Um, so now we'll transition from surgical interventions to medical intervention for a condition called tuberosclerosis. So here to present our next talk is Doctor David Ritter from the Division of Neurology at Cincinnati Children's Hospital Medical Center. Thanks, Doctor Frankintos and Doctor Markham for inviting me to talk and share about what we've been doing for fetal treatment and tuberosclerosis in our clinic and it's really for us one of the, uh, more exciting things that uh we're gonna be doing and talking about over the next few years in this disease. So as far as for me, I have, um, just some disclosures. One is that I received funding for a clinical trial that's not gonna be discussed in this talk. Then some of what I'm gonna show you will be from research projects that we're doing they're funded from the NIH and mainly from the Department of Defense. Then the last thing is that I will talk about off-label use of medications uh in this talk. My objectives for this is one, that we'd be able to identify the fetal presentation of tubersclerosis or TSC that we'd understand kind of the rationale for the medications we use in the disease, mainly the MTOR inhibitors. And then, um, I'm gonna highlight um kind of 3 recent cases that we've had here at Cincinnati Children's that really um highlight some special issues that we've been seeing and some special cases where we can learn from. So, tuberous sclerosis is a multi-organ disease uh that uh really provides many different symptoms that our patients have. It's caused by mutations in two genes, TSC1 and TSE2, which account for 90% of patients and about 10% are what we call no mutation identified, meaning we can't find the genetic change that's causing the disease. They, our patients will have, um, almost exclusively, all of them will have, uh, brain findings, and that can be cortical dysplasias or the tubers of tuberous sclerosis like highlighted here in the white. You can have nodules which are gross on the inside of the ventricles, or you can have segas which are actual tumors in the brain that are benign but have significant growth and cause um hydrocephalus. We also see in almost all patients skin lesions associated with tuber sclerosis. So ash leaf macules or the hypopigmented macules. You can have ungual fibromas or growths on the toes, angiofibromas on the face, or chagrin patches. Um, and so once again, the majority of patients have both brain and skin findings. Also, a lot of patients as they, uh, grow will develop either renal cysts in the kidneys or renal angiomyolipomas or tumors in the kidneys. Um, and then also we have many other findings. So lung, you can have lamb a cystic lung disease, you can have retinal hematomas, and importantly for us talking today, you can get cardiac rhabdomyomas which are found predominantly as tumors in the neonatal period. This is a rare disease. It occurs in about 1 in 6000 to 1 in 10,000 live births, but for being a rare disease is one of the most common rare diseases, and there's around 2 million people worldwide that are estimated to have tubersclerosis. We see this as a 100% penetrance. So if you have tuberculosis, you have a 50% chance of passing it on to one of your children, but only about a third of cases are familial, about 2/3 of cases just spontaneous or spontaneous mutations that occur. The interesting thing for us in the disease is that has variable expression. So while you could have a parent who is mildly affected with just a few brain lesions and a few skin lesions, you could have a child that has all these different symptoms and that is severely affected. And why in neurology, we see these patients often is that these brain findings often lead to um epilepsy and other issues. So, it's been long established in TSC that epilepsy can occur early. Usually about 60% develop epsy in the first year of life. Here you can just see um some initial um studies showing that uh patients can develop epilepsy at any age, really, but a majority of those are gonna be in those first few years of life that develop epilepsy. If you have epilepsy and TSE, over 50% or over half of them have, um, intractable epilepsy, so they have difficult to control epilepsy that don't respond to medicine. And we know that the patients who have early epilepsy develop other features of neurodevelopmental disorders including autism and intellectual disability. So this is a study done by Jamie Cappel when she was here at Cincinnati Children's in which the age of seizure onset was, is on the X-axis, and the probability of intellectual disability as evaluated at 6 months of age, 12 months of age, 18 and 24 months of age is shown. Here. And we can see is if you have epilepsy starting from nearly birth, you have almost a 90% chance of developing intellectual disability. Whereas if we can get you towards a year of life uh without having seizures, you have a much less chance of having intellectual disability. So, we like to know about these patients early, treat them early so that we can prevent uh future disease, future complications. So how is TSE being diagnosed now? Well, it's mostly prenatally by the development of cardiac rhabdomyomas. So this has been um some ongoing work trying to figure out um when we can diagnose and how we diagnose TSC but about half of patients have arrhabdomyoma in the heart as their first symptom of TSC. And most of those rhabdomyomas are just found on prenatal ultrasound. So the, the fetus doesn't have any issues. There's no heart failure, arrhythmia, um, other things that can be caused by these tumors, but really it's just a finding on the prenatal ultrasound. So this actually makes it to around 40% of all patients with TS. See are being found by prenatal ultrasounds. Only 12% don't have any rhabdomyoma when they're initially diagnosed. Um, and so, really, these cardiac rhabdomyomas are crucial for us to find and to know what to do and be looking so we can identify patients early and get them to treatment early. Interestingly, um, if you have a single or multiple rhabdomyomas, kind of alters, um, the risk for having TSC. So if you have multiple rhabdomyomas, it's around an 80% chance that we will diagnose you either clinically or genetically with tuberosclerosis. If it's a single rrhabdomyoma, that risk is around 50%. However, I will caution is that we don't know what other disease causes a single rhabdomyomas. So, these rhabdomyomas in the heart will regress after birth. And so there's not been detailed studies to try and figure out what these uh single rhabdomyomas are. Are they mosaic TSC patients where there's only tuberosclerosis changes in the heart and not elsewhere, or is there another disease process that we don't know about? However, if a, a fetal ultrasound has, um, Rhabdomyma, we're highly likely that we're going to be diagnosing TSC at some point in that individual's life. So what causes TSC? Well, we molecularly know exactly what the cause of TSC is, and that is overactivity of MTOR, the mechanistic target of rapamycin. So what MTOR does typically is promote cell growth and cell division. However, it is held back by an MTOR complex that's made up of TSC1, TSE2, and a few other uh proteins. So, in a normal situation, you can have activity of MTOR but that's regulated by TSC1, TSE2. When you have tuberous sclerosis, you no longer have that regulation. So you have a non-functioning TSC1 or TSE2 protein that allows MTOR to be overactive, which produces excessive cell growth, which creates the tumors in TSC and all the downstream consequences. What's nice about knowing this mechanistically is that we know we have medications that block MTOR activity. And so, those are MTOR inhibitors or MTORI's as we sometimes abbreviate. And the main ones that are used in tuberosclerosis are erolimus and everolimus. And so you can use both of these to inhibit MTOR and bring it back to a normal state. So we like to talk to our patients that in them, they have high MTOR activity. And what we're trying to do with these medicines is just bring them back to normal. We're not trying to eliminate their MTOR activity, but more give them a typical or normal functioning MTOR. So, when this mechanism was discovered, there were several um studies to look at that, and many of them were run um or led by uh my colleagues here at Cincinnati Children's including Doctor Franzi found the clinic, Doctor Bristler, who was a nephrologist here, and then moved uh to Saint Jude's, then, uh, Doctor McCormick, who's in pulmonary here at the University of Cincinnati. But you can see that there have been several studies with either erimus or everolimus for many of the different symptoms of TSE. So the first indication was for Segas. So these brain tumors, they will shrink or stop growing when treated with an MTOR inhibitor. The same is true for the angiomyolipomas in the kidneys or the tumors in the kidneys. They will shrink or stop growing if treated with an MTOR inhibitor, so they've been approved. The Lamb, uh, cystic lung disease where you can see here a woman with extensive cysts in her lungs. If you prescribe uh erolimus in the studies, they will have um improved lung function and they will no longer have deterioration in the lung function. And then the, uh, for epilepsy that's uncontrolled with regular anti-seizure medications. You can use everolimus and that will reduce the number of seizures the patients are having. And the last approval is actually for the facial angiofibromas for a topical uh serolimus cream to actually prevent the growth. So we have multiple symptoms, multiple organs that we can use these medications in tuberosclerosis and either slow down the progression or reverse the progression of the disease. So this is, has been exciting and something that the, the field has really changed rapidly since the first approvals in 2010, 2011. But after those, one of the first questions was, we have patients who are having these symptoms early on in life and is it safe to use these medications? And the short answer is it's safe. This, there have been multiple papers. I'm just showing 4 of them here, but many more keep coming out, that we can treat young infants with MTOR inhibitors and we don't have major issues, which is obviously crucial if we want to talk about fetal treatment, they can treat in the early postnatal period without issues. And another thing for cardiac rhabdeomis is does it work to treat those? And this was a study out of China. In which they treated all their patients with serolimus in a cohort and showed that there's a rapid decrease uh in the um number of patients who had rhabdomyma, so the rhabdomas would go completely away. And then that slowly um occurred over the initial treatment period. So, initially in the first few months, you had rapid response and then slow response for the remaining. And they actually looked at based on age and the patients who were the youngest when they were treated, so, um, less than 1 year of age, they had a rapid response that got down to 40% of patients saw their rhabdomyomas go away. Um, with treatment, whereas if they didn't start treatment until 4 years of age, which is the top line, some people responded, but not all of them. So this indicated that there's probably some response that's, um, of these rhabdomyas that's dependent on being treated early, um, for them. So, we've taken all of this information TS where we've had these nice uh responses to various symptoms of TSC to these MTOR inhibitors and have started to ask what happens when we keep pushing treatment earlier and earlier. And so, our team here has looked at what if we treated immediately after birth? Can we prevent seizures and um epilepsy? Can we prevent neurodevelopmental issues? And so this is um using serolimus as preventive therapy. These were 5 infants treated in an open label study that then led to a placebo-controlled trial that's currently going on called TSE SEPS. In which we treat patients as soon as they have a diagnosis of TSD they can enroll as long as they have not had a seizure. And so if we treat these 5 infants, what we can see is 3 of them still developed seizures, um, at, but only 1 of them developed seizures in that crucial time period in the first few 6, in the 1st 6 months. Another one developed it at almost 1 year of age, so 319 days, and another didn't develop seizures until 1 year and a half years years of age. Importantly, um, our patients have a high risk of intractable seizures. So 50%, 60% have intractable seizures. But when we looked at 12 months of age, none of our patients were having any seizures for the month going into, to, um, their 2 years of age visit. So while these patients had seizures, they were able to be well controlled with regular seizure medications. So this was a sign that, hey, we may have a way to prevent uh outcomes. However, we still have some of these patients who um 26 days after starting treatment, started having seizures and so we think early on was already destined to have uh some sort of phenotype. So what would happen if we could treat this patient fatally or before um they were born to help uh lower their MTOR activity? So, we've done this, and many others have done this. But it was, um, has been saved for patients with severe rhabdomyomas. So, we don't know the risk of doing fetal treatments with, uh, these MTOR inhibitors fully. Um, so it's been saved and not used as something that just if you have a rhabdomyoma, you treat them, but more having severe. So this is an example published from our group in which a patient had multiple rhabdomyomas. This rhabdomyoma, which is seen here was near the aortic outlet. It was causing hemodynamic instability. The, uh, the mother was treated with serullius. In 2 weeks, you saw a reduction in the size of the rhabdomyomas, although it's still, um, blocking the aortic outlet some. But after 4 weeks, you could almost see no rhabdomyomas and you could actually see Uh, improvement, um, in the cardiac function. And so this fetal treatment, we know in these severe cases can help, uh, reverse, uh, the enlarging and destructive rhabdomyomas, but we don't know how safe that is per se at this point. And so, um, we previously, uh, suggested in 2021, kind of an algorithm for deciding if you would treat or if you have multiple cardiac lesions that these are likely cardiac rhabdomyomas and that if they have imaging, fetal MRI's or other signs that this could be TSE to consider treating and actually we were said you should start treatment if there's hemodynamic instability. However, um, if you have a single lesion, we're less, um, because of the 50% chance this is not TSC. We're talking about that you should consider other diagnoses, but there's still a high risk that you should consider discussing with the family if there's a reason to kind of do this as a, um, last-ditch effort to, in case it is a rhabdomyoma. But really, both scenarios we're waiting for that there's, um, cardiac instability or troubles with your cardiac output. This, like I said, we're not the only group that has done this. This has been actually used in multiple different groups. So, for example, um, this summary comes from a recent review article of fetal trimethmTOR inhibitors. So there have been some women who've been treated through a pregnancy because they have, um, a kidney transplant or pancreas transplant. So 13 cases, they had used varying doses. Of um MTOR inhibitors, 1 to 5 mg per day. There are 5 maternal complications, 2 preeclampsia, 1 hypertension, 2 kidney failures, and there are 2 fetal complications. One had a low birth weight and one had cleft, uh, cleft lip. Um, and then there's 3 spontaneous abortions that all occurred in one individual. Um, in the fetal TSC world, there's been 11 reported cases. The dosing has been wide-ranging, 1 to 12 mg per day of the MTOR inhibitor, and there have been 4 maternal complications that have been elevated triglycerides, elevated cholesterol, tongue sores, and preeclampsia. In one, infant that is IUGR and then there's also some vascular malformations that respond to MTOR inhibitors. And so that's been used in some of those cases speedily. Once again, wide-ranging starting doses and, uh, one maternal complication. But if we include all of these together, What you can see is that it's now been 27 cases. There have been more published this year still. Um, so it's now more cases than this. But the maternal complications is around a third, with most of those being relatively, uh, easy to manage like elevated triglycerides, and the kidney failures have occurred in people already with transplants. And the fetal complications that have been reported have been minimal. And so this is exciting to say that we're starting to get data together that says maybe this is actually um enough information to say this is safe as we move forward and getting solid in that. We also Um, so I want to go from that saying it's safe to show you some cases that we've recently had that highlight some very, um, unique, uh, situations that we've encountered and I've started to expand what we're thinking can be possible by using fetal treatment with MTOR inhibitors. So the first is a significant rhabdoyma that is causing fetal high drops. So this was an infant that had um a pregnancy where at 24 weeks, there's an ultrasound with no concerns. At 20s, 8 weeks and 3 days, um, there was a repeat ultrasound because this was a twin gestation and just for routine monitoring, you can see this massive rhabdomyoma that it basically includes the entire left ventricle. When, uh, we looked on fetal echo, um, there was, uh, the, the infant was dependent on the ductal flow. So the aortic arch flow and the ductal flow were in opposite directions, meaning that it was a ductal-dependent lesion, no flow through the aorta essentially for this infant. And we saw on MRI that we got that there's pleural effusions. I'm not showing you that there's cardiac infusions, but you can also see uh edema or fluid in the abdomen as well. And so, this is over the course of 4 weeks, this rapidly progressive lesion. And so we had several things to consider when discussing with this family. One is that there's no family history of TSC. So we couldn't, um, kind of say that there's a high risk of twins, uh, of, of TSC. This is also a twin gestation. And so, while this is one twin, the other twin had a shared vessel, and so there's concern about that shared vessel between these twins. Additionally, there was a thought from the initial ultrasounds that this twin had, the twin had no um concerns for TSE. But when we did a fetal echo at 28 weeks and 4 days. The other twin did have several small rhabdomyomas as well, but nothing near the severity. And there's concern for the infinite, uh, imminent fetal demise because of the development of the, the hydrops. So, in discussion with the family and our MFM colleagues, we decided to treat with an MTOR inhibitor to see if we could uh have a reversal of this fetal hydrops and a reversal of this rhabdomyoma and protect uh the other twin as well. What occurred is after 2 weeks, we actually saw reduction in the cardiac um effusion, which I'm not showing. But at 4 weeks, we actually saw um reduction in the edema in the abdomen. Um, we still did not see a reduction that was significant in the size of the rhabdomyoma at this point, but at least showed us that things were reversing. And then two weeks later, the mother developed preeclampsia and so, um, she was brought in and we got a fetal echo to look at the flow. And look at the rhabdoma and decide, can we deliver or not. What you can see is that this rhabdomama has now significantly shrunk. We can actually see the left ventricular cavity and now the flow is no longer ductal dependent. And so we can, we actually have flow through the aortic arch, and we thought this if it could be delivered without the need of prostaglandins. And so, Um, we, um, um, delivered a recommended delivery and so it was born by C-section. This infant went on to go to a cardiac ICU, did not need any extensive support, was initially on prostaglandins until a postnatal echo confirmed what this, uh, fetal echo showed at 34 weeks and, uh, actually did not need oxygen or any other supports and was, um, able to be discharged after, uh, feeding and growing wounds they're closer to term. During this, we didn't know what dosing to do and knew we needed to be aggressive with the dosing for this patient because of the severity of the cardiacardoma. So our goal in TSC is to be between 5 and 10, 5 and 15 nanograms per milliliter for uh serolimus levels. And so we started off our patient at 3 mg per uh per meter squared, which was actually 6 mg per day. Um, we had a first level that was around 5, so within range but still want to push it and so we increased and made two-step increases and you can see that during the entire pregnancy, we kept mom in the therapeutic range and for most of it, we were staying above that 10 nanograms per milliliter, which uh was very important to us to make sure because when we're treating fatally, we don't want to look back and say, well, we tried but we didn't get the doses high enough or the levels high enough. Interestingly, because of this case and everything going on, we're able to get maternal blood shortly after delivery, which was around a level of 9, and we got fetal levels, which is the red point here, and the fetal level after delivery was around 8.5. Um, so really the maternal and infant levels were nearly the same. You can see we started dosing the infant right away and we actually had elevated levels and I'm just gonna show you, even though we're talking about fetal uh here, is that this infant actually needed less dosing throughout their entire first year of life to keep their levels within range. So to put it in context, their current dose is around 0.8 mgs per meter squared per day and typically at this age, we would expect a patient to be around 2 mgs per meter squared per day. And so, um, this infant for some reason doesn't clear the medicine as well, but has been able to stay on treatment and we've had reversal of this, uh, rhabdomyoma and actually, um, no seizures to date and they're, uh, the infant is currently around 10 months of age. We also did not see significant side effects for the mother, um, which is something that we monitor closely and knew we might have when we're aggressive. So she did have some mouth sores, but those went away within a few days. And then she did develop a hypertriglyceridemia, um, throughout the treatment that then after stopping treatment after birth, uh, the infants responded and she responded. And so, um, we expect to see this in our current practice in our group is that we see this and we just say, hey, we're treating for a finite period of time and we'll see this improve afterwards. Additionally, um, she did have a drop in her platelets throughout the pregnancy, um, and throughout the treatment. It's unclear to us how much this is related to the erolimus, uh, but then you can see how this dropped off when she was diagnosed, uh, with preeclampsia, but then recovered after the pregnancy. So it's unclear to us currently if any decrease in platelets would be related to the treatment with erolimus. However, um, everything that we saw, uh, from a laboratory standpoint was reversible after, uh, maternal sensation of treatment. So, our learnings from this are number one, that we can have extreme cardiac rhabdomyoma phenotypes that can be reversed, which I think is crucial because the initial counseling for this patient was about the imminent fetal demise, which was appropriate, but also we have something to do and we were able to see this uh family the next day after finding things and get them started on treatment. It also highlights that there are unique features as to why uh rhabdomyma developed. So I didn't focus on this, but this was a twin gestation. Twin also has TSC. Twin never developed largerhabdomyomas, um, and actually has no rhabdomyomas for on the last several echoes after only being treated fatally. And so, we've developed a cohort here that's part of our, um, DOD study. In which we can get timed echocardiograms and blood work to try and understand why these grow and why they regress. And having these twins in the study is amazing because now we have internal controls, both of the fetal life um and then the postnatal life as well, um, that can really compare why. And then the last learning we have is that early MTOR uh inhibitor levers are needed to adjust dosing. So this is from our preventive trial that was highlighted um by the fact that we dosed higher than a lot of the studies suggested we needed to and we still need to go up in the mother. And then at the infant, you did low doses, but the range of doses, uh, uh, that patients need is wide-ranging. So in our clinical trial, all of the patients have the same levels. We keep that the same, but when we look at the um amount of dose needed, some patients need a 5 to 6-fold increase over the first year of life to treat them. Others need, um, just 2-fold increase over the first year of life. So there's a, a large variability and we can see even within early at 7 days. Um, we actually have, um, changes at 7 days that could be up to doubling the dose, um, that's needed just based on those first blood levels. So for all patients, especially in the fetal period, we need to go quickly on this. The next case is one in which early delivery was recommended. Um, and so this was a, a, a woman with TSD. She had a pregnancy and at 23 weeks was found to have a rhabdomyoma and was told that she was gonna have to deliver early cause it was a large rhabdomyoma. So we saw her at 27 weeks. You can see the large rhabdomyoma here. It was not uh giving outflow obstruction, but we had several considerations for treating this patient. One is that there's multiple rhabdomyomas and a maternal TSC diagnosis. So we were confident that this infant was gonna have TSC. And also that there's, what's the risk of being born premature, so that your rhabdomoma doesn't cause um obstruction versus treating you and coming to a term gestation. And so in discussion with the family, we decided to treat with Sierraimus. We once again started our typical dosing, we had to increase significantly. We can see her level stayed roughly the same even with increasing. The rrhabdomyomas regressed significantly, and so we decided not to increase further to increase her goal levels, um, because, um, the rhabdomas were regressing. The mom only had side effects of mouth sores and elevated cholesterol which uh improved after delivery. And so this is one, this infant was then born at term, has not needed any support after the delivery, and actually is uh lived several hours away from Cincinnati, was able to deliver at home uh without any extra support, um, because the rhabdoma was regressed so significantly with the Cimus treatment. And so, this is one where we think the maternal diagnosis helped us. And that we learned that we don't always need the high therapeutic levels that some people will improve. And then maternal uh TSC we feel that should make us more confident about the safety of treating cause mom has the same molecular problems going on as the fetus. The last case I want to show you is that if we want to treat these patients early, I'm only showing you kind of severe rhabdomyomas that we treated. But what if we can diagnose TSC as early as possible and start treatment? And so that's things that are being discussed. But in our heart TSC protocol, we can do this and start looking for rhabdomyomas early on. And this is because we take families where there's uh familial TSC, which is about 1/3 of cases. And if a family member is, is pregnant, we offer to do early fetal echocardiogram. So this was done at 19 weeks. Our cardiologists were able to detect some small rrhabdomyomas. On that. These rhabdomyomas at 19 weeks, you would think how quickly things increased would actually be a concern. But, um, for this one, here's the echo at 33 weeks where is this um bigger rhabdomyoma but not causing any problems. You can see that the largest rhabdomyoma um only enlarged by about 3-fold, uh, throughout the entire pregnancy. And so not just the presence of rhabdoomma early on, it gave us the diagnosis. We knew, uh, that we would be diagnosing TSC in this patient, but it didn't mean that the rrhabdoomas were gonna grow aggressively. And so, um, this has been exciting for us, uh, in our study to start, start to push how early can we diagnose for setting up future studies to find how early can we treat. So, rhabdomyomas are likely detectable much earlier than we typically find them. But it should be considered uh doing early fetal echoes in cases that are at risk. And I think it's important for us to know that not all early rhabdomyas are going to grow. And the last thing is, um, we're debating within our group is what are the risks of treating every rhabdomyoma. So single rhabdomyomas, currently we think only have a 50% chance of TSC. So, What do we do, uh, from, from that end? Do we, um, treat those and, uh, make them prove that they're not TSC or consider lighter? Um, and so these are kind of the things we're talking about. But I wanted to bring in one last thing, and that's, is the maternal TSC a risk at all. And so we did a survey of TSC providers. And basically, I'm just showing that only 30% of TSC providers have ever seen a TSC, um, Patients and not known a maternal who had or a mother who had complications. And so majority of providers who take care of TSC patients have seen maternal complications during pregnancy, whether that's worsening of their TSC disease, preterm delivery, preeclampsia, miscarriage, uh, But we're seeing this in the women that we treat. And so, uh, medical student with me, Nura Izakudu, she looked and we asked all the women that presented the clinic, um, and so we got about 80% of our women to respond. We got 89 pregnancies and we just looked at what are the rate of different complications uh during pregnancy for our women. And so you can see prematurity, we hit about what the reported US average is. Miscarriages about the same, bleeding, spotting the same, gestational diabetes about the same. However, preeclampsia, our women are reporting getting diagnosed of that 14th of the time. Um, and so we really need to look into this. Is this because they already have kidney disease? Is it because elevated protein in the urine is already something that women with TSC may have? Um, and so it's not correct, or is this a real pathology, um, that our women are at risk for that can then impact fetal development. So, in conclusion, what I hope this helps with and what you guys can take home is that number one, the presence of rhabnomos should uh make us concerned for fetal TSC that the timing and role of other fetal imaging we have is currently unclear outside of our fetal echoes. For maternal treatment with MTOR inhibitors, there's starting to be enough data to say that it's safe based on uh all the case reports. However, we must acknowledge that those are case reports, so it's not something that we should be doing all the time for any rhabdomyoma. However, we need more studies. So we are currently collecting this data, but hopefully we can get others to start collecting to kind of look and see what kind of maternal field data out there that can help us decide which rhabdomyomas to treat. And then lastly, we think there's gonna be future uh trials to look at using fetal treatment, um, at the first sign during the pregnancy to actually improve outcomes in patients. And so with that, I'd just like to point out and think that our team is a huge team, uh, here at Cincinnati Children's that I just get to be one part of, uh, they're really helping push this and that I'm happy to have emails sent to me and questions asked about this cause we understand this is a, a unique and small field for a rare disease. Thanks.
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