Episode 7: UEG Journal Podcast Christmas Special 🎄

00:00:05: Hello everyone and welcome back to UAG Journal podcast.

00:00:09: I am Mohsen Subhani and as always I am joined by wonderful co-host Dr.

00:00:14: Maria Manvola Estevinho.

00:00:16: Today we are delighted to bring you a Christmas special edition.

00:00:20: So whether you're listening with a cup of coffee, tea or something a bit more festive,

00:00:24: we are

00:00:25: really glad you are with us.

00:00:27: Absolutely, Merry Christmas to everyone listening or happy holidays wherever you are in the world.

00:00:33: We are delighted to be joined today by our special guest Dr.

00:00:36: Daniel Kesseli, Associate Editor of the UAG Journal, and later in the episode by Professor Albrecht Nies, Editor-in-Chief of the UAG Journal.

00:00:46: Daniel, thank you very much for joining us today.

00:00:49: So Daniel, as an Associate Editor, you handled this RCT by Tenghi et

00:00:54: al.,

00:00:55: which was evaluating the effect of transcutaneous auricle vaginal stimulation on chronic constipation.

00:01:01: So to start off, Can you please tell us what stood out when you were dealing with this study?

00:01:07: Thank you, Mohsen.

00:01:07: So first of all, thank you for inviting me for this podcast.

00:01:11: It's really, really a pleasure to discuss some of the articles with you.

00:01:16: What stood out for me was the fact that I'm personally very intrigued as far as novel therapeutic entities is concerned, not just for conservation, but more broadly, with a neurogestinology.

00:01:29: And I think this is one of the upcoming areas that we are exploring as to what their therapeutic value could be.

00:01:37: And this trial particularly I thought was fairly high quality.

00:01:41: It was executed in a qualitatively good manner.

00:01:45: And even though the outcome might not have been what the authors were expecting, I think that in itself the topic is very interesting to discuss.

00:01:53: From a clinical perspective, chronic constipation remains a measure challenge.

00:01:58: Many patients don't respond well to lexatives and dissatisfaction rates are high.

00:02:03: How does this study fit into that broader clinical problem?

00:02:07: There's actually a knowledge gap or a clinical gap as as to put it that way because you have laxatives as you know more or less the first line therapy as far as pharmacological therapy is concerned and oftentimes you may use something like.

00:02:19: Transcendental irrigation or some kind of other method as to try to improve constipation symptoms and and then afterwards you go to very invasive.

00:02:30: therapies like ostomies or something like that.

00:02:33: So there's really a gap in between these laxatives and things like irrigation and in the end effect more invasive type of therapies.

00:02:41: So there's really a need for this kind of entities.

00:02:44: And I think that nerve stimulation and vagus nerve stimulation in particular is something that is very interesting to look into.

00:02:51: And there has also been some studies on sacral nerve stimulation for constipation, which I think might theoretically make more sense than vagus nerve stimulation purely on the basis of anatomy and innovation of the large intestine.

00:03:06: But nevertheless, I think that these are therapies that are interesting as to look into their efficacy.

00:03:13: And that's why we need to meet certain trials and methodologically sound RCTs to actually understand whether these are really valuable entities or not.

00:03:23: So just to frame a brief rationale for our listeners, There is a growing interest in your modulation as a treatment functional GI disorders.

00:03:32: Small study do shows that they benefit in IBS and constipation.

00:03:37: This trial aimed at to test this at a larger scale in a more rigorous phase.

00:03:42: What are your thoughts on this, Daniel?

00:03:44: Yes, so indeed there's a growing interest in this type of therapy for a number of disorders and not just IBS, but also indeed like you said metabolic disorders, even things like gastroparesis is something that is an area of interest in this sense.

00:03:58: But I think that before we are in the situation that we can broadly apply this type of therapy, we first need to understand whether they're effective or not.

00:04:08: And the other thing is that we have to have some more basic understanding of how this actually works.

00:04:13: If you're speaking about constipation, you'd assume that... the vagus nerve would act via the regular motor pathways that originate from the brainstem, for instance.

00:04:25: And that could be the reason that this eventually is helping because it increases colonic motility.

00:04:30: But that has not been established yet.

00:04:33: And although there are animal studies that confirm this hypothesis, human studies are still largely lacking.

00:04:39: So one thing is establishing the efficacy.

00:04:41: And the other thing is establishing a pre-tative mechanism of action that we can relate to this.

00:04:46: efficacy.

00:04:48: So the design here was strong.

00:04:50: It is a multi-center randomized shamp control and double line study.

00:04:55: Daniel, how important was that design in terms of evaluating a device-based intervention like TA-VNS?

00:05:03: Yeah, that's a very important point and that's something that we have always focused on within UEG Journal, not just with Albrecht, but yours before Albrecht as well.

00:05:14: So we particularly look for multi-center trials, randomized controlled trials with rigorous methodology and If there are methodological concerns that can be addressed during the revision phase, then we're definitely going to be open for that.

00:05:33: But if we have the impression that up front, there are some issues as to the conduct within the trial or, for instance, the definition of outcomes, the way things were analyzed, et cetera, then we might want to go forward with the desk rejection because the chances are that we're not going to be able to get that level of quality that we want to see for the journals.

00:05:54: That's a key reason that we look at these papers in this very strict manner.

00:05:59: And I think this paper in particular showed that the way that they conducted this with also an interim analysis for futility and the way they defined the outcome measures, the recruitment strategy, et cetera, was very well-defined.

00:06:14: And you can always find room for improvement.

00:06:16: When you finish the trial, you're like, oh, I should have better than this or that.

00:06:19: But that doesn't mean that this qualifies the trial itself if it was.

00:06:24: set up in a good way up front.

00:06:39: Yes, so the thing with auricular vagus nerve stimulation is that because it has become more popular and also for other disorders, not even related to gastrointology, for instance, for headache or tinnitus, things like that.

00:06:53: So this has become more available also in the lay media, so you can just Google it, for instance.

00:06:58: And you will probably notice that there's an anatomical location that you do the stimulation and there's the sham location, which is generally your earlobe, which is not.

00:07:06: uh, innovated by the vagus nerve, which is customarily used as the sham location in these types of studies.

00:07:12: So there's a chance of unblinding by virtue of googling on behalf of the participants to actually find out, okay, what is the, what is the real stimulation and what is sham?

00:07:21: So I think that's the risk.

00:07:22: And probably this was not so much of an issue in this particular trial because this has been done a couple of years before.

00:07:29: So that could have mitigated this effect, but that's definitely a problem.

00:07:33: And in terms of this type of intervention, having a proper sham condition or a control condition that is probably blinded as to the real intervention is crucial because there obviously is a very high placebo response in functional GI disorders in general and not just constipation.

00:07:51: So you might want to have to be sure of this blinding procedure as well.

00:07:56: And obviously, blinding is never perfect and not even in pharmacological trials.

00:08:01: So that's something that you should always consider in any sort of trial to actually assess for blinding, just to ask the patient at the end of the trial or halfway in between.

00:08:10: Okay, what do you think that you're actually receiving?

00:08:12: But that's particularly tricky when you're talking about this type of intervention.

00:08:16: Thank you, Daniel.

00:08:17: Let's talk about the primary outcome.

00:08:20: The study defined responders using complete spontaneous bowel movements and limited rescue medication use.

00:08:27: What did the interim analysis show?

00:08:29: I think the interim analysis was a very good point, a very good thing to do in the sense that it was directed at futility, also safety issues were obviously assessed during this interim analysis.

00:08:41: So that means if there is no significant... benefit of this treatment that you should not expose other patients to something that probably is not helping anymore than the control treatment.

00:08:52: So I think that's from an ethical perspective, that's such a good thing.

00:08:56: But also from a scientific perspective, it's good because you already have the firm evidence that apparently there's no big difference between these two treatments.

00:09:05: So I think that's a very strong point to make in this trial.

00:09:09: And when we're coming to outcomes, the response rate in both groups was identical.

00:09:14: The study has very clear predefined rules and the study was terminated earlier.

00:09:20: What are your thoughts on this one?

00:09:22: Generally speaking, people are less enthusiastic about negative trials than they are about positive trials.

00:09:29: And in general, I think it's easier to get a positive trial published than a negative trial.

00:09:33: Whereas I do believe that as long as the trial is methodologically sound.

00:09:39: If you are frank about what you've seen, if you report that in a proper way, if you're aware of the limitations of both your results as to the methodology that you used, then we should definitely go forward with publishing trials like this.

00:09:53: And I think this is a very nice example of how you can actually put something there.

00:09:59: even if it's negative, we learn a lot from this in terms of what we think we should take as a next step with regards to this type of intervention.

00:10:06: Is conservation the key area that we should focus on in terms of vagus nerve stimulation, or is it more relevant for upper GI disorders, etc.

00:10:15: Does that have to do with the stimulation parameters?

00:10:17: Is that have to do with the outcome definition or the length of the stimulation, etc.

00:10:21: So it raises a lot of questions that can help the field move forward, even though this was a negative trial.

00:10:29: Negative trials are sometimes harder to publish, but arguably just as important as positive ones.

00:10:35: From an editorial standpoint, how do you view the value of a study like this one?

00:10:41: Well, I think that in the past, probably there has been a lot of publication bias as to editors being more... reluctant in publishing negative trials out of fear that these trials would not be published.

00:10:56: I'm sorry, mood not be cited as much as positive trials would be.

00:11:00: And my impression is that the entire field has been moving away from this.

00:11:06: And in my personal experience, I have been able to publish some negative trials recently, even though I had the feeling, OK, nobody wants to have this because of the outcome.

00:11:17: But I think that, once again, the single most important thing is the methodology, discussing the limitations you've had.

00:11:24: And this is eventually what's going to keep us moving forward and not necessarily the result itself, whether it's positive or negative.

00:11:31: And oftentimes, as an associate editor, I come across papers that even lack a limitation paragraph.

00:11:38: And I'm a bit surprised at that because that just shows you that apparently these group of authors was not able to put their finding in the appropriate context.

00:11:49: And I think that's a very important thing to do regardless of whether your trial is positive or negative.

00:11:55: As we're talking about methodology, We saw that primary outcome was negative as well as the most of secondary outcomes.

00:12:02: So what are your thoughts on this?

00:12:04: Can this study would have been designed somewhere differently?

00:12:07: Yeah, so I think in terms of the sham condition, like I said before, so there's a lot of information out there that potentially risks on blinding.

00:12:18: So if you were to think of a stimulation that is at the same anatomical location as the real stimulation.

00:12:26: What does not elicit a certain sensation?

00:12:29: Because let's say you're stimulating at the same place and the active stimulation elicits a certain sensation like some kind of itching or whatever that you feel there locally and the sham stimulation doesn't.

00:12:39: That again gives you the opportunity to get de-blinded.

00:12:44: So there should be a way to be figured out as to How can I, for instance, use subliminal stimulation that you just barely don't feel or you're not sure whether you're feeling it.

00:12:55: So that way, you know, not risking, risking the blinding, the patient.

00:13:00: So I think those type of therapies or those type of approaches are something that we should definitely consider.

00:13:06: And the same goes, for instance, if you were to stimulate the cervical vagus, same goes there.

00:13:11: You have to make sure that ideally the sham condition that you're giving is a true sham.

00:13:16: and not necessarily something that the patient will fairly easily tell that they're not getting the real stimulation because that will influence your response rates, obviously.

00:13:24: The authors here discuss the difference between functional constipation and IBSC.

00:13:30: Since most patients have functional constipation, how do you think these might have influenced the results?

00:13:36: You know, the quick key question is what's the difference between functional constipation and IBSC?

00:13:41: And basically, the key difference is whether the patient has pain, abdominal pain, or no.

00:13:46: So in functional constipation, there's just a constipation, whereas in IVSC, there's also pain.

00:13:51: And that's also an interesting question as to ascertain whether the TVness or the vagus nerve stimulation is actually more acting on the constipation side of things or rather on the pain side of things.

00:14:02: So with other words, is this more a motility effect or is this more a sensory effect or a bit of both?

00:14:09: And that's I think something also that is very interesting to look into in the future because that will determine as to how you could also apply this type of therapy in other conditions that are either characterized by motility problems or by sensory problems or both of them.

00:14:24: So that's the important distinction that can be made on this basis.

00:14:29: So on the similar note, another important point, the defecatory disorders.

00:14:33: This was not formally addressed and many patients, especially women, we know that suffer with pelvic floor disorder and might have underlying defecatory disorder.

00:14:41: How do you think this has impacted the results?

00:14:44: Yeah, that's a very good point, Moses.

00:14:45: So I think that At least I would not assume that patients with defecatory disorders or dysfunction would benefit from vagus nerve stimulation because the problem is of a completely different nature.

00:14:59: So that could be one of the reasons that this ended up being a negative trial that there was too high of a proportion as to defecatory disorders in this particular population and that was not assessed properly.

00:15:11: In all honesty, I do not think that that might have impacted results to that degree because we can assume that both the active and the sham treatment group would have had the same proportion of potential inflammatory disorders among the patients.

00:15:27: So I would not think that they had a substantial influence on the results, but definitely that could be a factor.

00:15:33: Even though there was a lack of efficacy, safety in this trial was reassuring.

00:15:38: There were no serious adverse events and well-balanced minor events between groups.

00:15:44: From a regulatory and clinical perspective, how reassuring do you think this is?

00:15:49: Yes, I think it's definitely reassuring.

00:15:51: And what I mentioned in the beginning is that we have this clinical gap, so to speak, between conservative measures and more invasive measures.

00:15:59: And, you know, it's quite obvious that invasive measures will have a lot more side effects than conservative ones.

00:16:04: But at the same time, there's also a lot of drugs, laxatives that can have side effects.

00:16:08: Think of bisactyl or lenexatide, for instance.

00:16:13: So there's definitely a need for something that is safe and effective at the same time.

00:16:17: So based on this study, Daniel, is there any key take-home messages?

00:16:20: And also, as a neuroclerotic gastroenterologist, how do you see the future of neuromodulation?

00:16:27: So I think the most important take-home message is that I believe that there's definitely more into this area of electrical neuromodulation.

00:16:36: And I would think that the next years will be witnessed to more studies of this kind.

00:16:43: and what we really need to understand is what are we actually treating, what are we actually doing?

00:16:48: which pathways are we influencing by this type of therapy?

00:16:51: And by having that understanding, we can deploy these methods to a far more effective way than we are doing right now.

00:16:57: Because right now, this is not standard treatment for any of these disorders.

00:17:02: I think that you will just see this within the constraints of a clinical trial or at least research purposes.

00:17:08: But I believe that this is just one of the other milestones on this pathway that we're trying to understand what the exact position is of this kind of treatment.

00:17:19: And in this respect, I think this is very important trial that we published in the journal.

00:17:24: And looking to the future, where should research in this area go next?

00:17:28: For example, different stimulation parameters, better patient selection, or focusing back, for example, in IVSE populations?

00:17:36: I think that the most important thing would be to have next to clinical studies to have some more mechanistic type of work also in patients so not just in animals because we know that.

00:17:48: animal studies don't necessarily translate that well into human situations.

00:17:53: So I think that would be good to have that type of mechanistic understanding, potentially things like brain imaging or electrophysiological studies to really understand what we are influencing with this type of method.

00:18:06: So it's important to understand that auricular vagus nerve stimulation is a purely afferent stimulation.

00:18:12: So there's no motor element in that directly.

00:18:15: other than that you're influencing the brainstem and you have the dorsal motor nucleus of the vagus in there.

00:18:20: So potentially the way you are stimulating the intervals, the frequencies, etc.

00:18:25: will have an influence on these indirect effects that you're eliciting.

00:18:29: So I think this is the type of work that also needs to be done in parallel to the clinical work.

00:18:35: This was an excellent discussion and very thought provoking.

00:18:38: So as we wrap up this Christmas special edition, this study just reminds us that regress trial does matter.

00:18:45: It's not all about promsync physiology, but also about clinical benefit.

00:18:49: And as long as there is a clear message and study follow the regress methodology, it is as important as positive trial to publish the negative trials.

00:18:58: So any final thoughts for our listeners, Daniel.

00:19:01: Thank you again, Mohsen and Manuela for inviting me.

00:19:05: And the final thought that I'd like to share with you is that My experience within the Journal, within UEG Journal has been absolutely wonderful.

00:19:13: It's one of the most exciting experiences that I had in my professional career.

00:19:17: And we are very privileged at having the trainee editors like yourselves, which gives an excellent dynamic to the Journal.

00:19:25: And I think that is very unique at the same time.

00:19:28: I've not experienced anything like that within the Journals.

00:19:31: And more broadly, UEG is a wonderful organization.

00:19:35: If you ever have the chance to get to getting involved with UEG, whether it's with the journal, whether it's with a committee of some kind, whether it's a summer school, a traineeship, a visiting fellowship, somewhere within Europe, just do it because this is one of the greatest things that you can experience.

00:19:53: Great.

00:19:53: So that was excellent insight from our associate editor Daniel.

00:19:58: And then congratulations.

00:19:59: to moving on to your editor-in-chief role.

00:20:02: We will move on to have some further discussion with the UEG journal editor-in-chief.

00:20:07: Dr.

00:20:08: Albert Nesse.

00:20:09: Albert, thank you very much for joining us.

00:20:11: It's been an exciting year.

00:20:13: Would you mind introducing yourself and sharing some insights?

00:20:17: Well, Mo, thank you very much for having me.

00:20:19: It's a pleasure to be on air with you for the first time.

00:20:22: And

00:20:23: first and foremost, I would like to thank Manuela and you for taking up our new podcast series this year.

00:20:30: You really do a fantastic job, and I'm glad to have you in the UG team.

00:20:35: Please continue.

00:20:36: to entertain us with late breaking science and insightful interviews.

00:20:41: I really enjoy

00:20:42: listening to your podcast.

00:20:45: Well, it's been my first year as editor-in-chief, and it's been a very busy year for all of us.

00:20:51: And I took over a fantastic team, editorial team in January this year from Yoast.

00:20:57: And first of all, I would like to thank all outgoing associate editors, namely Alexander Meini, Fernando Margo, and Christoph Moreno.

00:21:06: for their outstanding contribution and for their continued dedication to the journal.

00:21:12: Their input has been absolutely critical for the success of UEG Journal.

00:21:18: And indeed, Moe, it's been a successful year for UEG Journal.

00:21:22: We continue to receive an increasing number of manuscripts.

00:21:26: Our impact has gone up to six point seven, which is great.

00:21:30: And we are continuously working with our publisher Wiley and the UMG head office to improve the service for our future authors by providing a fair and fast review process, by reducing the time to publication once the paper is accepted, and also by promoting your articles once they are accepted.

00:21:53: For instance, through social media activity and also visual abstracts that are free of charge.

00:22:00: And I would like to thank all associate editors and trainee editors that are involved in this process.

00:22:06: Today, Moe, as you pointed out, it's also my task to say farewell to Daniel.

00:22:12: Daniel has been associate editor for UG Journal since twenty twenty two and in particular for neuro gastroenterology.

00:22:20: And he will leave us as as you already announced by the end of this year.

00:22:25: Daniel was recently appointed editor in chief for neuro gastroenterology and mortality,

00:22:29: which is

00:22:29: obviously a great honor.

00:22:31: So, big congrats to you Daniel.

00:22:34: It was a pleasure working with you and I really appreciate your dedication, knowledge and your clear and in particular speedy decisions.

00:22:43: We had a great time together and I'm really sad to see you go but that's how life goes and I'm sure we will keep in touch through the UEG family and I'm sure we will meet up again at the latest in Barcelona next year during the UEG.

00:22:58: And I have appointed a successor for Daniel.

00:23:00: and maybe more.

00:23:02: And Manuela, we will reveal this news during the next podcast in January.

00:23:06: I can only say it's a great guy.

00:23:08: Finally, I would like to thank the whole editorial team, all senior and junior editors or reviewers who did a terrific job for the journal on a daily basis.

00:23:19: We are really dependent on your input.

00:23:22: I would like to thank the staff of the UEG head office in particular, Kati and Doris for continuously supporting us.

00:23:29: the Wiley team, and finally all readers, listeners, and authors of UG channel.

00:23:36: We are looking forward to your submissions in twenty twenty six.

00:23:40: Keep sending us your signs listening to us.

00:23:43: Follow us on social media for the latest breaking signs.

00:23:48: And finally, I wish you all happy holidays.

00:23:52: Thank you very much, Albert.

00:23:53: That was excellent and.

00:23:55: I'm very grateful for supporting editorial team and many editors.

00:23:58: It has been a great learning opportunity for all of us and for our listeners.

00:24:03: I hope you have enjoyed our latest podcast.

00:24:06: So please stay tuned for update in GI science and latest publication in UG journal.

00:24:12: And don't forget to subscribe, share and read the article recently published in our channel.

00:24:19: Thank you very much and Merry Christmas.