Latest / Medicine Matters: The Springer Medicine Podcast / Episode 29: A new era for Sjögren disease

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Episode 29: A new era for Sjögren disease · Medicine Matters: The Springer Medicine Podcast

• 0:06
  Speaker 3: Hello, I'm Dr Natalie Wood and i am delighted to welcome you to Medicine Matters the springing medicine podcast.
• 0:14
  Speaker 3: There are so many reasons to celebrate this episode which focuses on shogun disease –the second most common auto neuromatic disease.
• 0:23
  Speaker 3: We hear from Professor Raphael
• 0:25
  Speaker 0: Soror
• 0:26
  Speaker 3: about changing name from Shogun syndrome as well the vital role that patients and patient organisations are playing in driving transformation.
• 0:40
  Speaker 3: She also explains how research findings are deepening our understanding of disease heterogeneity, and opening a door to development of targeted therapies showing promise on clinical trials.
• 0:52
  Speaker 3: It's an episode full hope for future And I hope you enjoy listening.
• 0:58
  Speaker 1: Hello, I'm Shreya Nanda a Senior Clinical Content Manager at Springer Medicine focusing on rheumatology and also oncology.
• 1:05
  Speaker 1: But today the focus is very much on rheumeatology.
• 1:08
  Speaker 1: we're going to be talking about Sjogren's disease And along with our expert guest who was going to bring us up to speed on this very exciting topic?
• 1:16
  Speaker 1: I am very delighted to be joined by my co-host!
• 1:25
  Speaker 2: I'm Sarah Onora, the chief editor of Nature Reviews Rheumatology.
• 1:29
  Speaker 2: And today Shree and I are going to be speaking with Professor Rafael Saroura a rheumatologist and researcher based in Paris who specializes in sugar and species.
• 1:36
  Speaker 0: Rafael thank you
• 1:37
  Speaker 2: for joining us.
• 1:38
  Speaker 2: welcome!
• 1:39
  Speaker 1: There is a lot of momentum in this field at the moment as far as i can see there's lots going on.
• 1:45
  Speaker 1: uh one of the main shifts...and don't know if it's kind of driven the change or its response Is this recent change in nomenclature from Sjogren's syndrome to Sjögren's disease?
• 2:00
  Speaker 1: So can you talk us through why this change was needed and what it means for the field, and for patients.
• 2:06
  Speaker 0: Yes absolutely!
• 2:07
  Speaker 0: It is probably a mix of both.
• 2:10
  Speaker 0: The dermatology used by Sjögren has dramatically evolved over past few years And interestingly these changes were initially driven largely by the patient particularly through the Chagrin Foundation, which is an American patient organization.
• 2:27
  Speaker 0: The main concern was that the world's syndrome was considered a little bit vague and traditionally it refers to a collection of sign-and-symptoms without necessarily implying common underlying pathophysiology.
• 2:42
  Speaker 0: First with advance in pathophydology we now know that Chagran is well defined systemic autoimmune disease characteristic clinical immunological pathological features, of course anti-SSR antibodies, SICA symptoms and characteristics on salivary organ histopathology.
• 3:04
  Speaker 0: And importantly it can be severed with systemic manifestation potentially affecting any organ.
• 3:12
  Speaker 0: so in the mind of patients at that time continuing to use the word syndrome could minimize the severity of the disease and impact on his patient.
• 3:25
  Speaker 0: All this led to a constitution for an international consensus that aimed at changing it, replacing the term sound wall by the term disease.
• 3:34
  Speaker 0: That was done in order to better reflect what the disease is really improve its recognition among medical scientific community but also health agencies.
• 3:49
  Speaker 0: Another important aspect of this consensus that is frequently forgotten or neglected was the former distinction between primary and secondary chagrin.
• 3:59
  Speaker 0: I'm sure you are aware of that, And the term chagrongrabbing also considered problematic because it suggests somewhat that a chagrine was less important than other associated autoimmune diseases.
• 4:17
  Speaker 0: this patient could have a milder form of chagrin.
• 4:20
  Speaker 0: But it's not the case, and we know now with several studies that compared the former primary to chagrinary chagrine... ...that these patients—with what they call associated chagrens—have very similar disease course towards those with primary chagran including risk-of systemic complications….
• 4:40
  Speaker 0: …and the risk of lymphoma which is almost the same.
• 4:44
  Speaker 0: So Rather than talking about primary and secondary, we now prefer use the term chagrin disease.
• 4:50
  Speaker 0: And only when it's necessary for scientific study to define more or genius population will distinguish the primary and associated children with not-secondary chagrines.
• 5:03
  Speaker 0: The objective was really clear To make chagren a distinct systemic autoimmune disease With serious complications an impact on patient life.
• 5:14
  Speaker 0: It wasn't simply a collection of symptoms, but real disease that needs to be recognized and treated as such.
• 5:21
  Speaker 1: Brilliant thank you really wonderful to hear also about the patient involvement And we're going to be talking about that a bit more later on As well.
• 5:28
  Speaker 2: now We want to talk a little bit about treatment.
• 5:31
  Speaker 2: So currently it's treatment of chogrens usually involves symptom management and amine amondylation.
• 5:35
  Speaker 2: But there's a sense that That's changing.
• 5:38
  Speaker 2: so I was wondering if he could tell us a bit About their clinical trials that are going on they your most excited about.
• 5:43
  Speaker 0: actually We are really a very exciting time for the children's disease.
• 5:50
  Speaker 0: But if we look at what we're currently doing for treating patients, we must acknowledge that there is no evidence-based practice.
• 6:01
  Speaker 0: We use immunosuppressive treatment often by extrapolating.
• 6:12
  Speaker 0: We use hydroxychloroquine like in lupus, methotrexate and retuximab for joint manifestation like in rheumatoid arthritis.
• 6:21
  Speaker 0: Rheumatoids retuxima mycophenolate following involvement like we have seen in systemic sclerosis or autoimmune diseases.
• 6:29
  Speaker 0: And for symptomatic treatment, it's rather less standardized.
• 6:33
  Speaker 0: Many local therapies some of them are not reimbursed Some of that aren't available in every country.
• 6:40
  Speaker 0: so they create really a substantial financial burden on patients and there is clearly no consensus about this.
• 6:49
  Speaker 0: But the things now going to change we hope so probably quite rapidly because over past ten years seen a huge increase in interest from pharmaceutical companies with the explosion, I can use this term... ...in the number of clinical trials conducted in children's diseases.
• 7:10
  Speaker 0: And now for the first time we have several treatments that reach phase three which positive results some of them.
• 7:18
  Speaker 0: The first molecule is the Yanalumab.
• 7:21
  Speaker 0: It targets birth receptor And we really hope that it will be the first market therapy and available soon, maybe in next year.
• 7:33
  Speaker 0: We also have very exciting news just a few weeks ago with a press release announcing positive phase three result for Dazodalibep which targets CD-Fortillagum pathway.
• 7:49
  Speaker 0: Also last year at ACR Phase Three of Telitassicep which targets both an April through TASI.
• 7:58
  Speaker 0: And it was phase three conducted in China, in a multi-centric study and now there is an international phase three program that he's starting to confirm this result.
• 8:13
  Speaker 0: so two maybe three positive phase three uh...and we have other target like Nipokalimap targeting neonatal FCE receptor with interesting phase two results.
• 8:28
  Speaker 0: So really we are moving very fast and this therapeutic breakout may completely transform the therapeutic landscape of chagrin disease in the next few years, but there is some limitation.
• 8:42
  Speaker 0: most of these trials have focused on patients with moderate to high systemic activity Generally, defined in the clinical trial by an SDI score of at least five.
• 8:55
  Speaker 0: The SDI is a score for measuring systemic complications and the five thresholds that are used in clinical trials represent moderate to severe disease activity.
• 9:06
  Speaker 0: So this result may apply to patients with systemic complications which represents half of the patient And there is no other part of the patient with very high symptom burden and low systemic application that have been largely neglected from this clinical trial, but they represent a very important population.
• 9:31
  Speaker 0: More interesting we had some breakouts With two different targets That show their could work on symptoms.
• 9:41
  Speaker 0: The first is the Dazodalibep and Iscalimab, both targeting CD-IV and CD-VIV ligand that we have just talked about earlier.
• 9:50
  Speaker 0: I've shown results on systemic complications.
• 9:53
  Speaker 0: They also show a result of patient symptoms demonstrating their ability to decrease.
• 10:01
  Speaker 0: patients reported outcomes in clinical trials And more recently, during the last international chagrin disease symposium in Paris another interesting study was presented by Xavier Mariette.
• 10:17
  Speaker 0: The Necessity Trial rose results from a large European consortium Necessities.
• 10:23
  Speaker 0: This consortium was established in twenty nineteen with objective of improving outcome measuring chauvin, and particularly developing a composite index which is called the STAR.
• 10:35
  Speaker 0: As part of this project we plan to run a randomized control trial To evaluate the performance of these tools, the STAR.
• 10:45
  Speaker 0: And this trial compares two combinations of conventional immuno-medulatory treatment Mycofenolate mothetil plus hydroxychloroquine and leflinomid plus hydroxychloroquine compared to double placebo.
• 11:04
  Speaker 0: Importantly, it includes two cohorts of patients one with systemic complications as die more than five And the other with isentropic burden has pre-more than five.
• 11:17
  Speaker 0: At the end ,the two cohort have been analyzed together.
• 11:22
  Speaker 0: This was done because the star were supposed work on both patient population.
• 11:27
  Speaker 0: That's why we full together and we wanted to have these two populations in this trial.
• 11:33
  Speaker 0: And the results were presented at the conference, are positive with a very large difference between the placebo and the two treated arms with composite tool stars.
• 11:47
  Speaker 0: If you look into details there is an interesting result on patient symptoms In group of patients who has high symptom burden and low systemic activity.
• 11:58
  Speaker 0: So, I think it is even more exciting than having so many treatments reaching their primary endpoint and in patient symptoms where we thought that they will never manage to help patients.
• 12:16
  Speaker 0: But this isn't the case!
• 12:18
  Speaker 1: That's absolutely wonderful.
• 12:20
  Speaker 1: just know there are so much coming especially as you say for a particular group of patients who are symptomatic predominant patients, which as far I can make out just seems to be a population of great unmet needs.
• 12:31
  Speaker 1: So good to know that there's potential options coming for them as well but at this point taking a little step back in terms if could we maybe talk about what has led you talked the explosion trials?
• 12:47
  Speaker 1: What research or knowledge have lead to these explosions and made it happen?
• 12:54
  Speaker 0: Yes, absolutely.
• 12:57
  Speaker 0: There have been in the past... twenty years I think?
• 13:03
  Speaker 0: Many many breakouts in chagrin.
• 13:07
  Speaker 0: In understanding the pathophageology of course and role of B-cells, BAF and Interferon.
• 13:16
  Speaker 0: This has been deeply helped by development new technology particularly multiomics proteomics and even single-cell approaches where you can have information on the cross talk at a cellular level, which is very interesting.
• 13:37
  Speaker 0: And this allows to better understand different immune cell populations their interactions with different patterns of patients.
• 13:46
  Speaker 0: Another exciting development that we Emerge, I think in the next year is the development of salivary gland organoids that have been recently developed by two European teams including ours.
• 14:02
  Speaker 0: And they will probably help to study the glandular function and test the effect on different drugs on salivarine flow notably.
• 14:13
  Speaker 0: Of course we cannot talk about breakout without talking of artificial intelligence because it's open a tremendous opportunity not only to integrate this very complex data set of multiomic but also probably we will have some breakouts with the emergence of real-world evidence research through electronic LS record which are in in a natural language.
• 14:44
  Speaker 0: And with the use of artificial intelligence, natural language processing and probably large-language model we will really manage to extract valuable information from this data that are very important because they're less selected than patient population from clinical trial or clinical study.
• 15:08
  Speaker 0: They really represent real world of chagrin or any disease that could be evaluated through this process.
• 15:17
  Speaker 0: And it will probably help to have a better external validity and generalizability for the result of research.
• 15:29
  Speaker 0: So, having said that one important breakout using all these is the better definition of disease heterogeneity.
• 15:42
  Speaker 0: over five or six years, several research groups have tried to better understand this heterogeneity by identifying different patients who grew up using clustering and stratification approach.
• 15:56
  Speaker 0: And there is a different approach.
• 15:58
  Speaker 0: the first approach that was used by Tarn Jessica Tarn and Phi NJ in twenty nineteen Was to use only the symptoms The dryness, the pain and fatigue that are in the esprit complement.
• 16:14
  Speaker 0: And anxiety and depression score from HAD.
• 16:19
  Speaker 0: They identified four clusters... ...and they applied this cluster to previous conducted randomized control trials One on retuximum and one on hydroxychloroquine.
• 16:32
  Speaker 0: And interestingly these reanalysis suggest that treatment response could be different according to the different clusters with a possible benefit of hydroxychloroquine in some patients, which was not the case for overall populations.
• 16:51
  Speaker 0: So we have to know that there are exploratory analyses involving small numbers of patients but the process of discovering heterogeneity and trying to see if their response is different according.
• 17:10
  Speaker 0: that is very important.
• 17:12
  Speaker 0: And it has also been done with a second approach, which is the molecular profiling approach conducted by colleagues from the Breast Group in France, Sore and Colleagues In another European consortium named Precisades.
• 17:30
  Speaker 0: they use multi-omic data to identify four clusters.
• 17:35
  Speaker 0: Among these four cluster there was one cluster which a molecular profile was similar to those of LC controls.
• 17:46
  Speaker 0: And when they applied this cluster on clinical trial data, They found interesting results.
• 17:57
  Speaker 0: There are patients like Lc-like control that did not respond to treatment But there were patient more B cell and path driven or interferon driving that respond to treatment even if the treatment where the clinical trial were initially negative.
• 18:15
  Speaker 0: So, If we select correctly a patient We would have been positive result.
• 18:23
  Speaker 0: And finally...we propose third approach based on routine, clinical and laboratory data.
• 18:31
  Speaker 0: This was done with one of my PhD student Yannine Guillen And we use patient-reported symptoms, systemic disease activity, organ involvement and routine immunological factor on TSSR rheumatoid factors IGG level.
• 18:49
  Speaker 0: We identify three clusters that really correspond to the pattern of patients we see in real life one patient with systemic complication.
• 18:59
  Speaker 0: it's the high systemic activity cluster characterized by high SDI score prognosis, a long-term prognoses and high risk of lymphoma.
• 19:10
  Speaker 0: The second cluster was more B cell driven, B cell active disease with low symptom burden.
• 19:17
  Speaker 0: they have high level of immunological activity IHG levels rheumatoid factor, few symptoms usually articular symptoms and glandular symptoms.
• 19:29
  Speaker 0: And there are more younger.
• 19:31
  Speaker 0: we believe it's more earlier phase of the disease, and they might become after the high systemic activity.
• 19:40
  Speaker 0: And there is a third cluster which corresponds possibly to the LC-like cluster of breasting Which is characterized by high somtomb burden No systemic activity and no marker of B-cell activity on immunological tests.
• 19:58
  Speaker 0: So Now we have to see what is really the overlap between these two clusters, and if can only with this more simple clinical-driven approach anticipate what's underlying pathophysiological mechanism behind.
• 20:18
  Speaker 0: And even this cluster could be used for deciding who retreats... ...and probably with what?
• 20:25
  Speaker 2: That's a really exciting combination of developments.
• 20:28
  Speaker 2: when you have all these different treatments coming out and more information about the different kinds patients or what kind of disease manifestations they've had.
• 20:36
  Speaker 2: So, it sounds like there could be possibility for proper personalized treatment for Chagrin?
• 20:42
  Speaker 2: At the recent International Symposium on Sugar's Disease which you helped organized... There did seem to be strong focus on patient representation patient-centered outcomes.
• 20:53
  Speaker 2: You've already spoken a little bit about patients where we're driving the change in nomenclature, and I was wondering if you could talk a little patient
• 21:21
  Speaker 0: life and patient long-term outcomes.
• 21:26
  Speaker 0: And in this context, there are two particularly important aspects.
• 21:33
  Speaker 0: The first one is to improve a patient's symptom.
• 21:39
  Speaker 0: therefore develop better tools to assess the symptoms but also understand how to interpret these measures.
• 21:53
  Speaker 0: And it's really important not to underestimate the importance of symptoms.
• 22:01
  Speaker 0: Actually, recent data presented at the symposium in Paris suggests that the symptom burden itself may be an independent factor and an independent predictor a future complication and mortality notably.
• 22:17
  Speaker 0: So this is independently of disease activity.
• 22:22
  Speaker 0: So it's really important to measure correctly and follow the symptom burden.
• 22:29
  Speaker 0: It is not just about quality of life.
• 22:34
  Speaker 0: The second aspect, when we design a research project involving patients in this research project... ...is very important from beginning.
• 22:50
  Speaker 0: I think that makes a difference And I think the terms in French is passion partner, patient partners.
• 23:01
  Speaker 0: and i think that term partner is really appropriate because there are no longer simply participants in the church.
• 23:10
  Speaker 0: they're our partners.
• 23:12
  Speaker 0: They help us to define a research question.
• 23:16
  Speaker 0: That it's crucial to be sure The questions we ask Is really relevant for them.
• 23:25
  Speaker 0: If you do excellent research and answer to the wrong question, it will be useless.
• 23:37
  Speaker 0: We really experienced this directly within the Necessity Contortion because we had a patient advisory group that was there from beginning helping us in everything with it who wanted to make sure that the outcome measure we were developing was meaningful for them.
• 23:59
  Speaker 0: But patient involvement also helps us in many other ways, with not anticipating it and we are very happy to discover because Patient Organization can help us reach larger populations of research questionnaire but also communicate results more efficiently directly to patients.
• 24:23
  Speaker 0: So it will help that the research results are applied more rapidly.
• 24:30
  Speaker 0: Also, It can improve the recruitment into clinical trials.
• 24:35
  Speaker 0: For example with one of our patient partners probably Nora Coralibuyo which is president of Chogren Europe She organized and she asked us to participate a webinar to explain what is a randomized control trial and what it matters to participate.
• 24:57
  Speaker 0: So simple things like this really change the way research is done.
• 25:05
  Speaker 0: For me, patient involvement isn't just about consulting them from time-to-time.
• 25:13
  Speaker 0: It's making them a union partner throughout their project From defining questions conducting studies ensuring results.
• 25:24
  Speaker 0: We will probably do more better research like this than we did before, and probably more impactful.
• 25:35
  Speaker 1: That leads into my next question because I know you have quite an interest in clinical trial design with everything that now from the disease heterogeneity and stratification things.
• 25:51
  Speaker 1: How do you want to see clinical trials for children's evolve?
• 25:55
  Speaker 1: What?
• 25:55
  Speaker 1: what is your idea of clinical trial in a few years or even sooner, why a few weeks.
• 26:02
  Speaker 0: Thank you for this question because it really the out of my own research.
• 26:09
  Speaker 0: First clinical trial insurance disease have really evolved considerably over the past fifteen years.
• 26:17
  Speaker 0: Many very early trials were unsuccessful partly because they include very heterogeneous patient population as we have seen.
• 26:27
  Speaker 0: All this work on stratification was not available at that time and in some of the trials, even most of them were predominantly included based on fatting, penne and griness Because we didn't have any systemic activity measure.
• 26:47
  Speaker 0: so the major shift toward selection of patients with moderate to high disease activity, and even more complex and selective criteria was necessary.
• 27:04
  Speaker 0: Even though now we say or neglected a lot of patient I think it was necessary because finally it allowed us to demonstrate the efficacy of several targeted therapy as we discussed earlier.
• 27:19
  Speaker 0: And this is particularly important because systemic activity, it's not only a relevant outcome for clinical trial.
• 27:27
  Speaker 0: It also associated with long-term prognosis and several studies have shown now that the disease activities are linked to death or risk of lymphoma.
• 27:42
  Speaker 0: even in recent data we presented last week at the symposium, we have shown that being with a large cumulative systemic activity over time... Over twenty years of the ACES cohort increased mortality.
• 28:04
  Speaker 0: Each additional point of SDI for long term increase by fifty percent risk of death.
• 28:11
  Speaker 0: and when you go to the upper category from low-to moderate or for moderate to high activity, you approximately increase by three the risk of deaths in each category.
• 28:27
  Speaker 0: So reducing the disease activity is not just about decreasing DSI.
• 28:34
  Speaker 0: it's about decreasing the long term risks and complications.
• 28:41
  Speaker 0: but of course There was a downside for this approach.
• 28:47
  Speaker 0: We were living behind large proportions of patients with high symptom burden, but limited systemic involvement.
• 28:56
  Speaker 0: and more recently we have seen another shift And we come back to the inclusion of these patient But in separate courts.
• 29:10
  Speaker 0: So when you conduct clinical trial You are okay to take some risk, but if you want show the difference... ...you stay with this process of high systemic activity.
• 29:23
  Speaker 0: But try inpatient with a low-systemic activity and high symptom burden.
• 29:28
  Speaker 0: This is important because it allows us evaluate effect on both parts of the disease.
• 29:38
  Speaker 0: I think we can now go one step further With both the progress we have discussed about patient stratification, better understanding of disease heterogeneity and also with development on a new outcome like the STAAR.
• 29:55
  Speaker 0: We will be able to design trials that include the world spectrum of patients.
• 30:02
  Speaker 0: High systemic activity, high symptom burden Probably one where low systemic activities and low symptoms don't need any treatment For those who have a real impact on their disease, it could make the difference.
• 30:16
  Speaker 0: And the star was designed for that because its composite index which integrated the systemic diseases activity through the clean as dye –which is version of as dye without biological domain– The patient reported symptoms with DSPRI, objective measure of glandular function if you want to demonstrate an improvement on the production of saliva or tears, and the biological domain to see the biological effect of the drug by reducing the IgG level of rheumatoid factor which have been shown to be a marker for long-term prognosis.
• 30:55
  Speaker 0: Notably, the rheumatoid factor is a risk factor of death, it's a risk factors of lymphoma.
• 31:01
  Speaker 0: so we believe that if you decrease these two factors Having these two measures of clinical impact, SDI and patient-reported outcome it was specifically designed to be able to capture this type of cohort.
• 31:21
  Speaker 0: And so we believe that in the next step I don't know what time frame will happen We could do a single trial using this tool To evaluate both.
• 31:36
  Speaker 0: we will be able probably to have also a more personalized approach, to identify the right population for the right treatment.
• 31:49
  Speaker 0: And this will done by these first steps of stratification but also by more complex stratifications based on biological data and material data.
• 32:03
  Speaker 0: So next step is not only finding effective treatment.
• 32:07
  Speaker 0: It's finding the good treatment for a good
• 32:10
  Speaker 0: patient.".
• 32:11
  Speaker 1: Absolutely, that is always key thing isn't it?
• 32:14
  Speaker 1: And we are going to be seeing lots of exciting research coming over the next few years.
• 32:22
  Speaker 1: Sarah did you have any more questions or comments and thoughts?
• 32:26
  Speaker 2: No I don't think there was anything to add.
• 32:28
  Speaker 2: That was really great.
• 32:28
  Speaker 2: Raphael thank-you so much!
• 32:30
  Speaker 2: Really excited about everything happening with so many different strengths in development so many things going on in the field, it's great to hear your take.
• 32:39
  Speaker 0: Thank you very much.
• 32:41
  Speaker 0: I think there is a last comment that I can give... It's long-term outcome of the patient.
• 32:47
  Speaker 0: we have new project starting at this point.
• 32:52
  Speaker 0: We see with these new drugs probably will be able treat patients earlier short term of clinical trial, an important impact on disease activity and biological feature.
• 33:08
  Speaker 0: but it will be very interesting to see the long-term outcome with this drug.
• 33:13
  Speaker 0: And if we can approach what is done for example in rheumatic diseases modification We hope that we'll able show these drugs really modify the patient trajectories.
• 33:32
  Speaker 0: So those with this B cell activity marker, which gives the balls cluster... Which we think it's an earlier phase of disease.
• 33:43
  Speaker 0: We hope that treating them early will ultimately avoid they become patients with high systemic activities or develop lymphoma.
• 33:53
  Speaker 1: And on that hopeful note I'll bring to a close.
• 33:58
  Speaker 1: I could carry on talking about this fascinating subject for another hour, but it's probably best for all of our sakes and the sake of our listeners if i don't.
• 34:05
  Speaker 1: So I will just say a big thank you to You Professor Siraror For giving up your time And sharing Your expertise!
• 34:12
  Speaker 1: I'm sure Our audience Will greatly benefit from All The knowledge that you have shared with us today.
• 34:18
  Speaker 1: Thankyou also To You Sarah for being my co-host & for all Of your input in developing This episode.
• 34:24
  Speaker 1: Couldn't Have Done It Without You.
• 34:26
  Speaker 1: It's been a pleasure talking to both of you.
• 34:28
  Speaker 1: Thank you so much!
• 34:51
  Speaker 3: and do not represent the position of any third parties.
• 34:57
  Speaker 3: The information given in the podcast is subject to change as scientific field and clinical advances progress.