected by disruptions to their microbiome, to their host flora. And there's also something that I've talked about a lot is with contact with infected contaminated meat and animals, which are carrying resistance bacteria. They can also pass to humans as well. And of course, lots of antibiotics are used in animal production and is often very high levels of resistance there. So perhaps surprising thing is we don't we only recently really beginning to get a quantitative understanding of these processes, but there's still massive gaps in our knowledge about the relative importance of these sort of processes and to sort of complicate matters even further. The resistance, the genes that cause the resistance can jump around between kind of between species between bacterial species. So resistance in one type of bacteria can spread to another very often on small pieces of mobile DNA called plasmids shown here in the red circles. So we've known for a long time that this happens, but only really recently are we beginning to realize how how often it happens. So so in this paper here, I mean, it was found to be happening this transfer of resistance between bacterial species in just about every colonised patients in the hospital. So it's really ubiquitous and it makes control efforts much more difficult and understanding the epidemiology more difficult as well. So so what can we do about the resistance and what are the other drivers? So there was a nice review of sort of current thinking about AMR in Southeast Asia, but it's equally relevant, I think elsewhere as well. And there's a nice sort of graphic there that's really sort of highlighted these conventional thinking on what are the sort of key drivers of resistance So there's no attempt to quantify the relative importance of these and there's lots of uncertainties about them. And I think in some of them we don't there's potentially even uncertainty about direction of effects. So I think they have lack of knowledge is listed here. There's some studies have actually found more knowledge is correlated with more carriage of resistance as well. So it's not it's not necessarily clear that there's a simple solution in giving people more knowledge. I think there may also be questions about treatments, non non adherence. So it's a most selection of resistance is what we call bystander selection. So the resistance is developing in bacteria that aren't being treated for the infection. So actually non adherence to treatment. If anything might actually reduce selection for resistance in certain cases. So so there's I would say there's lots of uncertainty about these interventions. So in many cases it's not that simply we know what the interventions are and it's just a question of implementing them. In many cases, we're really uncertain about how effective different interventions might be. OK, it's next. OK. Oh, yes, let's go back. Yeah. So one thing people often talk about is rational and irrational antibiotic use, and I'm slightly uncomfortable with this term. I mean, it sort of implies if only people could be more rational, we wouldn't have this problem. And I guess what people mean by rational use is something like this definition that it's it's giving people the drugs that meet their clinical needs in the right dose for the right duration and also crucially, I think at the lowest cost to them and their community. And I think one of the issues with antibiotic use is that the interests of the patient and the community are not necessarily aligned. So the next slide will explain what I mean. So this is really about what economists call externalities. So if we contrast antibiotics with vaccines with vaccines, you get positive externalities. So if you get a vaccine, you protect yourself, but you also protect other people who don't get the vaccine because you're less likely to transmit to them. So it's a sort of win-win. So it's a bit of a no brainer, so it's clearly rational at the individual and the sort of population level to encourage vaccine uptake. For antibiotic use, it's a bit more complicated. So the patient taking antibiotics might benefit from them. But then that antibiotic selects for resistance. They're going to transmit more resistance to other people. So each time they use the antibiotic, it's kind of this more resistance in the community and the and the effectiveness of the antibiotic is degraded somewhat. So in that case, there's a sort of negative externality. So so so the interests of the individual and the community are not necessarily aligned. So what's rational for one person to do might not necessarily be rational for the community to do. And so this makes things complicated. And this is kind of the problem that antibiotic stewardship programs are really trying to address and which is how how you sort of trade off the benefits to the patient, but without selecting for more resistance in the population. And that's and that's a difficult problem. And I don't think we have the know all the solutions to that problem. So this slide, I guess illustrates another issue about talking about rational irrational antibiotic use. So often we have uncertainty about the effects of antibiotics. So if you sort of imagine a sort of antibiotic stewardship zealots traveling through Sub-Saharan Africa and coming across the village where all young children were given antibiotics twice every year, whether they were ill or not. So if that person wasn't also a sort of zealous reader of the New England Journal of Medicine, they might think this is clearly irrational use. You're giving people antibiotics when they have no indication that they need them. And in fact, when you do the randomized trial, as they did here, this intervention, giving asithromycin to children twice year twice compared with the placebo prevented one in five deaths in children under five months years old. So in that case, it clearly looks like a sort of rational policy, but there's been lots of debates about whether what doing this policy rolling it out with what impacts that would have on resistance. So these are real dilemmas. And I think as well as thinking about sort of overuse of antibiotics, it's also important to think about underuse, so lack of appropriate use. So and I think this paper preprint from Annie Brown, this is from her PhD thesis and Red Oxford, which are looking at antibiotic consumption globally and doing some sort of geospatial mapping. And there's kind of, I guess, clear suggestion that there are major problems with sort of underconsumption of antibiotics. So with some areas not using antibiotics as much as they should be or not using them in the right places, as well as overuse. And clearly the patterns have been changing over time, but sort of disparities have remained. So it's so major challenges to ensure fair and equitable access to essential medicines. So this slide, I guess, is really an infomercial. So this is just highlighting one other aspect of the problem that there are that sort of fake antibiotics are also a thing. And that also sort of has an impact on resistance as well. So this is really an advert for the sort of seminar three in this series on November the fourth, which if you haven't registered for, you should also, of course, register for the other seminars there. But there's a link to it there in case anyone interested. Okay, so what can actually be done about these things? So again, this graphic is from the O'Neill Report and this highlights, I guess, potential interventions of varying degrees of evidence base. There's sort of public awareness. And again, I mentioned this, it's not clear that just making people aware of the problem is going to have a benefit. In some cases, there's a good evidence base that sanitation and hygiene interventions can be effective certainly in sort of hospital settings, sort of hand hygiene and so on, but also waste water, sort of clean water. There's often contamination in water supplies. There's questions about interventions for antibiotic use in agriculture and the environment as well. There's a lot of interest in potential vaccines to reduce AMR and also rapid diagnostics. And all these areas are areas where the Oxford Link Africa and Asia program are really involved in interdisciplinary research that's sort of combining randomized trials and modeling and economics, as well as sort of qualitative research as well. So I guess this sort of seminar is just really going to give a sort of flavor of some of the work that's going on. But there's a lot more going on that's not going to be covered here. So what are the major challenges? Well, firstly, we don't have great data. There's limited variable quality AMR surveillance data and antibiotic use data. There's need to improve systems to collect such data and actually to improve methods to analyze the data that we have as well. I mean, there remains this substantial uncertainty about the best ways to use antibiotics, whether that's looking at the duration of treatment and the choice of empirical antibiotics. We both have kind of major projects looking at these questions. And but also we do have interventions that have been shown to be able to safely reduce a to a reduced resistance or unnecessary antibiotic use, both through sort of stewardship interventions, improved hospital hygiene, some cases vaccines and some cases rapid diagnostic tests. So in these cases, we also need interdisciplinary research to promote adoption of such interventions that ties into what Sassi was talking about in the implementation research. So I think the interdisciplinary research has a role in both these sort of challenges, when in fact all three of these challenges. And the third thing is just the sort of economic aspects of it. And of course, economics is one social science that policymakers often take a lot of notice of, but often the economic incentives to adopt interventions to reduce AMR are kind of not properly aligned. So there's a real need to understand these incentives, develop interventions that overcome these obstacles, but also there is a need to improve health economic methodology to better quantify the benefits for reducing AMR. I've just highlighted this paper, which is really kind of a first attempt to improve methodology to actually put an economic cost on the benefit of interventions that reduce AMR. So if you don't have this, it's very hard to justify use of say rapid diagnostic tests from a cost effectiveness point of view. So brief summary then. So bacterial AMR, I mean it's currently a leading course of death globally. Certainly the highest burden is in lower middle income countries. We have major knowledge gaps concerning both the sort of underlying epidemiology. And I think in many cases, there is substantial uncertainty about how we should best use available antibiotics to get the greatest health benefits. And interdisciplinary research is needed, both to sort of help address these knowledge gaps to better understand how and why antibiotics are currently used, to better understand the impact of AMR on human as well as animal health. And to inform, I think, policy changes that might have an impact on access to antibiotics. And when we do have sort of control measures that have a strong evidence base, there's a need to develop and evaluate really scalable behaviour change interventions to actually ensure they are used.