All right, good morning everyone. Welcome to the Department of Surgery Grand Rounds. This morning's Grand Rounds is always a fun one for us. Surgery go fellows because we get to know our research fellows well over the course of time, but it has nothing to do with what they're actually here for, which is to do research with our faculty. And so we get to hear a little bit about what they've been doing, what their actual day job is, and we don't, what we don't see them overnight. So I look forward to hearing from our speakers today, who are Emily Shirei, who's a resident from B.I.D.M. from Beth Israel, working with the primary mentor of Dr. Fausa, Sarah Wang, who's a resident at Cleveland Clinic, who's primary mentor as Dr. Pewter, and Megan Chu from Case Western Reserve University, University of the University of Hospitals in Cleveland. So we have a Cleveland double header today, whose primary mentor is Dr. Kim and Dr. D'Mari. So our first speaker today is Dr. Emily Shirei. Okay. Okay. Thank you. Good morning, everyone. It's such a privilege to be here with you today. It's been a humbling experience to get to be a small part of this department for the last two years. I've had a total of three white coats so far, and what a privilege that one of those has been from Boston Children's, which is always a standard of excellence for me, is of interactive with the hospital, is both a local patient and a training passionate about pediatric surgery. It's hard to believe that we're now at the point of reflecting back at our time on the lab, and I want to convey my deepest thanks to everyone who has been a part of this incredible journey. Today, I am grateful for the opportunity to share some of the work that we've been doing in the FAUSA lab, endeavoring to expand the field of trans-amniotic fetal therapies. I owe much of the last three years to the fact that Dr. Fausa was willing to take a chance on me. I had not had significant experience working with stem cells or nucleic acid-based therapies, and certainly not in the prenatal setting, but the prospect of doing work that was so clinically relevant, yet at the same time, at the frontiers of what was known, was incredibly exciting to me, and he was willing to run with that enthusiasm. I was originally taught that amniotic fluid was simply an isolated fluid medium for the protection of the fetus, circulated through fetal swallowing in your nation. But my perspective changed when I began to read the work of Dr. Fausa in my predecessors in the lab, who demonstrated that trans-amniotic injection of a talligous fetal mizenchymal and hematopoietic stem cells led to a liable delivery of these cells to the placenta and ultimately to the fetal circulation. This breakthrough opened up the field of trans-amniotic prenatal therapies, as they realized that this amniotic fluid placental interface is biologically active, allowing for the passage of cells in large molecules such as mRNA and immunoglobulins. In the lab's initial experiments, they consistently saw hematogenous routing of these donor stem cells and the different disease model studied. Specifically, cells traffic to the placenta in large numbers, and from there they reach the fetal and even maternal circulations, as well as other annexes including the fetal bone marrow. Using the amniotic fluid as the gateway to the fetal circulation has allowed us to continue to target a great variety of fetal pathology. Initially focused on stem cell-based therapies, coin tracet, for spina bifida, cdh, and other congenital anomalies, applications of this principle of trans-amniotic delivery for cells in large molecules have exploded over the last few years, as we began to look at trans-amniotic fetal immunotherapy for infection and alloeimmune disease, as well as trans-amniotic nucleogasted therapy for protein replacement and prenatal vaccination. And I believe in the near future gene therapy. Well, unfortunately, we won't have time to cover all of the projects that have taken place during the last few years, including a clinical study that I was able to undertake in collaboration with the fetal care and surgery center under the mentorship of Dr. Buckmiller, as well as an editorial fellowship I'm currently completing with the American Medical Association Journal of Ethics. I am excited to be able to share with you some key projects, primarily with the immunotherapy and nucleic acid therapy arms of the Fousal Lab, in the lessons that they have taught me. Our lab's initial studies with trans-amniotic fetal immunotherapy revealed that traffic delivers IgG to the fetal circulation, with likely gestational membrane uptake followed by placental transport, combined with a modest amount of fetal swallowing. My first independent study looked at the pharma-cognetics following typical maternal IV administration of IV IgAs compared to trans-amniotic fetal immunotherapy in a rodent model. The pooled IV immunoglobulin G, or IV Ig, is now widely used for a number of immune disorders and parodatal infections, which impact both mother and fetish during pregnancy, such as immune thrombocytopenia and hemolytic disease of the fetus and newborn. Overall, IV Ig is considered a relatively safe, passive parodatal immunotherapy. However, serious untruth effects, including thrombotic events, amolysis, renal impairment, and anaphylaxis, have been reported in between 2-25% of pregnant people who receive IV Ig therapy each year, typically when they are receiving higher IV Ig doses. Traffic's theoretical benefit is based upon a creating a more direct route to the fetus, and thus likely having a better safety profile, given smaller doses are used, and there's relatively little entrance into the maternal circulation. Thus, the aim of the present study was to compare the pharma-cognetics of traffic versus standard maternal peripheral IV injection, of IV Ig, to determine whether traffic may be able to reduce maternal exposure to these immunoglobulins. Nine time-dated pregnant dams were randomly divided into two groups, based on how a suspension of human IgG was delivered to their fetuses. Either via a single tail vein injection in the mother at the standard 1 gram per kig dosing, or via intramiotic injection at a previously adjusted 15 makes per amel, either method performed on gestational day 18. Damage from rural groups were used in eyes at three different time points, either E19, E20 or E21, and then samples of placenta, blood, stomach aspirates, lean, thymus, and bone marrow were procured from a total of 85 surviving fetuses. Finally, maternal peripheral blood and placenta were also collected. Levels of human IgG were quantified by ELISA in all samples. Overall, there was no maternal mortality or premature labor in either group. Feetal survival in the traffic group was excellent at 98.4%. All procured samples showed presence of human IgG across all time points. Overall, human IgG levels were significantly higher, at almost all sample anatomical sites in the IV group compared to the traffic group. The exception was stomach aspirate, in which overall levels were comparable. Of levels of human IgG were also significantly higher in the IV group, in almost all pairwise time point comparisons. It's worth noting the dose of human IgG used in the IV group was based on standard 1 gram per kilogram of maternal weight used clinically. It resulted in a roughly 37 fold higher average dose of human IgG being delivered per dam in the IV group compared to the traffic group, which received the dosing of 15 makes per ML in our standard 50 microliter injections per fetus. The optimal or maximum safe dose of traffic remains to be determined. In part to account for the human IgG dosage difference, our study included an analysis using maternal serum IgG concentration as a correction factor for the human IgG concentration in each corresponding fetal or placental sample. When adjusted by maternal serum human IgG level, the opposite findings were noted as you can see here. Feetal human IgG levels were significantly and several fold higher at all sampled anatomical sites in the traffic group compared to the IV group. Overall, and in nearly every time point study. With this, we concluded that while maternal IV administration of immunoglobulins, amenable to placental transfer, may lead to higher absolute fetal levels of immunoglobulin than administration via traffic. When normalized by maternal serum levels or as our proxy of maternal exposure, it can be possible to increase the levels of immunoglobulins significantly higher fetal levels of those immunoglobulins. Thus, traffic may become a safer alternative for passive fetal immunotherapy in mothers with hypersensitivity to immunoglobulins of the G class. Perhaps just as important, I took away from this first project the literal blood, sweat, and tears that research can require. Moreover, I had my first taste of Dr. Bows' model of mentorship, giving me all the tools to succeed, and to take ownership of the search for knowledge, which was critical for my development as a scientist. Moving on to something totally different, we did a study to examine the duration of the immune response following trans-emniotic fetal mRNA vaccination, first against CMB. Its importance relates to the fact that CMV remains highly prevalent is still linked to significant perinatal morbidity and mortality. In fact, perinatal infection remains a chief cause of neonatal morbidity and mortality worldwide. Multiple routes of transmission allow a variety of pathogens to reach the fetus or neonate. CMV is one of the most common of such pathogens in the U.S., often leading to permanent disabilities. Infection in the very early neonatal period has a particularly bad prognosis. Antiviral treatment or passive immunization after exposure are limited benefits to management. Prevention of both congenital and early CMV is therefore imperative, though not yet available. mRNA vaccines have been shown experimentally to be more effective than protein-based vaccines for CMV prevention, especially when encoding for the CMV glycoprotein B-endolope antigen. My prior cofellow, Dr. Moskwitz-Ova, demonstrated that trans-emniotic fetal mRNA vaccination is a viable option for perinatal active immunization, using an mRNA vaccine against CMB in a rodent model. In that study, we learned that glycoprotein B-antigen, encoded by the mRNA injected, was being produced in the center of the placenta, likely after transport of the mRNA via the antnioplasental interface. We also detected the production of antibodies specifically against that antigen, and the vaccinated pups up to 14 days of life. In this study, we saw to determine whether that humoral immune response could persist for months into early postnatal life, as well as to examine whether a cellular immune response would also develop in the same model. A custom human CMV glycoprotein B-MRNA was commercially obtained. The final sequence consisted of 2,800 nucleotides, including proprietary and sequence optimization, which allowed us to enhance mRNA stability and decrease immunogenicness. To minimize degradation in vivo, the mRNA was encapsulated in a self-assembling, lipid and polymer composite known as LIPO polyplex. A high-degree of encapsulation was confirmed by fluorescence assay. After that, seven pregnant spring-dolli-dms underwent volume-match and triamniotic injections, and all 82 of their fetuses of a suspension of the encapsulated mRNA on gestational day 17. At three different pine points spanning one to three months after birth, serum levels of antigen-specific antibodies of the IgG class were measured by ELISA, and the T-cell response was assessed on spleen lymphocytes. More specifically, spleen lymphocytes were plated and incubated for five days, with either in-rich media or in-rich media, combined with the mRNA-encoded antigen. This was followed by a quantitative flow cytometry of cell culture supernaynants to assess T-cell response. TNF-Alpha and IL-6 were measured markers of the early phase, in which cytokines are produced by antigen-presenting cells to signal naive CD4-positive T-helper cells. IFN-GAMMA, IL-2, and GMC-SF were measured markers of later stages, characterized by a factor in immunomodulatory roles. There was no maternal mortality or premature labor in any group. Overall, postnatal survival was 44% with no significant differences between the groups. Antigen-specific antibodies were present in the serum of vaccinated pups at all three postnatal time points, albeit decreasing significantly from one to three months. Not shown here, but maternal serum samples also display the presence of these antigen-specific antibodies without significant differences between the time points. Here we have the flow cytometry data, and the dotted line is used to separate the non-challenge cells on the left from the challenge cells on the right. When compared with non-challenge cells, spleen lymphocytes from vaccinated pups showed significantly increased production of TNF-Alpha and IL-6 in response to antigen-specific challenge at nearly every postnatal time point. The same was noted for IFN-GAMMA, IL-2, and GMC-SF. Notably, cytokine production tended to increase with increasing postnatal age, and taking together this really suggested to us a maturing, adaptive T-helper cell type 1 response that was developing. Of course, a limitation of the study is that the animals were not challenged with CMB. Yet, first, our goal was to really determine whether there was an immune response for robust enough to warrant such a challenge. Notwithstanding this, we conclude that transamniotic fetal mRNA delivery of a human CMB antigen can induce a maturing, adaptive, cell mediated immune response, while also exhibiting continued antigen-specific immune glibular production, extending the early neonatal period in a healthier antigen model. Fetal mRNA vaccination via the transamniotic root may become a practical strategy for the prevention of perinatal infections. Just to briefly note, we've also recently completed a similar preclinical study for prenatal vaccination against Zika virus using a custom mRNA vaccine modeled after an mRNA vaccine that's an ongoing human clinical trials. When controlled by mRNA-free injections, Zika virus envelope antigen-specific IGG was significantly elevated in vaccinated pups from day of life 5 to day of life 16. Plenty of sites from vaccinated pups, as well as lymphocytes from inglinal lymph nodes, which are shown here, demonstrated significant increases in cytokines involved in the T-helper cell type 1 response against viruses, which is what we saw for CMB. These projects tested my new skills in the lab, teaching me the importance of collaboration, believing in what you're doing, asking timely questions, and not being afraid to shy away from hopeless cases or non-surgical pathology. I'm very excited to say there are many ongoing and future projects planned in the lab. Most excitingly for me is seeing Alex working on developing minimally invasive CRISPR gene therapy, so I'm really excited to watch that. And then also some wonderful preclinical work has now opened the door for clinical translation in our fetal center for treating, intruding, growth restriction. Finally, this is a little cathartic slide I wanted to make as an homage to some of those projects that didn't work out or were there were setbacks that taught me just as much as those other projects outlined. As Dr. Falsace says, there's value in the struggle and failure is part of the process, but he always commended my persistence, which was a great encouragement to me. He also taught me to be understated, let the work first speak for itself, value integrity above all, embrace professionalism, never lose your humanity or passion for the work, and remember PowerPoint should be viewed not read. Not to mention what I learned from the other giants here, taking care of children at their sickest and giving oneself totally to that cause. I've been very blessed by the opportunities this department has given me and these are values that I will take with me in my life as a clinician and my family and beyond. I just want to thank again, Dr. Falsace and the whole Falsace lab, particularly my co-fellows Alex and Camilla in our lab manager, Ena, as well as Dr. Buck Miller, Dr. Langer and the whole department for your support on this professional journey. Thank you. I don't know, are we doing questions now or at the end? Okay, perfect. So I guess I will call up Megan then or no Sarah, I think. All right, Dr. Wong. All right, morning everyone, I'm Sarah Wong and I will just focus on one of my projects today and the topic of my talk is a digestive cartridge improves survival and reduces intestinal injury in a mirroring model of necrotizing entrocolitis. These are my disclosures. So, neck as we all know is a life threatening inflammatory GI illness that primarily affects neonates and the pathophysiology is complex, but relates to inflammation, which can result in preparation and subsequent sets. And of course, we know that the mortality and morbidity rates of neck are quite high up to 60% in some cases and it's actually the most common surgical emergency among neonates. There are multiple risk factors for neck, including pre-morturity and formula feeding, the latter of which I'll be focusing on for this talk. The various preventive approaches to necrolisted here. All to say that the ones with highest evidence of efficacy and safety include breast milk feeding from the mother, as well as gentle, entrial feeding where breast milk is not available. So, we know from previous research that dietary fat composition can actually affect the severity of neck in mice. We know that fats provide more than just energy. They actually play important roles in our immune function, inflammation, and actual normal organ development as well. Yet pre-term infants are relatively lipase deficient compared to their term counterparts. Previous mirroring neck experiments involving an experiment where mice are given one of three different formulas, either standard fat, pre-digested fat, or very low fat showed that the mice who received either pre-digested or very low fat outperformed the ones that received the standard fat. And in conclusion, these researchers from Johns Hopkins concluded that nutritional formula containing pre-digested fat can actually overcome the lipase deficiency of the premature gut. And so, the purpose of this project really is to meet a nutritional need. We know that pre-term infants are relatively lipase deficient. They need dietary fat, important for their growth and development. Human breast milk, while it's great, is not always available. There may be many barriers to breastfeeding, including low milk supply, as well as the limited availability of donor breast milk. And so, commercial formula tries to fill that gap, but it does lack many of the protective factors such as lipase, antibodies, and hormones that are not available. And so, this all comes down to triglyceride digestion. So, in a very simplified fashion, this roll call, lipase enzyme helps to break down triglyceride fat into the glycerol backbone and the free fatty acid, which are easily absorbed. So, this is where the immobilized lipase cartridge comes in. This is an X-Vivo device, which connects in line with tube feeding systems. It is not a drug, it is not to be ingested. You could think of it as an X-Vivo stomach, if you will, whereby as the formula passes through the cartridge, the triglyceride fats are digested. And so, actually, in our lab, we're running a clinical trial in patients with short bowel syndrome, and to see if the immobilized lipase cartridge use can actually reduce parental nutrition dependence. And we thought, could this cartridge be utilized in necrotizing enterocolitis? And I like this picture of the mama bird, you know, eating the food and regurgitating for the baby birds, the pre-digested food. We hypothesize that pre-digestion of infant and total formula by the immobilized lipase cartridge, which is capable of hydrolyzing triglyceride fats into free fatty acids, will reduce mortality and disease of ferrity in our mirroring model of nec, in comparison to undigested or plain formula. In this model, C57, litter mate pups are randomized to one of three groups, either to remain with the mom as normal, healthy controls, or to undergo necrotizing enterocolitis induction. In the neck groups, mice are subject to BID hypoxia at 5% O2, as well as four times salio-orocovage feeding with commercial formula that has been mixed with liplopolysaccharide to rye from E. coli bacteria. Group 2 and 3, there are two of them. One of them receives, group 2 receives formula that has been digested through a placebo cartridge, and group 3 receives formula that has been processed by an immobilized lipase cartridge. And so all animals undergo this induction from day of life 4 through day of life 7, and on day of life 7, they are euthanized for collection of tissue. The outcomes measured included mortality rates, weights, clinical sickness scores, the appearance of the gut, and as well as the histology of the terminal ilium, which is most frequently impacted in the mouse model of nec. In terms of mortality, the breast fed milk mice, or the healthy controls rather, had 100% survival. In comparison, the neck plus ilc group had better survival than the neck plus placebo mice on days 3 and 4, albeit the differences were small, but statistically significant. In terms of weight trends, the healthy controls experience steady weight gain over the duration of the experiment, where the neck groups both experienced weight loss. However, you'll note that the neck plus placebo group, faired worse than the neck plus ilc group in terms of weight loss overall, especially on days 3 and 4. Next, we looked at the clinical sickness score and the macroscopic gut score. So these were systems developed by a pediatric surgeon, Dr. Gostozzani, out of University of Toronto. I guess he's moved to wash you now, but the clinical sickness score is ranging from zero, being least severe to 12, being most severe, looking at factors such as appearance and natural activity of the animal. And so the healthy or normal controls scored zero out of 12 in comparison to the neck plus placebo group, which scored seven out of 12, comparison to the neck plus ilc group that scored four out of 12. And these differences between the two neck groups were statistically significant. Next, we asked the two independent mass evaluators to also look at the appearance of the gut. And so this is really to examine the cut consistency, the coloring as well as the degree of dilation. The macroscopic gut score ranges from zero to six, six being most severe, and you'll note that the neck plus placebo group, faired much worse than the neck plus ilc group. And again, the healthy controls to no surprise, fair the best. So what do these animals look like? So these slides represent the images at time of laparotomy. So the healthy controls on the left had normal coloring as well as intact intestines throughout. Whereas the neck plus placebo in the middle, not only had extensive dilation throughout, but also dark areas of discoloration, transluciency and intestines were friable upon gentle manipulation for specimen collection. You'll see that neck plus ilc group was not entirely normal in appearance as there were areas of patchy dilation, but overall the bow was intact and found to be normal in its coloration. So what does the histology look like in the terminal? I am. We were specifically interested in the preservation of the villas architecture as of course our villi are the observed surface area for nutrients. And so the healthy controls on the left had largely normal villas architecture with no areas of perforation along the basement membrane. And the middle is the neck plus placebo group, which had extensive areas of entire destruction of the lie. Compared to the neck plus ilc group, which had preserved villas architecture, but you'll know the presence of these empty clear spaces. And these are remarked to be inflammatory evacuals according to the mass pathologist. So we asked the mass pathologist to actually quantify the next severity in these images. And so he utilized two different scoring systems, one looking more at acute inflammation markers and one looking at chronic inflammation markers. And so the healthy controls bear the best scoring zero out of four or 59 on both accounts. And the neck plus placebo group scored the worst. The neck ilc group had improved scores in comparison to the placebo group. And these differences were statistically significant. This is very much a work in progress, but what can we conclude from this? We know that neck is a serious illness affecting premature infants and that breast milk while protective is not always available. We know that fat digestion requires lipases, which are relatively deficient, improved term children, and that the fat composition of infant formula can actually contribute to the severity of neck. And in this experiment, we have demonstrated that predigestion of fat in enteral formula by the immobilized life piece cartridge reduced mortality and disease therapy compared to undigested formula in our mirroring model of neck. I like to thank my research team, especially to Dr. Pewter, my mentor for the last two years, and I'm happy to take any questions. Good morning, everyone. My name is Megan. I'm a second year research fellow in the surgical innovations lab under the mentorship of Dr. Deneerie, Dr. Kim and Dr. Lee. Thank you for the honor of of sharing our work today. I pick two projects to summarize the work I've done in the lab over the past two years. I'll cover my clinical work on medagortic syndrome and my innovations work on simply prone, a patient, pruning and positioning device. So first, long term outcomes of mesenteric artery growth and prove circulation or a magic procedure for medagortic syndrome. Medagortic syndrome is a rare condition in children and young adults characterized by the narrowing of the thoracic and or abdominal aorta, with frequent visceral and renal artery involvement causing renal vascular hypertension. Treatment includes medication, in vascular intervention and surgery, traditionally with patchy or aorta, aortic bypass with prosthetic graphs as shown in this video here. The mesenteric artery growth and prove circulation or magic procedure is a novel surgical technique using a tallicus vessel, the meandering mesenteric artery as shown here. As an as a for the graph bypass for your aorta, aortic bypass. This avoids potential long term complications associated with prosthetic graphs such as increased infection risk and eneerism for Asian as well as accommodate a child's growth into adulthood. The very first magic procedure was performed in 2012. Now over a decade from the first procedure, our study aim was to evaluate outcomes following magic in patients with mediordic syndrome. We performed a retrospective chart review on all patients at Boston Children's with MAS that underwent the magic procedure from 2012 to 2023. Recording data on patient demographics like pressure control, post-procedural imaging and complications. We found a cohort of 19 patients with a median age at five years, with a median age at surgery at 12 years and a median vessel involvement of four vessels. Our median follow up was 2.28 years and as you can see here, our longest follow up was almost 11 years. For our patient population, we had four patients with associated syndromes with neurofibromatosis one, which is not uncommon in mediordic syndrome. And when looking at an organ dysfunction, we had 12 patients with left ventricular hypertrophy and eight patients with evidence of renal dysfunction. Most operatively, we found that there was a significant decrease in type-retensive staging from latest follow up to preoperative and that there was a significant decrease in the number of antihypertensive use from the latest follow up to preoperative. At MMA graph growth over time, we found that there was a significant increase on average by 0.8 millimeters per year of the MMA graph diameter. This is better shown on post-procedural imaging. This is a series from the second magic patient. Panel A is immediately one week post-op. Panel B is at two years and panel C is at five years and you can see the growth throughout these panels. We did have patients that required post-operative indivascular and surgical interventions as listed with indications listed as well. We had one patient that required intraoperative intervention, which was a bowel resection from compromised blood flow to the bowel. The patient tolerated the procedure well and has not required any other subsequent intervention since. We had four patients that required surgical interventions with the following indications and seven patients with indivascular interventions with the following indications, most commonly for graft stenosis. These re interventions occurred within five years post-operatively and to note we have yet to have any magic patient since 2020 that requires an indivascular intervention. We also note that we did not have any associated graft infections or thrombotic complications. With that said, we conclude that magic patients had improved blood pressure control with lower number of anti-hypertenses as well as decrease in the hypertensive staging. The MMA graphs used for magic continue to show significant growth over time, growing with the patients. These results support the use of native vessel for aortic reconstruction in MAS patients and we and also that we're able to help MAS patients with the touch of magic. Future work includes development of the MAS nomenclature as we build our MAS database. Next, I'll transition to talk about simply from this is a patient pruning and positioning device that we are currently developing in the lab. So to start everything off we usually like to start with a clinical need and with the clinical need we have a patient. So here's our patient Ms Helen she's an 80 year old female presenting in respiratory distress and found to have pneumonia that's complicated by severe ARDS. She's been integrated in the ICU now for over a week and she's been escalating in therapies, protective lung ventilation and antibiotics, optimization of fluid status and even discussion of initiation of paralysis. The patient is not improving and the team has decided to prone the patient. However, like many days in the ICU it's at capacity. The nursing staff is also short staff today, one of the nurse's aides called out sick, a code is called on another patient while you're discussing your team regroups. It's already in the afternoon and after a few hours of discussion and trying to coordinate schedules the stars align and you're finally able to organize a group of seven providers to help prone Ms Helen. However, during the pruning process, one of her IV lines is pulled out and one of the nursing staff hurts her back during the during the pruning, prone positioning. And now in prone position, you notice that Ms Helen has developed a sacral to cubitis ulcer. This is a frustrating situation, which is not uncommon, especially during the COVID-19 pandemic. We know that pruning position pruning improves clinical outcomes and patients with critically ill patients with ARDS. However, the practice of pruning is labor intensive, cumbersome, and dangerous for both patients and providers. Currently, the standard of care is that we need 68 providers to prone one patient with this burrito technique shown on the right. We thought there must be a better way so we conceptualized the patient prone positioning device to improve this process. Our proposed solution is an inexpensive, inflatable device that facilitates pruning with half of the staff. Here is a very simple schematic of our initial concept. An inflatable wrap with low friction, it's easy to rotate and that has easy patient access. And for the interest of time, I'll briefly go over what Dr. Kuh presented last year from prototype 1 to prototype 3. But here is where we started. Our initial prototype was very simple, two attachable inflatable tubes. However, as you can see here, these inflables may be providing too much compression and leaving the patient in chendellinberg position prior to proponing. Now we took that information to prototype 2. And instead of a single lumen in each half of the device, we had three sections creating a cavity, allowing better Venus return. We also shortened this device for it to go only go to the knees to help balance with the head. And here is a video of this prototype in action. For everyone here. Here we see three providers pruning the patient already cutting that work first in half from this Helen. We then collaborated with a contract contract research organization Archimetic for further development in this iteration. Several key concepts were developed and implemented. We had an inner and outer layer for our device. The outer layer was a low pressure inner layer that was used for patient centering and cushioning to accommodate for different size patients. And the outer layer is a stiff rigid outer shell to provide an easy service for the patients to be prone to. I want to show you any more angles for the air. 12 more to self. And then I'll be okay. I'm sure you can tell why this one of our favorite videos. Great to hear. And this is this prototype was actually part of some preliminary user testing. And when we asked users to rate their experience with the prototype compared to existing methods. As you can see, there was a significant decrease in the course the force required to prone a patient. And they felt that it was significantly safer for the patients as well. Overall, we had very positive feedback on whether this would improve provider pruning experience. If it would improve patient care and if they would recommend this product to others and also use it in the clinical setting. So this leads all to our fourth prototype. We wanted to focus on creating a more rigid outer layer. And what we found was a drop stitch material. This is what inflatable stand-up paddle boards are made of. And it was originally developed for the military use for inflatable aircraft. So that troops could use this to fly out of enemy territory. Unfortunately, that never came to fruition. However, we are using this material now as it maintains its shape extremely well and is incredibly durable. Thus, we had an outer layer created with the drop stitch material. And here you can see that cylindrical shape, again reducing the force required to prone a patient. And as you can see here, we actually took our prototype number two as the inner layer to test this prototype initially with this new material. So we optimized the outer layer providing an easier pruning experience for Miss Helen. Our of the inner layer was not optimized. As you can see here, this is that new that prototype number for an action. Right, providing a much easier pruning process. As you can see, Dr. Kim has to hold up Dr. Dominguez head there. As we're shifting the patient very high off the bed. That led us to prototype number five. We created a new inner shell with floor bladders on each side to help offload the midline. And one sheet having extension of the two medial inner bladders for a head rest. And from the words of 2013 Drake, we started from the bottom now we're here. And I think it's always a good sign when your boss goes from red in the face to smiling. Now, so with that and our confidence and our inflatable design, we shifted our focus to the pump system. We began work creating a 10 valve pump system to accommodate our inflatable sheet design trying to create our system within a 18 by 24 inch platform. We drew inspiration from the V8 engine and created this initial build shown on the right. The programming and presets allowed us to test the other function of the device, which is the automated patient positioning, hoping to prevent Ms. Helen's sacred to cubitus ulcer. Here is that in action. With those successes, overall, we're very happy with our latest prototype, both in disposable and the pump system. The future work is focused on finalizing our updates to our pump system to ultimately perform more formative user testing. Concurrently, we're working on risk of augmentation for future FDA regulatory submission. Well, let's get back to our patient with our patient, Ms. Helen and with this device, we envision that the team would be able to prone Ms. Helen earlier more frequently with much less providers without IVs being pulled without workplace interaries. And when Ms. Helen is prone, we hope to not see a sequel to cube dis ulcer as she started her hospital stay with an automated patient positioning device. I just like to say that this product has a special place in my heart as we fully started to develop this concept at the beginning of my research time. And also because my grandmother, who passed away a year and a half ago after developing severe ARDS, wasn't able to benefit from this technology, but we hope that many future patients will. And as many patients already benefit from thousands of innovations here from the research done at Boston Children. I'd like to thank the department and Boston Children for this opportunity and the privilege to be a part of this space. I also want to just take a little bit of time at the end to acknowledge and thank my colleagues, Donna, Sarah and Nina and Luke and Jeff is part of the surgical innovations lab, as well as the practice and NAS teams that have worked with me. And I want to thank my mentors, Dr. Kim, Dr. Demiri and Dr. Lee for their wisdom, guidance and humor during these past two years. They have changed and inspired me and are who I want to be when I grow up. Thank you so much for your time and attention and I'm happy to take any question. Wow. And Lee, Megan, Sarah, what a treat for us to see a trio of the range from molecular seemingly very basic to the very clinical all with visible translational opportunities in what some may have seen incredibly futuristic. But now as science has advanced, potentially applicable, all potentially incredibly impactful and I'm proud that our department has been able to support your development and and you're helping our your mentors develop it. So two two ways street they accomplished where they accomplished because of which we provide them. We have a little bit I have questions for all of you which I don't want to dominate so I will ask them all privately, but some comments from mentors and others who may have questions. It's been a privilege having this great group of fellows over the last couple of years. What you saw today is a relatively small excerpt of the work they've done and you're going to see someone a couple of weeks. They've also represented us very competently and proudly at multiple meetings locally nationally and internationally. Just a word, we forward on Emily for whom I was more directly responsible. Her projects were very involved. They involved they required a steep learning curve particularly for young surgical resident. A lot of attention to detail a lot of patients in the face of frustrations and a lot of work after hours. She should be rewarded by the fact that besides her academic achievements I think this will have significant impact. Her work will have significant impact to public health in light of the significant burden that perinecline infections still represent. Dr. Peter could not be here unfortunately so just briefly mentioned that as far as Sarah goes you should all remember the many notices of awards she's received lately which speak to the quality of the work she's done. He's going to speak a little more about you during the graduation in a couple of weeks. And I'm sure that Dr. the Megan's matters is going to speak a little bit. Congrats to everyone. Great work over the last couple of years and we all appreciate all your efforts. Megan, great, great job. This is not easy work and you did a fabulous job organizing the team keeping us on task. And getting through all these part of the types. Thanks for not sharing my full video of that near that experience I had. And you'll notice I never got back into the device again. But I did put Steve in there and think I'm glad you showed that picture. Best of love to all of you as you return and best you know and keep in touch. I'll see you soon. Thank all three of you for being so to join a work with and thank you for trusting all of us with your growth these last two years. Megan, fantastic work. I think we should you know rename the innovation fellowship the leadership fellowship because that's really one of the hardest things about is like you there's all these different people, all these different projects and you're jumping in and trying to lead the same thing fantastic job of doing that. Your creativity and figure outside the box. I don't know if anyone knows but maybe when when you when she was overseas to see families have you found a company to help us with a device and other device just on her own. So things like that are just over the box. So anyways, thank you. It's been a joy to work with you. Well, thank you to all three of you. It's been just a delight to work clinically. I'm always a grateful to Dario every year for letting me quote borrow some of his fellows with all of the free time that he gives them for a few clinical projects. But a special thank you to Emily was absolutely delightful to work on the fetal projects together and I would say Emily was the only president leading this project she had to work with for attendings that is not easy. So thank you for doing that gracefully for being very for cities with the work and for your elegant presentations all the very best. Okay, I do have time. Those questions. I'm going to admit my naive it was not ignorance here. The concept of I know you didn't do. You didn't infect CMV in in the. I mean, I'm not going to treat this, but demonstrated the immune response possible. And now in the last few years, we can see the real potential of the ability of. The therapy with mRNA, um, while the other treatments are happening. So, you know, vaccination is usually something we think of being broadly administered across populations at risk. How is it predictable who's at risk for CMV and how would you decide who to do this or there's something that will what happened and. For all pregnancies. Thank you, Dr. Fisherman for that question. That's a great question. And actually, I was sort of shocked to find out when I was looking into this. That I think it's somewhere between like 60 to 80% of people will ultimately be infected with CMV during their lifetime. And for most adults, especially, you know, immunocompetent adults, they're typically asymptomatic. And so that's sort of what makes this so insidious in the prenatal setting. Because a lot of people don't know if they've been exposed in the past. And really your highest risk for congenital CMV is if this you actually contract CMV for the first time during the pregnancy and specifically the first trimester. But really what we we were thinking about you, the clinical translation of this. And we would ultimately, I think you could imagine a scenario where this could become a universally recommended vaccine. But that we're very far off from that at this point, still in preclinical studies. But certainly we would want to start with those women who are at most high risk for themselves and for their fetus for developing congenital CMV. And we know that women who have children who are less than three years old are at the highest risk for this. And that is because there's just in the toddler daycare population, we already know that's kind of a petri dish situation. But they have a very high risk of having CMV shedding in their saliva. And so that's those are women who are identified as being at highest risk. Also those women who are immunocompromised or if there's a specific geographic region where CMV is more in-demand. So those are kind of the populations that we're envisioning for this first. I just want to echo Steve's sentiments to all three of you. It's so impressive to sit here and watch what you've done over the course of your two years. And the fact that you can see where this really impacts the clinical realm. The follow-up question Emily for you is as a former transplanter. And just in terms of your instilling those vaccinations, timing and the notion of fetal tolerance. And obviously you're inducing an immune response. Does that have to do with the timing or is it the specifics of your antigen presentation? I really appreciate that question Dr. Wilhae. Emily, I was going to say the current human clinical trials that are being performed for CMV vaccination and mRNA vaccination are a lot of the transplants population. Because we haven't gotten to the fetal realm yet. But that is definitely at risk population that they're considering as one patient type that would meet inclusion criteria for this vaccine. As far as when the timing for vaccination to be totally honest, we don't really know yet. That's not known because with the short gestation in the rodent model, it's a little bit tricky to translate. So we envision the next step would probably be doing this kind of work in larger animal models that have a longer gestational period that you can kind of map a little bit more closely to the human situation. But that being said, most likely the timing for this would be partially constrained by the timing when you can safely perform amniocentesis. So we're thinking probably second or third trimester. And that actually works out well because the fetal immune system, certainly people like to take advantage of the tolerance of that environment. But we know that by end of second or early third trimester, you're starting to be able to elicit more of an immune response because that fetal immune system is more mature. So probably this would be more applicable to later gestation pregnancies. Yeah, I hope that answers the question. Well, Dr. Will has a former transplanter and as we're all let's going through a move, exercise our offices and some emotional catharsis of going through all papers. I came across something probably only Dr. Files will recall. Dr. Farmer, fetal neck, model nutrition, enthusiasm and came across some of those data that regret having left behind with some of your predecessors want to go. We're now see your 50 and it's clear that what goes in the premature stressed bowel contributes to the rest. We're making image for bowel do things that's not ready to do. And it's clear and you've demonstrated so beautifully that modifying what goes in to make a difference. And the human production of breast milk Darwin made that happen right. What is it that you can do what you do at the point of entry like processing just before the formula goes in and the formula companies can't do that when they manufacture it in mass production. And if they can't or don't or it's not commercially feasible, one of the practicalities of the expense of manufacturing this which seems like kind of a no brainer the way you present. Thanks for the question, Dr. Fischmann. Yeah, it's preliminary work, but it is exciting results. And to answer your question, the reason why the companies are unable to initially digest the triglycerides before delivery is because digesting the triglycerides in advance would result in the rapid oxidation of the free fatty acids in the formula. And so to put it briefly, when you go into a fish market and you smell that fish, you smell that's the smell of oxidation of fats. And so it's important, especially for a fat digestion to do it at the point of care. And so what I've learned the last couple of years is while collaborating with companies can result in really exciting data and projects, you know, there are limitations of collaboration as well. And so these are designed to be single use cartridges. We are running clinical trials and providing them for free for those patients in the trials, but as for the commercial applications that is to be determined. And we hope to do more of the snack work, hopefully in maybe larger animal models in order to see if the translatability continues to be the case because obviously the mirroring model is involving mice which are, you know, different. Not only in their physiology to humans, but also in their microbiome. And so hopefully that answers your question. Well, great job again to all three of you. Thank you for those great presentations and for your work with us. Sarah, a similar question. Your controls were breastfed or breast milk fed. Did you have controls or formula fed also? And have you done comparisons between different types of formula? You know, clinically one of the things we do to mitigate some of this issues we give. Elemental formulas that have higher MCT component to them. So I'm wondering if comparisons to those kinds of things might sort of further bolster your findings to demonstrate a significant improvement from the cartridge. Yeah, thanks for your question, Dr. Modi. In short, yes, we have included other groups in our experiment, but for the sake of time, I did not include that data. We did test using formula only without the necrotizing and recalitis condition. So just simple formula, the mice are in an incubator. And they did well. They did much better than both of the neck groups, which we could expect because they're not subject to hypoxia and the LPS exposure. But what we would love to do next is actually to run breast milk collected from the mice themselves through the same cartridge and to see if we can have the same results. So stay tuned. And time for one question to address all for you. The innovation fellowship, I think people can see little pieces is designed to give experience with concept with design with prototyping, working with engineers, and then proof of concept and then commercialization. And you've actually been involved in all of those stages. I think everybody in the room could appreciate because we've all participated in pruning patients, the simplicity of this. And it even looked. Or we can see how practical this and those of us who have been within the donut know how well works. But then you showed the very sophisticated pump with the VA engine and all this and and and wow, we can make this device now in the rotisserie, but actually the wave machine to accomplish a second goal, same device. But it's more complicated bicycle pump. So what have you learned and what do you imagine about the commercial practicality of what I imagine is a disposable device with a multi use pump and you know one sort of plastic and one very highly engineered. And I think that's a great question and it's definitely a testament to the collaborative nature of the innovation fellowship. So like you said, we have a lot of engineering consultants as well as business consultants that help us with all these different aspects of innovation and commercialization, which is not really taught. And there's something that we as innovations fellow kind of learn and pick up and are able to have experts in the field come and talk to us and collaborate with us. So it is a very different approach when you're looking at the disposable part of the device, which is kind of like a for a black of a better term, like a simple, stupid solution to an existing problem. And then you have the pump system, which theoretically is is a simple is a simple component, but there's a lot of different working parts. So with the pump system, we had to have a lot of input from our engineering consultant, as well as just the amount of research and time before the first prototype was even made with planning and looking at different user interface, looking at different parts and materials. And really, I think is a testament to Luke our engineering consultant, he really did the large majority of that. And that is part of his specialty. And so Sarah and I were have a great opportunity to learn from him during that process and provide input as we could. But I think which was very different than our initial disposable prototype testing and learning and development, we were much more a part of designing that and creating different different aspects or components of that to address certain specific patient related issues. So we had a lot of clinical background that we can speak to. So this very engineering based product, of course, we rely it will heavily on our engineering consultant. And then with the disposal product, very clinically, very clinically based, which is something that we discussed a lot in lab. And as you can see, had multiple iterations of prototypes from our inputs. Thank you. Or you described as simple stupid solutions. Lots of things seem simple after somebody else thinks of them. And like the magic itself, you know, what did I think of that? Right? And then you have to go through all the stages you described to make them happen. Well, we are definitely at time. I think we can all see how incredibly fortunate we are at Boston Children's to, to attract such incredibly talented driven motivated people with fact, members who support them. And with resources to make that happen in the future is obviously incredibly bright. And we're so honored and humbled to be able to participate in that. We all are your champions for life and look forward to your ongoing development. Thank you all and congratulations.
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