Welcome to our second episode of Gut Instincts, G.I. Research Updates,
bringing you the latest research in gastroenterology and hepatology straight to your smartphone.
I'm Fitz. I'm a clinical lecturer in gastroenterology at Oxford with an interest in mucosal immunology and nutrition.
And I'm Tamsin Cargill. I'm a gastroenterology registrar and D students in Oxford.
Interested in hepatology, viral tests and vaccine development. The gastro literature can seem very overwhelming.
There's just so many P papers coming out, and so we started this podcast to bring you some of the G.I. related highlights
that have come out recently and discuss why we think they're interesting.
So each episode, we're going to try and talk through to cracking primary research papers in a bit of detail.
One will be clinical and one translational. And we'll give you our take on the research.
And we're also going to bring you our super speedy five in five section where we'll try and summarise the key points of five papers in five minutes.
Last week it took us eleven minutes, but five and 11 just doesn't have the same ring to it.
So we're going to stick with the same name and just ignore the time.
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Right. Last week, I did the clinical paper terms, and I think you've got something clinical and sort of bile flavoured for us this week.
Yes. So firstly, before I start, I just wanted to say upfront,
I realised there were two pretty important trials published last week in the New England Journal of Medicine.
These will get a mention or more than mention in a previous in future episodes to come.
But today, I'm going to focus on some different papers.
Two linked papers that focus on the treatment of refractory societies in psoriasis.
So both papers report the outcomes from the reduce study trial.
And that stands for repeated drainage of untreatable psoriasis,
which compared long time abdominal drains with large volume paracentesis for the treatment of refractory societies due to psoriasis.
So the first paper was actually published last year in July in AT&T.
And that covers the quantitative outcomes of the trial. And the second paper, which is the one I saw that caught my eye,
was published online ahead of print in December 2020 in the Journal of Pain and Symptom Management.
And that covers the qualitative outcomes of the trial.
So so this trial addresses an important but understudied area of end stage liver disease,
which is palliative interventions specific for some of the symptoms of end stage liver disease.
And everyone who's listening to this podcast will know that.
Deaths from end stage liver disease have increased massively over the past 40 years or so.
And one of the predominant symptoms experienced by individuals with end stages of the disease is refractory societies.
So this is where somebody has a side to ease, but they are intolerant to or unresponsive to diabetics.
And so they need an alternative form of management and to relieve the symptoms from that sort of large volume of sightings.
And what's the scale of this of this problem, Tamsen?
Unsurprisingly, it's pretty massive. So it's the most common reason for hospital admission in people with end stage liver disease.
So any clinician up and down the country will have seen patients with this issue.
It's prognostically a very bad sign. So median transplant free survival in individuals with refractory societies is only six months.
But despite this, most people don't receive optimal palliative care.
So we know that nearly 70 percent of deaths in cirrhosis with a sightings occurred in hospital, of which 97 percent followed an emergency.
So on the planned hospital admission. And that is an indicator in of itself because because these hospital admissions were unplanned,
the patients didn't necessarily choose to die in hospital.
So most refractory societies in England is managed by large volume, paracentesis in hospital.
And the scale of this is huge as well. So this is reported in Lancet.
Gastric happened 2018, nearly 14000 cirrhosis related deaths between 2013 and 2015.
That's nearly a third required. Large volume paracentesis in the last year of life at least once.
So although although the evidence suggests that most people have refractory societies are managed by large volume, paracentesis.
There is an alternative and that is a long term abdominal drain.
And basically what these are a tunnel drains inserted under local anaesthetic and the patient goes home with them in situ.
And then caregivers or community nurses drain one to two litres of fluid up to three times a week at home.
And many people might be and might have seen these used sort of plural drains used in a similar way,
long temporal drains where people have long term infusions that again need draining.
And this this enables them to be managed at home.
Now, in the U.K., several thousand long term abdominal drains are inserted every year for malignant societies.
And in this setting, sort of low complication rates have been reported.
However, they're not really routinely used for refractory sites. He's due to end stage liver disease.
And this, I think, is due to the potential risk of peritonitis.
But there's no previous research into the use in end stage liver disease.
So anecdotally, these drains are used in the setting of refractory societies for for some patients in stage liver disease.
But you say that there's not very much of that in the sense of sort of randomised controlled trials previously of using this technique.
Exactly. Sorry, there's no large scale trials of this. And the evidence that is published would suggest that actually most refractory societies
is actually managed by large weren't fully paracentesis rather than these drains.
So clearly, if they are being used anecdotally, it's not due to trial.
Not it's not due to evidence based trial based data. Yeah.
It sort of goes against so much of the, you know,
the sort of the teaching we get that these drains must be removed after six hours and that the risk of the risk of infection is is so great.
Exactly. So this was a trial that's on answering a pretty important question, really.
So reduce it was a non-flying at 12 week feasibility, randomised controlled trial.
And it compared long term abdominal drains to large volume, paracentesis in individuals of cirrhosis and refractory societies.
And this was conducted across five hospitals and and that resuscitated community
settings in the south of England between September 2015 and September 2018.
So because this was a feasibility study, it wasn't blinded and it didn't have a primary outcome prespecified.
But the authors did predefine some study success criteria.
And initially, you might think. But if they don't have a primary outcome, criteria of perhaps this trial isn't good quality.
But actually, because it's a feasibility trial, the success criteria that they set were actually really practical.
So the first one was that they wanted to see whether the attrition was above 50 percent.
And you hope it wasn't that? Actually, this group of people are really sick and they've got a median survival of six months.
So if you're recruiting to a study such as this,
quite a few people are going to potentially die before the end of follow up and therefore, attrition rates are going to be high.
Not necessarily because people are dropping out, but because people are dying.
So that's the first one. And then they used erm I'll discuss these later.
They used a lot of questionnaires and interviews to assess some of the,
some different outcomes from the trial and that might not be able to be assessed in a quantitative way.
And they wanted to see whether the completion rate of those questionnaires and interviews was over 80 percent.
They also wanted the long term drain group to spend under 50 percent of time in
hospital related to their societies compared to the large volume paracentesis group,
because that was really the aim of putting in the long term drain so they wouldn't spend as much time in hospital.
And the last success criteria was that the long term drains would be removed in under 10 percent of participants in that arm.
So the inclusion criteria were fracturing societies requiring over one large volume piracy, 76 per month, at least twice parch recruitment.
And the participants were randomised one to one using computer generated algorithm.
But it wasn't blinded.
So the intervention was a rocket drain under local anaesthetic, and that was inserted by an intervention radiologist or or trained to hepatologist,
and then guidance was given to the participants and community nurses and jeepneys about how to manage and the drainage of that.
And they drained once two units of society, two to three times a week, usually a trial nurse coming in to do that.
And a district nurse and no control necessary. And no albumen was given during the drainage.
And all participants were given Cipro, 500 milligrams once a day for the duration of the trial and invite the intervention in the control group.
The control group had usual care, which was day unit or hospital admission as required for large volume, paracentesis with albumin cover plus.
So they calculated the sample size based on the fact that they would probably have a really high attrition rate, as we've discussed already.
So they aim to have 12 per group, so 24 per group based on a 50 percent attrition rate.
And in the end, thirty six were randomised, so 19 in the large volume, paracentesis group and 17 in the long term acidic drink group.
So the results of the trial. And so the baseline characteristics were relatively balanced.
The other thing to say about these patients, of course, is that out of 36 of them, thirty five had a contra indication for tips.
And one of them had been offered tips but declined it.
So for the quantitative outcomes, the study success criteria were met.
So attrition was under 50 percent. Fifteen of the thirty six didn't make it to the last study visits.
80 percent of these were due to death and 20 percent due to withdrawal.
The completion rate of question is very high. It's between 79 and 97 percent.
And they were done longitudinally, so that's pretty good.
Long term drain ditch group spent under 50 percent of the time in hospital due to their S.A.S. compared to the large volume paracentesis group.
So data was available for 15 of 17 of the long term Pacific during group.
And out of those 15 people, five of them required extra drainage in hospital.
So 10 of them were managed in the community with their long term ascetic drain
without any need to be coming back to hospital for further paracentesis.
But five of them did have to come back. And they those five require a total of 13 further drains in hospital,
some of which which the emissions were due to other reasons, and they just drained them in hospital anyway.
But comparing that to the large volume, paracentesis group, all of them obviously required further drainage in hospital.
And that was a total of 69 further drains, which is actually when it's written down like that.
Quite a lot. And long term drain removal and only one drain was removed in the long term acidic drain group.
And that was because the participant pulled out accidently after it was inserted sort of the next day and they elected not to reinsert it.
Those are pretty impressive outcomes from from this trial.
So. So there's 10 of these patients who, as we said, are refractory to refractory to medications of contraindications for tips and not suitable
for transplantation who were managed in the community and didn't need any large volume.
Paracentesis.
And overall was at about an 80 percent reduction in the number of drains, the large volume person disease needed over again in the long term group.
That's that's that's pretty, pretty harmless. Yeah.
No, it is. I agree. The other things that they looked at quite a lot of other outcomes as well.
The other outcome of sort of interest,
I guess was peritonitis with the theoretical risk that the long term acidic drain might lead to increased risk of peritonitis.
But they found, obviously, it's a small study and know who was power properly for this, but only one out of the 17.
So six percent in the long term acidic drain group compared to 11 percent in the large volume, paracentesis group and developed peritonitis.
And just to say also with the with the diagnosis of peritonitis, they're pragmatic about that,
as we would be in real life, i.e. they they weren't routinely culturing the acidic fluid they were literally doing.
That's only if they were symptomatic with pain, fever, decompensation.
Westing renal failure, and then they did a tap and were there any other adverse events in either of the groups?
Were there were no serious adverse events in either group.
The main adverse event of having the long term acidic drain was either mild leakage or cellulitis, which was all self limiting.
In seven out of 17 of the participants in that group vs. two of the participants had bleeding or leakage in the large volume, paracentesis group.
And it will come out a little bit more in the qualitative data.
But the cellulitis and leakage if if you're at home, is obviously a bit of a different issue, too.
When youre in hospital and you've got people sort it out.
So it wasn't a massive problem, but it was a complication that was relatively common.
The other thing that they analysed and which was pretty impressive were the cost differences.
And they calculated this based on various aspects.
And they did try include staff costs and care costs.
And they found that the in the long term abdominal drain group,
the costs were much lower of the magnitude of sort of 300 pounds vs. a hundred pounds in the large volume, paracentesis group.
So overall, in this feasibility study, the the long term abdominal drains are associated with fewer drains, few admissions to attendances to hospital,
similar rates of sort of severe complications as in peritonitis and lower health care costs, pretty re driven by fewer attendances to hospital.
So you said at the start about qualitative work that they've also done.
And I guess that's really the crux of the matter here, because these patients on here at the end of their lives,
and it's really about the quality of their lives and the outcomes that matter to them.
Yeah, exactly. So when I realise anecdotally that qualitative work has a bit of a bad rep in some circles and certainly
it's discussed less by clinicians when we're considering the evidence base for an intervention.
I think that's often true.
But I did want to spend a bit of time on this past study to just explore, in my view, how it complements and enriches the overall study findings.
Qualitative studies really have a different aim and emphasis to quantitative work because they're very,
very good for answering particular sorts of questions.
So they're good at understanding some of the behavioural factors around an intervention and the perceptions of the care receivers and caregivers.
And that's especially important in the setting of palliative and palliative intervention.
So the methods of a qualitative study can also be critically appraise, just like a quantitative study.
So I'm going to attempt to do that here. What they specifically aimed to do was contrast the perceptions of the care pathways between
long term ascetic drain at home compared with large volume paracentesis in hospital.
The aim wasn't to find a representative voice, but a range in spectrum of voices, because really it needs to be able to inform future trials.
And the key, the information implementation of future services.
So the authors aim to recruit 20 people to the qualitative arm.
It was only carried out two out of five of the sites where they were recruiting.
And they chose that for practical reason because most of the patients were recruited at those two sites.
So there were twenty seven patients recruited at these sites and 21 were invited to participate.
The six weren't approached as they were dying quite rapidly.
Originally, the authors also aimed to conduct several interviews of peoples to try and
understand how people's perceptions of the intervention changed across time.
But unfortunately, they were unable to do to sort of put in this longitudinal element, mostly because people died.
The full interview soon. In the end, they did a single qualitative interview lasting about 30 minutes over the telephone in 14 patients.
Six in the long term acidic drain and eight in the large volume, paracentesis arm.
And in addition, a qualitative test telephone interview lasting about 44 minutes was conducted.
Eight nurses. So it sounds like they they had a lot of problems with with with their method or that
they sort of planned method for the qualitative elements of this of this study.
Do you think that the methods as has actually performed, as opposed to what they originally intended onto the questions that that they set?
Yes. If the aim of the qualitative work was to discover the full range inspection of perceptions,
this study might fall short because the recruitment was opportunity to date rather than purposeful.
So this means that the views and experiences of those not recruited.
So, for example, those who were dying rapidly, who weren't invited to participate or indeed those that were invited to participate,
said yes, but then died before they were able to participate.
And also the views of those at the sites that were away from the central sites were less recruitment was happening.
They weren't approached for recruitment either.
So we're missing some of the voices there that might have had quite different experiences in a peripheral site away from
the centre with different services or people that are dying much more rapidly and more aggressive cause of disease.
They might have quite different opinions to the people whose data was actually collected in the end.
And I think it is important to think about that. Remember that.
Yeah. Particularly people who are deteriorating rapidly.
May. Yes, exactly. See the benefits of a long term drain.
But I guess because this is a feasibility study, they they've set out to do something and found that it wasn't practicable in a bigger trial.
They can probably account for this now because they know some of the barriers that they're going to face.
They could employ a purposeful recruitment strategy to ensure that some of these voices are heard.
OK. So how how did the interviewers carry out these interviews to achieve this study aims?
So the aim was to sort of contrast and explore the perceptions of the care pathways.
And to do this, the interview is used a schedule and a topic guide to prompt the steering of the questioning.
So they don't say this explicitly in the text, but I think it's a form of semi structured interviewing.
So that enables the topics that the interviewers and the researchers think are important to be coverage.
And it also allows in-depth exploration of topics or new topics that might come up
during the course of the interview that the researchers didn't know about a primary.
And they used to sort of make this interview topic schedule.
They they based it on something called the Dixon Woods theoretical model of health care access.
And basically, this theory is just saying the stages of the journey as you go through health, as you access health care.
So, A, recognising you need to seek care. I've got societies I need it drained to identifying the right service to do that.
Three, getting there for the permeability of the surface, i.e., how easy or difficult is it to use and find the adjudication by professionals?
So I go to my GP and say I need to drain my GP says no, you don't sort of thing those kind of barriers.
So it tried to explore all of those arms of access and care.
And so I think that's that was reasonable.
And I think they could have considered other ways of developing the scheduled topic guide because they didn't involve stakeholders,
i.e., the patient's caregivers and nurses in its iterative development.
But it was a practical study, and I think they can use the results from the quality for analysis of this study
to inform further qualitative work and update their topic guide and things.
And I think overall, you know, the topics they were interested in were covered.
So what were the key outcomes from the interviews?
Overall, they found that the long term sediq drain was acceptable to patients that received it,
and it reduced or removed many of the negative factors that they attributed and associated
with going to hospital regularly for the long term at large for the paracentesis.
And they felt that it actually transformed the care pathway and transformed the care they received.
So a patient's experience of large volume paracentesis was kind of difficult negotiation, often between speaking to their GP,
ringing the local AMMU or whatever the arrangement was to get them in for a drain and sometimes in different places.
That was. That was easier than in other places. And there's potential for conflict there.
And then it's obviously there are several steps in accessing drainage that can be difficult, i.e., getting their booking, transport, parking,
paying for parking and then getting reassessed by the doctor in the hospital,
waiting and waiting and waiting and waiting and then having the procedure and then waiting.
Whereas they found that with the long term hypothetic drain, it was easier.
It was nicer. They didn't have to do one of those approachable ways, various every time they need to drain.
And the other thing that was added was they liked you know, there was somebody coming in three times a week.
And so that's a point of contact for emotional support and reassurance in case of crisis.
And some of the other things that they might be some of the other symptoms they might be experiencing,
can they've got an irregular advocate who's seeing them every day.
And I think they found that really helpful.
That's really interesting because that's not a I guess, a specific intended outcome of large volume, paracentesis versus long term drain.
But actually, when you phrase it like that,
in developing that relationship with a regular regular caregiver and and having that kind of reassurance and emotional support,
that that person who's sort of sharing the journey with you as part of the I guess, the package of of having a long term drain,
you can see how that could be hugely beneficial for patients at the end of their lives.
Yes, indeed. So so I think can the quality of outcomes of this feasibility study were actually some of the most important?
And it'll be interesting to see going forward what's larger trials of this intervention will find.
So so, Tamzin, based on these results, do you think there's a case for changing your practise,
or do you think that this is really the start of the evidence base needed to change kind of routine clinical care for these patients?
That's a very good question. I think that if a service was available to me locally,
a provision for certain individual patients that I thought might really benefit from this intervention.
And I think it's a really good option. But overall, I think this is the start of an evidence base.
And because and this kind of intervention actually isn't just taking a pill.
It relies on a whole network of services and people.
It's something that can't be done overnight.
Really, it needs buy in from the organisation. And that probably does need more evidence.
Also, there's a sort of another argument about this in that there is really good evidence from a very large,
pretty recent observational study in England.
Good quality observational study that attending planned large volume paracentesis was the factor that was associated with
the lower number of inpatient days and a lower probability of dying after an unplanned mission with end stage liver disease.
Should we actually be concentrating on providing planned large volume, paracentesis more broadly?
Okay, so there's a there's a balance there that maybe there's there's room for improvement in how we deliver large volume paracentesis to these
patients and the kind of reactive model where we're waiting for people to have this symptoms and be flagged up and often be delayed because of,
you know, bear bed issues and space on day case and all of the things that get in the way.
Actually, that model of care is a suboptimal.
And actually, if we can provide really good, large volume, paracentesis care, then that's probably the best comparator in a larger study.
Yeah, potentially. You know, if some of these barriers that patients talked about in the qualitative study could be circumnavigated by a really good,
dedicated, large volume, paracentesis service. Great.
Well, I think this is fantastic food for thought.
And I also think it's a really impressive for the researchers for taking on a topic that's so difficult.
End stage liver disease. Palliative care, these kind of complex interventions.
And I think it's you know, it's really important area to to to deal with.
But it's it's it's really challenging from a research point of view.
So, you know, sort of full credit to them for for taking this out. Absolutely.
So what have you got for me today? It's something totally different terms.
Something. Yeah, a million miles away from excited. We are going back to sort of single cell, single cell transcripts, homing methods.
Back to back to the lab, our favourite. So this is a paper that's from a group based here in Oxford.
The lead authors are David Forkan and Corbitt Agony and son of a CETA and call Patrick.
And they're all based in Allison Simmons lab here in Oxford.
Now, I haven't just picked this work because of its Oxford connexion or because we know some of the authors and they're generally delightful people.
But it's because I think that this really is an astounding piece of work and something
that's gonna be a really important and powerful resource for researchers for years to come.
This group, Professor Simmons, his group,
have been real pioneers in the use of single cell RNA sequencing to understand intestinal cell types and their role in disease.
And in previous papers published in both Nature and Cell, they've described novel cell types, both in the colon,
including a subtype of epithelial cell, the best for reptilian cell, and identifying different subtypes or fibroblasts.
And they've explored their differential roles in the context of inflammatory bowel disease.
Now, this work, which is sort of under the broad umbrella of the Human Cell Atlas project, is taking a very different perspective,
which is looking at the development of the human foetal intestine over time and applying some
of those same intestinal single cell sequencing approaches that they've used previously.
And then combining them with a very cool novel technique called spatial transcripts mix call.
This sounds like a massive piece of work. What is spatial transcriptase mix?
I've not heard of that one before. An extremely good question.
And I'll I'll talk I'll talk a bit about the detail of of both of the methods that they've used to.
They've used to characterise the development of these cell types within the human gut.
So what they're trying to do is create this kind of long detuned, not atlas of the developing human gut.
So they're looking at sort of several different dimensions, a first time.
So weeks post conception, looking at the different cell types that are there, but also looking at where they are range to both along the gut.
So for Gartin hind gut or small intestine, large intestine, but also where they are in the gut.
Are they in the epithelium, the lamen appropriate or in deeper and deeper layers, to kind of answer your question?
The scale and technical complexity of this work is is pretty mind blowing.
So it's worth definitely spending a couple of minutes talking about just the skin,
the scale and technical complexity of this work and the two key methods used.
So we talked last episode a little bit about single cell RNA sequencing.
In this in this study, they've performed this approach on human foetal intestinal tissue from different locations and gestational ages.
They analysed 77 samples in all.
That's a lot. And as someone who's done some single cell RNA sequencing.
And you have to. That's a lot of stuff. That's a scary number of samples.
Quite an expensive number of samples. Yeah.
So we mentioned RNA sequencing in the last episode, which is an unbiased method for looking at all the genes that are being transcribed in a sample.
And we're normally thinking about a sort of a bulk sample or blood sample or a piece of tissue,
and we extract all the RNA from all the cells in that sample.
We process it and then we get an idea of, you know,
maybe comparing health and disease and what what RNA transcripts are up or down regulated in disease.
This is single cell RNA sequencing. And that really just does the procedure in miniature.
And here we're looking at the level of single cells,
which is technically challenging in terms of both how to generate the data and then also how to analyse it and interpret it.
But the real power of it is that it allows us to understand different subsets of cells, different types of cells,
but also different transcriptional states of different cell types,
and how those gene expression profiles change in different conditions, ILIT diseases or locations.
And so in this world, they have they've created this atlas.
Looking at the transcriptional profiles of over seventy five thousand cells over this really important window in development where.
We're really all of the important structures, and so one of the gut develop,
including the development of the crypt of villus access and the colonisation of the guts by different immune cell populations.
And they describe an astounding 101 different cell states, not necessarily all different cell types.
Some of them will be a particular cell type,
but expressing a different sort of pattern and set of of genes because they're they're doing something slightly different in the tissue at that time.
But 101 different cell states, and that includes epithelial cells and fibroblasts,
but also endothelial cells and Perry sites and neural cells involved in in the gut.
Muscular, muscular cells, meesa, thallium. And all of the immune cell populations.
And then if that wasn't enough. If that wasn't enough.
They then go on to use this novel technique that you've asked about called spatial transcripts, OMX.
And this is to look at the localisation of genes expressed within the anatomy of the developing gut.
So what they've done is they've used a very cool technique called called visión,
where you can look at the gene expression within each area of a section of tissue.
So effectively, they've sliced some thin, a thin section of tissue.
And then you can take individual spots within that tissue and you can see what genes are being transcribed in that place.
And then using basically magic, but very clever bioinformatics analysis.
You can take your single cell RNA, see that you've used before to identify all the different cell populations and then integrate it with
your spatial data and say what kind of cells are likely to be a different places in the tissue.
So it really is. It really is truly, truly astounding.
Wow. I just want to say wow, because this is so much work and it's a really cool.
And so huge. It really is. You're right. This is going to be analysed for a year or used for years and years by scientists.
So what did they found using these amazing techniques?
I mean, in truth, I guess it's not really possible to scratch the surface within within a show, within a podcast.
This paper is huge. And I mean, it is ridiculous in a good way.
There is so much there and it's really relevant. Pretty much every cell type and process in the human guts that you can probably imagine
will highlight a few particular cool things that this work sheds some light light on.
First, I think the temporal relax aspect. So having having samples from foetal guts at different weeks post conception shows the development
over time of the intestinal epithelial compartments in a way that's not really been done before.
So it even it really early time points in gestational development even before the development of what we'd recognise is as crypts and Vili's.
So the crit develops access. You can see differences in gene expression in the small and large intestine epithelial cells.
So they're even even way before we've even got a villus in sight.
The small and large intestine are different in terms of their gene expression.
So, for instance, the small intestine expresses a molecule called CCL 25,
which is the ligand for a chemokine receptor called CCI nine, which is involved in immune cell homing to the developing gut.
We can see the developments have some really interesting cell types later on in gestation.
So want one that I've been thinking about recently are intra endocrine cells.
So these are the sensory and secretory cells that you find in the epithelium in both the small and large Vall.
And they they sense luminal contents and then responds by releasing gut hormones,
which we are increasingly recognising have have a really important role in metabolic responses to nutrition.
And we can also start to infer potential interactions between the developing enteric nervous system and the secretary cells.
And I think it shows this this really early interaction between those kind of neuro and neural and hormonal systems in the control of gut function.
The second thing this this this paper talks about in a bit of depth is the development of that cryptid villus structure,
which they look at one of the subsets of these Mease and Kime or cells, the the s to fibroblast that they've described before.
And they show that they have a role in both supporting and maintaining the epithelium creped.
And this work particularly shows that those those same cells are associated with the development of villus structures.
Right. Right at the start of the Krypto Villus actually axis developments and that they differ.
Gain between the small and large intestine.
Again, suggesting that these cells are involved in this distinct structure, distinct structures of the smaller large intestine.
And then it goes on and then just, you know, briefly discusses the development of gut associated lymphoid tissue,
the colonisation of immune cell populations and and the importance of the the stroma around.
Gutt associated lymphoid tissues to the fibroblasts and how they help with its development.
So, you know, not much not covering anything. Shall I?
And then, you know, and then just as the sort of the cherry on the cake,
the group used this data to unpick the potential cellular basis for a variety of congenital intestinal disorders.
So trying to work out which cells might be involved in those disorders.
So such as Hirsch Broom's intestinal mount mal rotation and on Fallas SEAL.
And I think this last bit really shows the power of this work because I think this
paper's real impact is not in necessarily the findings and the conclusions of the paper,
but in its in its role as just really an unparalleled resource to ask specific questions about gut
development related to particular genes or cell types or processes that you're interested in.
And the great thing is that you don't have to be a hard core coder with it, with a deep love of art or python to go and have a look for yourself,
because the group have put together a really nice graphical user interface, which you can access on the Web and you can look at the gene expression.
And so the single cell, but also the spatial transcriptase mix and look at gene regulatory networks and
receptor ligands interactions for whatever your your chosen gene of choice is.
And we'll share share the link to that in the show notes.
Amazing. Thank you. That sounds like a really impressive paper.
You also mentioned Human Cell Atlas. Is this integrated within that?
So I think it's part of this human cell atlas. Yes, Altium.
So this is a sort of an international an international consortium of different
funders and research groups who are supporting the use of single cell sequencing
approaches in health and in disease for the whole of the human body and the sort
of the broad aims to make an atlas of the human body within health and disease.
I think it's probably going to be more like, you know, hundreds of hundreds of atlas's more more like a well,
like a geography map room than it will be a single atlas.
I think this makes a fantastic contribution to that.
Yeah. Amazing. Thank you very much, Fits. That was a brilliant paper.
So now we'll move on to our five in five section and we'll we'll try and invite trouble.
We are definitely not going to manager in five. I've just had a leg papers, and I think we're both going to go off on one a bale manager.
I don't know about you, Tamsin, but there's just so many interesting things everywhere. I know.
I know. I've really, really struggled. I came up with about. We could have done about 20 papers.
Yeah, I guess we know so. And I think this probably tells us we should do the podcast more often better.
So to start with, I've got a good one which actually kind of riffs off the last paper because whereas talking about entero endocrine cells.
So this is the results of a trial in the New England Journal of Medicine
entitled Once Weekly Semigloss Glue Tined in Adults with Overweight or Obesity.
This is, I think, a really exciting trial of a pharmacological intervention in obesity that seems to work really well.
So obesity and its associated complications of metabolic syndrome and diabetes is really one
of the great global health challenges of our time and non pharmacological intervention.
Alton's of diet and exercise are broadly ineffective, and the current armamentarium of of drug interventions is also pretty limited,
both in terms of its efficacy and side effect profiles.
And there is a real unmet need for drug treatments for those with obesity.
Smugly side is a glucagon like receptor one or JLP one analogue, which is licenced for treatment of Type two diabetes.
And previous trials have noted that individuals with diabetes who are given this drug often lost weight.
Now JLP one is one of these peptide hormones released from entero endocrine cells in the small intestine after meals.
And it's got a number of functions, including inducing insulin secretion, delaying gastric emptying.
And importantly, it seems to to signal to induce the sensation of SIST satiety.
So this is a multicenter international phase three trial of nearly 2000 patients, either with obesity or who are overweight with complications.
And importantly, none of them had diabetes and they were randomised two to one to receive either weekly a glue tide or placebo.
And it was a nice, long trial. They looked over 68 weeks and the primary end point was the percentage of weight loss
and particularly the proportion achieving greater than five percent weight loss.
That's been shown in previous trials and observational data sets to be associated with improved cardiovascular outcomes in this trial.
The average age was around 46. The average weight of participants was about 105, five kilos with a BMI of 38.
So on the intention to treat analysis, individuals getting semigloss height lost fourteen point nine percent of their
body weight compared to a weight loss of just two percent in the placebo arm.
So importantly, 86 percent of those taking Samma glue tide lost five percent body weight or more.
But really amazingly, 51 percent lost fifteen percent body weight.
So that's that's really enormous changes in in body weight.
And. And they showed showed that that's associated with a number of other physical and biochemical improvements.
So rate reduction in visceral fat mass and then consequent improvements in blood pressure, HBK one, see lipids and so on.
All improved and also people felt better.
So those global improvements in quality of life indices similarly tied, as has been shown in previous studies, is associated with some side effects.
The most common are gallstone disease and pancreatitis, probably secondary to the same gallstones.
And we see that both with other JLP one analogues, but also with individuals with profound weight loss from any from any method.
So overall, seven glew tide is more efficacious than weight loss.
That's been seen with other anti obesity therapies, and it really has great efficacy at generating that five percent weight loss,
which is the widely used criterion for successful treatments.
So SOUNDS was about 10 minutes just on one paper, but it's pretty breakthrough.
That's actually that's a pretty important study. It's mine now.
Okay. Right. What if what have you got for. For me, Tamzin, first paper is a success story for primary biliary cholangitis.
Last week I presented a negative trial. This week, it's a positive trial.
So this was Thich Hippocrates for each tribe raising Colon Geography's and which was a double blind randomised placebo controlled trial published in.
Gastroenterology in the March 20 21 print edition, pruritus, as we know, is often,
quite often a really very difficult problem and an intractable problem, often in allostatic liver disease.
And there are various drugs recommended by current guidelines, say co-star Mean Fromson Naltrexone centrally.
But these often have limited efficacy, and with some they have limiting side effects.
Benza fib rate plus ursu oxy coated passage has been shown previously to be useful to
initiate complete biochemical response in some PBS patients that are resistant to us alone.
And they noticed that as well as the bike health improvement in these studies, which also improved in the groups receiving better hip rage.
But it hasn't been assessed for the treatment of H in the wider spectrum of Callisto's eclipses, including PCV,
also encompassing PSC and secondary SKERRIES and cholangitis,
and also in a wider group of patients who maybe do respond by chemically to orthodox killik acid alone.
So this trial randomised adults with PGC, PSC and SASE with moderate to severe itch to benefit BRAIT or placebo and the
quantified moderate or severe itch by a visual analogue scale of zero to 10.
So any antipathetic drugs that they were on except for Calista are mean or topical agents like menthol creams and things.
And so we continued. But other ones were stopped. So rifampicin, naloxone search.
The primary endpoint was a 50 percent or more reduction in the H intensity on the vast school day 21.
This study, like the other study that I reported recently in the last podcast about PPC and it was difficult to recruit to.
So they recruited seventy four participants in total.
So 38 were randomised to Benza for breach and 36 to placebo.
And most of them were either PPC or PSC patients.
Only two of them had secondary sclerosing cholangitis. The median vascular in each group at baseline was seven for each and in each group,
80 percent of the participants were also taking ESA jokes Kotick acid and four percent in each were taking care storming.
As I said, slow recruitment.
They planned to recruit over one year, but they ended up stopping the trial at three years, even though they hadn't met their recruitment target.
But they did meet their pre calculated power because they had a lower dropout rate than they expected primary outcome,
which was the 50 percent reduction in the visual alino score at 21 each.
Forty five percent of the benefit rate group reached that primary outcome versus 11 percent of the placebo group.
So that translates into a median visual annual score in the beneficiary group of seven day zero compared to four a day.
Twenty one. There were no serious adverse events seren creating an increased by three percent from baseline and with benefit bright treatment.
The median change of craton didn't actually differ between two groups. So though this was a short trial, only three weeks of therapy.
This is a good news story for paratus treatment and should really inform practise going forward.
And we'd need some longitudinal data on efficacy and safety because it was only a three week trial.
That's fantastic news. And I'm with 45 percent achieving the primary outcome.
I mean, that's sort of number needed to treat of two.
That's massive given how challenging the symptom is in the clinic.
While I totally agree with you that the longer term data is always needed.
You know, this is a class of drugs that we've been prescribing for, well, decades and have got a great deal of long term safety data on it.
So, you know, it's it's one of the you know, the real benefits of sort of repurposing these drugs or extending the licence for these drugs is there.
You know, we've already got quite a lot of experience in using them.
Yeah. That's fantastic. That's for sure. So if you got another one for me.
Yes. I've got something different for you. Everyone's favourite topic, pharmacokinetics.
Just what you're always after full on on a podcast. But I think this is relevant and I think this is important.
It's going slightly niche.
So this is this was in a peaty recently, a few weeks ago, flagged up by by a friend on Twitter, of course, where I love everything nice.
And the title of this is Maternal Thyer Pureeing Metabolism during pregnancy in
IBD and clearance of thigh appearing metabolites and outcomes in exposed neonates.
This is from a group in Australia, the Piccolos Study Group.
Pregnant and breastfeeding women often get a pretty poor deal when it comes to.
Clinical trials, particularly clinical trials of therapeutics,
and I think they're the current example that people are talking about our our kuvin vaccines
and the fact that they were excluded from all of the trials and now everyone's going,
well, oh, we don't have any data. And it's it's yes, ordinarily frustrating for, you know,
50 percent of the population who can potentially become pregnant to be excluded from from these trials.
It's very frustrating in IBD.
Pregnancy is a worrying time for women affected because of considerable concerns and justifiable concerns about drug risks,
as well as the dangers of active disease. And, you know, our general approach is that the importance is to maintain disease control,
as that seems to be the greatest risk to pregnancy outcomes, as well as to avoid obvious sort of known two antigens like like methotrexate.
However, there are real questions that remain about some of the agents that we use regularly, particularly about their pharmacokinetics in pregnancy,
as well as the transfer of those agents to the newborn and whether that bit beyond the sort of the teratogenic things that we worry about,
concerns about immunosuppression and potential vaccine efficacy in the newborn.
So this this study group, the picolo group which stands for pregnancy and Crohn's and colitis, observations, levels and outcomes,
have been looking at these factors with Thyer periods in a cohort of patients
in Australia THOI appearing so captive Puritan and the Prodrug ASIO Pareene
are generally considered safe in pregnancy and they are commonly used maintenance
therapies in IBD either prescribed alone or alongside anti TMF therapy.
Thyer periods are metabolised in the liver into the therapeutically active molecule, which is Thyer body nucleotides, or 60 GM.
The adequate levels of which are associated with disease control and excessive levels are associated with myelosuppression.
However, on that sort of metabolic pathway, you can get sort of hyper methylation or shunting of the of MoCap Superior metabolites,
and that can lead to the accumulation of six mith AAMA caps a period or six MMP, which at high levels is associated with hepatic toxicity.
Now both of these metabolites can be detected in serum masses and on the basis of which we dose titrate.
However, it's unclear how pregnancy affects those metabolic pathways and therefore what how those levels change in pregnancy.
There have been some previous studies that have suggested that it's six TGA levels may may drop during pregnancy and
there have been previous associations with severe neonatal anaemia at or raised liver enzymes with Thyer periods.
So in this cohort of 40 or pregnant women, the levels were measured before,
during and after pregnancy and where possible levels were also taken from the newborn,
both at the time of delivery from cord blood, but also six weeks postpartum,
which is sort of an important time because that's when the first round of vaccinations are given.
So the first finding of note is that this study has confirmed that six TGA levels fall during pregnancy
and they seem to be lowest in the second trimester compared to either pre or post pregnancy levels.
And the differences were pretty marks. So the median level in this cohort in the second trimester was was one hundred and seventy nine,
which is well below the therapeutic range compared to a median of three to three post-partum.
In contrast, the levels of six MMP that sort of the toxic metabolites generated by shunting
increased during pregnancy and they had the highest in the second trimester,
suggesting that that drop a six TGA levels, while it might be partly due to increased volume of distribution or other effects,
is partly due to alterations in shunting during pregnancy.
From a clinical point of view, the reassuring part was that in this in this cohort,
the reduced levels of six TGA in the second trimester didn't seem to be associated with an increased risk of flare.
Now, the second part of this, which I think is really important when we're sort of thinking about sort of counselling,
counselling patients, is what the what they've done when looking at cord blood and blood tests in the near NAIT.
So 60 Jaén was detected in cord blood at birth, generally at considerably lower levels than in the maternal circulation,
although the two did correlate as as you would expect. Now, reassuringly, both 60 gen and six.
We were undetectable in all of the infants tested six weeks postpartum,
so the these metabolites are cleared relatively quickly after delivery because
of the previous study that had flagged up this risk of postpartum anaemia.
They look specifically at haematological and biochemical changes in the neonatal and they didn't see any cases of severe postpartum anaemia,
which was reassuring. However, 80 percent of the children had some some either biochemical or haematological abnormality,
either with mildly elevated liver biochemistry or thrombosis like Tice's.
And both of those seemed to result resolve over the next few months.
Now, it's important to recognise that this is not a study that has a controller.
There weren't individuals who didn't have IBD or who didn't have the Iberians or weren't receiving type hearings as a comparative.
So it's hard to clearly link these particular biochemical or haematological changes to the drug necessarily.
It may be that, you know, potentially,
particularly the thrombus I ptosis maybe due to some subclinical inflammation of the underlying inflammatory bowel disease or another factor.
But overall,
I think this is an important study flagging up some issues with alterations in the pharmaco pharmacokinetics of five periods in pregnancy.
And also, I think providing sort of this sort of the clearest evidence of of of what happens in the near late for those.
And it's a great use of real world data to inform us sort of a challenging,
challenging aspect of practise in a historically pretty understudied patient group.
That was very interesting and actually leads to many, many more questions, I think, that we don't really have time to go into right now.
But yes, and kind of also begs the question, do we need to do more of this?
And so my next one moving on is another liver one.
And it's about Willson's disease. And I thought I'd do this paper in support of the recent Rare Diseases Day.
So this was published in Gastroenterology in February 2021.
And it's entitled Direct Measurement of ATP seven V Peptides is highly effective in the diagnosis of Willson's Disease.
So I didn't know much about Wilson's disease. To be honest.
But before I read this paper. But apparently it relies on the combination of clinical and biochemical features for diagnosis.
And so current practise guidelines recommend the use of the Leipzig school.
And basically this combines things like the presence of Kaisa Flash.
It rings some biochemical things like lonesome plasma.
And in the presence or absence of known genetic mutations to adapt to guide the diagnosis.
But what I didn't really appreciate about the diagnosis of Wilson's disease is it's actually can be quite challenging.
So low, Sarena, plasma levels alone aren't enough to diagnose or refute Wilson's disease.
And the gene that is involved in Wilson's disease is the ATP 70 gene sequencing.
It can be helpful and you can find some sort of no mutations should be held for the diagnosis.
But actually, there are lots of single nucleotide polymorphisms and also variants of unknown significance within that gene.
So you don't always get a clear answer. In this study,
the authors set out to measure ATP 70 peptide directly from dried blood spots using a mass spectrometry
technique that's modified cheeze monoclonal antibodies to target the protein of interest.
And this allows very small quantities to be detected. So they establish and will range by testing 150 healthy control samples.
And then they took blood samples from patients with known Willson's disease, diagnosed Wilson to these 216 patients and forty eight obligate carriers.
So these were family members of patients with heterozygous variants in the eighty seven Beijing.
So they found that the signature peptide levels in patients and the patients dried blood
spots were below Cut-Off in 90 percent of samples for both 80 p 70 one zero five six,
which contains the most common Willson's disease causing mutation and ATP seven B eight eight seven.
And they used the presence or absence of these to work out how good this test was.
The receiver operating curve analysis generated a really pretty good area under the curve of nought point nine eight.
Using these parameters, the peptide analysis of the.
T.P seventy eight, eight, seven was found to have very high sensitivity.
Ninety one percent and a specificity of ninety eight percent with high and positive and
negative predictive values and an impatience that are a bit more difficult to diagnose.
So with normal cerrillo plasma concentrations, there are only 16 of these in the cohort, but 87 percent of them were deficient in this protein.
So it would have been diagnosed with this test and in patients without clear genetic results.
94 percent were deficient and therefore would have been diagnosed with this test.
So obviously this needs separate validation in other cohorts, but it's pretty exciting because this might represent an off biomarker.
That might be a really helpful development in diagnosing Willson's disease.
And the last paper I wanted to cover published in Lancet Gastro Hepp in the January 21 21 print issue,
and it's entitled Redefining Fatty Delivered These Fatty Liver Disease and International Patient Perspective.
Briefly, this concerns the proposed change in nomenclature of NAFLD so non-alcoholic fatty liver
disease to Mathilde's metabolic dysfunction associated fatty to live liver disease.
And I'm a bit reluctant to admit that I wasn't aware of this proposed change before now,
even though it's been talked about quite a lot in the literature of the lost last six months and the proposed name change from NAFLD to Mathilde's,
the full details can be found in the May 20-20 print issue of gastroenterology and also the July 2020 print issue of the Journal of Hepatology.
You know, put links on the nights,
but basically it was an international experts consensus statement which called for the change of name from Nettle's to Mathilde.
They wanted to do this for several reasons. One,
because they wanted to move away from the NAFLD versus Nashed dichotomy of okay versus bad liver disease
and move towards a grading the liver disease severity on the grade of activity in fibrosis stage.
And also they wanted to move towards diagnostic criteria that have a focus on
positive presence of things rather than the absence of alcohol consumption.
NAFLD is to logically the presence of statuses in over five percent of hepatocytes in the absence of significant,
ongoing or recent alcohol consumption and other men cause of liver disease.
That's the accepted definition now.
But the proposed algorithm for Mathilde's is about icks decisis in an adult and that Seada detected by imaging biomarkers on bludge histology.
And if the individual is overweight or obese, they've got muffled or if they've got type two diabetes,
they've got muffled or if they are lean or normal weight.
But they also have the presence of at least two metabolic risk abnormalities, such as blood pressure, high blood pressure, high triglycerides, etc.
Then they were also diagnosed with Mathilde. There's been quite a lot of discussion since this has been proposed in the literature and the authors,
when they did propose it, acknowledged they need to.
This would need validation and prospective studies to assess its utility in clinical practise, especially with the proposed new diagnostic criteria.
The article and I want to talk about and is actually the patient's perspective on this.
So it outlines the patient groups, representative groups, and are in support of this change of name from NAFLD to Mathilde and for many reasons.
But in particular, they perceive that Mathilde has less stigma attached to it as a term that Nuffield.
So as I wasn't aware of this, I'd really encourage people to have a read of this and some of the other
editorials that have been published on the consequences of this proposed change.
And that's the five and five slash five and 10, we should call it five and fifty five.
And but like it, I think we I think we might be able to manage that and that last year the last articles are, you know,
it's really interesting until pretty I haven't read those and I will I will now go and have a look at some of those.
Excellent. Well, we seem to have got to the end of this was his had been a particularly long episode of our podcast.
I'm looking forward to our next episode because as we've said, it's been it's been a bumper bumper crop of papers in the last few weeks.
And I think we've pretty much got the line up for the next episode sorted.
We'll be talking a lot about Albumen and Turley Pressin in liver disease and in her of renal syndrome.
I'm also going to talk about the battle between Kitto and plant based diets for for weight loss
and and probably something about enteral nutrition in the context of acute severe colitis.
So, yeah, lots to lots. Tune in for next time. So that brings us to the end of this episode of Gut Instinct.
Please let us know what you think and leave us a review or get in touch on Twitter.
Actually, update Dr. Greenmail at Gut Instinct cast.
That's Gene and Lucy.