 So thank you for having me today to discuss this interesting topic is, as you mentioned, I've been in the GI world for some time and one of my main interests is the functional gastrointestinal disorders and motility disorders, as well as nutrition. So this is just, I mean, it's a very extensive topic and the main, my main goals for today is to discuss like the main, the gut-brain interaction, what is, what are the, what is the, the embryonal part, like then the microbiome, and then extrinsic factors that are involved in the functional GI disorders that help contribute to those disorders. And so I'm just brushing up on the general diagnosis and work up for all of these disorders and then just a treatment approach that we have here currently at our practice. So first we're going to discuss about understanding the gut-brain interaction, going, starting with the enteric nervous system. So as we know the enteric nervous system is the intrinsic innervation of the gastrointestinal tract. It's a complex network of neurons and glial cells that is located along the GI tract. It represents a very, very important component of the autonomic nervous system. And then it serves, it serves as we know as the intrinsic nervous system for the gut and it's capable of controlling most of the functions of the intestine independently of the central nervous system. As we see here on this graph, so the vagal neural crests derive cells. They enter approximately, so approximately from the oral end of the embryonic gut and then migrate along its entire length, giving rise to the majority of the glial cells in the enteric nervous system. Then the sacral neural crest cells, they enter the hindgut, this means hindgut, midgut and then the foregut, but so the sacral neural crest cells, they enter the hindgut and then migrate approximately in the oral direction to form the neurons in the glial and the distal portion of the gut. Here we can see, just like, as we already know from our anatomy and embryology, the my enteric plexus and the submucosal plexus, they are an essential component of the gut neuromusculature and control many aspects of the gut function, including coordinated muscular peristalsis. The enteric, I want to remember that the enteric nervous system is derived from the neural crest cells, as I mentioned, and then they are involved in a number of key processes, including the migration, as I mentioned, proliferation of the glial cells and later differentiation into the neurons and glial cells during the field life. So then this is just the proposed model from the Motodori Society that we will see multiple interacting brain networks that mediate the perception and modulation of the visceral pain. And then this model is replacing the previous conventional focus on individual brain regions and then controlling pain on one side and then separate from the enteric nervous system, kind of like two separate systems. However, this interesting integrative model proposes reciprocal interactions between the brain networks, which they describe it as the brain connectome, and then the networks made up by multiple cells in the gut, including the gut microbiota, which is the gut connectome. So then here we see the brain-to-gut interaction is mediated by the autonomic nervous system and then on the other way, the gut-to-brain interaction is mediated by neural endocrine and inflammatory pathways. So all of these interactions are very close knit and then they just evolve into a cycle that later on, if it's affected by different items that I will talk later, then that's when it leads to a disease. So then it leads us to another form of viewing the brain-gut axis and the more the unimportant theory of the gait control mechanism for the GI pain. So the pain that begins in the gut, it ascends to the dorsal horn of the spinal cord. It goes all the way up. Then remembering all of our anatomy goes into the second-order neurons into the midbrain and the limbic structures in the brain. Remember the limbic structures are the... Some of them are involved into the emotions that we put into that sensation, so that's important. And then the second-order neurons go into the third-order neurons and they go into the cortex where the pain is experienced. So the gait control theory relates to the brain's ability to reciprocally facilitate or block as a gait, basically, the ascending signal from the dorsal horn going into the brain so it can modulate how much it goes up and then thereby reducing the experience of the pain. So this is just moving a little bit forward into the therapy, like the psychotherapy aspects of these patients with functional GI disorders. A way that we can help control this gait is by distracting the patient, so distraction, focus attention, meditation, hypnosis, and also by neuromodulator medications that are involved in the neurodinergic and serotonergic pathways where we can control this theory. So this regulation of this brain gut pathway leads to chronic GI pain. They also... I was reviewing some mouse studies where they put a rectal probe and increased painful stimuli in the gut, like repetitive mechanical stimulation sensitizes the spinal cord and then there's up-regulation up in the spinal cord that leads to central hypersensitivity. So that's when we start referring to the term of hypersensitivity. These hypersensitivity at the level of the spinal cord amplifies the signal that's coming from the spinal cord up to the central nervous system and gives...leads from the acute state to a more chronic and persistent pain and then it's perceived, even if the stimuli is not as bad as it is, the brain perceives it as very no-sive. So then it just becomes chronic and amplified. So this is the theory behind why we have evidence that visceral hypersensitivity is a consequence of altered central pain processing in patients with, for example, irritable bowel syndrome or functional dyspepsia. So then these, after we know what's the basic physiology of the brain-gut system, then we're going to go into what factors affect this gut-brain interaction. And there's many, many factors. This is just one of the most important ones that we intervene, that we can intervene in our patient population and then it's the environment. So here in the environment, we have to consider social environment, the dietary. From the social environment, we already know that many of our patients are being bullied. I saw some data that at least 10% of the patients in the U.S. are being bullied. Also the parental influence of catastrophizing the symptoms as well as the seasons that I will delve a little bit more into that. Also the physical activity is very important. Physical activity plays an important prognostic factor in patients with chronic pain. Also other comorbidities, so for example, patients with functional GI disorders, 50 of them can have other comorbidities such as headache. So that's why it's very important to take a very good history. So then let's go into this. So this is an interesting study, a large retrospective study that they published in 2013. This is a database of 170 million patients where 20% of them were children and then 80% of them were adults and then they demonstrated the seasonal variation of the presentation of abdominal pain complaints and consultations for chronic or recurrent pain in children. So it's very interesting to see like how, and we see this in our clinic even now, how the frequency and the number of patients that consult to us about for chronic abdominal pain or for a new onset of abdominal pain decreases during the summer and then it just increases as the school year starts. So you see that brisk change. It would be interesting to see now that we have, now with this year of COVID, now that many patients have been at home and like they're not on that stressful environment to see if there's any changes. From just from my personal experience in my clinic, many of the patients that for example were having a difficult school environment or if they were having difficulties at school, they are thriving at home. So they're having excellent grades and they are, the symptoms have significantly improved. However, we also see the opposite and I'm pretty sure you've seen it in your practice that patients that were very social and really enjoy their interaction with peers, they are not doing as good and so they don't like the teaching mode. So what the authors in the study report is that like different factors may vary within the school year. So stress, anxiety, there's different sleeping patterns, which I will go into a little bit infection. So if you are in a different environment that you're exposed to different infections, dietary variations that we know are common in school. So then here it's just another show of like that is associated also with the consultation and depression. So here we see like in the summer months when they are more with the families and not at school, the consultation for depression also decreases. So it goes along, they go hand in hand. Some of the most common psychiatric diagnosis, they go hand in hand with the patients with functional abdominal pain. And it's interesting to see that what they reported is like that they speculate that there are no changes in the adult pattern because the adults don't have like we have like a straight line of schedule, stress, environment. So it doesn't really change in the summer. We just have some vacations, but it doesn't change. So that's why it's very linear pattern in the consultation for depression in adults and in the consultation for abdominal pain in adults as well. So going a little bit more deep into how sleep and stress affect the symptoms. So stress and anxiety may trigger GI symptoms in patients that have autonomic liability. So that goes back into our physiology. These patients get a decreased pain tolerance in response to stress. We see these decreased pain tolerance in patients with recurrent or chronic abdominal pain. We see that there's altered, it's been reported that altered sleep is highly prevalent in children with abdominal pain associated with unassociated functional GI disorders. As I mentioned before, like the changes in the sleeping patterns for kids when they are on summer versus when they are in school. So these changes and delays in the circadian rhythm has been associated with GI disturbances. And we know that serotonin and melatonin are essential neurotransmitters with roles that regulate mood and GI motility. And as I mentioned earlier, and as I will mention later on as well, is we use many serotonin-based medications that interfere in that cycle to manage these chronic pain in these patients. Another factor that affects these brain gut axis is pain catastrophizing. So this is a very interesting study that they did in Seattle. It's 70 patients and their mothers filling out a pain catastrophizing survey. All of these patients had a functional GI disorders. And then pain catastrophizing is characterized. But how do you perceive your pain? And when you catastrophize it, as you are perceiving it as highly threatening, dangerous, and beyond your ability to cope. So then it goes back into how we cope with negative experience and how we think how harmful they are, how dangerous they are. So this level of threat of the pain is what causes this catastrophizing. So in this study, they show that children of mothers that have higher in catastrophizing, so they said that this is the worst pain, is something is going on, there's something wrong. These children were more likely to utter anger words. So they had like some cue words in that survey. So they were more likely to utter anger words when talking about their abdominal pain. That were children with mothers lowering catastrophizing. So this is a very important factor in that we have to consider when we start, when we recommend psychotherapy or some of the behavioral methods to manage these conditions is how the families approach these symptoms, how they talk about them. So for example, one of the interesting, for example, one example that they mentioned in some of the lectures is that, for example, you have a kid playing soccer. So the mom is watching the kid playing soccer. She falls down. So one mom can just run and take out the kid of there like, oh, what's happening? Did you break a leg? And then another one will just stay there and then see what the kid did. And then at the end, she's like, oh, I saw that you fell. I saw that you hurt yourself, but you dealt with it. And then you kept playing and this is good. So just reinforcing those behaviors is the same with the abdominal pain. But for example, if we, in our setting of abdominal pain, so if we have a patient with chronic abdominal pain and then you have a mother that catastrophizes, so says there's something wrong and then they come to our office several, several times, the kid interprets it as like there's something wrong with me. There's something wrong and they haven't found anything, what's going on. And then this is a part that is very difficult into managing these patients with functional GI disorders is that some patients think that it's just a made up diagnosis that we haven't found the organic cause for it. And it's particularly frustrating. But once we explain the etiology and how we say kind of like separated, give like the physiology, like the nerve. It's like a nerve related pain more than it's psychiatric and then you're making it up. That kind of helps later on into the healing process. So this is a very important aspect that we evaluate in all of these families that have functional GI disorders and also help us guide what kind of management would fit into the family. Another factor is the diet. So we know what we all know about the FODMAP diet. And then in this study, they show that fructans can exacerbate some of the symptoms in a subset of patients with IBS. So this is a double blind placebo controlled study where they gave fructan and then they gave matzodextrin to patients with irritable bowel syndrome. This is a study from the Texas Children's and then they define fructans sensitivity. So they separated patients that were fructans sensitive versus insensitive. If there was a 30% or more increase in the abdominal pain following the fructan ingestion. However, it's very interesting that the fructans sensitive subjects, they did not differ from the patients that were fructan insensitive. So clinically different with respect on the hydrogen and methane excretion during the fructan challenge. So they didn't, both groups, they gave them different diets during like three or four weeks and then they measured how much of the hydrogen and the methane they excreted. So through the best test. And then they found that both of these groups, they had, there was no statistical difference between the amount of gas that they produced. However, patients that were fructan sensitive, it seemed to exacerbate several symptoms. And then another interesting part of the study is that they measured abdominal pain, they measured different labs. Again, they measured the hydrogen and methane production. And then they could not find any specific, for example, biomarker or predictor if a patient is going to be sensitive or not to fructans. So that's why from the Irritable Bowel Syndrome guidelines, the recommendation is to do a limited trial of low FODMAP diets. So low fructan, oligosaccharides and all of those sugars diet in patients with Irritable Bowel Syndrome. And then it's just a limited trial for a few weeks. And then you recommend the patients to slowly start reintroducing until the symptoms are tolerable. However, we have many patients that they start the diet and they continue with the symptoms. Then there's no point in just keeping the diet. We resume it and then we go into other therapies. But that is one of the recommendations for the management. So this is a very important part from the dietary therapy is this is one of the only dietary therapies that is recommended in patients with functional GI disorders and mainly Irritable Bowel Syndrome which is the most common one. It's present in about from all the big spectrum of functional GI disorders, Irritable Bowel Syndrome is about 10 to 20% of these patient populations. So this is very common. Then another very interesting aspect is how the microbiome plays a role into those gut brain axis. So we are already familiar that we have like there's the good bacteria and then the bad bacteria and how that balance and interaction helps a improved symptoms or changes the symptoms. But until recently we didn't know why specifically the microbiome is causing these change in the symptoms and then this change into the clinical presentations that we see. So in this study that it was published last year in Nature they saw that they discovered this factor a transcription factor which is called a real hydrocarbon receptor. It functions as a biosensor in intestinal neural circuits. And then these receptor, this transcription receptor is basically activated or suppressed depending on the microbiome that they have. So these study is made on rats. They had rats that were like given antibiotics so they did not have any gut flora versus rats that had just like the regular gut flora and they were fed with probiotics. So then they measured the activation of these transcription factor. And then they saw that in patients that had the healthy regular gut flora these transcription factor activated and it ended and it resulted in normal colonic transit time compared to the mice that didn't have any bacteria in their intestine, they had slower transit times. And then at the end of the study they feed the bacteria or like the diet from the mice that had the bacteria to the ones that did not have bacteria. And then they saw changes how these transcription factor activated and how the colonic transit time improved. So this is a very interesting study that I wanted to bring up and to see why the microbiome is so important into the gut motility and like the gut health in general. And then they were able to demonstrate, as I mentioned before, they were able to demonstrate how intrinsic neural networks of the colon exhibit these transcriptional profiles that are combined, that are affected by combined effects of the host genetic program. So if they had of course a knockout of that transcriptional factor of course they didn't respond to the diet so it's a combination of how your genome is configured versus the microbial colonization. In this study they just show like a normal healthy gut flora from mice but they did not show like dysbiosis or abnormal flora. So this is like ongoing studies. So this is just like another backup or more information that would help us decide the management in our patients. So for example, we recommend our patients, we do not recommend them to take probiotics as a standard of therapy. Actually the latest guidance lines for irritable bowel syndrome, they advise against and just giving probiotics to everybody is more guided therapy for patient for example is having diarrhea or if there is a concern for SIBO, they recommend more going into the nutritional therapy. So more eating prebiotic foods, for example, kefir that I know like there's some other studies that kefir has being reported as being a good factor in preventing C. diff infections and that sort of thing. So that's why the recommendation from the microbiome perspective is following a healthy whole food based diet that includes a lot of prebiotic foods and then if there is the interest not as a standard of care they can have periodic cycles of probiotics. It's not a standard recommendation but like our general practices is to recommend patients to kind of like cycle the strains in the probiotics not just like staying safe with one for example, cultural brand for years and years because we see many patients that do that. They have to take some breaks, change the diet and then that gives you promotes a healthy microbiome. So then just going back into just switching ears and then just like this will give us like a big definition for the functional GI disorder. So what are the functional GI disorders? A group of disorders that have GI symptoms related to a combination of the factors that I mentioned before. So mortality disturbance that can be affected by the factors that I mentioned before, ulterior mucosal and immune function. As we saw some of the central autonomic nervous system affects into the mucosal and immune function. There's many studies that report that even the autonomic nervous system affects the entire nervous system and it changes the tight junctions and how much permeability the gut has and that can create for example, when they report the leaky gut so there's increased tight junctions and there's increased permeability to bacteria and then it can cause inflammation and symptoms. Alteration in the gut microbiome and altered CNS processing. So this is an overview of how the functional GI disorders are classified based on the room for criteria for pediatric population. It's classified into three groups, functional nausea and vomiting, functional abdominal pain disorders and functional defecation disorders. As I mentioned earlier, our number one, one and two diagnosis that we see more commonly in our GI practice is functional constipation and irritable bowel syndrome. Third would be functional dyspepsia definitely. And then we define these diagnosis and so what they recommend is that after appropriate medical evaluation, the symptoms cannot be attributed to any medical condition. So then by providing specific guidelines and I can share this PDF with you which establishes very specific diagnostic criteria for every single one of these disorders is that if a patient fits into the category, for example, irritable bowel syndrome. So a patient has abdominal pain related to defecation or they're related to alter bowel movement more than three months. So then if a patient fits into that clinical category and otherwise it's a healthy patient that is thriving and developing well and eating well, then the clinician we may or may not select to do testing and they will dwell into testing in a little bit. And another important part that we need to take into consideration is that all of these disorders can coexist with other medical conditions that have their result in GI symptoms. For example, we see irritable bowel syndrome and functional constipation in many, many of our patients that have inflammatory bowel disease. These conditions, this functional GI conditions unfortunately are associated with many psychological and behavioral alterations as I mentioned. That psychological part and behavior and the environment plays a big role into affecting the brain gut axis. So it's always important to just obtain a good history to see how we can guide the patient for management. And then recommendations for basic workups just the basic things that we are recommending. So we recommend, well, the guidelines recommend to perform celiac disease serologies. The celiac disease serologies we just do two of them is just the IgA level and tissue transglutaminase IgA. There is other markers for celiac disease. However, the tissue transglutaminase IgA has been demonstrated to be the one that is most cost effective and the most sensitive for celiac disease. So if we have a patient with diarrhea that we have suspicion for possible celiac disease, just to rule it out is just to do those serologies. Of course, the recommendation for fecal cut protecting is an excellent biomarker of chronic GI inflammation so that when it's an easy test to do and see reactive protein. So both of them is just to rule out inflammatory bowel disease. As a standard of care, the guidelines do not recommend serial infectious stool studies. Some patients end up having like serial stool culture, diarrhea, oven parasites. So what they recommend is to do them in the appropriate context. Of course, if there has been an exposure but otherwise there's no need to check serial oven parasites here in the United States. And then they do not recommend standard testing for food allergies and food sensitivities unless there is reproducible symptoms that are going on with food allergy. So that's why the history is very important. Based on the results of course from the fecal cut protecting CRP and the growth then we in the GI clinics then we decide to do go with endoscopy and colonoscopy or not. For the most part when patients are referred with when we suspect functional GI disorders we do these testing, we perform these testing. And then if they are negative we give reassurance to the family, start the therapy that involves the diet the psychological part perhaps some of the other medications and then if there's no change or if there's depending many concerns or if the patient is not getting away then we go with the endoscopic evaluation. So just moving on to the medical and the non-medical therapies. So we have to remember that pain is a modifiable experience. As I mentioned, there's many factors that affect our perception of pain. So it's perception in acute and potentially even more so in chronic situations is influenced and shaped and shaped by the supraspinal processes. So by a central processes such as emotions, cognitions and memories. So these, all of these factors the psychosocial affects the cognition and the mood effect they can provide either a placebo effect which is the positive effect or a no-cebo effect or negative effect. So that's how you interpret the pain. So with this in mind, with this context in mind that we can discuss the therapy. So this is just like the list of the brain gut therapies. More commonly we, depending on the patient if there's comorbidities for depression or anxiety we use neuro modulators. Most commonly we use amitriptyline in low doses. Some patients we have them in fluoxetine but most of them amitriptyline is very good. We decide between amitriptyline and the SSRIs based on their clinical presentation. If I have a patient that has a lot of diarrhea then I would just go with amitriptyline and then if they are having more of the constipation we go with a patient with any of the SSRIs. Near stimulation I will discuss the device later on and then cognitive behavioral therapy exposure. All of these psychological therapies go back into the catastrophizing and then the environment part from the family. So the goal of all of these therapies is to teach the parents and the families and the patients to cope with their own pain. Instead of having the parents take it away or interpreting it as something harmful and then just taking it away to make it better. So then it's giving all of these tools for the kids to deal with the pain and then to set expectations that it's not that the pain is gonna go away and it's something bad is like, yes, I can manage I can decrease it to this level and then it can be functional. And then these therapies reduce pain and disability over time. And it's very important to explain to them that pain doesn't, I mean, we don't have to equate like hurt with harm. So with a negative experience. So just some data behind cognitive behavioral therapy. It's been demonstrated in some brain imaging studies and behavioral studies that it reduces the activity and the emotion related brain regions. So particularly in the limbic system areas that I mentioned earlier. There's also reports that meditation and mainly hypnosis also targets specific centers in the brain and the limbic system. So it modulates. So for example, one of the, these techniques that has been studied the most as hypnosis and many centers use in is that it modulates the pain perception and the tolerance by affecting the corticalness of cortical activity. So that is one of the most important things to recommend to our patients. Locally, I am not familiar with any center that does hypnosis. And then all of most of these behavioral therapies we send them to either Mon Washington, KKI locally. And then there's some other psychiatric centers that provide these therapies. There's also here in Maryland, we don't have these psychological therapies to offer, but some of the patients we send them to what it's called Amos Clinic in Hopkins where they can have like this holistic approach from the psychological perspective, the gastroenterology perspective, the nutritional perspective. So it's kind of like a multidisciplinary approach, which is the goal. So by looking at all these list of medications, the goal is that it needs to be a multidisciplinary approach to manage these patients because only with medications, only with psychotherapy, only with diet, these patients do not improve. There's also reports in yoga, but these are just like just some case reports with small groups of people. Most of these data actually comes from India. So that's where we have. So just some approach into our medical therapy. So as a base, we always recommend dietary changes and lifestyle modification. It's very important to educate the families and provide reassurance. Again, as I mentioned, this is very important. Peppermint oil, some studies have reported that it decreases the sensitivity of the pain and then the spasm associated with it. Manage if there is suspicion for small bowel bacterial overgrowth. Courses of refactamine have a demonstrated improvement. If a patient is having poor weight gains, it's perhaps that we use it as an appetite stimulant as it increases the gastric accommodation. And then on top of it is the SSRIs that I have mentioned, I have a pending to manage the nerve pain and amy-tripsiline, which is the most common. So depending on how the patient, how mild, moderate or severe symptoms they are presenting, then we address it differently. So for example, if it's more milder forms and they're not having any impairment or disability or missing school, then we just go with the basic approach and then we move up the ladder. This is just to show how, as I mentioned, like the different categories of the pain, but how all of these medical, like medication management, many of them they don't have like data behind, like specific data behind to back up the use of these medications, for example. There's one very interesting study on amy-tripsiline where it showed that it's efficacy for improving pain in patients with functional GI disorders. This was a study, just an irritable bowel syndrome. It had the same efficacy as placebo effects. So placebo effect is 50% amy-tripsiline, also showed 50% improvement in these patient populations. So that's the studies that we have behind it, but we do have the physiology in mind and that's why we use these neuromodulator medications. So that's why it's recommended and that's why we use it in our practice. Then these brings me to the neuro-stimulation device which we are bringing to Maryland soon. It's called IDSTEM. So these device is based into the stimulation of be a peripheral nerve, so it's a peripheral nerve neuro-stimulator that goes into the limbic system and the idea is that it modulates the response to the pain. So this is, as I mentioned, it's a percutaneous electrical nerve feel stimulation and stimulates the neurovascular bundles in the ear. And then we use it as the idea is to use it for three or four consecutive weeks. So the patient would come to the clinic the beginning of the week, we put the device is just some stickers, so it's painless. The reported side effects basically is just irritation with the tape. They leave it in place for five days and then they take it off. They have two days of rest and then they come back the next week. So the theory and then the pathophysiology this goes back into the, as I mentioned the neurovascular areas in the ear, they connect with the many of the nerves that are involved into the limbic system which is how we experience our pain. So the data behind this study was published in 2017. And then this was again a randomized controlled study that it was, they had like a, what they call the sham device, so a device that didn't have any stimulation. They showed that 70% of these patients had failed other therapies and then most of them showed clinical response after having the device. So I'll show you this one as easier to see here. So the dotted line is the sham device, the failed line is the patients that had the IB stem device and then it's again after three weeks and then they had a follow-up appointment. So there was a significant improvement in the worst pain score and then this is just a composite pain score where they also measured quality of life and their overall functionality. So there was a significant improvement compared to no device to a sham device. So this study was in their initial study in 60 patients. Another result from this study is they assessed the disability and the degree of the disability and impacting their quality of life after having this device. So here we can see the baseline. The both groups had a moderate disability but then the patients that had a, after the one cycle of the IB stem device, they had now minimal disability. So this is a very, very good outcome for these patients and especially there's some patients that are, have significant impact in their quality of life. They cannot function. So this just gives them hope. The reports so far what we know after the six to 12 months is that the effect is sustained. So even after one cycle, so one cycle is four weeks of the treatment. So even after one cycle, there is persistent, at follow-up there is persistent improvement in the pain index, the disability index, which is important, the general somatic symptoms. And then of course this doesn't affect the depression scale because this is just another entity, but at least the pain related to the GI symptoms is improving. So that is very good for this device. This is just to show, to put this device between, compared to other interventions that we use nowadays. This is FDA approved for patients with 11 to 18 years of age. So it's the only one that's FDA approved for that treatment. These are the other medications that I mentioned earlier that are not FDA approved for the management of IBS. However, we still use it. And then the potential side effects is localized skin irritation that was reported only in 2% of that patient population. This is important to keep in mind when we use these kinds of medications in these patients populations. So for example, the anti-EA, the present medications have increased risk of suicidal ideation. They have increased risk of dementia with long-term use. And then just the side effects of these channel blockers. Sometimes they can have diarrhea, but that's why we use it for constipation. And then this is just to see other medical conditions that are associated with chronic functional GI disorders where we could potentially use, it's coming down the pipeline where we could potentially use this IB stem device. And this is another reason why we got it. We're planning to get it at Maryland soon. So far, it's been approved by the FDA for IBS, but it's coming down the pipeline for functional nausea, for cyclic vomiting, and then more importantly here, which is what we're also planning to use it. Once it's approved, this is for chemotherapy and do nausea and vomiting. We see it in many of our oncology patients. And then functional abdominal pain disorders in patients with cystic fibrosis, which is also very commonly seen. So just a few summarizing points what I discussed earlier is just that different sensitizing medical events like distention, inflammation, motility disorders, they can affect how you process and interpret the pain signals that are coming from the gut. There's also has to be a genetic predisposition. So for example, as I mentioned, this transcription factor, if it's expressed or not in the gut and how it affects the microbiome, then you could be more prone to have visceral hypersensitivity. All of these factors, along with sensitizing psychosocial events, as I mentioned, mothers catastrophizing in different social situations like bullying, they can affect and cause gastrointestinal problems. However, a patient can have all of these factors affecting it, but the most important factor is how you cope with the pain and how you interpret these pains. Do you interpret it as fearing or threatening? How do you cope with it? So there's different factors that affect with it, but if there is a good coping mechanisms and we help and intervene in these families at this juncture, then you can potentially improve the long-term outcome. So they can either accommodate with their symptoms and eventually there's reports that two thirds of these patients that have functional GI disorders in childhood, they do not continue with these symptoms in adulthood. So it's very promising. So if they learn how to accommodate and how to cope with these symptoms and then promote healthy nutritional and physical activity environment, then this person can have normal development and no disability. And we are of course trying to avoid patients that have chronic pain and disability. So that's our goal for our management and thank you.