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Okay, so welcome back, everyone. I know the break was very, very short, and I hope you got a little bit and a chance to look at the posters. Um, So we are continuing with our last speaker, who's also our keynote speaker and who were very, very pleased and honored to have here. So is Professor Claus Mira. He's a professor of neurology at the Blizzard Institute, Queen Mary, University of London and the Royal London Hospital of Bars Health Trust. He's also the deputy director of clinical research, the research lead of neurology and the clinic lead of the day case unit and the M S service. He's originally from Germany, So we already checked it a little bit in German today. Um, which, which was really nice. Um, and he got his training at the Charity Hospital from the Humble University in Berlin before he then moved to London in 2001 to pursue a career in academic neurology so initially as a research fellow and then later on from 2005 as a welcome feller at the UCLA Institute of Neurology and then as a consultant neurologist at the National Hospital at Queen's Square in London, And I'm pretty sure most of you know clouds. He is very, very busy. Um, he, um, is on a lot of national international channels and scientific and advisory boards. He's also very active on social media, which were, unfortunately, still not allowed to use, um, due to respect out of the queen's passing. But, please, when you have a chance and you do not already please follow him on Twitter. It's very engaging and very informative as well. And also the bars. M s block is fantastic, and he's a co founder and big contributor to that. So and we're very pleased to have you here today, Claus, and we're very much looking forward to your talk. Thank you very much before I feel very humbled by this, um um, introduction and I thank you, even and the All Ireland Research Network in the Northern Ireland M s research network and the Ulcer Immunology group. And I hope I have acknowledged everyone, um, those who, uh, some of you might know my wife is from Dublin. So when I'm in Ireland and I'm on the south, but I'm always glad to come back to Belfast um, can you hear me better? I don't know if it interferes with the online audience. Online audience as well. Yeah, I can speak up. Okay. Is that better? Yeah, I better. Is it okay? Brilliant. Excellent. So thanks very much for inviting me. And I'm going to talk about implementing and trialling m s interventions. You had an overview from M a talented guy this morning who already attended, but I understand this is different audience, and obviously, a very different perspective, I think, or a different part is only very little overlap. So rest assured, I leave my disclosures here for a moment because I'll talk about some of this, mainly about three trials that I mentioned there, which I'm a chief investigator. Um, since they are all associated with industry. So, um, one of them with Mark one with a barge in And the third one which has yet to receive the sine off from the secretary of state, uh, with psychometrics from Belgium. Um, it's the season of morning. Um, and, um, I just want to pay tribute to them. Ingrid Allen, who really regret to say I only realized last night that she's passed away in fact, in already in 2020 myself, like everyone probably knows her, particularly her paper from 1979. Very well. About normal appearing, um, brain tissue in M s, which I think the last count has 449 citations. And from the work that I've seen presented just earlier by Rachel I'm sure it's going to be 450 plus very soon. So she's obviously left the legacy in many ways, including the tissue Bank, which is now we worked through, which is really or used, which is really excellent. So I'm gonna look at the topic from five perspectives. First, in that theme, I'll briefly have a look at the pathology of M s, then from look at the perspective of time, then that interventions, decision making and access. So let's have a look at the pathology first. And, um, for those who don't know yet, this is just a reminder that s is a progressive disease from onset, and you can see here on the right side, actually not quite as nice or as it's illustrative as Daniel and Tornadoes cereal, um, imaging that we saw this morning in Emma's presentation. But clearly you can, um, glean from this the degree of tissue loss that somebody with them as encounters over the years. Now, what does that mean? Well, we've looked at this in quite some detail and using steri ology on brain hemispheres a few years ago and, um, detected that you lose over a life with M s, you lose about 40% of your cortical neurons, which is obviously bad news. Um, the good news is that that, uh, loss is actually very strongly associated with the cortical thickness of the cortical ribbon, which, by inference, gives us essentially an enviable access to that change. If you measure that using MRI, um, we know this is not happening at some point in the disease course it's happening from the very beginning, including in the stage of radiologically isolated syndrome. So these are patients who had an MRI, for whatever reason, turned out to have BMS, and they also have experienced brain atrophy early on. So it's something that clearly demonstrates the progressive nature from the beginning. So you can also just go back to the to the, uh, the dictionary and, uh, see that progression is a, uh, the process of developing or moving gradually towards more advanced state or a number of things in the series such as Relapses. Okay, so I think this fits quite well. And the definition m s is, uh, an inflammatory disease. And, uh So here's an overview of some of the cell populations that are primarily seen. So CD eight positive T cells and, uh, CD 20 positive for 19 positive B cells. And on the right, you can see the original damage as it were, or at least early damage. We're not 100% sure whether it was happening in the brain first or in the periphery first. But certainly this is the blood brain barrier. Breakdown here is of significance importance for the how m s or how M s lesion evolution plays out. That again is something that is not happening only at the very beginning. This is a study from Amsterdam a few years back that looked at over 100 and 80 brains, uh, exploring over 7500 lesions. And what they saw is that you find in the majority of these cases you find a chronic active lesions. In fact, When you look at the patient, how many of these samples of patients had active or chronic active lesions? You find almost four and five have those lesions, and that was after a disease duration of 28 29 years. Um, which these These patients died. Um, there was some debate. I think for some time whether uh S is primarily degenerative whether lesions actually play a role at all or with essentially just the form of the waves. Um uh, PhD student of mine Natalia, She, um, explored this using spinal cord samples. And what she did, or what she confirmed in the first place was something that we knew that you lose about 60% of your corticospinal tracks in a lie with m s. Okay, so that is confirmatory. That was known before. I think what was very elegant in her work was done to look at the axon loss that is directly associated with lesions. And for that, she took out of court samples where there was no lesion, five levels above and no lesion, five levels below an area of lesions pathology that is very clearly with a home atopic contralateral area. That was not demyelinated. Okay, so just to exclude essentially any impact of lesions above and below onto the measurement of axonal loss. And as you can see here, um, the difference is almost 50%. So there's a massive impact of lesions pathology on the preservation or in fact, loss of, um, of accidents, clinical trials over and above what we have known from animal experimentation. Um, and other work have think contributed a significant, um, proportion of how we understand s today and how we can control it. I'll just give you one snippet overview of the needle. So there's no evidence of disease activity rates across clinical trials of drugs that we commonly use. And you can see here the most highly effective drugs are up here. Um, interestingly, So, kms to this was the trial of, uh, emphysema, Uh, didn't have such a great, uh, need a rate, but clearly opera and opera one and two. So the ocrelizumab trials had clarity was up there, and here's the other kids. Uh, this camp is one from the alemtuzumab study. I just bring this up because you can see all these drugs, particularly on the on the left side. of the graph pretty effective. Okay, so this is the best that we have at the moment and bearing in mind that this was not re baselined need a rates, but really taking into account right from the beginning and not sort of doing an MRI, say, three months later and then measuring future activity against that which increases the rate of nida yet further to 70 or above percent. This is just an overview that is not meant to confuse anybody. Just a really nice, uh, review by their hands or in nature, reviews that essentially just puts the the drugs into context. And I just want to put to pick out model is, um, up here Because, um, it refers to what I said earlier that although we don't know whether Block member disruption is actually the original sin or the original damage that happens in M s, Um, but we know that when we block access and Gavin, I think, showed that this slide this morning we can see how essentially drug flatlines new activity on MRI scans, and that also translates into a clinical activity. This was the, um, from the original, um Tysabri trial on the on the left side. So blocking access of adaptive immune cells to the brain is highly effective in M s, certainly in in early disease. Um, now, there was quite a bit of discussion, and I think it's still ongoing whether it is largely to be PSA mediated disease and, um, looking at the alemtuzumab data, obviously the the the impression was very much this must be t cell mediated because you can see how the cells are being depleted and then flatlined almost for for sometimes for years, until they completely recover and associated with very high efficacy. Whilst B cells actually recover very quickly. And then I seem to have an overshoot here. We also obviously know the problems associated with the compound, and we've we've been sort of looked into this further, which I'm going to show in a second. But when you look at the B cell depletion through ocrelizumab, you obviously then, uh, wondering what's happening because you get a T cell depletors and then the B cell depletors. And both of them seem to control m s pretty much to the same effect of the same degree. And I think one of the the answers is in looking at cell subsets. And so we've done that. We've got went back to the E. M. A and got the data for the subsets out and then published these a few years ago. When you look at the T cell, some populations they are. It's pretty boring because there's no difference between them. They all obviously, uh, depleted. And then they recover to an extent and they have the second course of treatment, and then you get a degree of recovery again. It is interesting what happens with with B cells, which is this so you can see the overall CD 19 population recovers within 3 to 6 months. And then there's a mild overshoot. But you can see here this is dominated really by immature and then maturing B cells. So this is 180%. You can't read that from the back well, and this is about 120%. So a significant so overshoot of those whilst memory B cells, a B cell subset stays flat, just as it does with Ocrelizumab and a number of other, uh, b cell depleting drugs. And I think the sorry this is just a little bit painting a final sort of element in this game is or this kind of concept is obviously the, um it's cladribine because cladribine does both to an extent but leads to relatively modest diesel depletion only and to relatively rapid release, uh, recovery as well. However, memory B cells again stay flat down here. So from this and I really cut this pretty short, we in for that, um, visa subsets are probably, I mean of significant importance in disease control. Now, time time plays a role in M s. It does matter. And it might just, for example, when you did develop M s and when you, uh, went on treatment. So this is from a paper by cab pride colleagues that looked at when people reached EDSS six. And so, in the pre DMT era, um, that was 80% of age 65. Um, when the the era of low efficacy or interference Inglaterra, um, asset drugs came out. You had a, uh, this percentage about 60% reaching EDSS six at age 65 now it's not quite 100% sure. But, uh, in the era of high efficacy DMTs you get it yet on Significantly Lower number. Now, this is obviously dependent on a little bit longer. Follow up. But I think the the inference Although there's also some data suggesting that overall the cause may have, um, become a little bit more benign, so that's not 100% clear. But there is, um, the impression that our treatment does make a difference and the more we have understood it and the more effective we treat you, we also get the clinical effect of that, um this, I think, was shown earlier on by, um by Belinda McGary Or at least she showed the Danish study. This is from the M s base registry, A study looking at early treatment with highly effective treatments versus platform treatments or the drugs used listed up here. So this includes the non licensed for M s rituximab populism, a mitoxantrone alemtuzumab journalism up, and you can draw this in various ways. So the blue line here is highly effective treatment, and the red is, um, late start of highly effective treatments or with the delay of six years, and when you look at the six year mark and essentially reset your timelines there and you can still see that there's a slight of diversion so clearly suggesting that when you start early, then you get I mean, the best effect and what you have lost your probably not able to fully recover. Otherwise, these lines would be parallel at this stage, and we've used this kind of in a summary that we've published just last year. So treating early is kind of the still the word of the day. And that brings me to interventions first, to say that we are still looking in M s at secondary and tertiary prevention. There's obviously a lot of discussion certainly revived since earlier this year about the role of the TV and whether vaccination or viral antiviral treatments combinations with disease. Modifying treatment might, uh, enable either better efficacy of existing drugs or, in fact, with vaccination prevention of the disease. All together, I think it'll it'll take time, okay to establish that, but clearly the particularly the American epidemiology study in the Army has has has thrown this up. So we're looking at secondary and tertiary prevention, and this is what I'm going to talk about. So, um, one study is the attack. M s trial. This is from our blog. Um, this is a and now registered project. We're planning to open this study very, very soon. In fact, the green light is going to be, uh, this month, I hope, actually, end of next week. Um, I'm sure you're all aware already because your daily mail reader and, uh, I yes, that's right. So, anyway, you have to You have to spread the message, all the channels, and I mean Joan Macfarlane for whatever the daily Mail otherwise does. She's written a very good article there, so it's all accurate. Um, but this is it was obviously also part of the story. Um, which is that, uh, conferences are important and face to face meetings are important. Okay, So this this whole trial concept actually emerged from a conversation that I had with Jeremy Hobart and Gavin, uh, juvenile me at the European Chocolate Foundation at that very date, Uh, in bovino. So that's now 55 years old. Was right. Just tells you I think we had a timeline earlier How long it takes to develop the drug pipeline. And I wonder how I mean, how much time passes from their first year together until you actually get to the starting point anyway. Um, yes. Why would Why would we do that? Gavin again earlier on showed data of the employment rates of patients and how they lose employment. EVSS 33.5. It's only half of them still in work. And, um, a significant part of that is obviously that their cognitive speed, their ability to problem solve to multitask declines, and therefore you're not able to fulfill their jobs as well as they did before. So the rationale for attack m s is, um the to answer the question essentially, how early is early? Okay. Because even in that study, I showed you the m s based registry trial. Those patients who had early, highly effective treatment, they had an average one year since diagnosis. Okay, so here we will shrink that down, and I'll tell you to what degree? In a moment can we change practice? Because, um, what we're planning to do is almost like a stroke, a protocol that is more akin to stroke than what we know as clinical practice in M s. It's highly effective anti inflammatory treatment, treatment and effective way to Ramadi in eight. Which compound is most useful in such an acute scenario and has no license for the indication clinically isolated syndrome? Because we obviously were keen to find a fund for this. And it turned out that natalizumab is, um, that drug VEDOLIZUMAB has great advantage in that it has very modest side effects in the acute setting. We obviously all aware of the long term risk when we use it over two years and beyond. And patients are positive for JC virus. But that doesn't matter in the very early scenario early setting. What matters there is more that you can get the drug in, but also potentially out again. If what is what is possible? The diagnosis isn't right. Okay, We know obviously that patients who have, uh, an MRI suggestive of demyelination in association with a clinically isolated syndrome have an 80% chance of development. M s okay, but there are obviously other, uh, occasion where that's not confirmed. Then over time, and it's better than to have metabolism of washed out rather than have the cell depleted that lasts for 18 plus months. Okay, so this is why we use that were randomized within 14 days. Well, that's what we're hoping for because that's you can see it's one of the primary objectives whether we can actually recruit within such a short time frame. And this is placebo controlled for the first three infusions and then all roll over into treatment, which will then be funded by the NHS six after those six months treatment period. So it's a relatively small study, 20 per um, but it will give us hopefully an impression based on a lesion magnetization transfer ratio. Uh, Emma referred to earlier that quantitative measure which is quite strongly associated with with myelin, as we've shown in earlier work in in postmortem, uh, tissue as well. Anyway, so three MRI is involved and hopes they go steroids. You can also give. And I've already told you about the prosthesis. Now, just by coincidence, um, shift m s has, which is a social media, uh, website and social media grouping, particularly for young people who have just been diagnosed with m s. And they have just asked, how long did did it take to get diagnosed? And this is here. The group that were particularly keen on right this bottom 30% or so, of course, were keen to reduce that number all together. Um, it's very easy to include for this study for I mean, the the criteria. All here. See, I s O. M s at first presentation. MMR shows two lesions or more, and, uh, patient is 18 to 45. There's only one relevant, really exclusion criteria in to remember, which is that you must have more than one t one black hole because t one black holes on MRI are indicative of longer standing disease. And we don't We want to avoid that. This is London, and these are the three sites charts in Westminster, ST Georges and US, and MRI would be at Queen's Square. Um, I'd have to say you can refer from anywhere. Um, um, so I'm not sure if Belfast but because patients have to have the scans and, uh, and the single side just have to do with funding and and other factors, but certainly outside London. No problem. Uh, these are usually young patients who are keen to have treatment and and, um, get done with m s as early as possible. This is just the network and bargain supports this. This is an investigator initiated study. So I'm just going to just highlighted Rachel Horn and John Myers here, who are both PPI members of the team. Rachel has done, um, a twitter, uh, survey. Because obviously this this is kind of new territory for us. Normally, you would have a few weeks, months, perhaps to to establish kind of the conversation with a patient about the diagnosis, etcetera here now, with suddenly compressing this into a very short time frame, just like, yeah, more similar to stroke. And she got some very interesting and generally very positive responses business. John Mayer. So I recommend you go to his website. He's, uh he's a very good, uh, cartoonist. Uh, this is a little book written. He's written about his own diagnosis or his experience of ankle prices. Um, and this is a reflection on his experience with me. So nobody can do anything to stop your body from slowly destroying yourself for itself. He said he wasn't quite as blunt, but yes. So we're really dealing with the situation or trying to, um, you know, improve the situation where, uh, just before the wave hits, we're obviously all aware of the the stages of grief that were that are not sort of a a series of not lined up they can be, you know, some mixture of that, etcetera, but all of which we need to be aware of particularly obviously challenging in a time when there's 10% vacancies in the N h s. Um, so we'll see how that will impact this is our patient card. So with the key inclusion criteria and then to contact the team, So just breathe. I've inserted that. Just take a little break. And what I usually do at this stage is to do my brief t one and 22. you're the only one you can remain seated or the only one obviously discipline disabled. So all the others can just get up just for a brief time. And, uh, stretch up your arms. You go, you go and then bend over like this. All right, so this is t one, because this is so called spin lattice relaxation. Now, if your arms like this and be careful with your neighbors, okay, you just stretch to the side. So this is t two. There's a spin spin relaxation in MRI. Okay. How much time have I got? As much as Okay. So I spoke about really early study, Okay? Really early trial. Um, And now the question remains, what is early? Because what I you know, tagging on to what I said earlier. Inflammation plays a role throughout the disease. Okay, so what I'm saying is start early and never give up. I think this is a bit the message. This is, uh, website that also one of our PPI members, Christine Chapman, Um, uh, produced. And, um, we have obviously, we've had a have a big landscape of M s drugs now. Okay, so this is really a rich. Um, it's not a pipeline anymore. They're all there and out there and and and usable. But obviously they're limited. Confined to the trial populations they were originally tested in. And that resulted in about 35% of the population not being, uh, even potentially eligible because they're two disabled. Okay. And this is what, uh, we're focusing on here. Uh, there was a reference to John Kirstie already. I actually had forgotten about the, uh, his moved to, um, to Ireland and then to the pharmacy islands and and and no sorry to to Denmark and then to fire islands. Uh, and as a you know, as a way to essentially have the the, uh, his data collection funded and and obviously produced a lot of work out of that. So John Kerensky wrote the design, the EDSS. He himself was always against using it in a trial. All right, so and he drew this on the right side as well. Right? So this this drawing is from cuts himself and that describes one important hypothesis were testing in chariot M s, which is that there's a length dependency of axonal loss so longer tracks. That's why you lose function in lower limbs earlier. Longer tracks are more vulnerable to attack by M s lesions because they are longer have a higher risk of being hit by lesions. And therefore, um, they can be functionally effective longer. There's other reasons. Obviously, the corticospinal tracks half of them terminate at the cervical level. Okay, so you have a naturally higher redundancy of, um of tracks to the upper limbs and to the lower limbs, and we kind of refresh this hypothesis. About five years ago, as part of the preparation for child. I was there yesterday in leads at our fifth investigators meeting. Um, and because there was a little reference earlier on, it's very kind of, um uh to say this, but it was a really long track actually to get there. Okay, so this is just a brief timeline of cladribine the drug testing here, which was rejected in 2010 11 by the regulators. And this is where we then kind of picked it up. Um, where, um, to to essentially resurrect the compound. Okay, because the manufacturer market left it for, for, for dead. And we made several attempts. First Clear M s. This was a study. We planned to test Claritin against alemtuzumab. And then we had there was a funding scheme to fund something in Mexico, and I didn't get that either, and, yeah, and eventually Then child was supported. If you want to read up this David Baker's written a long piece on the block about it all, Um, we had also to do quite a lot of sort of preparation of the community, as it were, uh, to, uh, to come along as it were. So this was a burning debate back in 2016 to discuss the that people in wheelchairs should be included in progressive Ms Trials. And I remember pretty tough discussion with Patricia Coil. I don't know anybody knows her, but she's quite a hard nose of New Yorker. And there was some some funny comments on the on the uh on the on Twitter at the time. Anyway, it's a good, uh, opportunity to thank everyone. These are the funders of the of the studies who are full hand of supporters, Um, who all in all give the well over 3, 3.5 million to this study, and obviously there's a lot of other supporters as well, so that's really great. We also have to do a video at the time. So one of our PPI members is a digital editor, so she produced that she did a few more in due course. We started using the compound as well, after we had reassured ourselves about the absence of an excess cancer risk, which we did through a meta analysis which was published in 2015. We started actually using a off label compound version of the abdomen, an injectable preparation. And this is, um, here on the left, left. Very similar to how we use Klonopin. Now in clinical practice, just as an as an injection. Uh, all the information is still available on slide chair. So we have the patient information we have to sign up, etcetera. And, uh, this is kind of a way of trying to repurpose bladder. Been when nobody was interested in developing Otherwise, uh, I was talking at the A. M and 2014 about this. Um, that big farmer way is very established for repurposing drugs while we're still trying. So here's some examples. How is this happened? Right. So, um, the use of the campus, I'm sure some of you remember that Campath was suddenly taken off the market and then repackaged and, you know, the price went up, etcetera. So this is all part and parcel of the game, and we get something in return for that, you know, farmers support for education activities, but also for patient support, etcetera. So this is not kind of all black and white, but we're just we're testing out all ways to make this happen. So this is the eventually the cohort that actually emerged from this. And some of the co authors, I think in the in the in the audience here. So thank you very much. Which is which produced preliminary evidence for in favor of doing the trial, actually. Right doing, um, doing charity So you can see that the knee pads and there's no evidence of progression or active disease. Um, rate here was 56% and this is actually people. Plus, we excluded the walking test here in order to reflect those essentially, the charity population, the overall ends of the small. This is more audit type of data, but it is the anecdotal evidence that, uh, the NIH are likes. This is a logarithmic scale. Okay. And this is, uh, CSF neurofilament in patients before and after treatment. And except for this one absolute outlier with over 10,000 micrograms, uh, micro liter, um, all of them landed in the normal range after a single course of the drugs. So good evidence of supportive biomarker evidence that it might work. This is the overview of the study. I'm not going to repeat that. You can find that on online or email me or, uh or the team placebo controlled study with Nana Practice upper limb function as a, uh, as the primary outcome. Is that me? So my timer. All right. Okay. Just thought, um, worth mentioning that the study also has no upper age limit. Okay, so this is, um, specifically focusing on people with high high degree of disability. And we have no upper age limit, which obviously also emerged very much into patient feedback and I think is supported by the pathological pathology evidence and are anecdotal evidence as well. I can go over that quite quickly. Chariot address is number one priority of the much eh society's top 10. Now these were produced, I think, nine years ago. Now I think there's a there's an update do, but still, it's very important. And there's several others that would potentially be affected if the drug actually works. This is our first patient. She's kind of a model patient. Really. She's a painter, and she's 70 years old, and here she is with her grandchildren and on Ms Society website. Here's another patient who's hobby is chariot driving. Okay, so there you go with a T shirt. Um, so it's really great. These are the sites. The green ones currently active, including Belfast. Very active center here. So stellar and team, stellar job. And yes, so three more to actually activate soon. If you're greenlighted, then you have the honor of being on my WhatsApp list. So thanks to everyone. Yeah, so far, uh, on on this here. Um, yes. So here's the team. I think that society initiation visit is that right? Uh, for screening. Okay. Very good. And, um, yes, this is a This is Sonia who is working actually with us at the Royal London and then moved to Belfast. So there you go. It's taking the gospel along. Um, right. Yeah. Just to say no pressure. Okay. We all just I mean, some of us get this type of letters from the NIH are, um and not only one, but, you know, several, um saying that. Yeah. Where's your recruitment? Come on. Okay. And there's, uh I mean, they have 60% of their studies are currently under review. Okay, so we have one of them. We I think we're not acute risk, but clearly, we need to make sure we, you know, keep the momentum for in recruitment. Everything's out. Their patients are absolutely keen. There's loads in the pipeline. We're trying to remove additional hurdles. Some of you were the investigators meeting yesterday. Just try and keep keep the momentum. Otherwise, that wave washes over us. Um, yes. So why don't come come up with this? I think that's the That's a model model on the Old Bailey. But it's in in, uh, in Canada and obviously refers to medical legal issues. And, uh, and that refers to the MD T multidisciplinary team decisions. Treatment decisions are important, and we must be must be aware that when people are eligible for treatment, they are actually entitled to that treatment, at least for the offer. And I think there's probably more to come in the future at the moment, nobody can even think about that. But, uh, so we are addressing, obviously not directly the medical legal issue. But we're hoping with this study, which is the, uh, key one third one that I want to discuss with you, Um, that that will help to be just more accurate in detecting disease activity. So this study is called Assist M s, using an artificial intelligence tool developed by icon Matrix, which is a company based in Belgium and one of the leaders in the in the field in the multidisciplinary team meeting to assist decision making. Um, so, um, it's clear that we have effective disease modifying treatment, key tourism, MRI, But for radiologists, I can tell you, looking at M s scans is one of the most boring activities in their life. And therefore it also gets like, I mean easily on a on a stack, and they have to sometimes rush through the under a huge pressure, particularly now with the backlog from the pandemic. So it is likely there is, you know, more mistakes than if you can spend 20 minutes or half an hour per per data set. And obviously a I technology doesn't ask for any time. So there you go. There's a bit of PPI activity in that respect. Interesting. How many patients actually want to see their scans okay and want to have the analysis out there? It's part and parcel just of actually opening the whole, um uh, disease and the understanding to patients just going to go over that. It's quite clear that we're looking for superiority over visual detection. of MRI. So we're cluster randomizing the mg t s with and without the assistance of the tool. Um, this is, um it's a collaboration together with the University of Nottingham and emerald as well, and in health are involved in the MS Society. So this is Rachel Horn. She's one of our PPI advisers. She's here, the patient just illustrating the current pathway as she experiences it. So she has her MRI, goes back to her clinician and then discuss is the result. What happens in the background is obviously, currently, um, that And this is Rob DeNeen from Nottingham, um, that it's being discussed in the MG T. And then decisions are being made or proposals for decisions. And what the technology would add is essentially this year, um, that it provides annotated images, as you can see here, and the report that will support the, uh, the radiologist to analyze the scans quicker. And hopefully, uh, more accurately is, uh, six work packages altogether. And this is the important work package, for this is the one. I was alluding to cluster randomization of the MG tea with an intervention and control arm. And yeah, so it's 650 patients per side is essentially our population of patients on disease modifying treatment that are being enrolled here. Uh, yes. So adoption. Um, I just wanted to to to round off with just two examples How implementation can simply not happen, despite the best evidence. Okay. And and one of them is a little bit of an older example would be published this in 2013. But the clinician's among among the audience will say, Ha ha ha. I've done this already already This 30 years ago. If you're that old or read historic literature, Um uh, and it's true, right? So that the use of a traumatic needles. So this is just for those who don't know these are a traumatic needles, and this is traumatic needles. These are the normal ones that, you know, from, uh, being a puncture. Was these here they have. They don't have kind of a cut, right? They have a little hole on the side and, like, pencil tip there, rather pushing the dural fibers apart rather than cutting them. Okay. And that prevents the occurrence of what's called post lumbar puncture headache. Significantly. And we knew that nevertheless, we did an audit, of course, because we have to prove it in our trust that it's happening. And of course we did exactly that. Okay, we have different inclusion criteria, so it's it's substantially reduce, is it? And when you realize this is actually we have actively ask people were actively called them. So, um, you know, most of the time people would go home, suffer at home through it, maybe go to their GPS, but hardly ever come back. Um, it also needs to be costing, of course, right, because a traumatic need it costs three times of what? Cutting needle costs. But when you look at the number of days of work, you save the number of, uh, secondary interventions or blood patches and hospital admissions and visits to the GP is much cheaper. Okay, so the safety about 3400 lbs, right? Anyway, for what it's worth, But then shortly after we had wrote this right, why has nobody changed? As if why we have written the paper? I didn't nobody would follow it. Okay, so anyway so But as I said, there's plenty plenty of evidence, right? And more recent, I think more higher profile papers that essentially, um, say the same. Now, our approach to this is now that we're trying to empower patients, right, so that they know that they could potentially choose. Okay, To have the LP done with an eight or a traumatic needle, they just need to be in power to ask. So this is a little, uh, html five. Okay. People can just open up, and they're in the in a and E and can see what's happening during an LP. And that includes information about a traumatic needles. Anyway, um, we're still looking for this here to happen. Okay, I think there's still some where down here, Uh, with that one. And I'm not really getting over that hump quite yet. So lots of evidence out there. I don't know. Emma are using a traumatic needles. Did you hear about money? They got almost Don't believe it. Open it. Yeah, Yes, and I've I've actually pinch this slide from you because it's such a lovely studies. It's just more repetition for those who have been here in the morning, um, of the neuron study, which is kind of really an eye opener and a great example for me that even when you do the study, you're already changing practice. Okay, so it's not. You don't wait as it were for the for the result to change practice. It's already changing. And this is the first time that we actually systematically and regularly assess cognitive function now in our population. And this is the readout from from these. Okay, so you get a full report. This is the patient's score. Then there's a questionnaire about fatigue and and, uh, mental health. Um, there's another one here, and then you get get kind of an out read out, and just to show this is my clinic letter based on that. Okay, where the yellow sections have already incorporated parts of this. So this is a beautiful project by Russian and and the team in Nottingham. And, um and so So we're really glad to be part of that alongside Cardiff and now leads, I think as well, very briefly on decision making. This may have sort of gone a little bit unnoticed by now. The Ms society a few years ago has supported a project, um, considering risk and benefits in M s treatment selection. Crimson, uh, several papers have amount emerged out of that was very much about decision making. How people make decisions, how they are impacted. Upon and out of that one output has been this year. The decision. A booklet. You don't have to have the booklet. It's online, available for free on this website. And so it takes people with m s really through a, um it's not exactly a decision. Algorithms information plus, uh, support to, uh, information. So here, making my DMT decision. So something that I want to highlight because it sits quite nicely, I think, alongside the M s trusts, decision aid, for example, I don't know what you use here. And you might use that to send people there, huh? To the decision. Zetia? Yes. Yeah. So this is, um I think a nice sort of position. Additional tool Finally access. Um, we've got nearly three million people with m s worldwide. Um, and you can see that that is the number of, uh, prevalence as it were. But in seven out of 10 countries, people with Ms have barriers accessing DMT. Okay, so we're kind of the privileged here. We don't think so. Um, we'll look around us But we are. And, um so I think it's off label treatment comes a little bit into the mix again. There's been a recent paper by the group from the M s I f e m s International Federation. There's an initiative to get rituximab and azathioprine on the essential medicines list as treatments for M s. And we've written already years ago. Um, that obviously cladribine is a cheap compound here. If you look at it as a as an off label treatment, you, um and compare that with with the on label once, it's quite significantly lower Rituximab as well, particularly now with the with the off label variance of the Maxima. Anyway, um, let me thank all the supporters. Let me thank you for your attention and good gymnastics. This is from our away day last Friday. We were took everyone out to voting lake and Regions Park in the morning because the weather forecast was sunshine in the morning and rainy afternoon. Everyone into the boats first shower, arriving. So it was great bonding activity. Okay, thank you very much. Thank you so much closer. Fantastic five perspectives. I'm sure there's questions. They're online questions. You can see. Yeah, I I'm not a radiologist, oncologist, but I just have a general question. You talked a lot about the different trials. If you look at the incidents of M s across the world in different socioeconomic, uh, communities, is there a difference in the rates? Um, to what extent is there evidence that there's an environmental impact like asthma? You know, symbiotic infection. Is there any evidence for, uh, I mean, I think the strongest evidence is for, uh, HPV infection on the base against the backdrop of, uh, Dandelion Genetics plus plus h l a backdrop. So this is these are the major risk factors plus smoking. Um, uh, vitamin D depletion. Although that's not 100% sure. That seems to be quite a strong ethnic element. Uh, that that is modulated, I think socioeconomic factors. Unless others no better and not that strong as as as predictors. Um, I think the fact that we that, uh, patients are under diagnosed or seemingly under diagnosed in areas where that are closer to the equator is probably in part perhaps due to that, because these are also poor countries with very few MRI scanners, even hardly neurologists around. And as we all know, once, neurologists, uh, pictures up suddenly have m s. Okay, because somebody recognizes the condition. So that may play a role. But not not that I'm aware of the real systematic studies that have demonstrated that, uh, interestingly, I mean, even ethnicity is is highly. I think it's more debated now than and then it was 5, 10 years ago. Uh, since the figures from the particularly in the U. S. Military came out showing that the incidents between black and white is quite similar. Thank you. Yeah, we went online. I'll shout for the microphone from Judy Bradley. Um, so thank you, class. We are currently building new research infrastructure called Irish for clinical trials in Belfast. Could you give us your thoughts on what is the key research infrastructure needed to support trials in this field? Well, I think, uh, space and and research staff really, I think the key elements when I look at what What's missing Now what? What? What keeps trials on hold or slows them down is really the throughput. Um, it's not lack of interest in patients or anything to do with the design or so It is very much that, um, you need the funding for both space. And, um and that also includes MRI capacity. I think MRI is a big shortcoming as well. Um, so all all these. Yeah. I mean, if you can, if you can build an imaging center is focused on on on research would be fantastic. We're trying the same failing. Okay, so but I didn't know that answer because there was a discussion we had. All right? Yeah. Okay. Yeah, it's good that you see that as a court. It is really, really important. Priority? Um, yeah. Thank you. How's, um so I get more and more important. Um, if you can give us your own thoughts on that and also do you see this producing cost or increasing costs initially. And I mean, the idea is very much with, I mean, that work, that that ultimately it will reduce costs. I mean, whether whether anybody will ever kind of feel that I don't know. I mean, I think that it will be, uh, less hassle for the radiologists, which will remain a finite resource, I think. Certainly. Expert neurologist, We have a an arm in that study. that actually tests also the the increments learning that non expert neurology, non expert radiologists gain from using the technology. So that would essentially broadened a little bit more of the the number that that can actually review these scans. Okay. Um, yeah. So So we're expecting it takes less time. That means it will be cheaper. And it'll be more accurate. And people will hopefully therefore be on the right treatment at the right time. Because remember, if you have somebody, if you don't detect disease activity, that is. Actually they're You've wasted the scan. You've wasted a year of treatment and the year of life, as it were for somebody who has been not an effective drug. Right? Any other questions to close our keynote speaker just deflated. I'm sorry. I should maybe I should have done another t one t two. That was it. Thank you very, very much for this fantastic talk