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Hello and welcome to episode four of Gut Instinct research updates, bringing you the latest research in gastroenterology and hepatology.

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I'm Tamsin Cargill and I'm a clinical lecturer in Gastroenterology in Oxford.

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Interested in hepatology, viral hepatitis A vaccine development.

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And I'm Fitts. Michael Fitzpatrick and I am times in the sidekick animal.

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So a clinical lecturer in Gastroenterology in Oxford. My main research interests are in nutrition, coeliac disease and GI immunology.

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Now we started this podcast to bring you the most interesting and illuminating GI related research papers that have come out recently.

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Hopefully saving you some time and assuaging your guilt for not reading enough journals.

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Each episode we're going to take you through, hopefully two really interesting primary research papers in a bit of detail.

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One more clinical and one more translational. And we'll give you our take on the research and what we think of it.

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And clearly, there are loads of great papers coming out every month. So in addition,

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we're going to give you a rapid fire rundown of what else is out there in the world and our five

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and five section where we'll try and give you the key points of five papers in five minutes.

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We're aiming to give some context and critical appraisal of the papers that we talk about.

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And whilst trying not to take ourselves too seriously in the process, we both love guestroom research.

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Fitz is more interested in IBD, small bowel disease and nutrition,

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and I'm more into liver disease, so hopefully this podcast will have something for everyone.

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Now, a few disclaimers just to get a start is clearly nothing in this podcast consists constitutes medical advice.

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If you're a patient, you should consult your medical practitioner about your management.

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For doctors, I'm sure you wouldn't believe anything solely because a couple of people had told you it on a podcast.

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The other disclaimer is that there is no way we're going to cover all five papers in five minutes.

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We only take about 15 minutes, but it's a little bit shorter than the the first two papers do.

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Let us know what you think.

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Reuters A glowing review on whatever streaming platform you listen to the podcast through connects with us via Twitter on Guy Update,

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and we're both on Twitter also, and you could email us at Gut Instinct podcast.

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All that were all one word at Gmail dot com. So, Tamsin, for the main papers today, I've got a good clinical one,

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and I think you're doing a translational paper this week with a little bit of lots of cell biology in.

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Yeah. So do you want to kick off? Sure.

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I saw this paper a few months ago, and I I think this is I think this is a game changer, Tamsin.

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I think this is huge. I saw this to you and I was like, Oh, this is really good.

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This is about something that is a massive problem and is really important worldwide and particularly particularly in the US and UK.

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This is a big problem. We're talking about C. difficile infection.

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This is a paper entitled ACR one 09, an oral microbiome therapy for recurrent Clostridioides difficile infection,

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which was out in the New England Journal of Medicine earlier this year, I think in January 2022.

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So for scale, C. difficile causes around half a million cases of infection in the US each year in the UK.

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It's a bit lower per head of population around fifteen thousand a year.

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That's probably because if you remember 10 or 15 years ago,

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there was this massive outbreak of C. diff and there was a huge emphasis put on antimicrobial stewardship to try and reduce the cases.

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But it's still a big old problem, and it causes a lot of deaths in the US.

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Around 20000 deaths a year are directly attributed to C. diff infection.

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And we have some quite good antibiotics to treat C. diff.

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We have vancomycin and for dexamethasone, which are both effective at killing the toxin producing bacteria.

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But Clostridioides are spore forming bacteria.

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And those antibiotics don't kill the spores, and as such, recurrence is really common.

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Antibiotics are the major risk factor for C. diff infections,

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particularly things like broad spectrum cephalosporins, ciprofloxacin and things like that.

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And that sort of mediated by their effects on the microbiota.

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And in particular, there are commensal spore forming Firmicutes species,

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which seem to have a role in kind of filling the metabolic niche that C. diff would want it to

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to to grow in because those those kind of commensal Firmicutes are consuming the metabolites,

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which. C. difficile requires for growth.

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Now we know that faecal microbial transplantation FMT can be a really effective therapy, both for refractory C-diff,

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for it's often used for is treating recurrent disease, so preventing recurrent infection.

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However, there are lots of problems for FMT as we know there's a range of efficacy in different trials.

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There are risks of pathogen transmission and there's that, you know, there's just the fact that it's a massive pain in the proverbial to do FMT.

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We have the challenge of obtaining the material of often getting it from, you know, in the in our in our area in the UK,

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you have to go and request it from Birmingham, where they where they sort of run the sort of the FMT service has to be sort of courier down.

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And then you administer it. And the most efficacious method for administration is colonies gothic installation.

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So you know, it's a real pain to do and there are some concerns and some risks.

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And I kind of think of it a bit like a sort of victory.

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It's a bit of a kind of a black box half-empty because we're not really sure what in the donor's poop is actually really helping.

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We just sort of putting it all in there and hoping that it sort of does does some good.

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But we're not really we don't really know what in it is specifically helping prevent C. diff coming back.

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And so the prospects of taking the good bit of FMT, basically,

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how do we reinstitute the normal something like the normal microbiome said to stop C. diff persisting?

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But but but without those without these inconveniences, if the therapy is really attractive.

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So an oral administered microbiome therapeutic is a really attractive prospect, and this is the first in class.

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This is ACR 109,

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which is a microbiome therapeutic which can be administered orally following antibiotic therapy to reduce the risk of recurrent infection.

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And it's comprised of a sort of a proprietary mix of five Firmicutes species in spore form.

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Say the spores are in a capsule, and it's developed by this interesting company Series Therapeutics,

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which have a number of different mike microbiome agents in development, including,

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interestingly, a treatment for UC, which I think is in phase phase two development.

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So this trial was a Phase three, double blind, randomised, placebo controlled trial of this,

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this agent in patients who had had at least three episodes of C. diff infection.

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So these are people who have got proper recurrent C. diff,

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and they were stratified according to age and to stratified based on the antibiotic they'd received before.

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So either vancomycin Orthodox emissive and then they were randomly allocated one to one to either the treatment or placebo.

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The intervention itself is not particularly burdensome.

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You basically take some laxatives to clear out the bowel 300 mills of magnesium citrate and then you take four capsules once a day for three days.

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And you know jobs are good and you're done.

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The primary outcome in this was a reduction in recurrent infection within the first eight weeks following treatment.

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So it is quite a short duration trial, and they collected a range of safety data,

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as well as microbiota and metabolic sort of metabolite outcomes from from the stool as well, which were also measured.

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So looking at the trial and what they did, 182 patients were enrolled,

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and this was an intention to treat analysis for both the efficacy and safety outcomes.

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I'm looking at the demographics. I think overall, this is probably pretty similar to what we would expect.

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And reassuringly, this was an older population. So half of the participants were over 65 with a slight female preponderance,

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and I'm really glad that you did sort of older patients who are sometimes excluded from trials because these are the patients I,

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you know, I certainly really worry about when they have recurrent C. diff infections and the ones who are often most debilitated by it.

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Interestingly, about 40 percent of these patients have had at least four episodes of C. diff infection.

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This was a predominantly white population from this a North American study,

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and around three quarters have been treated with vancomycin and the rest with FedEx amounted.

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Most of these. Patients were being treated as outpatients, so these are people who've had their recurrent C. diff treated.

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And then after they've had their their course, if mice and they're then discharged and then that's when they were enrolled in the trial.

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So looking at that sort of consort plot and and so on,

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about a third of the patients were excluded when during screening and from the eligibility criteria,

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and that was mainly due to any concern about whether they had a kind of ongoing C. diff infection because this

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was specifically a trial about preventing recurrence as opposed to treating refractory C. diff infection,

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which I think is something I mentioned at the end, which I think is really important to think about for future studies.

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So the headline news is that this trial met its primary endpoint.

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This was an efficacious treatments. The treatment was superior to placebo in reducing the risk of recurrent C. diff.

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So in the placebo group at eight weeks, about 40 percent had had a recurrence of infection.

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And from clinical experience, that seems about right.

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When you've got this cohort of people who have had multiple C. diff infections, it's really likely to occur in the therapeutic arm.

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Only 12 percent had a recurrence of their C. diff infection.

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And so that gives a delta of about 28 percentage points.

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And so a number needed to treat to a number needed to prevent one recurrence of just less than four.

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So this is a, you know, really highly, highly efficacious treatment from that perspective.

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And they did some helpful subgroup analyses. So that seems to hold for both the younger population as well as the older cohort.

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So looking below and above 65 and overall recurrence was more common in the older age group, which is what we clinically see.

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But the treatments seem to be just as effective. The treatments seem to be effective irrespective of which antibiotic you'd had.

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So after either vancomycin or Firaxis, and there was a signal that perhaps following for that, somebody said it was more effective,

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but that wasn't statistically significant, and the numbers in the FedExed in mice and arm were smaller.

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Overall, this is a really well tolerated treatment. Adverse events were really similar between treatment and placebo.

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And although there were three deaths in the trial, none of them were attributed to the treatments.

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And just to just to remind you, this is an older population to start with in this trial,

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they've compared to placebo, not F.A., which is the current treatment for this population.

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So it will be very interesting if if they did another trial looking at whether it's better than FMT or not from an efficacy point of view.

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Yeah, I think that's a really good point.

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And I think we kind of need a number of different bits of data to work out where this fits in the kind of treatment algorithm.

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So, you know, in my my experience, there's sort of there's two or three things we do for these patients.

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So often they've had courses of vancomycin and they've had courses of practise of medicine.

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And then we often either give extended courses.

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So the UK will forgive extended courses of vancomycin Orthodox.

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And I said all sort of pulsed treatments of of those over a period of, you know, wee a couple of months, maybe.

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And the evidence for those those treatment strategies is is not particularly strong,

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but we kind of give them because it's easy and and relatively inexpensive.

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And it's, you know, it's very easy to kind of organise somebody taking oral antibiotic.

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Um, so is this treatment more effective than that?

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And is it more effective than FMT? Or is it just sort of, you know, equal and it's it's an alternative.

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And then we can come down to a kind of a cost benefit analysis in terms of both the inconvenience and and the cost of the therapy.

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Yeah. In terms of how it compares to F.A.

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Clearly, there's no head to head trials and actually there aren't that many are totally equivalent FMT trials to really compare it to.

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But there are some good FMT, he her analyses.

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And that would suggest that the kind of the sort of the delta in terms of efficacy between FMD and placebo is again in the region of about 25 percent.

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So similar kind of range.

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So I think I think we've got no convincing data that this therapy would be more efficacious than F.A., but if it were appropriately priced,

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it would certainly, you know, compete against F.A. in terms of cost, particularly once you factor in that.

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These patients are often admitted for therapy and it's given via colonoscopy.

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So there's a whole load of additional sort of cost implications as well as that, you know,

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the concerns that we have about, you know, risk and and so on and these patients.

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And one thing that I like, I guess from a translational perspective, is they did a little bit of translational work in parallel to the trial.

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So first, they looked at the microbiota composition in the two groups.

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So at the start of the trial, basically them had effectively a devastated microbiota.

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So all of these lovely Firmicutes had disappeared.

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And then over the course of the trial, as soon as the therapeutic was administered, those Firmicutes species kind of successfully engrafted.

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And what's what's really interesting is that they then persisted.

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So after the treatment, which is only three days, three days long, they species persisted out to eight weeks in the trial and the placebo group.

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That sort of kind of devastated scorched earth microbiome to kind of continued for the first

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few weeks and then was slowly starting to recover at the end of the eight week period.

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And as we know that? Microbiota does does recover after some time, and then they also looked at some of these metabolites,

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so which are thought to be required for the C-diff to kind of survive in the in the guts.

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And what's interesting is with increasing levels of these Firmicutes,

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the we get increasing levels of secondary bile acids and decreasing primary bile acids.

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And it's thought that effectively the primary bile acids are required for death and the secondary bile acids can inhibit C-diff.

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And so this does look like the kind of the metabolic niche that C. diff requires is being is

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being kind of reduced and filled by these these Firmicutes species in this in this treatment.

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Very interesting. And the other question, I guess, is refractory C. diff and whether this might work for refractory C. diff or not?

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Yeah. No, I think it's I think it's a great question and I can totally see.

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I think if I were designing this trial, I would have also started with recurrent C. diff.

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I think it's probably a a kind of a cleaner patient population to do.

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And there are patient population who are a bit more kind of stable and suitable to to enrol.

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But we we all recognise those patients who remain in hospital.

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They're often really, really crook. They're really unwell, have this refractory C. diff infection and they're just getting weaker and weaker with it,

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and they just aren't responding to anything. And we often use FMT as a sort of a kind of a last resort before, you know,

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before the, you know, the possibility of surgery or anything, anything like that.

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And it would be it would be great if we had a treatment that was kind of easy to do that we could do after,

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you know, the second line antibiotic, it was just the third line thing.

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So I would love to see those data be really interesting to see if the company are running any trials in this.

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And that would be great to see and it's really promising. They what brilliant people thank you for and presenting that one.

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No rice. So, sir, my paper today going back to Basic Science, really and with a translational flavour,

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and I wanted to present this paper because it's something that a lot of kind of gastroenterologists wouldn't read unless you're a scientist.

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But actually, it's really interesting, and it is really important for our basic understanding of how the liver works and how it

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goes wrong in diseases and the different techniques we can use to try and work that out.

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So the paper is entitled Spatial Protein Genomics reveals distinct and evolutionary conserved hepatic macrophage niches.

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So it sounds a bit niche and excuse the pun, and it's been recently published in Cell this January and online online only so far.

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And the first author is Gilliam's, and the research was done at Ghent University in Belgium.

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So I'm going to come away from the paper first and go back to what we already know about the

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liver in terms of what it looks like down a microscope and icon needed reminding of this as well.

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So it's organised into hexagonal globules, and in the middle of each globule is a central vein, which flows into the hepatic vein and the IVC.

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So that's sort of systemic rather than portal venous system.

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And that central vein is surrounded by 15 or so concentric layers of the pesticides.

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The parent, the parent kibel cells. And then each corner of this hexagonal abule is a portal.

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Try it. So there's a branch of the portal vein,

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a branch of that particular tree and a ball duck and blood flows from the portal vein into the into the central vein through venous sinus.

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Or it's almost like tiny capillaries that link the portal vein branch to the central vein in the middle,

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and they're lined by a layer of liver, sinusoidal and the cells,

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and then some hepatic stellate cells, which sits in the space of this, which is a space between the al.6, the individual cells and the two sites.

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And they kind of are a bit fibroblast like. And then there's that sites, and there are also other specialised cells in the liver.

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So, for example, one predominant population are called Kupfer cells, and they are specialised liver macrophages.

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So this blood flow that goes from the portal to the central vein creates gradients of oxygen, nutrients,

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hormones and then different sort of morphed genes and that produced by endothelial

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cells that actually sit near the central vein produce signals such as wouldn't.

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And both of these phenomena lead to differential expression of genes within the hepatocytes.

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And this means that across the the lupu, from the portal vein to the central vein, the hepatocytes have different functions.

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And this is called zone. So Zone one tends to be the Perry portal areas.

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And in these Perry portal areas, for example, there's a higher oxygen gradient.

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So there are two sites in zone. One often produce more liver drives secreting plasma proteins, which require oxygen.

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And for their production, Zone two is the in-between bit the middle zone and then Zone three and sort of the central,

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lobular the bit next to the central vein. And so we've known for a while that the liver globules and hepatocytes within them have different functions,

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depending on their location within the lupu.

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What we know less about is the liver non-power and control cells.

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So the non-power in common cells are all ourselves, except for the hip hop sites.

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So, so there's a wide variety of cells here.

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So they include myeloid cells like the four cells, these macrophages, but also other types of macrophages.

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So tissue macrophages and dendritic cells,

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endothelial cells and mesenchymal cells like the hepatic satellite cells and all these cells have a role in liver health and in disease.

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And we it's really important that we understand what their roles.

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And to identify possible therapeutic targets to reverse sort of disease pathogenesis if they're involved.

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There's been a little bit of work on human liver non-parents carbon cells, which was published a few years ago in Nature,

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and that looked at people with healthy livers and cirrhotic livers and looked at the gene expression of the known

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power and control cells and particularly looked at the macrophages and which identified novel cell phenotypes,

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including something a subset of macrophages called scar associated macrophages,

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which were found to be expanded in fibrosis and cirrhosis to pray fibre, fibre, jenek.

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Now what Previous studies haven't been able to do because the nature of single cell RNA sequencing is that you,

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whether it's from animals or from humans, you have either a liver,

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from a mouse or a liver biopsy from a human,

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and you then dissociate the cells from one another so they lose that zoo nation where they are in space within the liver.

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And then you analyse gene expression via RNA sequencing at the single cell level.

220
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But what what you don't get is where they were in the liver in the first place.

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And this can be, well, this is potentially important because we know that with the hepatocytes,

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there's this donation and they have different functions depending on where they sit in the liver.

223
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But we don't know whether this happens or not with normal parent common liver cells and whether that has

224
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an impact on their function and the normal function of the liver and that and what happens in disease.

225
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So this paper,

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the main aim of it was to map the spatial resolution of non-power and chemo liver cell types in healthy and obese human and mouse livers.

227
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And I'm going to present some of the results, but it's a very detailed paper, and I think that I haven't got my head completely around some of it.

228
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So I just wanted to get the main points across and kind of demonstrate what these kind of techniques

229
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can do in terms of and furthering our knowledge of the cell types in the liver and how they work.

230
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So in this, when you say noncurrent Clonmel cells are these are these just immune cells,

231
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these just sort of fortifies immune cells while they obviously don't know.

232
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Yeah. So non-Power and Clonmel cells that they looked at included all the Lone Pine kind of cells.

233
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So yes, it means cells that also mesenchymal cells, mylo derived cells, you know, every, you know,

234
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endothelial cells, all the different cell types in the liver that are not hepatocytes, essentially.

235
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So how did they do this? So they took mouse whole livers and did both in vivo and ex vivo digestion to isolate the

236
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single cells from those mouse livers or single nuclei as an alternative to single cells.

237
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Or they took human livers from liver biopsy samples,

238
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and then they performed RNA sequencing at the single cell or in the case of the mice as well at the single nuclei level.

239
00:27:47,380 --> 00:27:51,520
So they did several different experiments in parallel,

240
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and that enables them to compare the results between experiments to look a little bit into the advantages and disadvantages

241
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of each method and what each the results of each method came up with and how they differed from one another.

242
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The reason they looked at single cell RNA sequencing and compared it with single nuclei sequencing is there is a

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theoretical advantage of the single nucleotide sequencing because the nuclei can be isolated without enzymatic digestion,

244
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which might alter in some cases alter and damage the cells, and they have a higher resistance to physical stress than themselves.

245
00:28:33,310 --> 00:28:42,430
So from a scientific point of view, they were asking some scientific methodological questions in this paper as well.

246
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In addition, they also did something called site SEAC of the single cell RNA sequenced cells.

247
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So what this is is basically it's like flow cytometry, where you add antibodies to cell surface proteins of interest is less, but it's not.

248
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It's not completely unbiased. You can add loads like you might do with a really big multiplex flow cytometry panel,

249
00:29:13,900 --> 00:29:23,620
but instead of having a flower cream attached to these monoclonal. And they have an oligo that you can reach by sequencing.

250
00:29:23,620 --> 00:29:33,610
And so at the same time as getting the dataset from looking at the gene expression of these cells at a single cell level,

251
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you also get a dataset of the surface cell markers that they are expressing at the single cell level.

252
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And that means you can use both datasets together to get really detailed idea of what kind of cells and they are.

253
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And also the functions that they performed because with with RNA sequencing, you're looking at the gene expression,

254
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which doesn't always translate to protein expression, whereas with the sites, you also are seeing protein expression as well.

255
00:30:07,300 --> 00:30:11,440
So really good methods to use together.

256
00:30:11,440 --> 00:30:23,590
And it also has the advantage that you can then use the the neologism proteome genomics in your title, which which makes it makes sounds super swish.

257
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And it is a very, very cool technique.

258
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That's not something that can be used with the spatial transcriptomics, I don't think,

259
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but I think they I don't think they used it, then used another method.

260
00:30:39,940 --> 00:30:49,030
Exactly. Yeah. So then in addition to these methods, they also then said that so for those for all of those methods,

261
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they had to do with the usual cell disassociation.

262
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So the cells that they derived from the liver biopsies or the mouse livers were disassociated

263
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and then sequenced so they didn't retain those where they were in space in the first place.

264
00:31:05,260 --> 00:31:14,440
So in order to look at the spatial and gene expression and protein expression of the cells,

265
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they did a parallel, another parallel experiment where they used a single cell platform called 10X Vision.

266
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And this does perform RNA sequencing from fresh or frozen tissue sections.

267
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So it maintains where these cells are in space and it localise gene expression and that can allow,

268
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identify and ification of cell type within the tissue section. Now you might say, why can't you just look under a microscope?

269
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Well, you can. But looking under a microscope is one of these methods where you'd have to stain with certain things that you're interested in.

270
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So it's not unbiased because you would be looking for particular cell types.

271
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And also, it doesn't give you the level of detail that these kind of sequencing methods give you that enable you not to just identify, say,

272
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a macrophage, but ultimately enable you to identify different subsets of macrophages and where they're sitting in space, if that makes sense.

273
00:32:23,200 --> 00:32:31,430
And these spatial transcriptome techniques, what's the kind of the resolution, how how, how kind of small can they zoom down?

274
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Because at some point you've got to run out of RNA that you can sequence if you if you zoom down to two smaller, small an area of your section?

275
00:32:40,030 --> 00:32:45,130
Yes, that's correct. And the answer is, I don't actually know.

276
00:32:45,130 --> 00:32:48,460
So this was something that was very new to me. I've heard of it.

277
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I've literally heard of it and I've watched on the 10X platform, you know, the the pipeline,

278
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but it's not something I've done myself, so I'm not sure if they get it right down to the single cell level or not.

279
00:33:00,430 --> 00:33:04,540
I'll have to look into that because that's an important question, really.

280
00:33:04,540 --> 00:33:09,550
Yes, I think it's I think I think the technology at the moment isn't quite at the single cell level.

281
00:33:09,550 --> 00:33:16,780
I can't quite remember the kind of diameter of the sort of the circles, the little dots that they they look at.

282
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But it's I think it's kind of at least several cells.

283
00:33:20,560 --> 00:33:28,510
But as you say, yes, you can kind of look for a signal of a particular cell subsets and say sort of where they are.

284
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And the other thing they used, I think, to try and delineate where exact cells were was at the same time as doing spatial transcriptomics.

285
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They then did very complex microscopy.

286
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So they they had to test lots and lots of different antibodies, could not allow.

287
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Antibodies will stay in tissue sections effectively, but they created over 100 plaques panel.

288
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So i.e., you know, they were looking for over 100 different cell surface markers and then looked at them under a microscope

289
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to also delineate alongside the spatial transcriptome data where particular cell types were set up.

290
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That's astounding. I mean, you know, from a microscopy level, I was.

291
00:34:16,820 --> 00:34:22,420
Actually aware that you could you could perform that kind of level of complexity

292
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for that look and that with that many antibodies at a single tissue section.

293
00:34:27,480 --> 00:34:33,810
Again, I'm not very familiar with these kind of microscopy techniques either.

294
00:34:33,810 --> 00:34:42,920
But I mean, they had they said they had to test all the antibodies because, you know, really hard to get them all to work.

295
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So the whole thing is,

296
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is is quite impressive the amount of work and the amount of detail and the different methods they used to try and elucidate exactly what was going on.

297
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Bearing in mind, the different methods have different advantages and disadvantages and can tell you different things.

298
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So what did they find? Well, the first thing they found was what they set out to do, really as the primary aim of the paper.

299
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And that was the mapped the distinct locations of liver, non-power and climate, i.e. non hepatocyte cells.

300
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And they found that lots of these cell types were spatially arranged within a level

301
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of you in zones akin to the hepatocyte zone nation that we're more familiar with.

302
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So some cells, B and T cells and EsEle of cells stromal cells were found across all zones,

303
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but cut for cells were found more in the parimutuel amid zones in mice and in the middle zones in humans and dendritic cells were found.

304
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Harry quarterly and then they used to.

305
00:35:52,710 --> 00:36:00,870
After looking at this data spatially from the spatial transcriptomics and protein and mixed data,

306
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they then use a single cell RNA data to kind of zoom in on particular cell types to identify the heterogeneity within those cells and

307
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then go back to the spatial transcriptomics data and see whether they could identify some of that heterogeneity within that data.

308
00:36:19,620 --> 00:36:28,650
And therefore, was there more? So nation of these non-power and animal cells than first appeared?

309
00:36:28,650 --> 00:36:33,660
So when they zoomed in on the myeloid cells in the single cell RNA sequencing?

310
00:36:33,660 --> 00:36:46,380
So when I say zoom in, basically the dataset you get from a bunch of single cells that have been sequenced is a big array of gene expression of many,

311
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many different genes. And the expression level of each gene is compared between each cell and

312
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differentially expressed genes is singly and then they kind of cluster together,

313
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often cluster together.

314
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So a B cell, for example, might express a particular sets of differentially expressed genes that make it a B cell.

315
00:37:14,940 --> 00:37:20,340
And you can visualise that on a particular particular.

316
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Graphs and identify this cluster is the myeloid cells.

317
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This cluster is a different type of cell, and then you can just take those cells and look at them in more detail and say,

318
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Is there even more differential gene expression between different clusters within these myeloid cells?

319
00:37:40,690 --> 00:37:44,280
So that's what I mean by zooming in so they so they looked at the myeloid cells

320
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that they derived and identified from the single cell RNA sequencing experiment.

321
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And they found that they could identify things like lipid associated macrophages,

322
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which have been previously described and associated with fatty liver,

323
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and they further characterise them using the protein microscopy data and and the by using the protein microscopy data,

324
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they could identify which cell types they were interacting with and and therefore a little bit more about what their function might be.

325
00:38:18,930 --> 00:38:27,450
And they also showed that in livers, both in mice and humans, actually with six or obese mice.

326
00:38:27,450 --> 00:38:39,780
And these particular type of lipid associated macrophages were located in in in the very central area in the state of the liver,

327
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alongside areas of steatosis. So that and points that they might be involved in the Stewart-Haas process,

328
00:38:47,520 --> 00:38:56,100
either as a bystander, as a protective mechanism, or they could be, you know, pathogenic.

329
00:38:56,100 --> 00:39:01,860
And then they they zoomed in on the CD4, which five negative signal immune cells.

330
00:39:01,860 --> 00:39:05,910
And although in their original spatial transcriptomic analysis,

331
00:39:05,910 --> 00:39:16,640
they found that endothelial cells and stromal cells were found right across all zones of the liver lobular and the single cell RNA.

332
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A sequencing analysis identified different subsets within within these and aethereal stromal cells,

333
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which and the macrophages in particular could be done locate two distinct vaccination patterns within the Liberals.

334
00:39:35,210 --> 00:39:41,990
When you analysed and put that data together and then finally,

335
00:39:41,990 --> 00:39:53,390
they looked at the signature the genetic expression signature of four cells and the basically in Inhumans,

336
00:39:53,390 --> 00:40:05,270
there was no really good way of identifying a cut for cell, the expression of various surface proteins or gene expression at the RNA level.

337
00:40:05,270 --> 00:40:12,860
It was, they were they were expressed by other cells as well, so it's difficult to pull them out.

338
00:40:12,860 --> 00:40:19,200
So they looked at this in detail and using the site data.

339
00:40:19,200 --> 00:40:25,610
So the single cell level and the RNA sequencing data at the single cell level,

340
00:40:25,610 --> 00:40:37,850
they could identify i.e. a better gating strategy which can be used in flow cytometry or microscopy to identify cells accurately.

341
00:40:37,850 --> 00:40:47,240
So that's important for experiments going forward. So I've just demonstrated some of the results in brief detail, really.

342
00:40:47,240 --> 00:40:51,350
But to kind of demonstrate, and I think this is what this paper was all about,

343
00:40:51,350 --> 00:41:00,620
it was demonstrating how to use multiple different methods to build a picture of what was going on in the liver.

344
00:41:00,620 --> 00:41:12,650
So this is it to mention the Victorians, again, you know, this is the kind of like definitive map of these of these known paroxysmal cells.

345
00:41:12,650 --> 00:41:19,010
So like not only the types of cells that are there, but also where they are.

346
00:41:19,010 --> 00:41:26,990
And then and then what they've kind of hypothesised is is speculated about different interactions or protect.

347
00:41:26,990 --> 00:41:36,860
But these potential like ligand receptor pairs. So not only what are the different types of cells where they are and who might be talking to who?

348
00:41:36,860 --> 00:41:47,570
Why? Is this going to change the way we kind of think about, I guess, the more translational studies where we're looking at kind of disease processes?

349
00:41:47,570 --> 00:42:00,020
So I think that what it might enable us to do is look at healthy versus disease process livers, for example,

350
00:42:00,020 --> 00:42:08,480
and understand how some of these cells are arranged differently in disease compared to health.

351
00:42:08,480 --> 00:42:21,500
And it will also enable us to understand which cells they are talking to and more directed questions will need to be asked in order to do that.

352
00:42:21,500 --> 00:42:32,330
It's not going to be a let's map all the cells in livers with autoimmune hepatitis necessarily, although that could be done.

353
00:42:32,330 --> 00:42:38,480
But then you'd have to drill down like this paper did drill down into the macrophages and say,

354
00:42:38,480 --> 00:42:44,510
we weren't particularly interested in this cell population. What happens in autoimmune hepatitis compared to healthy people?

355
00:42:44,510 --> 00:42:54,650
And ultimately, the hope really is that we understand the pathogenesis of disease better and that we can then develop better therapies,

356
00:42:54,650 --> 00:43:03,560
you know, identify therapeutic targets or identify things that we can answer better to better treat these diseases.

357
00:43:03,560 --> 00:43:07,010
I mean, that's a long way down the line, but that's the ultimate aim.

358
00:43:07,010 --> 00:43:15,050
I think I think autoimmune hepatitis is an interesting one to mention because I'm and I have to remind myself about the power,

359
00:43:15,050 --> 00:43:21,110
the histological findings. But from sifting through many histological liver meetings,

360
00:43:21,110 --> 00:43:29,300
the the cellular infiltrate that you see is is not evenly distributed throughout, you know, the liver biopsy.

361
00:43:29,300 --> 00:43:40,430
And, you know, the cellular infiltrates Apache and they have a sort of specific like orientation within the kind of the portal tract structure.

362
00:43:40,430 --> 00:43:49,850
And you know, if we can then start to understand where those cells are and what what might be driving that localisation,

363
00:43:49,850 --> 00:43:56,390
then he gets a little bit closer to try and understand what's actually driving these autoimmune processes in terms of.

364
00:43:56,390 --> 00:44:04,850
Antigens and things like that. Exactly. Super exciting when there's and and yes, you can do that partially by looking under a microscope,

365
00:44:04,850 --> 00:44:09,260
as I said on a liver biopsy, because you can steam for different cell types.

366
00:44:09,260 --> 00:44:14,750
But that is a biased approach because you have to decide which stains you add to that biopsy.

367
00:44:14,750 --> 00:44:24,350
Whereas all these kind of transcriptomic approaches the single cell level and not biased in that way,

368
00:44:24,350 --> 00:44:33,050
they're not asking which cells are next to the cells were interested in, they just finding what the different cells are.

369
00:44:33,050 --> 00:44:43,490
And and that has far greater possibility of therefore identifying what might actually be important in the pathogenesis.

370
00:44:43,490 --> 00:44:49,580
So hopefully that's, you know, I mean, probably clear as mud, but it is a complicated paper.

371
00:44:49,580 --> 00:44:56,090
But I thought it was important in general to discuss about some of these different methods,

372
00:44:56,090 --> 00:45:02,630
and it's quite exciting to think about what kind of things that we can elucidate from them.

373
00:45:02,630 --> 00:45:09,350
Yeah, it's a pretty astounding, but, you know, sort of programme of work that they did in terms of both, you know,

374
00:45:09,350 --> 00:45:17,000
just the the scale and cost of the experiments that they've run, but also, you know, their eye watering amounts of work.

375
00:45:17,000 --> 00:45:22,430
And you know, also I can imagine there's all sorts of little things that are hugely important for,

376
00:45:22,430 --> 00:45:28,280
you know, other other researchers with much more targeted translational questions, as we've discussed.

377
00:45:28,280 --> 00:45:35,840
Exactly because with that sort of data status, you can ask all sorts of questions with it.

378
00:45:35,840 --> 00:45:46,880
Yes, it's very interesting that Sokratis won't.

379
00:45:46,880 --> 00:45:51,890
So we should be five and five. So this is our five in five section,

380
00:45:51,890 --> 00:45:56,180
we should probably rebrand it five and 15 or something like that where we try

381
00:45:56,180 --> 00:46:03,470
and rapidly whiz through five interesting papers and a little bit less detail,

382
00:46:03,470 --> 00:46:08,630
but just sort of makes you aware of some other things to kind of guide you or your reading.

383
00:46:08,630 --> 00:46:13,460
So I'm I'm going to start with one, if that's right. Tamsin, yeah, go for this.

384
00:46:13,460 --> 00:46:17,330
This is super topical and actually it's not a not a research paper.

385
00:46:17,330 --> 00:46:23,480
This is a cool briefing from the UK Health Security Agency.

386
00:46:23,480 --> 00:46:27,980
This is the first technical briefing from the Health Security Agency that I've ever,

387
00:46:27,980 --> 00:46:37,850
ever read, and this is this is published the week before last 25th of April.

388
00:46:37,850 --> 00:46:50,150
And this is there is a UK government investigation into the outbreak of acute non-native hepatitis in children in England.

389
00:46:50,150 --> 00:46:58,310
So as you may know, up until the 20th of April 2022, since the beginning of this year,

390
00:46:58,310 --> 00:47:06,170
there have been 111 cases of acute non a non e hepatitis in children.

391
00:47:06,170 --> 00:47:16,070
So these children have had trans. Amina's is greater than 500 alto AEST greater than 500 in kids less than 16 years old.

392
00:47:16,070 --> 00:47:22,850
And that presentation is really uncommon. And you know, some of the historical data suggests that, you know,

393
00:47:22,850 --> 00:47:29,750
this is a big increase like an order of magnitude increase in the kind of the usual rate.

394
00:47:29,750 --> 00:47:37,190
And this rang alarm bells quite early on back in sort of late February, early March.

395
00:47:37,190 --> 00:47:41,240
And then they've they've been doing this investigation, this technical briefing.

396
00:47:41,240 --> 00:47:45,260
And so they're really reporting about the children who've been affected and what

397
00:47:45,260 --> 00:47:50,600
sort of going on with them and their current hypotheses for for might be happening.

398
00:47:50,600 --> 00:47:55,460
And I mention this because it's been in the newspapers. You know, there's lots of talk on Twitter.

399
00:47:55,460 --> 00:48:08,960
It's raised, particularly given the setting is of COVID 19, a lot of a lot of concerns about whether this is directly COVID related or so on.

400
00:48:08,960 --> 00:48:14,030
And so there's been a lot of speculation about it. This technical briefing is super helpful.

401
00:48:14,030 --> 00:48:20,450
It's it was actually quite a good read. I was expecting a super dry documents, but actually it was.

402
00:48:20,450 --> 00:48:29,090
It was pretty punchy and it was very clear about what their findings were and kind of refreshingly compared to an academic paper that wasn't,

403
00:48:29,090 --> 00:48:34,400
you know, knowing paragraphs of introduction, discussing, discussing it all.

404
00:48:34,400 --> 00:48:39,020
So of these 111 cases, almost all of them are under fire,

405
00:48:39,020 --> 00:48:47,690
so most of them aged between three and five years old and they are as as often in these cases,

406
00:48:47,690 --> 00:48:52,160
they often present with non-specific GI symptoms, lots of nausea, vomiting,

407
00:48:52,160 --> 00:48:59,790
mild diarrhoea and then followed on with with jaundice, lethargy and and so on.

408
00:48:59,790 --> 00:49:08,210
I'm in the very detailed histories from these, from these patients who, you know, sort of contact tracing and and so on.

409
00:49:08,210 --> 00:49:12,350
And there's no obvious notable environmental exposures.

410
00:49:12,350 --> 00:49:20,510
That's these these kids have above above the usual. If we look at the that of the total group of the 111 cases,

411
00:49:20,510 --> 00:49:24,650
some of them have been really unwell and actually seven have gone on to acquire a liver transplant.

412
00:49:24,650 --> 00:49:33,590
So this is not this is not a benign outbreak. You know, these couple of some of these kids have been been really unwell reassuringly and recently,

413
00:49:33,590 --> 00:49:39,830
you know, none of these children have died from that from this outbreak of hepatitis.

414
00:49:39,830 --> 00:49:48,740
So they then go on and talk about their kind of work in progress of looking at potential viral causes,

415
00:49:48,740 --> 00:49:52,070
which was the sort of the number one kind of suspect.

416
00:49:52,070 --> 00:49:59,540
And they tested for most of the kind of usual suspects things like, you know, either EBV, CMC path, a virus.

417
00:49:59,540 --> 00:50:07,310
They also looked at a den of viruses that have that were suspected as well as SARS-CoV-2.

418
00:50:07,310 --> 00:50:20,210
So COVID 19 of the samples that have been sequenced, 53 have been sequenced for adenovirus and 40 of those have been positive.

419
00:50:20,210 --> 00:50:26,420
So that is that no one's suspect pathogen for triggering these cases.

420
00:50:26,420 --> 00:50:36,080
So of the samples sequenced around 80 percent to be positive for adenovirus in the blood, and 11 of them have been typed.

421
00:50:36,080 --> 00:50:46,360
There are loads of different types of DNA viruses, and all 11 are a particular type side effects like 41 f for those those who are interested.

422
00:50:46,360 --> 00:50:53,890
And what's interesting, if they've looked at total numbers of sort of adenovirus positive samples in the general child population,

423
00:50:53,890 --> 00:50:59,950
and what they've noticed is that during lockdowns, these these are generally very benign viruses.

424
00:50:59,950 --> 00:51:06,340
Minimally symptomatic, which are commonly everyone's commonly exposed to, particularly in kind of nursery age kids.

425
00:51:06,340 --> 00:51:13,240
The number of those adenovirus cases went massively down during lockdowns and really stayed low until the sort

426
00:51:13,240 --> 00:51:22,180
of second half of 2021 when they've shot right up and actually at much higher levels than we would usually see.

427
00:51:22,180 --> 00:51:28,630
They did look for the SARS-CoV-2 virus of the 60s,

428
00:51:28,630 --> 00:51:36,400
60 patients who were the sort of the testing was performed, 10 of them were positive for SARS-CoV-2.

429
00:51:36,400 --> 00:51:41,740
So sort of at a rate, a rate of sort of 17 or so percent,

430
00:51:41,740 --> 00:51:47,740
which is in their discussion is actually kind of not far off what they would expect from

431
00:51:47,740 --> 00:51:55,570
a sort of a pretty random vaccination on these in terms of the strain of the SARS-CoV-2.

432
00:51:55,570 --> 00:52:04,390
So in the variants, these these were the currently circulating, you know, based on the current strains.

433
00:52:04,390 --> 00:52:15,430
So this doesn't seem to be related to a new new variant. And they they then discussed some of the data about severe COVID and trends,

434
00:52:15,430 --> 00:52:22,260
ominous trends, laminitis and actually in sort of large international data sets trends.

435
00:52:22,260 --> 00:52:26,830
And it's really, really uncommon presentation even in severe COVID.

436
00:52:26,830 --> 00:52:34,060
So in their dataset of 8000 kids who had severe COVID. Only 13 of them had a trans laminitis greater than 500.

437
00:52:34,060 --> 00:52:43,510
So. And they make the point that this this seems to be unlikely to be directly related to SARS-CoV-2 infection.

438
00:52:43,510 --> 00:52:51,280
So that number one hypothesis is that this current outbreak is related to adenovirus.

439
00:52:51,280 --> 00:52:55,450
What they're unsure about is why it is causing this.

440
00:52:55,450 --> 00:53:03,340
Severe trends overnight is when these adenovirus is normally circulate and this is a very unusual cause,

441
00:53:03,340 --> 00:53:08,080
unusual sort of set of symptoms from adenovirus.

442
00:53:08,080 --> 00:53:17,410
So they think that for some reason, either because of the virus or because of, you know, the immunity of the of the host.

443
00:53:17,410 --> 00:53:23,170
There's there's some kind of cofactor that's causing more severe clinical manifestations.

444
00:53:23,170 --> 00:53:30,940
And what that is is is unclear. Could it be that it's just because these kids have been exposed to fewer of

445
00:53:30,940 --> 00:53:36,130
these infections and that maybe I'm getting the infection a little bit later?

446
00:53:36,130 --> 00:53:42,100
I in in childhood increases the risk of these, these complications.

447
00:53:42,100 --> 00:53:52,630
Could it be that prior SARS-CoV-2 infection, given that 90 percent of the UK population has had COVID over the last two years,

448
00:53:52,630 --> 00:53:59,920
is it that prior SARS-CoV-2 infection somehow? Potentially it's this affects when they then get adenovirus?

449
00:53:59,920 --> 00:54:03,190
Or is there another key factor that's not being looked at?

450
00:54:03,190 --> 00:54:09,130
And there's no evidence that this is a novel adenovirus strain, but they want to sequence sequence more.

451
00:54:09,130 --> 00:54:13,030
So those are they're kind of working hypotheses,

452
00:54:13,030 --> 00:54:19,600
and I think it's a really helpful documents to kind of to kind of show the work that

453
00:54:19,600 --> 00:54:26,590
goes in in in these in these agencies to kind of work out what's causing outbreaks.

454
00:54:26,590 --> 00:54:31,630
And also, I think to provide some kind of reassurance and clarity as what what are the likely causes.

455
00:54:31,630 --> 00:54:34,930
So in that sense, I think it's quite a helpful document.

456
00:54:34,930 --> 00:54:41,880
I guess the big caveat is that this is all still early days and there were additional reports from other countries who are seeing similar effects.

457
00:54:41,880 --> 00:54:50,650
So I think this is all very much a work in progress and I guess we might be be returning to it at some point.

458
00:54:50,650 --> 00:54:57,590
Very interesting. It would be very interesting to see what comes out of some of the research into this as to what the cause is for.

459
00:54:57,590 --> 00:55:07,450
Yeah, I guess the thing the sort of the big picture, I guess as a as a parents, I was sort of, you know, bit freaks when I first saw these things.

460
00:55:07,450 --> 00:55:13,390
Is that actually in the grand scheme of things? This seems to be a really rare thing.

461
00:55:13,390 --> 00:55:20,290
You know, this is 111 kids, you know, when there are several million children in this age group.

462
00:55:20,290 --> 00:55:26,440
So this is a really uncommon thing, but it's clearly really important that we understand what's what's driving it.

463
00:55:26,440 --> 00:55:30,820
You know, it's very good. Slowly, one quickly.

464
00:55:30,820 --> 00:55:36,400
Yeah, that's right. So this isn't a research paper either.

465
00:55:36,400 --> 00:55:46,270
But and I think a lot of people will know about this. It's been heavily discussed on various platforms, but this was in.

466
00:55:46,270 --> 00:55:50,350
The recent addition of front line gastroenterology,

467
00:55:50,350 --> 00:55:58,750
so this may and it's the Jack consensus statements for training and certification in so that's in the UK.

468
00:55:58,750 --> 00:56:15,040
So basically they've they've reviewed all the requirements for training in upper GI endoscopy and the they used a modified delfi process.

469
00:56:15,040 --> 00:56:26,380
And the people sort of on the panel as such were Jack So Joint Advisory Group on Gastro Gastrointestinal Endoscopy, which is UK based,

470
00:56:26,380 --> 00:56:39,640
the British Society of Gastroenterology and the Association of Upper GI Surgeons and all in the UK and the came up with several different and over 30.

471
00:56:39,640 --> 00:56:50,970
I think the statements in relation to training and certification in Ogidi and the panel members were asked to to vote with it.

472
00:56:50,970 --> 00:57:04,510
The evidence was reviewed and they provided recommendations based on what, what the different people in the panels thought.

473
00:57:04,510 --> 00:57:10,570
And this is going to have an impact on everyone who's training in the UK for John Speak.

474
00:57:10,570 --> 00:57:15,640
So I'm just quickly going to summarise what the recommendations are.

475
00:57:15,640 --> 00:57:21,310
Some of them are the same as previously, and some of them have changed, so they recommend an early training.

476
00:57:21,310 --> 00:57:24,790
You need to do a basic skills course, you need to do one offs,

477
00:57:24,790 --> 00:57:31,810
every 10 procedure and a reflection, every 50 clinical cases, which I don't think I have done.

478
00:57:31,810 --> 00:57:39,400
So I think that is new. And then the other thing is, how do you determine how does how does one reflect on an endoscopy?

479
00:57:39,400 --> 00:57:48,480
Is that on jets? Well, I think I presume so, and they have recently changed the Jets website.

480
00:57:48,480 --> 00:57:58,950
So I wonder if I think this is something that's coming in because I certainly haven't reflected on any yet in objets, but I think this is on jets.

481
00:57:58,950 --> 00:58:07,500
And then they also recommend having a regular appraisal with a $10 to be trainer. One particular industry trainer rather than, you know,

482
00:58:07,500 --> 00:58:15,030
you might go to lists with several different and Oscar fists over the time of your training just to see how you how you doing,

483
00:58:15,030 --> 00:58:18,450
how you progressing and then what's.

484
00:58:18,450 --> 00:58:25,650
What's really changed, I think, is the eligibility for summative assessments for sign off.

485
00:58:25,650 --> 00:58:34,260
So previously you needed to have done at least two hundred and procedures and logged on jets and and four people.

486
00:58:34,260 --> 00:58:39,480
So I was going to say to people outside the UK, but probably no one listens outside the UK anyway.

487
00:58:39,480 --> 00:58:44,370
Jets is where you record all your industries and training in the UK.

488
00:58:44,370 --> 00:58:53,850
They've increased up to 250 and this is based on not on data that isn't necessarily the best quality,

489
00:58:53,850 --> 00:59:05,610
but that does suggest that although by 200 cases, most people can get to D2 and do a procedure fine.

490
00:59:05,610 --> 00:59:12,330
Some of the other skills that they want you to acquire so management is pathology management and detection pathology,

491
00:59:12,330 --> 00:59:21,750
and some of the non-technical skills place procedural skills are actually achieved after more than 200 procedures.

492
00:59:21,750 --> 00:59:31,530
So it's to allow for that. You also have to have over 95 percent in the last three months.

493
00:59:31,530 --> 00:59:40,560
Ninety five percent of the time you need to have got to D2 unassisted and have performed the manoeuvre, and you need to have done nine dots,

494
00:59:40,560 --> 00:59:47,640
say three from three different assessors in the last hundred procedures that have shaped and in the last five dopes,

495
00:59:47,640 --> 00:59:59,340
you have to be competent in 90 percent of the items in those jobs. So I think all of those stipulations, most of those stipulations are new.

496
00:59:59,340 --> 01:00:04,830
And then you can go and have your summative assessment to two independent assessors for subject tops.

497
01:00:04,830 --> 01:00:08,380
And the other thing that I think is also a change in currently,

498
01:00:08,380 --> 01:00:14,610
if I'm wrong and they've recommended that post certification now you do at least 100

499
01:00:14,610 --> 01:00:19,290
procedures in the first year after that and you do have an assigned kind of supervisor.

500
01:00:19,290 --> 01:00:28,770
And I have some sort of overview as well post certification, continuation of of training because I guess,

501
01:00:28,770 --> 01:00:38,430
you know, even by 250 procedures, we're still learning or learning all the time and and and improving.

502
01:00:38,430 --> 01:00:48,600
So that's the summary. And I just wanted to mention it because it's going to affect all UK trainees and I think

503
01:00:48,600 --> 01:00:51,600
different people will have different opinions on whether that's a good or bad thing.

504
01:00:51,600 --> 01:01:01,350
Personally, I think overall, it's a good thing that just trying to strengthen the the training that we get and ultimately improve,

505
01:01:01,350 --> 01:01:10,300
hopefully that will translate to improvements in in patient outcomes and make us better or better endoscope tests.

506
01:01:10,300 --> 01:01:12,880
Yeah, I think.

507
01:01:12,880 --> 01:01:28,000
I think the JAG training standards are, you know, from an international perspective or, you know, a great driver for both training quality.

508
01:01:28,000 --> 01:01:34,370
You know, in the UK, but also just, you know, standards of an industry in the UK, and I think they've been a great force for good.

509
01:01:34,370 --> 01:01:38,860
Yeah, I think I think there's a balance.

510
01:01:38,860 --> 01:01:48,970
I think quite a lot of the less positive reception on social media in particular about this is that it

511
01:01:48,970 --> 01:01:59,290
creates sometimes a lot of slightly officious hoops in order to to jump through in order to get signed off.

512
01:01:59,290 --> 01:02:05,980
And some of the things I have slight questions about educationally, I think, you know,

513
01:02:05,980 --> 01:02:14,110
mandated reflections at certain intervals doesn't really have very much, you know, basic, you know, educational basis.

514
01:02:14,110 --> 01:02:23,690
I don't think it's an unreasonable number of reflections, but. The concept of mandated reflections is a bit is a bit odd.

515
01:02:23,690 --> 01:02:30,590
And then things about like numbers of assessors and things like that, and I can totally see the principle why?

516
01:02:30,590 --> 01:02:35,790
But again, in some units, if you're working in a small unit, small unit, actually, that's very difficult.

517
01:02:35,790 --> 01:02:46,010
This actually starts becoming quite tricky. And you write in small units, different rules at the time when you know, gastro training is shortening.

518
01:02:46,010 --> 01:02:54,110
When I think all the specialities are surgical trainees often struggle to get endoscopic competency training.

519
01:02:54,110 --> 01:03:02,420
They can feel that like, well, we're creating more barriers to people progressing in their in their training.

520
01:03:02,420 --> 01:03:09,620
So I think there's a there's a balance there, and I'm not quite sure exactly where where this falls.

521
01:03:09,620 --> 01:03:15,530
But overall, my opinion is that the drug trading criteria are overall a force for good.

522
01:03:15,530 --> 01:03:28,040
Yeah. And I think I think you're right and it's a very sensible and I hope that I get shot by any of this via the endoscopy police, those companies.

523
01:03:28,040 --> 01:03:33,620
Hopefully, they're balanced swiftly. Moving on, would you like to do another?

524
01:03:33,620 --> 01:03:38,480
Yeah. Well, I just I just want to say the pickles for the end. Yes, absolutely.

525
01:03:38,480 --> 01:03:47,210
Right. Why don't I do a couple and we'll say yes, that's just a little taster for the sweet taste of pickles will come the end.

526
01:03:47,210 --> 01:03:49,760
Right? Okay. I've got two more.

527
01:03:49,760 --> 01:03:57,950
The next one is a randomised, controlled trial from the New England Journal of Medicine, which only slips in in the five and five.

528
01:03:57,950 --> 01:04:10,430
This is another dieting. Weight loss obesity trial, which is kind of resonates with a couple of the things that I've picked out recently.

529
01:04:10,430 --> 01:04:16,970
It's not only because I need to lose a bit of weight, but I guess I'm very much of the opinion.

530
01:04:16,970 --> 01:04:19,760
You know, obesity is due to just such.

531
01:04:19,760 --> 01:04:29,360
It is the major driving health problem of our time, and yet we really have a pretty terrible range of of treatments for that.

532
01:04:29,360 --> 01:04:38,750
So in terms of dietary therapies most dietary approaches have, we'll probably only be described as a modest effect on weight.

533
01:04:38,750 --> 01:04:43,500
So, you know, we're only looking at trying to generate a five percent weight loss.

534
01:04:43,500 --> 01:04:48,740
And generally dietary therapies are pretty rubbish at even getting to that pretty low bar.

535
01:04:48,740 --> 01:04:52,280
And often, what we see with dietary therapies, even when done well,

536
01:04:52,280 --> 01:04:59,630
is that people may lose a few percent of their body weight, but the more rapidly we accumulate it, we don't have some drugs.

537
01:04:59,630 --> 01:05:04,640
So semaglutide a trial that I think we mentioned a few episodes ago,

538
01:05:04,640 --> 01:05:13,250
which has shown some some efficacy if if weight loss in the region of sort of 10 to 12 percent for memory.

539
01:05:13,250 --> 01:05:19,640
Although in the UK, it's pretty, pretty hard to get hold of a prescription, certainly on the NHS.

540
01:05:19,640 --> 01:05:28,010
And then we've got bariatric surgery, which I think is underused, underfunded in this country and is really highly effective.

541
01:05:28,010 --> 01:05:33,830
But it's certainly resource intensive and is in this country,

542
01:05:33,830 --> 01:05:41,330
is not well funded and clearly comes with considerable risk and we're really stuck with dietary therapies.

543
01:05:41,330 --> 01:05:46,340
And so when people try weight loss, weight loss strategies,

544
01:05:46,340 --> 01:05:54,500
I'm quite rightly I think people have moved away from the sort of very simple calorie in calorie out equation.

545
01:05:54,500 --> 01:06:03,500
And if people have incorporated other strategies to try and reduce it to sort of suppress appetite and overall calorie caloric intake.

546
01:06:03,500 --> 01:06:13,520
And one method that's often espoused are different versions of intermittent fasting and one intermittent fasting strategy is time restricted eating.

547
01:06:13,520 --> 01:06:18,260
And the premise of this is that you only eat food during a shorter period in the day,

548
01:06:18,260 --> 01:06:23,510
and this both makes a certain amount of intuitive sense that you know you,

549
01:06:23,510 --> 01:06:27,890
you, you, then you know, you're kind of satiating yourself with, you know,

550
01:06:27,890 --> 01:06:32,420
a couple of meals quite close together and then and then fasting afterwards.

551
01:06:32,420 --> 01:06:36,860
There's a little bit of support from some kind of a circadian biology aspect about the

552
01:06:36,860 --> 01:06:42,320
controls of appetite that maybe this could be helpful the way appetite is regulated.

553
01:06:42,320 --> 01:06:53,030
And certainly you feel it's the evidence suggests that a big evening meals may be worse the kind of weight gain than eating earlier in the day.

554
01:06:53,030 --> 01:07:00,600
And it's a pretty simple option. You basically just restrict your eating between like, you know, eight eight a.m. and four p.m. That's that's it.

555
01:07:00,600 --> 01:07:06,830
So it's gained popularity because it's nice, simple method, and there is some supporting observational data,

556
01:07:06,830 --> 01:07:12,860
although short term trials haven't shown a great deal of effect.

557
01:07:12,860 --> 01:07:17,610
So it's affecting kind of the longer term situation setting over the kind of.

558
01:07:17,610 --> 01:07:20,820
A year time scale is not well understood.

559
01:07:20,820 --> 01:07:31,410
And so this randomised controlled trial was looking to examine the effects of time, restrictive time, restricted eating on weight loss.

560
01:07:31,410 --> 01:07:36,240
So this is an act from China, and it had two arms in it.

561
01:07:36,240 --> 01:07:41,160
One was just doing caloric restricted restriction.

562
01:07:41,160 --> 01:07:50,370
So they told them to eat approximately 75 to 80 percent of their their normal intakes of around 1500 218 kilocalories a day.

563
01:07:50,370 --> 01:07:59,850
And then the other arm was told to do that, but to do it within a time restricted window, say, between eight a.m. and four p.m.

564
01:07:59,850 --> 01:08:07,290
The trial was looking out over 12 months when we look at the entry criteria,

565
01:08:07,290 --> 01:08:14,410
the BMI entry criteria were 20, were were between 28 and 45 and 28 is in this country.

566
01:08:14,410 --> 01:08:25,320
It is not obese. So we are looking looking at some people who are certainly from, from a UK perspective, not particularly chunky.

567
01:08:25,320 --> 01:08:29,220
They had to be in pretty good shape. I had to have. I think this is one of my biggest concerns about this.

568
01:08:29,220 --> 01:08:38,370
They basically excluded everyone with any kind of circulatory disease, stroke, TIA, heart disease, diabetes, anything like that.

569
01:08:38,370 --> 01:08:42,180
So basically, all the people who really need this,

570
01:08:42,180 --> 01:08:51,840
they've excluded and that that does worry me and it does worry me about the sort of the generalised generalisability of these data.

571
01:08:51,840 --> 01:08:59,700
So as I said, they were all told to eat about 75 percent of their normal caloric intake they had.

572
01:08:59,700 --> 01:09:02,970
The diet was generally kind of carb predominance.

573
01:09:02,970 --> 01:09:11,910
So sort of 50 odd percent carb randomly, they gave them a protein shake for the first six months of the trial, just one day as a freebie.

574
01:09:11,910 --> 01:09:17,140
I think, and I don't really understand what it is, it makes no sense in the setting of this trial.

575
01:09:17,140 --> 01:09:20,820
I can only see that it was maybe an incentive to join the trial.

576
01:09:20,820 --> 01:09:22,560
I don't really know.

577
01:09:22,560 --> 01:09:29,910
And and importantly, probably the most important thing is that they controlled the amount of inputs they had in terms of kind of support, like diet,

578
01:09:29,910 --> 01:09:38,520
dietetic inputs and info and stuff, because there is pretty good data that if you give people more like dietetic support,

579
01:09:38,520 --> 01:09:42,240
they're better at following the the advice that you. Yeah, yeah.

580
01:09:42,240 --> 01:09:51,090
So the primary outcome was a difference in weight loss between the arms. And they looked at lots of interesting metabolic secondary outcomes.

581
01:09:51,090 --> 01:09:59,790
So they had 139 participants. They power to this, looking for 2.5 kilo weight difference between the arms.

582
01:09:59,790 --> 01:10:04,860
Those 139 participants were not enormously fat.

583
01:10:04,860 --> 01:10:09,360
That's the first thing I would say. So the mean BMI was 31.

584
01:10:09,360 --> 01:10:12,750
So the mean BMI was in the obese category,

585
01:10:12,750 --> 01:10:20,190
but certainly means there's a good chunk of these who of these participants who were in the BMI of like 28 to 30.

586
01:10:20,190 --> 01:10:24,870
So only in the overweight brackets, adherence was pretty good.

587
01:10:24,870 --> 01:10:32,610
So they had 85 percent of of participants completed the 12 months, which I think is pretty, pretty impressive.

588
01:10:32,610 --> 01:10:37,020
Impressive adherence. Yeah, we adherence between the two arms was similar.

589
01:10:37,020 --> 01:10:39,540
So I guess the first thing is time restricted.

590
01:10:39,540 --> 01:10:49,320
Eating doesn't seem to be any more onerous in terms of adherence than just a caloric restriction in the calorie control arm.

591
01:10:49,320 --> 01:10:56,680
They the participants lost 6.3 kilos, so that's actually a really good weight loss for a for a dieting diet.

592
01:10:56,680 --> 01:11:02,070
So you add in the time restricted arm, they lost about eight kilos, so slightly more.

593
01:11:02,070 --> 01:11:09,060
But that difference was only sort of 1.7 1.8 kilos, and that was not statistically significant.

594
01:11:09,060 --> 01:11:13,270
I'm looking at the kind of graphs of how people's weight went.

595
01:11:13,270 --> 01:11:21,300
What's kind of interesting is that both groups lost about nine kilos at six months, but then by 12 months,

596
01:11:21,300 --> 01:11:31,510
the calorie control alone was then gone to six kilos, whereas the time restraints had got eight weight kilos.

597
01:11:31,510 --> 01:11:40,560
So perhaps time restricted eating helps helps kind of maintain that that initial weight loss.

598
01:11:40,560 --> 01:11:48,660
Although that wasn't the primary outcome of this study, they looked at loads of interesting metabolic outcomes of insulin resistance and,

599
01:11:48,660 --> 01:11:53,940
you know, body fat capacity and also composition and so on.

600
01:11:53,940 --> 01:11:59,880
And the broad summary is that none of these metabolic outcomes were any difference in the trial.

601
01:11:59,880 --> 01:12:08,400
This basically everything seems to be mediated by weight loss as opposed to the kind of the eating pattern.

602
01:12:08,400 --> 01:12:14,340
So overall, I think this is somewhat of a negative trial, which is a bit of a shame.

603
01:12:14,340 --> 01:12:18,660
But I think it shows that this approach is not necessarily a bad approach.

604
01:12:18,660 --> 01:12:23,520
This approach didn't seem to be more harmful. It didn't compromise weight loss.

605
01:12:23,520 --> 01:12:27,960
It didn't compromise adherence. And maybe it makes the.

606
01:12:27,960 --> 01:12:35,250
Maybe it's a way of eating with which, if sustained, enables people to maintain their weight loss for longer.

607
01:12:35,250 --> 01:12:39,600
I think the kind of key take home is like lots of these dietary studies.

608
01:12:39,600 --> 01:12:47,550
I think the key factor is is what works for the individual and what enables the best sort of weight loss for them.

609
01:12:47,550 --> 01:12:54,300
And I think, you know, it's it's about horses for courses, and I will sing the praises of dietitians as a speciality.

610
01:12:54,300 --> 01:13:03,660
You know, this is this is why we need people who are real experts in advising people on personalised dietetic plans because they all lost weight.

611
01:13:03,660 --> 01:13:08,190
Actually, they did so well. Yeah, yeah, yeah.

612
01:13:08,190 --> 01:13:13,470
How to change human behaviour. We still haven't cracked it basically. Very tricky.

613
01:13:13,470 --> 01:13:20,130
Very tricky. Okay. And your last patient to another, you do another so that we can save the pickles.

614
01:13:20,130 --> 01:13:28,890
This one looks good as well. Yeah. Lovely. So this is an interesting one, as it's essentially it's a UK based trial.

615
01:13:28,890 --> 01:13:38,190
And I know some of the authors on the paper. So I I did want to mention this,

616
01:13:38,190 --> 01:13:44,970
and I think it's it's quite I have to say I saw the title and I got mild palpitations

617
01:13:44,970 --> 01:13:51,330
because it's about a topic that certainly challenges quite a lot of dogma in the IBD world.

618
01:13:51,330 --> 01:13:57,480
It's the title of this paper was ambulatory care management of 69 patients with acute severe

619
01:13:57,480 --> 01:14:06,720
ulcerative colitis in comparison to 60 695 inpatients insights from a multicenter UK cohort study.

620
01:14:06,720 --> 01:14:15,270
And these are collaborators in the Protect You Protect as you see trial, which sorry study,

621
01:14:15,270 --> 01:14:23,880
which is a multicenter observational study of ulcerative colitis I think set up during COVID and is

622
01:14:23,880 --> 01:14:32,610
looking at the management of acute severe ulcerative colitis in different UK centres during the pandemic.

623
01:14:32,610 --> 01:14:40,590
So just to sort of the brief prices of acute severe ulcerative colitis is that it affects, you know,

624
01:14:40,590 --> 01:14:46,320
around 20 percent of patients with ulcerative colitis during that, you know, during their disease course.

625
01:14:46,320 --> 01:14:51,390
And you know, it's considered a sort of a gastrointestinal emergency.

626
01:14:51,390 --> 01:14:58,740
This is something that needs inpatient urgent management with high dose IV steroids.

627
01:14:58,740 --> 01:15:05,010
And and then I think consideration of kind of secondary rescue therapy and in some patients surgery.

628
01:15:05,010 --> 01:15:11,370
So approximately 10 to 15 percent of patients with acute severe ulcerative colitis

629
01:15:11,370 --> 01:15:18,480
will require collectively during that episode of that that that flare historically.

630
01:15:18,480 --> 01:15:25,350
And I think this is important. There's a there's a there's an approximately one percent mortality from acute severe ulcerative colitis,

631
01:15:25,350 --> 01:15:30,720
although I think most specialist centres, you know, think that that should be much lower.

632
01:15:30,720 --> 01:15:35,580
And certainly I think especially since as those numbers are often often lower.

633
01:15:35,580 --> 01:15:43,380
So during COVID, we were quite rightly really worried about these kind of vulnerable groups.

634
01:15:43,380 --> 01:15:46,530
And this particular group, I think, is particularly vulnerable.

635
01:15:46,530 --> 01:15:56,430
They are having high dose IV steroids, often after a course of oral steroids, often while they were on immunomodulators or other therapies.

636
01:15:56,430 --> 01:16:04,770
They're likely to have follow on immunosuppression, longer courses of oral steroids and anti-TNF agents,

637
01:16:04,770 --> 01:16:16,170
which we know from from follow up studies not only increase the risk of severe COVID end and poor outcomes, but also reduce vaccine efficacy.

638
01:16:16,170 --> 01:16:28,500
And these patients may well require surgery, and there was a great deal of concern about patients and COVID in the context of requiring major surgery.

639
01:16:28,500 --> 01:16:30,750
So very reasonably,

640
01:16:30,750 --> 01:16:41,430
there was interest during the pandemic about how to keep these patients out of hospital and were there ways that we could ambulate these patients?

641
01:16:41,430 --> 01:16:47,040
To be absolutely clear, I'm national and international guidelines,

642
01:16:47,040 --> 01:16:54,240
and expert consensus recommends that acute severe ulcerative colitis is managed as an inpatient,

643
01:16:54,240 --> 01:16:59,760
and they specifically state that outpatient or ambulatory practise is not appropriate.

644
01:16:59,760 --> 01:17:07,860
And I think that's why this report is of relevance, because this is, you know, challenging dogma to some extent.

645
01:17:07,860 --> 01:17:17,370
So what they did is they looked at a cohort of patients from 2019 and then compared them to a cohort of patients from 20 20.

646
01:17:17,370 --> 01:17:24,300
I think I got that right out of this cohort of 764 patients.

647
01:17:24,300 --> 01:17:31,800
The vast majority were managed as an inpatient 94 percent and 54 were managed.

648
01:17:31,800 --> 01:17:35,160
54 patients were managed, partially ambulatory.

649
01:17:35,160 --> 01:17:42,780
So they were admitted and then discharged on an ambulatory pathway for their acute severe ulcerative colitis management,

650
01:17:42,780 --> 01:17:48,090
and 15 patients were managed purely in the outpatient ambulatory setting.

651
01:17:48,090 --> 01:17:54,480
And I'm effectively the sort of the pathway for treatments is the same.

652
01:17:54,480 --> 01:18:03,870
Patients are given high dose Mishel Pred, which is once daily steroid as opposed to four times daily hydrocortisone and methylprednisolone,

653
01:18:03,870 --> 01:18:09,060
is often used in Europe for the management of inpatient flights of IBD.

654
01:18:09,060 --> 01:18:15,600
So you know that in itself is not unusual. So they compared a few of that.

655
01:18:15,600 --> 01:18:29,160
A few of the. Outcomes and kind of criteria for the sort of, you know, good inpatient, acute severe ulcerative colitis care between these groups.

656
01:18:29,160 --> 01:18:40,010
And the first thing. Is that the patients who were ambulate aids were more likely to have certain things missing from their their management,

657
01:18:40,010 --> 01:18:44,690
so they were less likely to have stool culture sent during their acute admission,

658
01:18:44,690 --> 01:18:50,750
they were less likely to have a flexible sigmoidoscopy to assess the severity of their disease.

659
01:18:50,750 --> 01:18:56,220
And, you know, certainly in the way that I practise it, I've been taught to practise.

660
01:18:56,220 --> 01:19:00,350
These are really cornerstones of health management. These are not kind of optional extras.

661
01:19:00,350 --> 01:19:08,930
And I guess that is that is a real concern that these things were missed, albeit in a small patient cohort.

662
01:19:08,930 --> 01:19:17,450
They looked at colectomy rates between these different arms and the colectomy rates were similar in all the arms approximately 13 percent,

663
01:19:17,450 --> 01:19:23,690
which fits with, you know, prior data, and there were significant differences between the groups.

664
01:19:23,690 --> 01:19:32,450
But one, this isn't randomised. So these are patients who've been selected for an ambulatory pathway, so potentially having less severe disease,

665
01:19:32,450 --> 01:19:42,000
but also the numbers that are concerned it just really not powered to detect an effect in colectomy rates.

666
01:19:42,000 --> 01:19:49,130
But I think it's interesting that overall, it looks like the colectomy rates were similar and that overall,

667
01:19:49,130 --> 01:19:55,550
you know, efficacy of the first line and second line treatments looked similar between the different arms.

668
01:19:55,550 --> 01:20:01,310
And so I think this is really interesting because as I said, it challenges this, you know,

669
01:20:01,310 --> 01:20:08,480
this paradigm of acute severe ulcerative colitis management and I don't think we should hold on to,

670
01:20:08,480 --> 01:20:13,880
you know, the way the way of of particular ways of working, just because that's how we've always done it.

671
01:20:13,880 --> 01:20:23,830
We've got it is a reasonable question to ask whether these patients can be safely managed as an outpatients alone and ambulatory pathway.

672
01:20:23,830 --> 01:20:29,950
Having said that, I am super sceptical, and I have to say I've got a lot of concerns about it, not because this study,

673
01:20:29,950 --> 01:20:38,590
which I think is quite helpful, but because I, you know, I think a lot goes on in those admissions for acute severe ulcerative colitis.

674
01:20:38,590 --> 01:20:44,200
And having admitted for patients over the last few days with acute severe ulcerative colitis,

675
01:20:44,200 --> 01:20:50,230
there's a there's a lot involved in it in order to try and get things right and really get the best outcomes for patients.

676
01:20:50,230 --> 01:20:54,370
Not only are there all the right blood tests throughout stool cultures,

677
01:20:54,370 --> 01:21:02,200
getting early scopes by an experienced IBD endoscopy est un but also discussing the diagnosis.

678
01:21:02,200 --> 01:21:12,430
The different treatment options involving IBD nurses, pharmacy stoma, nurses, surgical input dietician inputs.

679
01:21:12,430 --> 01:21:17,650
All of these things take up a lot of time, and there's actually a lot to fit in,

680
01:21:17,650 --> 01:21:23,230
particularly within those first 48 hours of admission on the sort of high dose steroids

681
01:21:23,230 --> 01:21:28,870
before the kind of day three assessments for response and leading onto that thing.

682
01:21:28,870 --> 01:21:37,420
You know, those that we want to make those decisions quickly. We need to be deciding about rescue therapy, you know, on on day three.

683
01:21:37,420 --> 01:21:47,980
We don't want to be waiting, you know, days and days, and you need that close monitoring and really responsive tests in order to do that.

684
01:21:47,980 --> 01:21:49,750
And I just think that's those things are really,

685
01:21:49,750 --> 01:21:57,340
really hard to do in an ambulatory setting just because services aren't set up or commission that way.

686
01:21:57,340 --> 01:22:04,070
And until they are, I'd really worry that we are shortchanging our patients.

687
01:22:04,070 --> 01:22:09,400
The second thing is that I think the outcomes that really matter are going to keep severe colitis.

688
01:22:09,400 --> 01:22:15,170
Oh sure. Their response to therapy, their control at one year quality of life.

689
01:22:15,170 --> 01:22:19,040
But there are also things like colectomy rates and mortality.

690
01:22:19,040 --> 01:22:31,730
And we would need really big studies to demonstrate whether ambulatory care had better outcomes or indeed worse outcomes in terms of some of those,

691
01:22:31,730 --> 01:22:39,050
some of those things. And given that these are often young, otherwise well, patients, you know,

692
01:22:39,050 --> 01:22:47,750
we we really have to take we have to be very careful, I think, before changing them of the sort of management paradigm.

693
01:22:47,750 --> 01:22:53,810
And I think until we can convince sort of the body of physicians that the ambulatory setting is

694
01:22:53,810 --> 01:22:58,550
likely to at least meet all the clinical care goals that we would usually do as an inpatient.

695
01:22:58,550 --> 01:23:06,560
I think it would be really hard to enrol into any kind of randomised trial of ambulatory

696
01:23:06,560 --> 01:23:12,620
managements because I think it would be very challenging to justify that as equipoise.

697
01:23:12,620 --> 01:23:22,340
So my slight rant is over, but I think this is really important and relevant paper that raises the issue of maybe there are a group

698
01:23:22,340 --> 01:23:28,400
of people with acute severe ulcerative colitis who could be appropriately managed as an outpatient,

699
01:23:28,400 --> 01:23:34,430
which I'm sure they would prefer would put less but less sort of strain on the health care

700
01:23:34,430 --> 01:23:42,530
service and with maybe the right patient choice could still generate good outcomes for patients.

701
01:23:42,530 --> 01:23:48,200
And the only thing I'd add to all of that is that it's probably not impossible to achieve

702
01:23:48,200 --> 01:23:56,870
that if the right care was put in place to be able to be given in an ambulatory setting.

703
01:23:56,870 --> 01:24:08,070
Because I think most a lot of the care that we give to people with acute severe colitis is possible in an ambulatory fashion.

704
01:24:08,070 --> 01:24:14,460
But the mechanisms to deliver that would need to be very, you know.

705
01:24:14,460 --> 01:24:15,870
In short, you know,

706
01:24:15,870 --> 01:24:25,980
they need to have a flexi SIG that would have to be a pathway that says this is our ambulatory team for managing keeps their colitis.

707
01:24:25,980 --> 01:24:33,430
And there was a flexi SIG slot. Do you see what I mean? You know, it would really need to be thought about.

708
01:24:33,430 --> 01:24:40,350
And oh, totally. I completely agree. My issues are mainly practical rather than philosophical.

709
01:24:40,350 --> 01:24:43,830
Yes. You know, I think I think it could be done.

710
01:24:43,830 --> 01:24:49,920
It could be appropriate. You know, why can't the patient go home and sleep in their own bed and then and then come back,

711
01:24:49,920 --> 01:24:55,320
come in in the morning for their set of appointments with different therapists and so on?

712
01:24:55,320 --> 01:25:03,600
But as I said, until those things were generated and were able to be delivered in different centres, I'd be very reluctant.

713
01:25:03,600 --> 01:25:06,780
Yeah, there need to be a specialist service that was developed.

714
01:25:06,780 --> 01:25:15,150
Yeah, the right way to do that, and I'd have to really think very carefully about which patients would actually benefit from it.

715
01:25:15,150 --> 01:25:21,330
Yeah, yeah. And what I wouldn't want to do and what I always worry about about the push for ambulatory is that

716
01:25:21,330 --> 01:25:29,310
we're doing it for the benefit of the health service to safe bed days and free up room in our,

717
01:25:29,310 --> 01:25:36,150
you know, overcrowded hospitals as opposed to it being for the patient benefit because we know they're going to get better care.

718
01:25:36,150 --> 01:25:44,490
So I think in the COVID 19 pandemic, particularly that first, that first sort of spring and summer,

719
01:25:44,490 --> 01:25:48,450
I totally understand the rationale for trying these pathways.

720
01:25:48,450 --> 01:25:54,240
And I think that was very reasonable. I think in the future,

721
01:25:54,240 --> 01:25:58,380
those those sort of practical issues really need to be ironed out if we're going

722
01:25:58,380 --> 01:26:04,540
to say that this is like an equivalence and safe and appropriate pathway.

723
01:26:04,540 --> 01:26:12,370
So very interesting, anyway, very interesting to think about. So the last one is pickles.

724
01:26:12,370 --> 01:26:18,400
So this trial is a randomised controlled trial entitled People Use Intervention for Service it cramps reduction.

725
01:26:18,400 --> 01:26:26,970
The Pickles randomised controlled trial that was done in America, and it was published last month in the American Journal of Gastroenterology.

726
01:26:26,970 --> 01:26:36,220
It's an application. It's not in print form yet. And so the rationale behind the trial muscle cramps are very common in people with psoriasis.

727
01:26:36,220 --> 01:26:37,930
And in previous studies,

728
01:26:37,930 --> 01:26:46,090
they've been shown to be one of the main kind of symptoms that the people psoriasis get that really affects their quality of life.

729
01:26:46,090 --> 01:26:51,610
But we don't really have very good treatment options at the moment with strong evidence base.

730
01:26:51,610 --> 01:27:03,520
And there's some sort of previous evidence that the acetic acid in pickle brine might help to alleviate cramps,

731
01:27:03,520 --> 01:27:10,240
and this has been sort of previously demonstrated in an experimental setting.

732
01:27:10,240 --> 01:27:15,040
And the mechanism is thought to be the acetic acid antagonises.

733
01:27:15,040 --> 01:27:21,730
Some sensory receptions in the fall got on.

734
01:27:21,730 --> 01:27:26,590
This leads to nerve conduction within the oropharyngeal nerve, so increases vagal tone.

735
01:27:26,590 --> 01:27:31,690
And that puts the cramp without changing the serum electrolytes, so it works quickly.

736
01:27:31,690 --> 01:27:41,560
So, so this trial recruited patients with cirrhosis and either for muscle cramps in the previous month, and they enrolled 82 participants.

737
01:27:41,560 --> 01:27:50,870
They did include patients that were already on a variety of other cramp relieving medications, and I think they were allowed to continue those.

738
01:27:50,870 --> 01:27:59,170
The intervention was one sip of pickle juice and one tablespoon of pickle juice and the the patient.

739
01:27:59,170 --> 01:28:04,900
The participants in the trial were allowed to buy whatever pickled cucumbers they wanted to,

740
01:28:04,900 --> 01:28:15,700
but they needed to be dill or kosher and quite right to go to the they are the best of the best first pickles.

741
01:28:15,700 --> 01:28:19,720
I was just trying to remember the brand of pickle that I particularly.

742
01:28:19,720 --> 01:28:24,520
I'll say that I've mentioned in the next post, you could have chosen the brand that you particularly liked,

743
01:28:24,520 --> 01:28:33,370
and all the rationale for choosing whatever brand you wanted was that basically all brine for

744
01:28:33,370 --> 01:28:42,580
these pickles has by regulation to be under the age of under four and they're interested in.

745
01:28:42,580 --> 01:28:47,260
They think that's the mechanism by which the pickle juice might work.

746
01:28:47,260 --> 01:28:54,760
And so they saw the intervention was one sip of pickle juice at the at Rumson onset of the Krump.

747
01:28:54,760 --> 01:29:03,610
They limited to it and limited this to a maximum of three sips or doses a day

748
01:29:03,610 --> 01:29:07,120
just because they were slightly worried in some of the patients with cirrhosis.

749
01:29:07,120 --> 01:29:14,740
If they were decompensated, particularly the sites about the sodium burden within the pickle juice they were.

750
01:29:14,740 --> 01:29:21,230
So there were randomised 1:1 to either the pickle juice or instead sips of tap water.

751
01:29:21,230 --> 01:29:28,490
And the patients were not blinded to which intervention they'd been assigned to.

752
01:29:28,490 --> 01:29:37,370
So the outcome was the primary outcome that was measured was a visual analogue scale of severity between enrolment and day 28.

753
01:29:37,370 --> 01:29:44,270
So it's a short trial and they assessed this at the beginning and then by an interval SMS.

754
01:29:44,270 --> 01:29:58,330
So text message surveys and and participants completed between eight and nine krump surveys within this 28 day period.

755
01:29:58,330 --> 01:30:03,310
And. And the secondary outcome of several secondary outcomes,

756
01:30:03,310 --> 01:30:09,790
one of which was the proportion of cramp days with a visual animal scale and that of cramps that are less severe,

757
01:30:09,790 --> 01:30:19,810
so under five on this visual analogue scale. So they had quite a high completion rate of these sort of text message, Krump surveys,

758
01:30:19,810 --> 01:30:25,180
which basically text you and said, you know, have you had cramps in the last three days?

759
01:30:25,180 --> 01:30:37,060
Yes or no? How severe where they on a scale of one to 10, not being not severe, 10 being severe, you know, that kind of thing and a baseline.

760
01:30:37,060 --> 01:30:43,770
The visual analogue scale median was actually Sorey average because I don't know

761
01:30:43,770 --> 01:30:51,550
if there was median or mean was 4.2 for these patients with cramps by day 28.

762
01:30:51,550 --> 01:30:58,360
Analysing all the data together, the visual and musical score was significantly lower in the group that was randomised pickle juice compared to water.

763
01:30:58,360 --> 01:31:08,380
So it decreased by two point twenty five units, I guess, compared to nought point three six in the water only group.

764
01:31:08,380 --> 01:31:10,690
And that was statistically significant.

765
01:31:10,690 --> 01:31:19,240
But there wasn't a difference in the proportion of cramp days where the visual animal scale school was under five.

766
01:31:19,240 --> 01:31:38,650
So it seemed that pickle juice was able to effectively cramp onset effectively reduce quite quickly the UM the severity of the crime,

767
01:31:38,650 --> 01:31:45,340
but it doesn't seem to decrease the cramps coming on in the first place, if that makes sense.

768
01:31:45,340 --> 01:31:51,100
And I thought this was a great little trial, although it's, you know, short not blinded,

769
01:31:51,100 --> 01:31:58,330
but it actually provides some evidence base for a very simple intervention that people can

770
01:31:58,330 --> 01:32:03,940
do at home very easily for something that significantly affects their quality of life,

771
01:32:03,940 --> 01:32:10,690
and it might make a bit of a difference is I thought it was nice that it was funded and published.

772
01:32:10,690 --> 01:32:15,820
I think it's absolutely brilliant and also it has a great name. It has a great name.

773
01:32:15,820 --> 01:32:26,200
They gave a lot of thought that in terms and you know, the NHS, I think, will be able to fund the pickle supply.

774
01:32:26,200 --> 01:32:34,390
Yeah. So that's that's good. And in terms of my favourite pickles, I've just just remembered the brand.

775
01:32:34,390 --> 01:32:41,630
It's Mrs Ellsworth's Mrs Elswick. Come back. Yeah, cucumber spears with dill as the dill ones that are particularly good.

776
01:32:41,630 --> 01:32:46,390
There's a, you know, little bit of a sweet and sour thing going, although other brands are available.

777
01:32:46,390 --> 01:32:53,650
Other brands are everything and this is our word. If you're if you're listening and you're a key listener and you'd like to sponsor us.

778
01:32:53,650 --> 01:33:00,760
Very happy to take the sponsorship money in return for more, more eco based recommendations.

779
01:33:00,760 --> 01:33:05,860
I think this is great. And I wonder, you know? You know, I look after the patients on p.n.

780
01:33:05,860 --> 01:33:07,430
Quite a lot of them get cramps.

781
01:33:07,430 --> 01:33:13,450
We always attribute it to the electrolyte imbalance, but luckily funniness, even if actually their electrolytes, right?

782
01:33:13,450 --> 01:33:18,310
Yeah, I and and we don't we don't have good treatments.

783
01:33:18,310 --> 01:33:21,400
Yeah, I'm yeah. And in a way, they're in a similar situation.

784
01:33:21,400 --> 01:33:30,730
So, you know, one of the issues with this was the sodium content of the brine and also the drinking, you know,

785
01:33:30,730 --> 01:33:42,130
so it's volume and that would be also important in nutrition patients, potentially, but actually because they limited it to a small amounts.

786
01:33:42,130 --> 01:33:50,340
You know, they it was safe and it wasn't a problem. So it would be interesting to see if it worked for nutrition patients as well.

787
01:33:50,340 --> 01:33:56,440
Yeah, super. And you know, the only real side effect is becoming incredibly addicted to pickle juice pickles.

788
01:33:56,440 --> 01:34:00,170
So, you know, I think that's also something we can live with.

789
01:34:00,170 --> 01:34:04,420
I'm asking, well, what what are absolute banger to end on?

790
01:34:04,420 --> 01:34:06,130
That's that's a great, great one.

791
01:34:06,130 --> 01:34:15,430
So, yeah, a bit of a long episode that people can listen to it in segments and think, I think we covered some really good papers.

792
01:34:15,430 --> 01:34:21,280
Thank you for listening. Give us any feedback via Twitter or email, and we'll see you next time.

793
01:34:21,280 --> 01:34:53,431
Super Goodbye.