. . . Steve, you give us the word when we should begin. 701 word. We have three speakers today. We will have time for a session or two and comments from their mentors. We will have time for the next session. We will have time for the next session. We will have time for the next session. We will have time for the next session. We will have time for the next session. We will have time for the next session. Thank you so much. I am Danny Levis. I am nothing discos. I was able to complete a number of clinical products both in the lab and in the clinical realm. I am going to focus on my bench work. I am going to focus on my bench work. I am going to focus on my bench work. I am going to focus on my bench work. I am going to focus on my bench work. I am going to focus on my bench work. Initially, our lab used this model to test trace it for exposed phlegal anomalies like gastro-schicis and spinopiphyl. This model was used in the clinical realm. This model was used in the clinical realm. This model was used in the clinical realm. This model was used in the clinical realm. This model was used in the clinical realm. This model was used in the clinical realm. The heart and lungs were then procured and turned for gene expression analysis. Similar to what Alex found, both cell types decreased markers for vascular tone and arterial remodeling, which are consistently elevated in the CDH groups, with the amniotic fluid embassies being slightly more effective. Further, I looked at new markers in the lungs to assess parental, parental remodeling and inflammation. Both trace it groups normalized collagen expression in the lungs, and drastically reduced the inflammatory response seen in CDH. Speaking of new findings, these were our first studies looking at cardiac remodeling in CDH with tracin. In these initial studies, we found that important markers for heart development were increased, particularly with placental MSCs, and that tracin exacerbated an isoform switch for the cardiac myosin heavy chest. The cardiac myosin heavy chest to favor the fetal version, which confers improved function during the acidosis and hypoxia. In summary, both cell sources seemed to have an effect on CDH. With perhaps amniotic fluid cells having a greater effect on the lung, while the placental cells had a greater impact on the heart remodeling. But this is all gene expression analysis, which is difficult to translate into functional outcomes. So, to try and assess the functional cardio-pulmonary effects of tracin in CDH, I've been performing fetal ultrasound in rats, which is super cool, and can help show assessment of cardiac function and pulmonary resistance to flow. But, despite being super cool, it also turns out to be rather challenging. Here you can see the experimental setup. Here's the ultrasound machine. Here's the sale room. It's called an arch. Here's my rat being prepped and ready to go. And what we do is we perform a little laparotomy and expose a single fetus at a time, and then on each fetus we perform focused ultrasound assessment. This is Fred. So, he is the Fuji film, or the visual sonic ultrasound rep for Boston Children's, and just a major shout out to him. He's put a lot of time and energy into teaching me how to do these echoes, as we both essentially learn how to work with fetal rats together. But eventually you start to get the hang of it and start to be familiar with the different landmarks that you can see in a fetal rat. For example, you can see my pointer. I hope I can point out certain landmarks. Here's the right ventricle, which is more anterior displaced next to the sternum, which you can kind of see right here. And you can see some super fine details per diacol as well. So you can see the h-reventricular valves flooding a little bit, and the tracuspid and mitral here. And then what I think is the used station valve, kind of just fluttering the breeze in the right age room here. It's a very cool, very awesome. And with these details, we can start to look at color flow doctor assessments. So from the ventricles, you turn on the color flow doctor and slowly approach the base of the heart to see these outflow tracks. With the pulmonary artery coming out more anteriorly and crisscrossing with the aorta, which you can see here, pulmonary artery aorta. The rat fetal heart is actually rather mobile. So if you difficult to replicate views, so again, the landmarks are important. Here you can actually see the main pulmonary artery branching into the right and the left, and actually entering the right lung. So here's pulmonary ventricle going to the left lung and then entering the high lung on the right lung there. We can then do powerful post acquisition analysis to assess ventricular function. So by outlining the ventricular endocardium, speckled tracking technology can assess things like ejection fraction and ventricular valve strain. You can see the vector strain analysis for each, for the movement of each individual speckled here. And the staff work and then calculate the change in chamber volume between system and diastole to give the ejection fraction. Similarly, we can assess resistance to flow in the pulmonary artery by looking at the daffodil profile. Here on the left we see a normal fetus and on the right we see a fetus with 3DH, which is a short and acceleration time and mid systolic match, both of which are characteristics for increased pulmonary flow resistance. Unfortunately, I'm not quite finished with the data gathering and actually I have my last two moms to echo later this morning. So final results are pending. Shifting gears slightly, somebody recalled that my senior fellow staff last year presented on a new role for traces to deliver amniotic fluid arrived from an aquatic stem cells that will reach the fetal circulation. My next project and I was to follow up on some of this work, namely to better define exactly how the MSCs are reaching the fetus and also to investigate a possible role for ex-fibogenetic manipulation of the HSCs. So first to assess HSC routing, the cells released syphorase labeled and injected on gestational phase 17. Then on each subsequent day, the gestational membranes and fetal organs were harvested and the syphorase fs were performed to detect cell presence. This project was based on similar with my serotracy, which actually stuff I have been shown us how to procure these fetal membranes. Looking at the raw of the syphorase data, there was a clear increase in the syphorase expression of the fetal membranes from gestational vein-rainteen onward. There was such a wide range between fetuses that it was difficult to analyze. But by normalizing to total syphorase expression in each fetus, one can clearly see a trend of the HSCs moving between the amnihan and the coreion. After injection, the HSCs seemed to favor the abascular amnihan for a few days and then eventually began to move into the coreion. This transition to the highly vascular coreion was reflected in the hematogenous fetal organs, where the syphorase expression was not consistently seen until after gestational day 20. So overall, this would suggest that the HSCs run from the amnihan to the coreion to reach the fetal organs, which seems to take about three days or so. Next, we want to look at the possibility of performing X-b of genetic manipulation to deliver genetically corrected HSCs back to the fetals. We chose a denacing deaminase deficiency as a theoretical target. Since its deletion causes immunodeficiency, stem cell transplants, fetal stem cell transplants, is easier to accomplish. There was actually the first disease to be cured using gene therapy several decades ago. We then went about designing our own vector from scratch using a self-enactivating antivirus to a prompted safety and no-integration. A strong promoter was chosen and we decided to do a coexpression of both ADA and Luciferase to help facilitate and be both self-training. The experimental setup was again very similar to our other trace of miles with cell delivery and gestational day 17 and then procurement of the organ's ed term to look at both Luciferase activity and expression of the ADA gene, either of which either of which would indicate self-present. It was modest Luciferase activity detected, but unfortunately there was actually no gene expression detected by standard PCR techniques and any of the field issues. So I switched to a more sensitive version of PCR, something called digital droplet PCR, where the single sample reactions partitioned into over 10,000 discrete reactions droplets, or send undergo PCR amplification, and each droplet is assessed for fluorescence, which would indicate the presence of our ADA CDNA template. Using this technology, we were able to detect low levels of ADA expression near the all fetal tissues, as you can see here. So overall, we were able to design and safely affect our HSCs with the gene of interest, and these modified HSCs were then able to reach nearly all fetal organs and at least some degree in the fetal tissues. Finally, I think I have enough time to really quickly go over a new model for our lab that I've been really excited about, and you're using your own droplet restriction or IUDR in placental dysfunction. So IUDR is a relatively common complication pregnancy with up to 30 million cases worldwide every year that can have significant impact on the child, increasing risk for a range of metabolic and psychiatric diseases. It is caused by insufficient spinal artery remodeling, which reduces fetal blood flow, and is not to be brought on by an inappropriate prone flamethrower state in the placenta. Since we have already shown that the MSC is home to the placenta and that they can modulate information, I wanted to find out if they could possibly have a role in treating a placental dysfunction. To test this, we used the well-established hypoxia myeloma of IUDR, which accurately recapitulates the clinical pathology. The model involves placing a pregnant rat into a hypoxia chamber starting on just vacation in May 15. In some moms, two days later we would do our intra-amÊatic injection of saline or MSCs and then a term SSV-8 to the central weight and then placental gene expression. I was, frankly, surprised by our initial results while the MSC's rescued placental efficiency, which is a gross measure of placental function, they actually exacerbated the hypoxia and due to gross restriction. Obviously, not exactly what I was looking for. So, I looked to modify the MSCs in an effort to improve their therapeutic function. To do this, we used a process referred to as priming, where the MSCs are exposed to certain factors prior to infusion, which licenses them toward a certain therapeutic niche. For this experiment, we briefly cultured the cells with cytokines interferon gamma and IUDR in the hopes of potentially the anti-inflammatory role of the MSCs. So, I performed the experiment again using a new group, the primed-at MSCs. And just like before, the MSCs normalize the placental efficiency, but unlike before, the primed MSCs actually completely normalize fetal weights, as you can see here. The gene expression and protein levels for the placental tissue are unfortunately still in process, but we'll hopefully get done before I leave it in the little over a week. So, a little bit of crunch time, but that's OK. Meet. OK. This is probably my most important slide. A huge thank you to everyone first off in the Fauzo lab, Ashley and your rock star. That's amazing. On the prior fellows are all awesome, so involved in this great and my thesis isn't big enough to come up with enough nice words to say about Dr. Fauzo, but he was, he's been perfect for these last two years. And then doctors, these great, everyone within the surgery department working with Dr. Buckman and Dr. Jennings has been the best and really anyone who took the time and effort to teach, which is literally everyone I ever interacted with here just a huge thank you. And of course, my co-fellows have all been wonderful when it makes me and it's been a whirlwind of two years. And I think we have time for questions. All right, thanks, Danny. So if anybody has any questions or if Dr. Fauzo or Dr. Buckman, I want to make some comments. Yes, I will have actually a graduation celebration for the the party fellows, at which time I'm going to speak a little more about Danny, but for now, I'm going to highlight something that perhaps was evident by the top, but doesn't hurt to emphasize, which is the fact that these projects are highly demanding on many fronts. Danny spent a lot of evenings and weekends here working very hard. There are a lot of new techniques to be learned both in the animal or and on the bench. How did he handle all that very beautifully? He actually adopted research and adopted new techniques that we have incorporated in our procedures moving forward that were all original from him. So I could not have been more pleased and impressed by Danny's performance. Very, very grateful to him. Danny, congratulations. Thank you very, very much. And we'll chat some more other graduation. Yeah, this is Terry. I want to echo some comments as well. I was lucky enough, Danny, to have to borrow you from Dr. Fauzo's lab and considering the the depth of the work that you've done. You really were able to focus on several clinical projects and take them on with a lot of enthusiasm and vigor. And I had no idea that you were actually this busy in the lab because you really made us feel like you were the, this was your primary focus. So I thank you for working so hard on those the clinical papers, the laparoscopic sheet catheterization paper. They were very masterful and you took them to the finish line and I'm very grateful. So congratulations on the hard work. Exactly. Thank you. I'd like to add a comment that echoing with Dr. Buckman said, you know, you don't know what somebody's doing when you're not face to face with them and some of us interact with you clinically and in professor rounds and know you're doing some stuff in the lab and see some of the abstracts and presentations, but, but to Dr. Fauzo's point, you sort of revolutionize some techniques. I think you could be the professor of making things smaller. The measuring strain in the microquart of a, of a fetal rack is quite an accomplishment and then not getting too discouraged by PCR and taking it to the DPCR to look with a finer comb. It just goes to demonstrate persistence and this is part of the environment that allows you to do that and congrats to you. These are serious scientific endeavors that people saying you, you know, in the emergency room or in the conference room or on the zoom screen, don't understand that the hours of sweat and brain power you put into this is really beautiful work. Thank you for the present that I might add and we will certainly miss this issue in the short term, but I look forward to your accomplishments in the long term. Thank you. All right. Thanks, Daning. All right. So next up is Dr. Jordan C. Corp. He graduated with a BS in Biology and MSN Pathology from Ohio State University, followed by Medical School at University of Illinois, a Chicago College of Medicine. He then completed three years of surgical residency at Massachusetts General Hospital before joining us for his research time. He has spent his time here over the last two years, primarily working with Dr. Pewter and our department in the Vascular Biology program. He'll be sharing some of his work today, which is one several awards, including the Excellence in Research Award from the American College of Surgeons Clinical Congress. I congratulate Daning here, a tough fact to follow, but it's kind of fitting that I should go after you. So the work that we do is funded by both industry and some support from the department and from the Vascular Biology program, which I'm very appreciative. And in fact, you know, if I could do one thing and only one thing in the next 10 to 15 minutes, it would just be to convey my sincere sense of gratitude I have for having had the opportunity to be a research fellow here. Boston Children's Hospital is really a special place and I sort of came to appreciate that in 2015, where I came as a visiting medical student. So I think I'm going to be a little bit unorthodox and start by doing my thank yous first, because it's the most important thing to me. I want to leave enough time for that, but to sort of go in chronological order in 2015, it was Dr. Schamber and Dr. Lillahy that sort of welcomed me to Boston Children's Hospital. You know, I've sort of been in love with this place ever since. So it's really them that I have to start by thanking and you know, for reasons that are unclear to me, they took an interest in me and sort of helped me along the way and I'm very appreciative. And they help me, I think get to mass general, which has been a dream come true also in many respects. And then when it came time to look for a place to do research, they introduced me to this guy. And I'm not sure whether to thank them or not. I'm not sure if it was a practical joke in the long run, but in all seriousness, there's so much that I could say about Dr. Peter, not all of which would be appropriate for this forum, but I my sense of gratitude for Dr. for having that had the opportunity to work with Dr. Peter is, you know, so overwhelming. I think, you know, if I had to distill it down into a few sort of life lessons or ethos that I've learned from Dr. Peter and there are there are all things that I've learned from, you know, watching him practice medicine and be a scientist as much as things that he's told me directly, but the thing that most apparent thing is this devotion to patients, he always has his page on his head, he's always available to go see a patient and sort of be there for his patients and he takes care of them for the rest of their lives. And also his willingness to undergo personal sacrifice is probably greater than anyone I've ever met the amount of pain that he's endured to bring his, make a vent to the market or to bring his, you know, advanced science of intestinal failures, just sort of incredible and sort of awesome to learn from. And other lessons I learned from Dr. Peter is to always be in play by that and it's this perpetual sense of being available and as a mentee that is incredibly important because if I know if I ever need Dr. Peter, I know exactly where to go and that's Honeywell 339 because odds are he'll be behind the desk they're willing and ready to talk to you about whatever it is that's on your mind and that has been, you know, invaluable to me as a trainee. And also his, he has a sort of perpetual commitment to doing things the right way no matter how inconvenient or how difficult it might be, you know, there's no cutting corners, there's no taking the easy route, it's things are done the right way and I think that's an important lesson to learn as a trainee. And also the, you know, in this era of the surgeon scientist is sort of a dying breed, Dr. Peter is very much the sort of one of the last bastions of being a surgeon scientist and it's incredibly important to see that someone can still do it and do it well so I'm appreciative of that. And also, you know, when science is hard and you can be discouraging, you can be discouraged easily but I think this is a line that he's adopted from Dr. Fulkman and that is kids are dying, work faster. And so he's able to convey the importance of the work and why we need to do this and even though there are setbacks that we have to keep our notes to the grindstone, keep working. So Dr. Peter, I just can't say thank you enough for letting me have the opportunity to learn from you. I'm very appreciative. But also to the Peter lab in general, you know, it's an incredible place. The stakes are high and we work hard but it's very much a team effort to Jenny and Tori. To Jenny and Tori, Tori, congratulations on your match. She'll be going to Miami as the pediatric surgery fellow there and I'm very happy for her. Jenny's returned to the BI. The two of them I should just publicly apologize for having subjected you to working with me for the last couple of years but I'm very appreciative and thankful. Kathy, our pharmacist who's one of the world's experts in the PN and PN liver injury. It's, you know, an invaluable resource to learn and work from her and her help has been very appreciated. Kathy, our, our, our, our, Amy our lab manager who's sort of the master of many trades and, you know, couldn't do things without her. Of course, Dr. Fisherman support, you know, I'm very appreciative that you allow us the opportunity to be funded and, you know, trace whatever gene, whatever project it is that we hope to accomplish. Dr. Moses runs the BASCO Biology program and it's quite a team of scientists there. And then I, you really have to spend a minute for Bennett Cho. So Bennett was a Harvard Medical student in Dr. Peter's lab when I sort of joined the lab and then Bennett ended up applying for surgery and now is an intern at Mass General. So it's sort of fun that we have this sort of relationship now. I inherited many of his projects and I'm extremely appreciative to Bennett and all of this hard work and his generosity and sort of handing things off to me. Okay, so with all that I should actually talk about some of the research projects I've done and some of the things I've been involved with are outlined here. Today I want to focus on our work with a structurally engineered fatty acids, which some of you may have heard me speak about before, but it's really sort of exciting work and I'm excited to share it with you. So the one of the focuses and probably the primary focus of the Peter lab has been pediatric intestinal failure, which I think many of us were all familiar with. So I won't belabor it. There are many causes, but the epidemiology, there's about 25 cases for 100,000 births and about 1,000 new patients per year in the United States. But the most feared and deadly complication of intestinal failure is liver disease. That's pediatric intestinal failure associated liver disease and it's really the consequence of intestinal failure. Liver biopsies, the gold stator for making the diagnosis over due to the invasive nature of liver biopsy, you know, it's typically not performed. And so in the top panel, you can see what a biopsy form patient with intestinal failure looks like and below you can see what a normal looks like for comparison. And early in the course of intestinal failure associated liver disease, it's primarily coal stasis. So patients have elevated billiardubin and liver enzymes. And the best treatment is attaining antiretonomy, but we know there are many barriers to attaining antiretonomy. And the disease is often progressive if TPN is continued. And advanced stages of intestinal failure associated liver disease, it becomes the statoosis and stato hepatitis fibrosis and ultimately in stage liver disease, you know, requiring transplantation or causing death in 15 to 40% of cases. And it accounts for 1.4% of all mortality for children less than four years of age. So as we all know, Dr. Peter has spent the early part of his career bringing OmegaVento market and some of the important differences between OmegaVento, which is a fish oil lipidimulsion and interlipid, which is a soybean lipidimulsion, are the composition of fatty acids. So an interlipid is primarily composed of Omega6 fatty acids. And Omega6 fatty acids in and of themselves may not be necessarily a problem, but what certainly is a problem or the pro-inflammatory metabolites seeing here and one of them, which we've been studying recently, is this 12-heat, which is a particularly inflammatory fatty acid derivative, has actually been associated with many adult cancers, so sort of an active area of research. And then the Omega3 fatty acids are thought to be much less pro-inflammatory and can first some of the benefit of OmegaVento. So this sort of, the economy between Omega6 and Omega3 fatty acids is something we spend a lot of time researching. But without a doubt, OmegaVento has been a game changer for children with intestinal failure associated liver disease. This is a paper published by Kathy and Dr. Peter last year, and it just shows that a multi-institution study that OmegaVento works and it reduces co-estasis. It's also reduced to the need for liver transplantation, you know, 2-PN liver injury or iPod has gone from leading indication for pediatric liver transplant and now I'm not even being in the top 10. However, despite the advances with OmegaVento, the more talented the higher the quality is still somewhere between 10 and 20%. And as I mentioned earlier, the ideal treatment for iPod is attaining antireltronomy, but for some patients, even after attaining antireltronomy, TPN liver injury or iPod can be progressive. So in the first panel, you'll see a patient who's on PN who has indications of fibrosis. And then even after attaining antireltronomy, you can see in the middle panel there that the patient has progressive fibrosis, despite being weaned off TPN. And then in the third panel is the control over for comparison. So the problem that we were trying to address in these studies is that there are new therapies needed to prevent and treat iPod. So going back to that notion that Omega3 fatty acids may be protective with, we partnered with an industry partner to look at other ways that we can use Omega3 fatty acids to treat TPN liver injury. And one thing to know about Omega3 fatty acids is that they have many effects in the body, and if anybody who follows the cardiovascular disease research knows that their effects are certainly mixed. And what one thing to know is that only 8 to 16% of unmodified fatty acids reach the liver after meal. And the majority of them are either metabolized as fuel and then or a starified and incorporated into cell membranes. So this concept of structurally engineered fatty acids is that by altering this naturally occurring Omega3 fatty acid, you can avoid, you can allow the compound to avoid certification or modification and as such, exist as a signaling molecule. And our theory was to try these structurally engineered fatty acids which have been developed for other indications and try to use them to treat TPN liver injury. So we hypothesized that the structurally engineered fatty acid, C-F-6179 would prevent PN induced hepatocetosis and armurium model by FOP. And to test this hypothesis, we used the model which has been developed in our lab and used in the development of Omega-Benn. In this model, mice are given PN. The first group of mice are just on-challenge service control. The second group received PN and service on a disease model. The third group received MCT which is medium chain triglycerides as a vehicle control. And the fourth group received the drug of interest. And I note this first experiment is one that is fat deficient, and is really just sort of a screening for drugs that may potentially help treat TPN liver injury. When we see after 19 days on PN mice on PN alone developed elevated serum AST and ALT which are indicative of liver injury. And mice treated with C-F-6179 that serum AST and ALT are attenuated suggesting that this drug might be protective. And the histology is really sort of telling. We know when things are working or not based on the liver histology which as I said is the gold standard for diagnosis and patients. The first panel you can see that with a normal mouse liver looks like there's very little to know hepatic statoces. And the second panel you can see those large white droplets and those are fat. The top panels, the top rows, H&E stand in the bottom rows, well-radic O staining which is a confirmatory staining for fat. And we can see that mice on PN developed this market intrapatic macro and microvacicose statoces whereas animals in the third panel here treated with C-F-6179 have essentially normal liver which is really sort of dramatic. So this was our screening experiment so to test to see whether or not this drug might be able to help patients. We repeated the experiment for this time with the addition of introlipid which of course is the sogino lipid emulsion. So we repeated the same experiment 19 days and again we go back to the histology and we see that in the first panel mice on child have normal liver but mice on PN even with the addition of introlipid they still develop that market intrapatic macro microvacicose statoces whereas when treated with C-F-6179 the liver is essentially normal. So next to better characterize what exactly the lipid component of those droplets are seen on histology we isolated fatty acids from the liver and used mass spectroscopy to characterize the fatty acids. So in the first graph here you can see that the triglycerides and mice on PN are markedly elevated and then they're reduced by treatment of C-F-6179. In addition cholesterol esters and the racodonic acid derivatives are elevated and mice on PN and then reduced by C-F-6179. And then again we see that 12-fidi which is that particularly inflammatory and megacix fatty acid derivative is elevated with PN and then reduced by C-F-6179. So the next goal is to see if how we can translate this to patients. So an ideal therapy for treating intestinal fethersis of liver disease is one that could be given enterally but still absorbed and have an effect on reversing or preventing intestinal fethersis of liver disease. So to test this hypothesis of whether or not C-F-6179 would be absorbed in patients with short bowel syndrome we used a piglet model and our control piglets had no bowler section there are six week old Yorkshire piglets about 20 pounds. And to test whether it was absorbed in piglets without short bowel syndrome essentially the model we use is that we place a central line we give them the drug we measure the blood levels of the drug over 24 hours. We use two different formulations because this drug has ever been used before one in saline and one in MCT to see which was absorbed better. And then for our short bowel model we do the same thing we place a central line but when we do that we also do a 90% small bowler section and then allow them to recover and then repeat the same protocol in which we administer the drug and then we measure blood levels of the drug serially. So just to sort of better illustrate our short bowel model the control piglets again just had a central line placed in no bowler section whereas the short bowel syndrome piglets underwent a 90% small bowler section they it's kind of amazing the piglets in adult human has about 12 feet of small bowel or these 20 pound piglets have about 20 pounds of sort of 20 feet of small intestines. So without an energy device like a harmonics all clamp clamp cut tie so it's quite a bit of bowler section to do but they tolerate procedure very well and then after the bowler section we perform a hand zone end to end bowel and asthmosis. Part of the fun of this work is that you know it allows us to keep our technical skills sharp so here you can see an interoperative photo that's that 20 feet of small intestine and a 20 pound piglet there and then on the right side you can see one of our hand zone and asthmoses. And the results of the study show that again there's two formulations the first is the MCT formulation that the piglets without short bowel syndrome absorb cf6179 without any problem as do the resected piglets I'll be it with a maximum absorption of about one order of magnitude less than that of unrestricted piglets over both the resected and unrestricted piglets exceeded the predetermined a priori the a priori threshold of minimum effect. Meaning that the drug is in fact absorbed and piglets within without short bowel syndrome and the same was true in the saline formulation albeit with slightly lower absorption in the piglets with short bowel syndrome so sort of in summary what we've seen so far is that cf6179 prevents tp and induced the arpeotitis it prevents tp and induced in paddock like with toxicity within without interlippid and that cf6179 is absorbed after interal administration and piglets within without short bowel syndrome and it's very much a promising new therapy for a real patient. So it's sort of our future direction we've worked with my supercrapics and then based on our data there's actually a phase one clinical trial of cf6179 which will start in now July of this year and we will be evaluating cf6179 in the I filed neonatal piglet model this year we just had a conference with our industry partner in their full board had very excited to fund this work and the ultimate goal is to translate cf6179 into the next one. So it's really been sort of an amazing journey for me to be a part of and I'm very appreciative to sort of made a small contribution to hopefully bringing this start to market and hopefully one day helping patients with I filed and I'll end sort of where I began and that's by thanking all the people who have helped me along the way I'm incredibly appreciative and I would be remiss if I didn't thank Dr. Fowze and Dr. Z you know the and Dr. Fisherman Dr. Jackson, Dr. Jackson, Dr. D. Moody, all of the people who have contributed to this sort of incredible environment it's really a fantastic incubator and I can't imagine a better environment for people who are aspiring pediatric surgeons or pediatric or certain scientists in general to learn and sort of develop and learn the right way to do things and I'm incredibly thankful for that. And I guess I'll steal a line from Dr. Lilomo and he says that you know if you see it turtle at the top of a flagpole he's you know he's had a lot of a help getting there and that's sort of how I feel right now is that I you know I can't believe the things I've got to do and and be a part of the last two years and I know I wouldn't be able to done it alone so I thank you to all of you who have helped me and I really appreciate it so I welcome any questions comments or heckling so thank you very much. We have a couple of minutes for questions or comments from the computer. Jordan thank you so much and also for your kind words. Thank you for the two years of hard work that you put into the lab and you represented children and regionally nationally so well. You know this work with Gilly and Bennett shows started in Jordan wrapped a lot of it up and as he said it actually is led to phase one study for a peanut and this study will be done in July and we we've had a lot of luck with this and it's worked out well and also in primates it's already been looked at in primates so this has a lot of potential. But the other part of the work too is the work that's been done in naffity is also naffity has been a basis for work that's gone to phase one and is about to go to phase two trial and also thanks to Jordan this is also led to another 400,000 also research that we've agreed to over the last week. One thing I do want to say especially is that this is not part of the research but during the. COVID crisis mass general was hit pretty hard with the patients and opening units in Jordan spent several months working days and nights taking care of those patients and I want to thank you for doing that. I know you were really exhausted throughout that full time. I'm looking forward to seeing all the future manuscripts as you had on that list that are all pending and you're on your way on those and I do wish you best of luck in your success as a cardiac surgeon as you've been accepted to the program at mass general and your goal of being a pediatric cardiothoracic surgeon. Thank you again. Thank you. I would add Jordan here things are going to be different with that you're around here again we don't all get to see you in the laboratory sliding away over these incredibly detailed efforts and you've become essentially biochemist. I'm going to come to the studio and you are contributions will live will live long in laboratory but but also you've been over a presence I don't know that professor runs rubber you the same again. I don't know if you're getting about a kind of size of the differential or the information for that matter you guys hope always make sure that I'm in things would not succumb a present that any expert and enjoy to the to the department and I know that doctor's a chamber you're in my eye. I always have a talent but it's appropriate that you recognize that I'm making that that opportunity for you and we wish you the best of luck back down across town and would not be an all surprise to see you back here and some capacity taking care of them babies with messed up hearts and making them better as well and we will sort of wish you wish you well along that journey. Thank you very much. All right, thank you Jordan. All right, our last speaker for this morning is Dr Amanda Harrington she graduated with a BA in chemistry from Harvard College followed by medical school at New York University School of Medicine. She completed her surgical residency at Yale New Haven Hospital prior to joining us here in 2018 for her surgical critical care fellowship with Dr Weldon. She then spent the last two years here as a research fellow primarily working with doctors in they has a meta on a sapodial trisia and nutrition related projects. She is also receiving an MPH in clinical effectiveness from the Harvard TH trans school of public health this year. A special thank you to Amanda for helping me this year with administrative things related to ICU and scheduling and we're so excited she'll be starting her pediatric surgery fellowship in August at Rady Children's Hospital in San Diego Amanda. Thank you so much. So I have no disclosures. I just wanted to first give a quick review of how I spent my time at Boston Children's so from 2018 to 2019 I was a surgical critical care fellow with Tim Turell and Kyle Thompson. I really enjoyed learning the physiology of neonates and children and I'm very grateful to have this foundation going into PD search fellowship. In the past two years I've completed a master's in public health. My personal goal is to learn statistical methods for quality improvement research and thanks to COVID my puppy was able to complete about three quarters of her credits as well. And so I've also been working on quality improvement research and today wanted to present two studies there are two separate studies evaluating growth outcomes in a sapodial trisia patients but obviously share some background so I'll present the background and then the results separately. So I know we're all familiar with the sapodial trisia but it's a rare congenital anomaly where the ends of the esophagus fail to grow together it is a spectrum of disease. But surgical repair has good outcomes now surgical repair depends on the gap length which is the distance between the upper and lower esophageal pouches. So type C esophageal trisia which accounts for about 85% of esophageal trisia is where you have esophageal trisia in a distal teephistula and typically these patients are able to undergo a primary repair early in life and have relatively uncomplicated courses. Long gap esophageal trisia on the other hand is more difficult to manage and there's really no consensus on the best surgical approach or consensus on the definition of long gap. At our institution we define long gap as the inability to repair the esophagus in a single operation and we've embraced the folk or process which allows preservation of the native esophagus where obviously very familiar with the procedure and have had good outcomes. What I wanted to discuss today are growth outcomes in these patient populations so growth outcomes are largely unknown there's a perception that patients are small for age but current literature is mixed there's some studies that suggest patients can catch up to their peers in childhood or adulthood and other studies that suggest they stay small for age. But the current literature tends to group together all types of esophageal trisia which likely skews the data and so we have obviously a very high volume center and we're able to design well powered studies with very specific patient populations. So the primary outcome for both studies is wait for HC score growth charts are derived from population based data and as these scores the standard deviation from average so when I say this score for this talk I'm referring to wait for HC score so an average these score is zero and that corresponds to the 50th percentile of wait for a given age. We chose to follow wait for age these score because acute malnutrition results in a decline in wait whereas chronic malnutrition results in sending our short stature and wait is also most frequently collected in the hospital technically definitions of malnutrition do rely on multiple anthropometric measurements including height wait for length heads circumference but in principle definitions of malnutrition are these scores. So mild malnutrition is defined as a z score of negative one to negative two moderate malnutrition is negative two to negative three and then severe malnutrition is a z score of less than negative three. So my first study is focused on type C esophageal trisia infants who are repaired within the first week of life. They presented to Boston Children's from 2013 to 2019 and 46 patients met criteria for this study which was a retrospective review we collected these scores at birth discharge and every six months after surgery to three years when available and the goal of our study was to describe growth and feeding outcomes in these patients and potentially identify predictors for poor growth. So the majority of these patients were full term they were born at a median of 2.8 kilograms which corresponds to a z score of negative point seven. Agent operation was a median one to two days of life hospital length of say was median 20 days half of this was spent in the ICU these patients were only intubated for a median of two days in terms of complications there were two infants with a sapagelic one with a bloodstream infection and one with a UTI. So this is sort of a modified box and risk or plot showing growth over time as defined by z score for this cohort and you can see that at birth the median z score was below average and there is a dip down at discharge but using longitudinal median regression with discharge is the reference time point we did find statistically significant improvement out to three year follow up. And by three years obviously within the limitations of some nutrition we only had 14 patients at three years the median was essentially average weight for age c score. Using a multi variable regression we identified that discharge z score was the only variable associated with poor growth which we defined as a z score of less than negative one at one year. Length of stay days mechanically ventilated leak and backdral were not associated in terms of feeding outcomes these patients all did quite well so this is a bar chart showing the percent of patients who have full who are on full oral feeds that discharge and then out to three years. So about 70% of patients were on full oral feeds at discharge but of the 30% that had additional actual access half of them just had an NG tube which was removed by one year and of the five infants that did have surgical tubes still in place at one year four had G tubes they were all premature and three of the four required airway pecsies there was one patient that had a gastrogeogenoscomy tube that had a significantly more complicated course within a sapagelic after the the sapagel. The sapagel a treasure repair but also an additional anomaly to clue eight go which required other surgeries. So we do have to acknowledge that we're a high volume multidisciplinary center with a dedicated a sabagel a treasure team and we obviously have some referral bias due to being a tertiary care center. We noticed some variability in the follow up at three years so we had more data from our feeding tube and oral intake data. Then we did these scores at three years and that's likely because these patients tend to be followed by pediatricians after discharge for growth and really only see us for endoscopic surveillance. So one conclusion is that these patients that are discharged with lower Z scores should have closer follow up with us as well and be referred early to a dietician for nutritional rehab. But we did identify and demonstrate that this cohort is capable of achieving standard growth curves by three years old so we hope that practitioners will not assume that these patients will remain small for age. And the big picture message to pediatricians and families is that these patients typically have uncomplicated hospital courses with good feeding and growth outcomes. So I also got a puppy and that has been an adventure. So my second study is looking at long aposavidial atreasia patients specifically patients who presented from 2014 to 2020 for primary folgar process meaning no previous attempt to repair. So we identified patients met inclusion criteria for this study. We also wanted to describe growth but we collected significantly more granular data on the macro nutrient and nutritional management of these patients while in hospital. And again, we examined factors associated with growth at one year. So I know we're all familiar with the folgar process but just a quick review. It was developed by Dr. John Foker who was a cardiothoracic and pediatric surgeon from Minnesota and he helped Dr. Jennings establish our E.A. team. So the process involves tension associated esophageal growth and from left to right. The first stage of the folgar process is establishment of the traction system, which is typically done by thoracotomy occasionally thoracoscopically. Traction tutors are placed on both ends of the esophageal pouches so the cartoon here is of the lower pouch. And then this is a picture of a baby who's on traction. So the process relies on relatively long periods of paralysis, sedation, mechanical ventilation to avoid complications with the traction system. So the traction tutors from the upper pouch are coming out here from the lower pouch here. We use these little feeding tubes to tighten the tractions and pull the ends of the esophagus together. And this period where babies are paralyzed and sedated, we also don't weigh the babies and there are also other sort of complications to optimal nutritional management including clinically relevant. And edema and also sort of a presumed lower resting energy expenditure will paralyze. We monitor growth of the esophagus on serial x-rays and you can measure the gap between the clips. And then when the two ends of the esophagus are overlapping, the infant will undergo the second stage of the folgar process, which is creation of the anastomosis. And then to evaluate that that is healed well, the baby undergoes an esophageal and if that shows no evidence of leak, we're ready to start entral nutrition. So for this cohort, 40% were full term and the rest were some degree of pre-maturedity. The median birth weight was 2.3 kilograms, which corresponded to a median Z score of about negative one. Age at first operation for these infants is four months and the majority are referred from outside institutions. So these infants have a more complicated hospital course. They're total length of stays and median of about 80 days and half of that is in the ICU. They spend a median of 14 days on traction, 13 days paralyzed and 21 days intubated. And then in terms of complications, 15% of these patients have an esophageal leak requiring intervention and then the other complications as listed. So this is a similar graph, modified boxing whisker plot showing growth from birth to three years as described by Z scores. In this case, longitudinal regression showed no differences in Z scores over time. So the takeaway here is that we're able to maintain their Z scores in the hospital and to three years, although we only had four patients at three years, despite their complicated courses. And looking at predictors of change in Z score from admission to one year, the only variable associated with change in Z score was a lower Z score at admission. So this is a graph showing change on the y-axis and Z score admission on the x-axis. And you can see that the majority of patients, we maintain their Z score and they have a minimal change from admission to one year. And then we have to highlight the outliers. These patients present with very low Z scores between negative three and negative four, but improve quite significantly by three by two to three Z score units, which brings them almost to an average of an average Z score. A couple outliers here. So these patients start out with a good Z score of greater than zero, but declined over time. They did have more complicated courses. So one of the patients had in this off a geolique, one of bloodstream infection, and one four months after the focal process had a nishin and repair of a type B to official, which was identified incidentally. And so, you know, notably, duration of paralysis and ventilation, we're not associated as a geolique days on PN and days to full neutral, neutral nutrition, we're also not associated with change in Z score. So this is obviously, I'm not sure if you can even read it, but our nutrition strategy that we're hoping to publish, which is incredibly detailed, but the big picture is that we start these patients on PN early. While they're on traction, we're very careful with fluid balance and judicious use of diuretics. And then we transition them to enteral nutrition as soon as possible. But the take away is that we also identify these patients early and make sure that they are optimized prior to starting the focal process, and we typically don't start until they're over three and a half kilograms. Looking specifically at patients who presented with a Z score less than negative wanted admission, these patients did have a statistically significant improvement with a median of 1.3 Z score units. So there obviously were a couple patients that did not improve, but you can see visually that the vast majority did very well in this far as the median of this cohort at admission and then one year. In terms of feeding outcomes for these patients, 73% of them had a surgical tube still in place at one year, but only 60% were utilizing the access, which suggests that this is the time when they're transitioning away from the additional support of a feeding tube. So this time point was not a statistically significant decrease, it sort of approached significance with the p-value 0.06. It does likely reflect the time when we're starting to remove their tubes. And so it's that something we can look at closer in the future in terms of optimizing their nutrition and growth during this time. Again, we did have some limitations with this study as well, and it's though it's a relatively small cohort. It's the largest study to date, focused specifically on growth and long gap EA. We did include internal traction patients and patients who underwent minimally invasive vocal presses due to the crossover and subgroups. But our takeaways from this paper are that our nutrition algorithm allows us to identify malnourished patients and help them could catch up to their peers before starting the vocal process. And we're able to maintain patients these scores despite these complicated hospital courses. So obviously the vocal process is a very specific surgery and not all pediatric surgeons do the vocal process, but we hope that our nutrition algorithm and lessons from our experience will help to out. We hope that our program will help to optimize growth in other critically ill pediatric surgical patients. So I do want to take a minute to say some thank you. There are a lot of people that I owe a lot of gratitude to, but first Dr. Walden who took a chance on me. I spoke, I remember I was post call from a 24 hour trauma call. So I managed to I guess be coherent enough that he was willing to take a chance on me and also thank you so much for all your support in applying to pediatric surgery fellowship. Dr. Mehta who really got me off on the right foot with research. Doctors and day has who taught me a lot about effective and clinically relevant research and for being so available. And then lastly Jane who was really my research partner in crime who collected over 1000s e scores and without his nutritional wisdom and friendship. These papers definitely would not have come to life. So thank you. I just want to say thank you for all your hard work and to be honest, I had the least involvement in all of this when Dr. Katie called me and said he had a near finished product. It was pretty simple to make the decision to take you and it's not really a gamble. It was pretty much a sure thing. You came as build and better and I think you were exemplary in all your efforts and all your abilities and I think it truly is shown by all that you have accomplished. And you know, kudos to my colleagues both in the department and in the ICU who really have helped to kind of refine the research component of the critical care program. We have wonderful mentors, we have wonderful clinical projects and now with Dr. Maiden the outcome center through the ICU. I think it will continue to expand on the reach your opportunities that you have shown and that others will follow. So I wish you all the best. I pray that you get along with your junior fellow who I know is a difficult person, but I know you will be a success and best of luck. Thank you. I agree, Amanda, congratulations. You took a topic that I'd glance would feel non sexier, non standard for most research fellows, which would be like nutrition. I mean, critically old patients and you really made it look something that is esoteric and complex, a lot more digestible. I'm going to quiz everybody on z scores after this though, make sure you grab that concept that it matters so much and we really have very little data on this and it's been tremendous to see how we can help kids not just from a circle sample, but actually grow and and be healthy. And we can do better. I mean, I think what Amanda has shown us is that we are okay, but we can do a lot better with the nutritional follow up that we have in our kids and we've made a lot of changes. I'm going to be doing a lot of things to help to keep tracking this kids long term. Thanks for grants. I'm not going to talk about that time, but I do want to add my congratulations as well. We all knew Amanda how expert you were taking care of us because children and your application of the science of techniques that you've learned and applied it to a patient population that's burgeoning our institution. As you say, this is relatively new the way we care for it, but we have enormous family patients and we take it for granted, which is assumed that we're doing the best. But we need to improve this and as Dr. Smith says, you've now lit a huge foundation for following these patients long term to understand I'm actually visiting professor at UCSF right now for any netology. It's still early there, so I'm going to join you. And yesterday I made rounds in there in the ICU virtually in the head. What they call a long gap patient and it's all in the eyes of a holder who is long. And I asked how they're going to manage it and they were sort of just plan was different than our food be. It would have been a pretty you know screwed forward, but it's got a, you know, a pull and fix here. I mean, straight forward to minimize it. But we don't know that our ways better than what they're planning and your work is a huge foundation for continuous improvement. And it is on us as a department as a center to support the long term follow these patients because having three year data, you know, because the pediatrician sort of didn't send us the weight is not going to be good enough for the long term. We had to prove it. And so, so you laid their groundwork. You also have laid a tremendous groundwork for your career and we're pleased with any small part we might have made as an opportunity for you, but you did all the work and and really does know how lucky they are to have you basically pre trained. And they're going to have a great couple years. Congratulations to you and thanks to all of them. Sorry, we're a couple minutes over. Hester, thank you so much. Thank you.
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