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Gavin: Hello, welcome to a new year and a new episode of The Lancet Voice. I'm Gavin Cleaver, 

Jessamy: and I'm Jessamy Baganal. Coming up in this episode, we've got Professor Alex Ford talking about Irritable Bowel Syndrome, a very common but often misunderstood condition, and Dreams Deferred, an award winning essay written by Rachel Fleisman, ND.

First 

Gavin: though, the worldwide conversation on COVID has been dominated by the emergence of two variants over the last few weeks. These variants, often referred to as the UK and the South Africa variants, are purportedly more transmissible, but there's a lot of speculation about them, a lot we don't know, and a lot to find out.

We spoke with Dr Emma Hogcroft of The Next Strain Project to find out more. We're really pleased to be joined today by Dr. Emma Holcroft, who's an evolutionary geneticist from the University of Basel and part of the team at Nextstrain, which tracks COVID strains across the world. Emma, thank you so much for speaking with us.

Emma: Very happy to be here. 

Gavin: So tell us a little bit about the Nextstrain project. 

Emma: So the idea behind Nextstrain is that we can use viral genetic material to actually track how viruses are moving and how they change over time. And the way that we do this is we actually look at the little mistakes that viruses make when they're replicating.

So when they're in your body, they have to copy themselves, of course, millions and billions of times. And eventually while they're doing this copying, they'll make basically a typo. So a little mistake, a mutation in their genetic material. But what's really important to remember is that most of these mutations, they don't change the virus at all.

They really are like typos, but a few of them obviously can sometimes change how the virus works in general. So we just use all of these mutations to figure out how the viruses are related. So if they have more of the same mutations, then we assume they're more closely related. They came from an ancestor that had those mutations.

If they don't share many mutations, then they're more distant relatives. And we essentially create like a giant virus family tree. And since we know where the viruses were sampled and when they were sampled, we're then able to use this to look back in time and see how viruses have moved and how they've changed over time as well.

Gavin: To give us an idea of the kind of scale, how many strains of COVID roughly do you think you're tracking at the moment? 

Emma: We actually are pretty careful about the use of strain when it comes to COVID because we generally use strain to describe differences in viruses that are more extreme than what we see in SARS CoV 2 so far.

But we do see lots of different viruses and lots of different variants. In fact, there are probably millions of unique SARS CoV 2 viruses out there already. But as I said, it's important to remember that the vast majority of these mutations don't actually change how the viruses work. The reason that we usually start calling something a variant or kind of paying more attention to how it's moving is if it seems to be associated with a change in behavior.

So most likely, and of course most recently, this has been, for example, if we see a particular cluster of viruses that share mutations starting to expand faster than we would think is caused by chance. Of course, a perfect example of this is the recent variant that's predominantly found in the UK right now, this seemed to really speed up in how quickly it was spreading in the population.

Jessamy: It's so interesting and affecting all of our lives at the moment. So how does a virus become more transmissible? 

Emma: So there's a few different ways that this can happen. In general, it's thought that one of the most basic things is that if you produce more virus, then you will have more virus, for example, in your nose and mouth.

And so then when you breathe, cough, talk, or sneeze, you're spreading more of this virus out into the air, which could then increase the chances that someone else will inhale it and get infected. But there's another way that a virus might be more transmissible if a lot of people in the population have already been infected.

So this would particularly become true in areas where they've had really big outbreaks and we think a lot of the population has already had SARS CoV 2. We think that probably protects you from getting infected again with the same variant. But if the virus is able to change itself enough so that your body doesn't recognize it that second time, then a virus might become more transmissible just because it's able to reinfect people.

Jessamy: That's interesting. So even with say a zero prevalence of 10%, that kind of. drive for the virus to change might be there. 

Emma: It's hard to know exactly what level it might take before this really becomes something that is advantageous for the virus. Certainly, if most of the people, the vast majority of people in a population haven't been infected yet, then we wouldn't expect that reinfecting people gives the virus a real advantage, and we wouldn't think that mutations that give it this advantage would spread in the population.

But it's hard to know exactly what level of people already having been infected would start to drive the virus to seeing these mutations as beneficial in that it gives them an advantage that they can reinfect people. 

Jessamy: If a variant might mutate to become more transmissible, it might mutate to do other things.

As physicians, we're interested in clinical presentations. So how do these viruses mutate to develop different clinical presentations? And what might that look like? 

Emma: So this is something I think that we know a little bit less about, but certainly we can think about some scenarios where this might be the case.

So certainly if the virus, for example, starts infecting different tissues than it might normally, or is able to move through the body so that it can access, for example, maybe deeper parts of your lungs or more parts of your respiratory system, this might mean that you have then a worse infection.

Similarly, if it starts infecting different parts of your body, so it gets into different. organs. That might mean that it's had a mutation that means it can bind to, which is what it needs to do to reproduce. So it can bind to different cells. That of course might mean that you have a more systemic infection that's harder to fight in a hospital.

I don't think we have a lot of information yet about the, even that this is happening with SARS CoV 2 or how it might happen, but certainly it's something we want to keep an eye out for in the future. 

Gavin: Of course, in the news a lot recently, we've been hearing a lot about to use the shorthand, the UK version and the South Africa version of these supposed to increase transmissibility.

Have any other virus variants displayed like these kind of distinct characteristics so far? 

Emma: So I guess the most famous example in this pandemic would be the D614G mutation. Now this is one that we heard a lot about in the media over the summer, but it actually appeared really early in 2020 and it very quickly became the dominant variant that spread through the world.

It still is today. And if you live in the U S. or Europe. It's the variant that you're most likely to have been infected with if you've already had SARS CoV 2. And the way this mutation worked was that it seemed to actually increase the ability of the virus to attach onto cells so that it could replicate, making it slightly more transmissible and more successful in spreading around the world.

But I do want to emphasize that we have seen other cases where a viral variant of SARS CoV 2 has spread in a manner that. caught scientist's eye, but doesn't seem to have had anything to do with transmissibility. So a key example of this is actually a variant that we studied over the summer called 20 A EU 1.

It seems to have first expanded in Spain in mid summer, and then right when travel restrictions started being loosened and kind of general restrictions and behavior started loosening across Europe. It took advantage of holidaymakers and it managed to spread to pretty much every country in Europe and start expanding in those countries.

From initial lab studies, we don't actually think this variant is more transmissible. It was basically just in the right place at the right time. time and it was able to take advantage of the behavioral setting that we put it in through our summer behavior. So I think it's also important to remember that we as humans through our behavior and our restrictions, we can have a big impact on how variants spread.

It doesn't necessarily take a mutation that changes the virus behavior to do that. 

Gavin: Yeah, that's really interesting. It's a great point to make about the evolution of viruses. Talking, of course, still about the, again, to use the shorthand, the UK and South Africa variants has there been much evidence for their increased transmissibility outside of the UK and South Africa settings so far?

Emma: So far, the evidence outside of the two countries where it seems these variants have expanded is somewhat limited and mostly this is just because we don't see a large number of cases, at least identified cases in countries outside of the UK and South Africa. Certainly, though, in countries that are really doing Good genetic screening and sequencing.

A lot of people, for example, like Denmark, we can see that they have at least about 70 sequences that come from 5 0 1 y v1 or the variant that originated in the uk. And so if this is spreading as it seems to be in Denmark. It might not be too long before we're able to gather information from other countries and see if they have comparable estimates for transmissibility as they do in the UK and South Africa.

Jessamy: Thanks, Emma. Just on that point, obviously because it's so fast moving and particularly in the UK when this. This new variant became generally known. There were scientists, some scientists saying actually, it's about non compliance with the restrictions that are going on place.

That's why we're seeing a rapid rise. It's not necessarily because of this new variant. What's the process by which we're able to really pin down how much more transmissible a variant might be? What's the evidence that we need and how is 

Emma: that accumulated? So this is a great question, and I do think it's a really important one because as I spoke about with some variants like 28EU1, we do seem to think that this was mostly about behavior and travel rather than the virus being more transmissible.

I think that a great way of putting the situation that we have with the new variants predominantly in the UK and South Africa is that we don't necessarily have perfect evidence yet that they are more transmissible, but the imperfect evidence that we have and that is growing all points in the same direction.

So for example, we have independent models that have been made at different universities that take into account lots of different behavioral compliance. and restriction factors and really hundreds of different parameters and try and figure out what could explain the rise that we see in the UK. And essentially, even though they're independent models, they're coming out not only with the same conclusion that it seems the virus is more transmissible, but actually really similar estimates in how much more transmissible.

On top of that, we can also look to the UK's great wealth of information on, for example they've actually looked at the difference between how many contacts got infected for those that had the kind of original or the previously circulating variant of SARS CoV 2 versus the new variant. And they found that people with the new variant were 15 percent of their contacts got infected versus 10 percent with the older variant.

So again, this is just an example of kind of a few different pieces of information that I don't think any of these on their own would necessarily be so convincing, but when we put them together, they do start pointing in the same direction and becoming increasingly convincing that there is a real change in transmissibility here.

Jessamy: And out of interest, historically within the Nextstrain's work and projects, what other viruses have you looked at and where you've seen these sort of similar movements, these similar changes and you, this is obviously kind of science being applied in real fast time, but when you look back at your, your time at Nextstrain and your career, have there been similar situations?

So 

Emma: I don't think we've ever had a situation quite like SARS CoV 2. The number of sequences and the speed with which we've received them with SARS CoV 2 is really unprecedented. We have over 300, 000 sequences for SARS CoV 2, a virus that, just over a year ago, we didn't even know existed. And just to put that in perspective, before I switched to working on the pandemic, I was working on a much less well known virus called enterovirus D68.

We discovered that in 1962. So it's been around for a while. And I was incredibly proud of the fact that we have. 800 sequences of enterovirus D68, something we've been, we've known about for 60 odd years. So when you put that in comparison to 300, 000 sequences in a year, you can really see that this has allowed an unprecedented amount of tracking and investigation of this virus.

The nearest comparable example would be influenza. So Nextstrain has been involved with influenza actually since day one, originally we were called Nextflu. And the purpose was to track flu specifically, and in particular to try and help predict what flu variants might be circulating or what flu strains might be circulating in the next flu season to better pick the vaccines that we would give people or that we wouldn't give people, but that would be given.

And I do think here, this is the best comparison in that we have lots of countries around the world that have a real coordinated effort in making sure that they. generate flu samples regularly and share them openly so that we can have a good idea of how flu is spreading year on year. I think with SARS CoV 2 it would be great to see a similar setup where countries are equipped in the long term to monitor where SARS CoV 2 is, how it's changing and what variants might be arising.

Certainly the general hope would be that this is something we could eliminate and just not have to worry about. But I think we need to prepare for the fact that this might be a more longterm problem. And in that case. We definitely want to keep our eye on it and make sure that it doesn't evolve into something that is more dangerous, particularly once everyone has vaccines.

Gavin: Yes, so just to finish up and along those lines then, I guess the kind of million dollar question of horror is what does a kind of vaccine escape version of SARS CoV 2 look like? 

Emma: So the nice thing about our bodies is that they're actually pretty flexible in how they recognize pathogens. So the way that the current vaccines work is that they actually give your body the spike protein, which is the most sticky out part of the SARS CoV 2 virus.

And they teach your body how to recognize that. And luckily, your body's pretty good. It looks at all different parts of that protein. Just like you or I learn to look at, all of our friends faces to recognize them. So even if your friend puts on sunglasses or a hat, You can probably still know who they are.

It's the same with our bodies because they learn to recognize lots of different parts of the spike protein. The hope is that even if the virus changes a few pieces of that, your body will still notice it if it starts coming in and we'll be able to protect you by mounting a really good response. The concern of course, is that.

Certainly if you, if your friend wraps up in an overcoat, a big scarf, a hat and sunglasses, your chances of recognizing them probably do go down. So with SARS CoV 2, the worry is that if it changes in enough places on the spike protein, your body might not recognize it anymore. Luckily, this is unlikely to be something that happens with just one or two mutations.

But certainly longer term, this is something we want to be keeping an eye on and have a good amount of information about what mutations might be concerning. So that if we start to see them popping up, we can come up with a strategy for how we're going to take control of that before it becomes a big concern.

Gavin: I think what I'm going to take away and think about for the rest of the day is a SARS CoV 2 protein disguising itself with an overcoat and some sunglasses, maybe a mustache, that sort of thing. Dr. Emma Hopcroft, thank you so much for speaking with us today. It's been incredibly informative. 

Emma: Thank you so much for having me.

Jessamy: I think that there's some anxiety within the general media and within the population because we're only hearing about variants in a more meaningful way now because they're actually doing something and I think there is a sort of slight misconception that this is something that's new but actually we've seen variants all along it's just that we haven't necessarily see them do anything.

more, and as the numbers get into more and more millions, we're just going to see more and more variants. So this is something that we need to sit back and be ready for the long haul on. 

Gavin: And it's something that's been speculated on, hasn't it, since the early kind of days of the pandemic that, because of course mutation is such a scary word anyway, especially when you think about a kind of unknown quantity like SARS CoV 2.

And I think a lot of the temptation, especially, in the kind of rush to headlines, is always to go, Ah, the UK variant is a lot scarier, or this particular variant's happening. You can even probably get a lot of attention just by saying that there's a new variant arrived, without actually really offering any details on it.

So it was really interesting to speak to Emma about actually what all of this means. 

Jessamy: Yeah, and I think that point towards How we compile all of the evidence to decide what these new variants are doing is actually a relatively slow process. And the headlines that, this is more transmissible or this is more dangerous do not often reflect the underlying level of evidence and data That's pointing towards those things and as she said, everything at the moment is pointing towards the fact that the UK, the South Africa they're in are potentially more transmissible.

It's not written in stone that is the case. No, 

Gavin: of course, and it's the drawbacks of kind of real time science, I think, as you said in the interview, isn't it? As we've, I feel like we've been saying it for the last year by this point. We say it 

Jessamy: every time, don't we, Gavin? We say it pretty much every time.

We say the same thing. We're just like, it's moving so fast. How do we cope? 

Gavin: It was really interesting, I think, to hear Emma talk about how the what she was working on before was one from decades ago, a virus from decades ago. And how now, actually, the project is real time, trying to keep on top of this kind of massive exponential spread.

And like you said before, It is worrying that the virus is present in so many people and of course we've seen it jump across to a couple of animal populations as well along the way with the mink population in Denmark. And of course, that's how the more serious mutations occur.

I guess the two things that we can emphasize are that The mutations themselves aren't necessarily bad or scary, and there's not been a lot of evidence so far to suggest that they are, beyond this kind of increased transmissibility. But, the more people that we allow to be infected with SARS CoV 2, the more mutations will occur.

And of course the mutations can go either way. They can make something less transmissible, they can make something less serious 

Jessamy: clinically, which is often we hear people say the way that these things go is, in order for the virus to stay alive or to continue.

Replicating for longer, they become, they have less serious clinical manifestations. We've seen no evidence of that so far, that's always also a possibility. One of the things that I really wanted to ask her, which we didn't get to, was what they're planning on doing with this huge database of evidence now.

We must just have so much data. I would imagine it's a sort of goldmine for research. 

Gavin: Maybe we can do a follow up tweet, if people look us up on Twitter. Maybe that question can be answered. We'll just we'll tweet it out. I'd like that, 

Jessamy: Gavin. I'd like that. But yeah, the reassuring thing, the most reassuring thing was obviously about the vaccines, and the analogy that she gave about, your friends wearing your sunglasses and stuff.

Gavin: Which was fantastic, actually. Since we've done that interview, I've sent that to a couple of friend groups to be like, actually, this is a really good way, a really good way of understanding Vaccine efficacy in the face of these mutations and it was quite reassuring wasn't it that it'll still work It will just be you know, the more mutations as we go on the less likely the body will be able to recognize and the less efficacy we'll have but it's 

Jessamy: Yeah, and this Brazilian variant, which I think has now got two mutations on the spike, I think there's still the same feeling that there will still be some recognition from the immune system.

Gavin: Yeah I feel like we could sum it up by saying the thing that we always say, which is lots more still to find out.

Jessamy: Irritable bowel syndrome, or IBS, is a really common condition with up to 1 in 10 people with symptoms at any given time. However, it's commonly misdiagnosed, and for something so common, there's relatively little that's understood about it. Professor Alexander Ford of the University of Leeds spoke with Gavin to help illustrate the problems people with IBS face.

Gavin: I'm very pleased to be joined today by Professor Alexander Ford, who is Professor of Gastroenterology at the University of Leeds. Professor Ford, thank you so much for joining me. So we're talking about irritable bowel syndrome, and you've published a paper on this recently as part of the Lancet series on functional gastroenterology issues, and so specifically your interest is in the area of IBS.

So let's kick off with a very broad question, then. How serious is the worldwide burden of IBS? Now, I think everyone knows at least one person that's had a IBS or suffered with something similar to this. So it seems to me that the layperson that it is quite widespread, but is that correct?

Alex: Absolutely. Yes. IBS is very common in the general population at any one point in time somewhere between five percent and ten percent of people in the community will be reporting symptoms compatible with IBS and those symptoms include abdominal pain in association with either altered stool form You or altered stool frequency.

So between one in 10 and one in 20 people, basically, depending on how you define IBS. So depending on what criteria you use to. Define its presence. Prevalence remains pretty stable really, because onset and disappearance rates over time tend to match each other. But there are other implications of having IBS, and IBS is a burden to the individual, but also to society as a whole.

So IBS is associated with much higher rates of surgery, inappropriate surgery usually. So having IBS is independently associated with a three times higher rate of having a chelicystectomy, so a gallbladder removal, a two times higher rate of having an appendicectomy or a hysterectomy. and 50 percent higher rates of back surgery compared to people who don't have IBS, so healthy people without irritable bowel syndrome.

So if you take that and also the fact that around about two thirds of people with IBS have seen a doctor over the last 12 months or so, and around about four in every 10 people are taking medication for their symptoms, then you can start to see that IBS has considerable healthcare costs. And although there's no increase in mortality in people with IBS compared with healthy people without Irritable Bowel Syndrome.

Morbidity is quite striking due to the impairments in quality of life that result from the symptoms, reductions in social functioning, and also impaired ability to work with days sick, and also presenteeism, so when you turn up to work but can't do your job properly because you don't feel well. 

Gavin: That burden of unnecessary surgery seems quite serious for both the patient and for the healthcare system.

Alex: Absolutely, but it's been well described in, in, in several studies, so I think it's it's genuine, so obviously it's to do with the symptoms of, the typical symptoms of irritable bowel syndrome, so the tummy pain and the bowel habit being misattributed to another problem, so misattributed to gallstones, or misattributed to fibroids, or misattributed to in inverted commas, a grumbling appendix.

And then having a procedure or an operation to deal with that and then the symptoms recur at a later date and then, it becomes clearer that, oh, this was probably Irritable Bowel Syndrome all along and we did this operation to try and improve the symptoms but actually the symptoms are still the same.

Gavin: No, that's very interesting. For something that has the kind of burdens you describe, it seems like we know quite little about the mechanisms underlying IBS. It seems very widespread, but the, I guess the store of knowledge surrounding it seems quite disorganized. 

Alex: Yes, and I think that highlights the issue really, which is that despite the sort of fundamental importance of IBS and these other functional gastrointestinal disorders to healthcare systems and societies they're not very glamorous areas, so they're not a priority for research funding versus other, much less prevalent.

diseases of the intestine, which are viewed as being organic, so things like celiac disease, inflammatory bowel disease, that have prevalence in the population of around, somewhere between 0. 5 percent and 1%, so you can see that obviously IBS is much more common. But it it's not an area that attracts a great deal of research funding.

And that's one of the reasons why I was so delighted, really, to have been asked to to provide this series of articles for the Lancet. Because it really highlights the importance of these conditions for everyone, really. So yeah, pathophysiology, physiological, Mechanisms for IBS are, you're right, poorly understood.

The best sort of described model as to why they develop is this model called the biopsychosocial model, where they're characterised, conditions like IBS are characterised as complex, bi directional dysregulations of the gut brain axis. So the gut and the brain interact through the nervous system. That supplies the intestine, which is called the enteric nervous system.

And that nervous system is hardwired at birth, just like our own central nervous system. And the theory is that there is abnormal communication between the gut and the brain, and that leads to abnormal peripheral sensitivity, what's called visceral hypersensitivity, so abnormal peripheral pain perception in the intestine, abnormal motility of the intestine food moving either too quickly or too slowly through the intestine.

And also, more recently, there's been recognition that there are actually probably microscopic changes in the intestine that may be contributing to symptoms. So that's things like low grade inflammation of the intestine, abnormal intestinal, permeability leading to substances probably in the environment from food or bacteria then being able to actually activate the host immune system.

And this is proposed now to be potentially involved and lead to symptoms. There's also the microbiome, which is a huge area of interest in all gastrointestinal diseases and actually another non gastrointestinal diseases like depression. and diabetes and rheumatoid arthritis and things like that.

So disturbances in the microbiome have been identified in some people with Irritable Bowel Syndrome. So all of that challenges the idea that there are no structural changes. So one of the things that we say about functional disorders are that there's no structural pathology to account for the symptoms.

But 15 years are in stark contrast to that because what we're now being told is that there are actually probably organic changes going on in people without in, in some people with IBS in these experimental studies. The other thing to think about with the pathophysiology is that from epidemiological studies it seems that there are some people where the symptoms start in the gut and that causes problems in the brain, usually with mood and psychological health, and there are other people who start with psychological health issues or mood problems and then develop IBS type symptoms, so again that adds weight to this bi directional communication between the gut and the brain.

But all of this is incompletely understood. None of these pathophysiological mechanisms are the same in everyone. IBS is a very heterogeneous condition and that's one of the problems we face when we're investigating people when we're trying to elucidate underlying causes and also when we're trying to treat it so that heterogeneity means that you can't reproduce these findings in every single person with IBS and so there is a variability in terms of what the underlying pathophysiology probably is because what we're talking about here is a syndrome it's a cluster of symptoms rather than a disease entity.

Gavin: Yeah absolutely that's very interesting so wide ranging so What are some of the kind of currently proven treatments or management techniques that are being used? 

Alex: So I think we're talking about management. The first thing to do is really to confirm that this is IBS. To confirm the diagnosis using usually what I would say a limited panel of investigations judiciously.

And that's to exclude the common sort of mimicking organic conditions like celiac disease. or inflammatory bowel disease, we need to also explain what the condition is, so educate the patient, that's vital. There's evidence from randomised controlled trials that structured education about Irritable Bowel Syndrome, compared to no education at all, can improve symptoms.

Once the diagnosis is confirmed, then a proportion of people probably will only require explanation and reassurance, probably a small proportion of people. Along with some lifestyle advice like diet, some simple dietary changes, advice to eat less Insoluble fiber and things like that and exercise can help some people.

And people who've got symptoms at the milder end of the spectrum, they'll probably be fine with that sort of advice. But there'll be others who've got more troublesome symptoms. One of the things that's increasingly being used. In people with IBSs that you'll have probably heard of is this low FODMAP diet, which is a diet that's based around removing fermentable sugars from the diet because these are felt to exacerbate diarrhea, pain and bloating, but that should only be undertaken with guidance from a trained dietitian.

So one of the problems with the low FODMAP diet. is that often people are just told to look it up online and get on with it themselves, but it's a restrictive diet and you're supposed to reintroduce certain foods back into the diet to tolerance and things like that, so it should be done under guidance.

Beyond those sort of first line treatments and recommendations, treatment tends to then be symptom based. For those who've got diarrhoea, anti diarrheals like loperamide can be helpful, first line. And for those with constipation laxatives, although evidence for both of those is actually quite limited.

For people with predominant pain, anti spasmodic drugs like hyacine or mebevrine can be helpful. Second line treatments, again, they tend to be dictated by the predominant symptom. And we have, this is where we start to use more novel drugs and drugs that are more precise in their mechanism of action.

So drugs that act on gut serotonin or opioid receptors, or drugs that act on iron channels in the intestinal cells are used to manage. Diarrhoea or constipation and also we use central neuromodulator type drugs which are usually antidepressants at a low dose for pain and for those whose symptoms remain troublesome despite these sort of second line treatments and the next stage beyond that is to start using psychological therapies like cognitive behavioural therapy or gut directed hypnotherapy and they're recommended by NICE.

One of the problems with with those treatments is availability and access is limited in the UK. And also, although we're told to use those treatments in patients whose symptoms are refractory, the evidence to support that is limited. It may actually be better to use treatments like CBT and gut directed hypnotherapy earlier on in the disease course.

It might be that you can change the natural history of IBS by deploying them earlier. But at present because of their limited availability and the fact that they're recommended as third line treatments by NICE, that's how we use them in the UK. 

Gavin: So we, we've talked throughout about things like problems with diagnosis and unnecessary surgery, as you mentioned there at the start.

So what could the first kind of contact line GPs and first line doctors do better in then handling IBS patients? 

Alex: That's a really good question. So yes, people who are seeing a patient for the first time who has typical symptoms of IBS So I think the first thing to say is an empathetic approach is key.

You need to be able to understand the patient's symptoms and validate them and validate the impact that they're having on the patient's life and this approach can actually improve both quality of life and symptoms and it can reduce health care visits and it can enhance adherence to recommended treatment plans.

The main issue I think in first line management is a failure to recognize that this is IBS, that these symptoms are likely to represent IBS. Earlier recognition using symptom based criteria, which we have to diagnose IBS, called the Rome Criteria, and then communicating this diagnosis effectively is very important.

You need to have clear, concise communication, so when you're giving the diagnosis, you need to be using what's called qualified language. So you shouldn't say I've heard your symptoms, I'm not really sure what's going on, but this sounds like it might be IBS. You should instead be saying, you have IBS, and this is almost certainly the diagnosis, I'm going to organise some confirmatory tests, but I'm expecting all those to be negative, and so that's my initial diagnosis, and we're going to start treatment.

And again, this more certain language increases acceptance and reduces apprehension on the part of the patient and generally just leads to a better what's called patient provider relationship. We need to avoid over investigation. So in a young person who's got very typical symptoms of IBS, unless there are alarm symptoms or other atypical features in their history, then there's really no role for exhaustive investigation to exclude an organic disease.

You just need to be excluding. The mimics, as I said earlier, like celiac disease with a blood test and inflammatory bowel disease with a stool test, and then pressing on, making the diagnosis and starting effective treatment. 

Gavin: So just me like you said in the intro there and like Alex and I talked about throughout It's really interesting to think how little we understand generally about IBS, you know for something so widespread It's obviously it's not as Alex said a glamorous research area, but it is something that causes a great deal of Morbidity and general illness and it's pleasing to hear that this work is being done And this knowledge is all being summarized in one place as we did in the lancet But yeah, it's it's just actually a really fascinating area, 

Jessamy: right?

And it's a relatively new condition I mean I was looking at I was reading about this You know before we were chatting and I think there are some first descriptions of sort of mucous colitis that's in about 1892 then it goes off grid for a while and then in 1920s, it comes back as maybe some colonic spasm and then we get to more of a sort of condition or disease entity towards the sort of 1940s and 50s But one of the major issues is as Alex was saying is that patients present in very different ways and for the most part With the technology that we have, there's nothing that you can pathologically see on a CT scan or a blood test to suggest that there's anything really very strong that you can treat, even though it's causing patients.

a number of, very debilitating symptoms. And so you get this situation which is very much self perpetuating. You have a research system which is set up to deal with, perhaps, things that are, one, gonna kill people in the immediate setting, but two, also that are easy to research.

You've got good primary outcomes because you understand that, say we're talking about an appendix. that, removing the appendix is a hard outcome that you can measure and that you could do a randomized control around or, readmission to hospital. But things like irritable bowel syndromes, those types of outcomes are more difficult.

So they're more difficult to research and you also have a research system which has less funding for those kind of more benign diseases that are not immediately going to, cause life threatening injury to patients. And then that, that, this sort of cycle goes on, because doctors also find it difficult to, one, identify Irritable Bowel Syndrome, as Alex was saying, but also to treat it, because If you have somebody come with, again, say appendicitis, people have, a very set form of symptoms that the majority of patients have.

It's easy to diagnose. Patients come in with some right iliophosa pain. They'll have blood markers that show an infection and it will get worse and this is this. You can do a CT scan and you can see it there. With irritable bowel syndrome, there's none of those things. There's no set pattern of symptoms.

There's no real tests or diagnostics that you can do to prove the fact that this is Irritable Bowel Syndrome. And for the most part, the treatments are, more lifestyle to begin with and more kind of conversational and talking about it and trying to manage the disease rather than treat it.

So you get this self perpetuating system which really makes patients often feel that their symptoms are diminished and they become marginalized. It's one of these issues that as med, that medicine is not very good at dealing with and there are lots of other things that are similar.

Chronic pain is a sort of other classic example. 

Gavin: That's of course how Alex and I ended up talking about. The how frontline doctors need to treat it in a kind of almost more holistic understanding manner, where they have to actually monitor the tone when they talk to patients about it, because it is such a debilitating but poorly understood condition.

And as well, I wanted to highlight that on our website, thelancet. com, if you go to the series on functional gastrointestinal disorders, you could just Google those words, then there are some great infographics, including one that's a decision tree for clinicians to use. Which looks at how you can eliminate different conditions and eventually get to a diagnosis of IBS and how it's best to manage it and how it's best generally to treat the patient presenting with what is, of course, a pretty debilitating condition.

Jessamy: They're very beautiful infographics, so definitely look them up. 

Gavin: Yeah, our infographics editor will be very pleased to hear that. But one thing I wanted to chat about as well with this, of course, as I spoke about with Alex, was the kind of the burden of unnecessary surgery. Now we were talking about how poorly this condition was understood, and of course how there are lots of other diagnoses that could be made, because as you said, it's not obvious when a patient presents that it is IBS and there's so many other things it could be.

Do you, as a surgeon, have a particular kind of insight into this kind of burden of unnecessary surgery? 

Jessamy: I don't think that there's any negligence or any malice involved. Often I think it's a really open and honest discussion almost between a patient and a surgeon where actually patients get to the end of the line with their symptoms, there's nothing else that you can find.

There's nothing else that you can see on any diagnostics and both come to a decision that actually will maybe we'll try and do a laparoscopy and we'll look inside and see if perhaps, the appendix looks like there's some adhesions around it or, maybe the gallbladder looks like it's a little bit inflamed and so you get this, situation where People are just trying to rule out different parts of it, and sometimes people do feel some relief from it, and sometimes they don't.

I'm, haven't looked into the data that is based on, but I would imagine it's based on observational data, and so there's obviously other aspects. that are at play there. It's an association rather than a causation. So there will be all of those other factors involved like the fact that these patients are more likely to present to hospital at different times they might have, ongoing relationships with surgeons that, where they're both aware that actually the diagnostic, the diagnosis is very unclear, but we're just trying different things.

Gavin: No, really interesting insight and a lot that's really interesting there to think about with OBS, especially as we As we move forward into a greater understanding of the condition. 

Jessamy: He's hoping.

Gavin: Every year since 1996, The Lancet runs an essay competition, the Wackley Prize, named after our founder, Thomas Wackley. It's open to anyone working in a health related field. 2020's winner was Rachel Fleischman, MD, for her essay, Dreams Deferred, which examines the physician's role in the trauma of newborn and parent separation during the pandemic.

Here, Rachel reads her essay for us. 

Rachel: Dreams deferred. What happens to a dream deferred? Neonatologists such as myself are trained to discuss hard truths. Birth defects, genetic disorders, the limits of viability and intensive care. The hardest conversations, however, are often those for unexpectedly ill babies born after a healthy pregnancy.

These discussions gently dispel the nurturing visions parents have harbored. I spent the first decade of my career pushing myself to cultivate fluent phrases I could offer as a benediction when parents faced these hard truths. I learned to steady parents frightened stares across radiant warmers during infant stabilization.

Sometimes parents calmed when we spoke, tears slowed, breaths deepened. Sometimes they sat or stood, silent. I held their silence, quietly. Sometimes, a barrage of questions tumbled out, or parents yelled at me or to me. I found strength in these conversations. Making daily space for tenderness in speech, for kindness in a locked gaze, for compassion in a hand held, gave me purpose as a physician.

My heart knew what I would need were the roles reversed. The looks of relief, of trust, of assurance from parents in crisis, suggested that I gave some small comfort. I believed I had almost mastered communication in these contexts. That I knew how to help heal with words. And then COVID-19 brought a new type of consultation.

My first such consultation began when I met a woman alone in her hospital room a few hours after her delivery. She had COVID, 19 when she gave birth to a baby boy. When I met this new mother, she had not held or touched her son. She'd had no visitors, not even her partner. Masked, shielded nurses and doctors had cared for her.

Her son remained in the neonatal intensive care unit to protect him from her severe acute respiratory syndrome coronavirus 2, or SARS CoV 2 infection. Her misery was manifest in a quiet stream of tears. I sat, smoothed my gown, and introduced myself. The first question she asked me was, Can I ever have my baby back?

I felt disturbed when she questioned her maternal rights. I had nothing to offer but my willingness to witness her suffering before she spent a few days coughing her way through COVID 19 alone and apart from her son. I stood in her room, shattered. In that moment, I could not reconcile well intended national practice recommendations based on limited available evidence with her solitary suffering.

I met her eyes, red from crying without her son at her side. I said his name. Early in the COVID 19 pandemic, with scarce data on COVID 19 in newborns, experts worried that mothers with SARS CoV 2 could infect even healthy newborn babies with the virus. These infections might be mild, lethal, or they could not occur at all.

No one knew. Experts drafted recommendations with the laudable goal of protecting newborn babies from this undefined virus. Clinical guidance suggested neonatal intensive care units would not knowingly host parents with COVID 19. Babies who were ill and needed intensive care would have no parental presence while their parents convalesced.

Healthy babies whose parents had COVID 19 remained initially apart from their parents until more was known about the puzzle of COVID 19 free newborn care. The onus to explain newborn separation as a means of infection prevention to women during their deliveries fell on neonatologists. I found myself donning N95 respirator masks and face shields before going to delivery or postpartum rooms, where I sat, my shoulders hunched and my own breaths shallow, preparing mothers for the days to come when they could not hold their own babies.

My words stung. Many of the parents I served were essential workers, unable to work from home or self isolate. Separation from their newborns amplified the difficulty of contracting this novel coronavirus at a time when their bodies were meant to be healthy. The questions these mothers asked me, the tears they shed, exposed unparalleled anguish.

After months of pregnancy, they craved the rub of their lips over velvety infant skin. The grasp of their baby's fists around index fingers, their cravings were left to fester. The parents of my former patients had taught me to understand the emotions parents typically endure in the neonatal intensive care unit.

Navigating this pattern of grief was a learned skill. Before the pandemic, I anticipated which days might be hard and which decisions needed an extra explanation or middle of the night telephone call. I had no strategies with which to repair the grief of newborn separation. I felt wholly inadequate. I numbed myself to this inadequacy at work by dwelling on the joys of my own children.

I drove home after those early pandemic shifts to their antics. Pillow forts before breakfast, hands free bike rides after dinner, football tosses by floodlight at dusk. Returning to work each day meant recognizing those precious moments at home were perhaps the same dreams deferred from my patient's parents.

Contemplating the separation they were going through brought me heartache. The exposure to this new variant of maternal grief consumed me. People around me were dying from COVID 19. Hospital systems, including my own, faced unprecedented numbers of COVID 19 cases. As I sat with the mothers at my hospital, I tried to reconcile my understanding that while theirs was a single space of sorrow against a vast backdrop of global upheaval, to them it was an experience of boundless enormity.

During this time, another mother asked me if her child would ever be returned to her. She, too, had COVID 19 when she gave birth. Her question was uttered with imploring sobs. I did not speak her language. Despite the need for an interpreter, I recognized sounds akin to the noises I have heard parents make when their babies die.

Each question she asked seemed born of fear. Is my baby alone or with other babies? Are you sure I can bring him home and not another baby? I listened, lamented. When she asked, Do I need papers to claim my own baby? I wondered if she was undocumented. I could have been wrong. If I was right. My asking could make her feel vulnerable, unsafe, exposed.

I did not ask. I was all too aware that my intentions might be informed by unhelpful societal stereotypes, but I worried her fears stemmed from the well publicized policies of the U. S. Department of Homeland Security that encouraged immigration and customs enforcement to separate children from their parents at the U.

S. border and detain these children in facilities. Although the context was different, she had been separated from her baby in the neonatal intensive care unit. I felt powerless because I could not change the situation and became angry that I could be perceived as an agent of mistrust. As a physician at a safety net hospital, I aspired to be sensitive to systemic mistrust.

Safety net hospitals were born of necessity in the United States to care for patients irrespective of insurance or immigration status. These hospitals are often in impoverished neighborhoods and set apart from the elite medical centers. whose patients are more likely to have private health insurance.

My hospital remained devoted to providing exceptional and humanistic care to our community before and during the pandemic. The families I served were disproportionately affected by COVID 19. The babies delivered in our hospital were often born to Black, Brown, or Native American women, to teenagers, to women living in shelters or homeless encampments.

I wanted the world to know that COVID 19 had made the days after childbirth harrowing for these women, that efforts to protect their babies from a new disease had unwittingly morphed into an undignified act, and that these women were suffering alone. Weeks later, when anti racism protests outside my hospital highlighted the suffering of so many, suffering kept behind red lines for so long, the world outside helped me feel hopeful for change.

The privilege of whiteness, privilege in which I share, was being identified and challenged, and the rights and dignity of Black people decisively affirmed. But the weeks before the protests, the weeks I spent seeing parents grapple with grief, were arduous. During those long weeks, a third mother asked me, Will I get my baby back?

I apologized while providing reassurance. She had spent a couple of days without being able to see her baby. Alone in her hospital room, she pumped milk for her baby with such dedication that her nipples bled, chafed by the plastic shields of her breast pump. She was self assured and firm as she asserted that the cardiac view camera, the photographs, the clinical updates were inadequate.

She was right. Distressed, I nodded in agreement as she said, I need to hold my baby. I know I told her, I did know. But at that time, in that moment, I could not make it as the ramifications of newborn separation became clear, my peers and colleagues began to speak out. Ethicists partnered with physicians to argue against newborn separation.

And data suggested infant infection was rare and usually well tolerated. My hospital shifted away from newborn separation as a means of infection prevention. My own angst over the maternal rights of the parents I served felt validated. Experts revised the policy, but not before many women withstood the pain of a dream deferred.

COVID 19 had taught me a hard truth. I had never mastered communication. The words I spoke with such conviction had always been inadequate. My efforts served as mere sticking plaster for deep wounds. Wounds that could not begin to heal until infants were held, cuddled, caressed, home. This parental tenderness infused a lifetime of dreams into the lives of my patients.

Dreams to nurture these future adults along a path to one day help heal the world.

Gavin: You can read every Wakley Prize winning essay at thelancet. com slash wakley hyphen 

Jessamy: essays. Thanks so much for listening to The Lancet, boys. Remember you can subscribe wherever you usually get your podcasts, and we really welcome any feedback that you have. You can email us at podcasts at lancet. com.

Thanks for listening, and we'll see you again next time.