Good morning, everyone. Welcome to this morning's grand rounds, which will be four of our research fellows who will be presenting their work. I'll just introduce all four of them altogether and then they can come up each and see plans for their presentations. The first is Nicole Symbac, Nicole completed medical school at Sydney Kimmel Medical College at Thomas Jefferson. We went on to internship and residency just down the road from here at Boston Medical Center. We eventually lured her down here for her critical care fellowship that was about three years ago. And since then she's been since completing her fellowship. She's been working with doctors, Zeleska, Sticky, DiMarie, and Buck Miller on research surgery focus on CDH. She's published on the history of the disease as well as variations in long term outcomes. We've also worked with doctors, Zeleska, on something that many of us know and love which is the ECMO SAM, which we've come to know during our ECMO CRM sessions. She also found time in all this to earn her MPH from the Harvard School of Public Health with a focus on clinical effectiveness. And we've also enjoyed continuing to have her in her clinical role, which is on the weekends helping cover the ICU, which is always a welcome sight to the surgical fellow in morning rounds. And even spending a month with us recently on service helping us with case coverage and getting back on the swing of things clinically. The next fellow who you'll hear from is Tom Purge. Tom completed medical school at the Medical College of Wisconsin in Milwaukee. He then went on to residency across the street from here also at Beth Israel, D.K.S., and completed two years of residency before coming to Children's to join Dr. Puders Lab during his time in the lab. Tom really has excelled in basic and translational science. Dr. Puders known for his high expectations of his research fellows. And Tom, I think, has thrived in that environment. His work has focused on Brenner and nutrition associated liver injury and molecular mechanisms of lung injury and development. He has earned awards for this exceptional work recently, the basic science oral presentation award at the Massachusetts chapter of the American College of Surgeons. The next fellow is Emily Ness. Emily completed medical school at Texas Tech and then went on to residency at Baylor's Scott and White Medical Center at Texas A&M. She completed the first three years of residency and then joined us here in Boston as a critical care fellow. She also recently finished her Masters in Public Health from the Harvard School of Public Health with a focus on global health. She spent her research time here primarily working with Dr. Jacksick and the Center for Advanced and Testinal Rehabilitation. Her work there focused on the management of outcomes of intestinal failure, necker tizing on her colitis and extremely little birth weight and prematurely. She also, like Nicole, stayed very clinically active in the MSI CU in NICU and serving similarly as a walk-on face on the weekends, staying very busy with them and the ICU helping take care of our patients there. And the final presenter will be Claire Austin Taghill, Claire graduated from medical school at Oregon Health and Science University and then came across the country to Providence and Brown University for her general surgery residency. She completed two years before coming here for her research during which time she's been the VASPR and Amelie Center Pediatric Surgery Research Fellow. During that time she made really important contributions to our understanding of congenital of angiomas and both our venous malformations. She also done some clinical research in colorectus surgery with Dr. Dickey and Nandavada. And then one of the more interesting things that I came across was her development of novel anesthetic agents in the department of anesthesiology, critical care and pain medicine. So, and not only has she been a remarkably productive researcher, but she also has grown to be a really key member of the VASPR and Amelie's clinic who I have no doubt will miss her when she returns to Oregon for her clinical time. So with that, I'd like to invite Nicole to come up and start her presentation. Good morning, everybody. For those of you who I haven't had the pleasure of meeting, my name's Nicole and I've completed three years here, the first of which was in the ICU and then the latter two years completing CDH research. And during this presentation, I'm really going to give you a very brief overview of some of our largest projects we've worked on and then some personal reflections that I've had over the past three years. And so everybody in this room knows that CDH is a really complicated disease and it still affects a large number of patients. About 25% of our patients are born prematurely. The range of pulmonary hypertension is from 5 to 60% at our institution, about 30% utilized ECMO. And the survival across the world really ranges from 30 to 90%, depending on the center that you're cared for. And all of this is to say is that CDH really requires multidisciplinary and dedicated care to help improve outcomes in survival. And so this is where I came in. In 2021, this is my first day here and this binder I'm holding was created by Catherine and Dr. Weldon handed to me and it's 200 single spaced pages about how to live in this hospital, mostly about how to interact with the NICU and the PICU and the surgical services. And this actually proved to be incredibly useful. During my ICU time I served as a clinical liaison between these three teams and then during my research time because the care of a CDH patient really spans these three departments. I was able to have multiple mentors in these facilities to help me work with my research which was very rewarding. And so this is an overview of the number of projects that I've completed and I'm going to go through a number of these in the context of a clinical case to really show you how the care of a CDH patient progresses in this hospital. And so as I mentioned before, about 25% of patients are born prematurely with CDH which is higher than a patient who doesn't have a congenital anomaly. And something we think about when a premature patient is born is how their physiology varies from a term neonate. Specifically in what therapies we can offer them, it to help manage this physiology. Because after a premature neonate is born, I'm sure all of you have been in this situation. The question everyone wants to know is can we put them on ECMO to bridge them to repair and to bridge them to growing. And in the new neonatology literature, there's a lot of consideration of when we should cannulate these children and if we should cannulate them. The current ECLS guidelines really have strict cut-offs based on gestational age and weight for cannulation. But in the current age of neonatology, both in medical management of premature infants, as well as management of ECMO, we've really made great strides in how we're able to manage the morbidity and survival. And so we wanted to look at our population of patients and see how we were doing. And so what we found was on a simple univariate analysis, there of course is a difference in survival between 67 and 80 percent between pre-term and term infants. But after we control for a number of factors, including cardiac anomalies and defect type, what we found is that prematurity alone at our center is not predictive of survival. And equally important, we found that intracranial hemorrhage, which is known to be a significant morbidity in premature patients, really doesn't differ between our pre-term and term populations here. And equally significant is pulmonary hypertension, which is a marker of severity in these patients, is actually worse in patients who are termed compared to our pre-term patients. And we use this information when we're considering ECMO candidacy for our neonates here, and it's really contributed to this larger body of literature in the neonatal population. And so now we have this premature patient, and like 30 percent of our patients here, they went on ECMO for management of their severe CDH. And so each day we round, it's all you've been on ICU rounds, and we always talk about the markers of homolysis and billy rubins. And we think about, you know, the billy rubins are in the 20s. Okay, we'll check it tomorrow, now they're in the 30s. What do we do? And so the biggest intervention when we're managing homolysis in these patients is to actually exchange the ECMO circuit. However, this can cause severe cardiovascular circummise in these patients, as you've probably all witnessed or been a part of. And so we really wanted to know, can we do something else to manage this physiology aside from a neckmost circuit change? And this is where therapeutic plasma exchange entered. And so TPE is a therapy that's used in a number of other immunological diseases in pediatric patients. And we thought, well, maybe we could use this to help control the hyperbibylubinemia in these patients, and to obviate having to do these circuit changes. So with the help of the transfusion medicine team, we were able to offer TPE to a number of patients here, which is really the first that has been done in a series of ECMO patients. And what we found is that with each successive course of TPE, the hyperbibylubinemia improved, and we really felt that this was helping to prevent having new do circuit changes on these patients, and really preventing them from having increased morbidity associated with our ECMO course. And equally important is that their homolysis got better, so their plasma for hemoglobin went down and their fibrogen went up. And now we've continued to use this therapy for our patients here. And what this project really taught me is that following the physiology of your patient is what medicine and science is about. And so that's what we did here. We thought about a problem we had and a therapy that existed, and we were able to apply it to this patient population. And we continued to do this here at our center. And so now we've gone through the labs and we've made it to the imaging. And so we're looking at this image and we're wondering in this left-sided CDH, do we really care that the media's thinam is completely on the right side of the chest? Doesn't matter. And we do think it does matter. And so because of this, we've actually started broning our patients on ECMO in an effort to move the media's thinam off of that right-sided lung, which we think contributes to the majority of pulmonary function in these patients and recovery. And so we wanted to figure out a way to track and measure this over time. And so we created something called the media's thinam shift index. And this was completed at the day of cannulation, the day of CDH repair, and then the day of decannulation. And you can see over time how the ECMO cannula are moving from the right side to the left side of the chest. And the theory is that the lower the MSI or the further that the media's thinam is pushed onto that good lung, the less able that lung is to recover and contribute to pulmonary recovery in the future. And so we think this was associated with the worse outcome. And that's what we found was that patients who were initially cannulated with a significant portion of their media's thinam compressing their right lung did worse. Their survival was poor compared to patients who were able to shift off that good lung over time. Not only that, we were able to show that this new index predicted survival with a better sensitivity and specificity than the known marker of ODE-LHR. And so now we continue to prone these patients and we're working on developing a protocol with the PICU and the NICU on how we're able to measure this over time in a prospective manner. So I've talked about how the mortality varies considerably in this patient, so does the morbidity. So a lot of these patients, as you all know, have feeding difficulties, ventilator dependence and a number of other anomalies that need to be managed. And so we wanted to know, is in the country looking at G-Tube's trakes, fund implications and hernias, what is everyone doing and how do we standardize it or should we standardize it? And so we do this, we use the FIS database to look at a very large sample of CDH patients, which not only includes CDH specialized centers, but all pediatric hospitals in the United States. And what we found is that the region that you live is associated with the number of surgeries you have. And this is after controlling for a number of markers of severity. So one might say, well, of course, this hospital sees more sick patients, so they do more surgeries. But what we found is that actually isn't true. So we controlled for pre-matured comorbidities, anomalies, ECMO use, pulmonary hypertension rates. And what we found was where you lived matter. And so this really shows that the way that these patients is are managed varies incredibly and contributes to how we counsel patients prenatally. And so now our pre-mature patient was cannulated. They got plasma pharesis for their high-billy rubins. They were on ECMO. We proned them. Two months later, they were ready to go home. And they got a G2 because they didn't feed very well. And so where are they? Well, they're probably in our very comprehensive multidisciplinary long-term clinic, fortunately. But we wanted to know how many of our patients are coming back. And in the patients that aren't coming back, why aren't they coming back and how do we find them? And so what we found was we do a really good job of getting our patients to come back to clinic. But expectantly, we saw that patients with smaller defects, which are a marker of less severe disease, came back less. And that makes sense because patients with type D defects or type C defects who are on therapies for pulmonary hypertension, use oxygen or diuretics, they come back to clinic more than patients who had smaller defects. But what we found was that patients who used public insurance or were of specific races actually came back to clinic less often than other patients. And what this has done is helped to inform policies about how our patients are followed, specifically with nurse practitioners, case managers, and social workers as they transition from the out to inpatient to the outpatient setting. Through all of this, ICU research and work, the most rewarding and motivating part has always been the patients. These are three of our CDH survivors, Scarlett, Mila, and Nolan, who have really taught me so much about what it is to be a physician and a researcher. And turning these amorphous research years into examining clinical problems that I witnessed during my ICU time has been so incredibly rewarding. And what I've been shown is that there's a lot more to do, which I continue to find incredibly motivating for future research and clinical work. Thank you to everybody who has shown their time and energy with helping me turn this person into this person through clinical skills and surgical expertise of this department. I specifically want to thank Dr. Swellden, Zaleskis, Dickey, Demiri, and Buckmiller, who have all shown me not only incredible patients, but by example with their sincere dedication to taking care of this patient population. To a fantastic group of research fellows, the pediatric surgery fellows, who have shown me significant support as well as friendship. And finally to my family, who as always has unconditionally supported me throughout these endeavors. Thank you. All right. Hello, everyone. My name is Tom. I was in Dr. Puders Lab. I did many projects during my time in Dr. Puders Lab, and I'm going to be talking about one of them called inhibition of run related transcription factor one, improved pulmonary function and structure in a marine model of gliomisin-induced pulmonary fibrosis. There's one disclosure related to this project. Pulmonary fibrosis is a devastating and fatal lung disease. It has a five-year survival of only 20% after diagnosis, and that is despite FDA-approved therapeutics. It has risen in prevalence after COVID. It's a common cause of lung transplantation and surgical complications. One related transcription factor one, or run X1, is a transcription factor that was initially discovered because of its role in the differentiation of hematopoemid stem cells during development. It was also found to be a master regulator of the epithelial to mesenchymal transition, be a transforming growth factor beta, promoting lung fibrosis. Pro-247429 is a small molecule inhibitor of run X1 and it's of immediate translational interests. It was tested and phased to clinical trials for its potential effect as a tattentagonist in the treatment of AIDS patients infected with HIV. The proposed mechanism of run X1 is complicated in terms of its role in fibrosis, but in summary the pathway involves TGF beta and TNF alpha. Ligand binding to TGF beta and TNF alpha leads to an increase in signaling through SMAD and junk pathways. After phosphorylation, these pathways increase AP1, which leads to an increase in run X1 expression. This potentiates the junk pathway and ultimately leads to an increase in TNF alpha and TGF beta. Our group has previously performed a study on the inhibition of run X1 for pulmonary fibrosis. Treatment of mice with Ro-24 prevented histologic fibrosis and attenuated markers of fibrosis on Western blotting. However, no functional or human studies were done as part of this work. We hypothesized that pulmonary fibrosis in humans is also associated with an upregulation of run X1 and that treatment with Ro-24 will prevent fibrosis and improve pulmonary function in a myriad model of gliomisin-induced pulmonary fibrosis. First, we aim to identify run X1 in human disease. Slides were obtained from normal patients and patients with pulmonary fibrosis. Slides were rehydrated under one antigen retrieval. We're incubated with primary and secondary antibody and then we're stained with DAPI, which stains the cell nuclei. On the left, Mason's trichrome-state slides demonstrate an increase in blue in the disease subjects which stains for collagen. On the right, patients with disease had a corresponding increase in run X1 denoted by the red staining. The blue is staining for DAPI. Next we start to establish a murine model with pulmonary fibrosis and impaired pulmonary function. C57 adult mice were obtained at 8 to 10 weeks of age. They underwent direct tracheal installation with one of two doses of gliomisin or isovolumetric saline. 14 days later, they were sacrificed for analysis of lung function and lung histologic analysis. mice that received the higher dose of gliomisin had a decrease in compliance, an increase in elastins, and an overall increase in work of breathing. This was significant at the higher zero point unit per kilogram dose of gliomisin. Unifluorescence was performed using tissue from this experiment. Mason had received the higher dose of gliomisin had a clear increase in red, which is staining again for the run X1 transcription factor. This is mirroring the human immunofluorescence staining. Again the blue here is staining for DAPI, which stains the cell nuclei. Finally, we wanted to evaluate the efficacy of row 24. mice were obtained again between 8 to 10 weeks of age. They were pre-treated via oral gavage with one of two different doses of gliomisin or vehicle, which is methylcellulose. After seven days of pre-treatment, they underwent direct tracheal installation with either gliomisin, which caused the pulmonary fibrosis or staling. After additional 21 days of every other day waits and daily oral gavage, they were sacrificed for lung function analysis and analysis of histology. On the left, animals receiving gliomisin experienced a weight drop that peaked at day 18, treatment with row 24 significantly improved weight loss at the 18-day time point, which was no different from the control animals. In each graph, the far left is the control. Animals receiving gliomisin had an increase in elastense and work of breathing, and treatment with the higher dose of row 24 demonstrated a normalization of elastense and work of breathing, and this effect clearly occurred in a dose response manner. The same was true for the compliance and the resistance. Significant changes in compliance and resistance in disease subjects compared to controls that was improved with the higher dose of row 24. Histologic analysis was also performed. Slides were seen with hematoxylin and eosin, which is demonstrated on the top, and Mason's trichrome, which stains the collagen blue, which is demonstrated on the lower portion. Phybrosis scoring was performed and demonstrated a decrease in fibrosis in animals treated with row 24 at the higher 150-mix per cake dose. Next, we repeated this experiment adding two additional groups, which used the clinical standards that treat fibrosis, perphenidone, and intetinib, and we also added an additional endpoint, the treadmill exercise tolerance testing, to evaluate pulmonary function. I said underwent row 24 treatment had a significant improvement in exercise tolerance, and this was compared to both the disease group and the clinical comparisons with the intetinib and perphenidone drugs. Long function analysis was performed in this cohort. There was an improvement in the row 24 group from the disease group, but no change from the intetinib or perphenidone clinical standard drugs. This was also true for the compliance and the resistance. In conclusion, Runx1 is up-regulated in fibradocument lung tissue, targeting Runx1 in a myriad model pulmonary fibrosis, improves weight loss, lung function, and structure. Row 24 improves exercise tolerance in mice compared to the currently used clinical standards, and row 24 demonstrated safety and face-to-clinical trials in humans and has translational potential. Several studies are needed in humans to investigate the potential benefit of Runx1 in hibition in this progressive, often fatal lung disease. I like to thank the study team, which is our collaborators at MGH as well for assistance in this project. Of course, I'd like to thank my mentor, Dr. Puter, who's done an incredible job teaching me all of this during the past three years. I've learned a lot, including how to move VPN boxes across the street, and many lung techniques as well that have been really critical in my learning here. I worked with great people and feel lucky to have had these experiences, obviously great mentorship, and this is the team. There's additional people I like to thank, Dr. Kathleen Garrow, who's not in this picture, and then, of course, Amy Pann, our lab technologist, and all the co-fellows I've worked with. I've had a great experience, and of course, I'd like to thank my family and my parents and my fiancee as well, who are here. Happy to talk to you again, questions. Hello, everyone. As you know, I'm one of the research fellows that works with Dr. Jackson and Dr. Modi. I've had the opportunity to work on several projects during my time here. However, I will only focus on these three of Vaughn Project, a care project, and a long-term project that allows my future career goals. I will begin by starting with our project, Predictors of Motality, and very low birth weight neonates with congenital diaphragmatic hernia, which I became interested in after my time in the ICU. We all know what CDH is and how it's associated with respiratory failure and pulmonary hypertension. The overall reported mortality for CDH ranges widely from 21 to 48 percent. Verilo birth weight neonates with CDH have a potentially worse prognosis due to additional underlying pulmonary disease and limitations on the use of some therapies such as ECMO. In your discussion with the congenital diaphragmatic hernia study group, we discovered that there is a gap in the literature and the morbidity and mortality of very low birth weight neonates with CDH. Because of this limited data, this study aimed to quantify and determine the predictors of mortality and very low birth weight neonates with CDH. Data were prospectively collected from all VLBW live-core neonates from 2011 to 2021 enrolled in the Vermont Oxford Network VLBW database. The primary outcome of interest was in hospital mortality and to account for possible intention to treat bias, a subgroup analysis was performed on neonates who were inspected in the delivery room or mechanically ventilated as an indicator of active treatment. Adjusted risk ratios of mortality in neonates with CDH were calculated using generalized estimating efficiencies. Of the 426,140 VLBW neonates born during the study period, 535 also had CDH. Neonates with CDH had a markedly higher incidence of additional congenital anomalies of 48.4% compared to neonates without CDH at 5.5%. Of the VLBW neonates with CDH in the Intent to Treat Group, 67.7% were intubated in the delivery room. Of the 389 that survived to NICU admission, 372 or 95.6% were mechanically ventilated. There were 38% of VLBW neonates in the Intent to Treat Group who were surgically repaired during their initial hospitalization. The risk of mortality was significantly higher in the VLBW neonates with CDH at 70.4% compared to those without CDH at 12.6%. Of those with CDH, 73.3% died by day of life 3, which you can see in the steep decline in blue, compared to a much more favorable and hospital prognosis of the VLBW neonates without CDH and red. Mortality in the Intent to Treat Group was 62.7% for VLBW neonates with CDH compared to 16.4 without CDH. These mortality differences were further evaluated by birth weight categories. As you can see in red, the risk of mortality declines continuously with increasing birth weight for neonates without CDH, but in neonates with CDH in blue, mortality plateaus at approximately 60%. In the Intent to Treat Group, the presence of additional congenital anomalies, which is associated with a higher mortality with an adjusted risk ratio of 1.14. In conclusion, these benchmark data reveal that VLBW neonates with CDH have an extremely high mortality. These types of neonates with CDH have an additional congenital anomaly, which is associated with an even higher risk of mortality. These quantitative findings can inform providers and families regarding their prognosis of VLBW neonates with CDH. I've had this opportunity to present this project at CAPS and it has been published in GPS. Next moving on to one of our care projects, factors associated with D-Light Agacity Nosis and pediatric intestinal failure, a case control study. As you all know, small bowel bacterial overgrowth is a common complication in children with short bowel syndrome. A component of intestinal adaptation is bowel dilation. Small bowel bacterial overgrowth is thought to be a direct result of dilation resulting in stasis, which promotes bacterial proliferation, inflammation and malabsorption. Vacteria act on incompletely absorbed carbohydrates to create both L and D-Lactate, which is clear L-Lactate is feared rapidly, but D-Lactate is metabolized at once of the rate and can accumulate in the body. This accumulation can lead to metabolic acidosis and neurologic symptoms. Current literature describing D-Lactate Gaseousis and intestinal failure consists of case reports and small case serious with the majority only focusing on the adult population. Because of this, we aimed to identify factors associated with D-Lactate Gaseousis and children with short bowel syndrome. This is the retrospective review of Children in Our Care program from 2010 to 2018. In the program criteria listed here, the primary outcome of interest was the presence of D-Lactate Gaseousis and children with intestinal failure. And multivariable logistic regression was performed to identify factors associated with D-Lactate Gaseousis. 46 patients met inclusion criteria, 23 had D-Lactate Gaseousis and 23 did not. Meeting residual length was 40 centimeters with a predicted bowel length of 15.3%. 15 or 37.5 had an attack-liosecule valve and the median percentage of internal nutrition at time of D-Lactate Gaseousis episode was 100 percent with a majority of patients using amino acid-based formulas. After performing a multivariable backward elimination, Midgut-Vovulus, History of intestinal lengthening procedure and anion gap were retained in multivariable analysis. Multivariable analysis demonstrated that an diagnosis of Midgut-Vovulus was significantly associated with an increase odds of D-Lactate Gaseousis by 17-fold. Additionally, History of lengthening procedure and high anion gap was significantly associated with a higher odds of D-Lactate Gaseousis. To our knowledge, this is the largest study of children with intestinal failure complicated by D-Lactate Gaseousis. We found that a diagnosis of Midgut-Vovulus, History of having undergone an intestinal lengthening procedure and elevated serum anion gap were all features that were strongly and independently associated with D-Lactate Gaseousis. Children with Midgut-Vovulus have a 17 times increase odds of having D-Lactate Gaseousis and therefore should be monitored closely for the occurrence of this rare but serious condition. And this project was published in JPGN. Now moving on to a long-term project that aligns with my future corregals in global surgery and why obtained by MPH and Global Health. I'm currently working on a project with Dr. Jackson, Dr. Langer and our goals to improve the mortality in neonates with gastroskecis with the use of parental nutrition. Dr. Langer is currently in Begonge Medical Center and Moons of Tanzania as we speak. So there's a huge global disparity in the survival of neonates with gastroskecis and many low-income countries mortality approaches 100 percent. In comparison mortality is less than 5 percent in high-income countries such as the United States. Service delivery is a major component in the high mortality of neonates with gastroskecis and low-middle-income countries. Two important contributors are inappropriate care after delivery and lack of emergency services. This leads to hypothermia, hypolemia, coagulopathy and sepsis which contributes to the high mortality. Lack of equipment and life-saving medical products such as central lines and parental nutrition is a major contributor to high mortality since many neonates with gastroskecis are unable to receive nutrition via their gut for the first month of life. A study published in the Lancet in 2021 performed a multi-center international prospective cohort on patients less than 16 who presented to the hospital for the first time with several GI anomalies. This study included 264 hospitals in 74 different countries. Focusing on gastroskecis you can see that it has the greatest difference in mortality in country-income strata with a mortality of 90 percent in low-income countries and 1.4 percent in high-income countries. So why choose gastroskecis as an etiology to intervene on? Well as you saw previously there's a huge global disparity between low- and high-income countries and for neonates with simple gastroskecis the median duration of PN is just 23 days. Although thought to be an extensive resource PN can be cost-effective in terms of valleys or disability-adjusted life years averted and this is especially true for neonates with conditions such as gastroskecis who can potentially be cured with a short term course of PN and have a full normal life. In addition providing more reliable Venus access such as PIX can provide other treatment possibilities such as chemotherapy for cancer patients. Modular PN or pre-mix are ready to use PN as what we hope to use. It's a triple chamber bag that contains amino acids glucose lipids and electrolytes. It can be stored at room temperature and has a longer shelf life about 18 to 24 months compared to compounded PN which only lasts about 30 hours at room temperature and nine days is refrigerated. Some hurdles are challenges to consider. There is certainly a great deal of harm that can be done and we want to be responsible when bringing PIX over to Tanzania. In order to mitigate the risk of sepsis, introduction of central lines will take extensive training and education. Secondary, secondly, nurses are used to sending these infants home to die and they focus their time and energy on other infants that are more likely to survive. Therefore we missed shift or mindset of the key members of the medical team in order to improve survival. Lastly, getting PN to LMI sees is a huge venture and will take collaboration with numerous stakeholders including manufacturing companies, physicians and surgeons, nutritionists, laboratory team members and hospital management. So in order to mitigate the risk of live sepsis, we will involve a multidisciplinary team which is listed here. We will also develop a multifaceted intervention bundle which will include an education program for nurses and doctors on pick line care, a weekly audit and feedback session, and we will also implement a pick line bundle which will involve safety and care when inserting and handling the line. Here's a snapshot of our safety checklist. And some next steps for the project involves looking for manufacturers of PIX near Tanzania which I'm currently working on now. Performing a cost analysis per insertion specific to lines and disposables such as how often we may need multiple lines for occasion if one falls on the floor gets contaminated. And we also want to make sure that we include the cost at least one to two days of antibiotics since a lot of patients have to spend their own money to buy antibiotics and this can delay care. And we also need to develop a protocol for ultrasound guidance to confirm placement of pick lines. This has been shown to be effective in several studies in the US and for our target population is preferred over X-ray confirmation since the X-ray machine in Begonne of Medical Center is in a cold basement far from the surgical floor which is not ideal for small babies. So I want to make sure to take the time to thank you all. Thank you Dr. Jackson and Dr. Modi who unfortunately sick and not here today but for your mentorship and guidance and everything that you've taught me on how to take care of your patients. Dr. Zaleskis, Dr. Weldon, Dr. Demiri, thank you for everything you've taught me nice to you and there are too many people to thank individually but thank you all. Good morning everyone and thank you Brian for the introduction my name is Claire and it's been an absolute honor to service the Vascular anomalies fellow for these last three years under the foreign nominal mentorship team of Dr. Fishman, Dr. Dickey, Dr. Kani, and Dr. Bouland. I've heard you have my excellent mentors and the breadth of their expertise. I have the opportunity to engage in research in three different arenas. I'll do my best to share a little bit from each area today. As the Vascular anomalies fellow, I've come from space-sake and clinical science research in Vascular anomalies and join our outstanding Vascular anomalies team in caring for patients. Venus malformations or VMs are slow-follow vessel malformations that occur in approximately one to five out of 10,000 bursts. Symptoms include pain, quadrilopathy, bleeding and cosmetic concerns. Importantly VMs do not regress but rather a most will increase in size and some will progress result in a significant reduction in quality of life. Current treatment options include compression garments, medical therapies and procedure interventions that are of high technical difficulty and often associated with hemorrhage. Now if no surgery does have a role in the treatment of some VMs. In this paper that we published last year, we shared our experience in treating bulvar labial VMs. In our cohort 88% of patients that had recurrent or persistent symptoms had a median follow-up of 14 months following surgery. However, current therapies do not eliminate large and complex VMs. Foto-symbol therapy or PTT is an effective and non-invasive alternative to pharmacotherapy. PTT entails inducing cell death from heat by photo-thermal agents that are irradiated by light. In humans, PTT is currently being used in phase 3 clinical trials with both good safety and good effect. Our hypothesis was that nanoparticle-based photo-thermal therapy will effectively ablate in its non-formations. We aim to develop a nanoparticle-based system to treat VMs with PTT. In this system, a photo-thermal agent is delivered systemically, passively accumulates in VMs and the VMs are then irradiated with near-for-bed light. The near-for-bed light induces local hypothermia that are violating the target tissue. Importantly, heat and tissue ablation only occurs with the near-for-bed light supplied. The design-doll nanoshales, because gold nanoparticles have been used extensively for PTT as a biocompatible, non-toxic, and responsive to near-for-bed light. We characterize these particles determining that their size distribution is optimal for passive accumulation in VMs and that they have maximum light absorption in the near-for-red wavelengths. To determine the therapeutic effect of PTT, we design the following experiment. We use the Hu-vec-type-2-n-mall model. We created my step to VMs on an age flank, and also then inject it systemically with either saline or gold nanoshales. 24 hours following injection, 1 VM per animal was irradiated, either for four treatment groups. Saline, saline plus irradiation, gold nanoshales, and the group that receives PTT, which is gold nanoshales plus irradiation. We compared the absolute VM volume for each treatment group. We found that in the control animals, their VMs tripled in size. In contrast, in our treated group, the VMs were gandregressing approximately 48 hours after treatment, and by day 11, were reduced in size by greater than 6-fold. At the time of net prophecy on day 20, all of the VMs in the three treatment in the three control groups were significantly larger than the VMs in the treatment group, and they overall cured more vascularized. Two of the eight VMs in the Golden National Plus irradiation group were completely eliminated. While PTT significantly reduced or even eliminated the VMs, skin burns did occur in all eight animals in the Golden National Plus irradiation group. Thermal injury was most notable by day three. In all animals, the burns were healed as early as 13 days following a radiation and left behind minor residual scarring as shown in the bottom right hand image. Golden Nationals did not cost toxicity. We saw no change in animal body weight, organ function, or organ weight and histology. In conclusion, we designed Golden Nationals to passively accumulate in the abnormal vascular VMs after administering them systemically. We found that with giving Golden Nationals and laser light, the VMs in our mouse model showed significant regression and often elimination of the VM. Overall, nanoparticular approaches have the potential to markedly improve the treatment of vascular nummies. I would be a miss not to acknowledge the comprehensive education that I have received in caring for patients with those simple and complex vestuonomies. Over the last three years, I've seen nearly 600 patients in our vestu... Friday morning vestuonomies clinic and I've participated in operations, spanning vestuotrimers, vestuomathemations, and syndromes. These are pictures of just a few of the cases that stand out. Now thanks to Dr. Cohani's expertise in drug delivery biomaterials from the Flanesthesia, I've engaged in several projects in this area. 15 years a little bit, now focusing on a discovery that could have direct application to the treatment of post-surgical pain. I'm excited to share that we recently discovered that a molecule called 265-polloslydean, which I'll just help the Px for the remainder of this presentation, provides sensory selective local anesthesia. We've recently submitted these findings to nature communications. Long and localized pain is treated with opioids or local anesthetics. Conventional local anesthetics are highly effective in LGX, but they can cause motorblock in addition to sensory nerve block. This can be problematic in Lyraepidural anesthesia, acute post-salt pain, and chronic pain. Additionally, conventional local anesthetics can be associated with local tissue injury and potentially lethal systemic toxicity. Therefore, yet, implication and development of safe-selective local anesthetics would be a major advance in the treatment of many pain states. With this in mind, the Cohani lab has been working on several projects to make sensory selective anesthesia a reality. We made a variety of chemical modifications to conventional local anesthetics and we examined their effect on the aesthetic properties. One of the compounds that we decided to examine is displayed here, again, Ppx. Today, I'll share a rather certain dipitus finding of Ppx providing sensory selective local anesthesia. Due to time constraints, I'm going to focus just on a few select pieces of data, and for all of those, I'll be comparing the effect of Ppx to reprivocaine clinically used a conventional local anesthetic. I won't go into the details of the chemistry that's involved, but here are the reactions that are needed to create this compound. We confirmed that the correct compound has been created using several analytic tools. To examine the local anesthetic effects of Ppx, we used a well-established photo-satoc nerve block model peripheral anesthesia and ensure a fecal anesthesia rodent model for or axel anesthesia. After injection of the compound of interest at the satoc nerve or the intersecule space, respectively, we then performed nerve behavioral testing to assess for sensory nerve block and motor nerve block. We used the hot plate test for sensory testing and extensor posterior thrust test for motor block. These were asked for sensory and motor maximum percent effect on the y-axis, where 1% effect refers to full sensory block or full motor block. Sensory block is in blue and motor block is in red. With the peripheral nerve site and the intersecule space, Republican produced maximal sensory block and maximal motor block. In contrast, as shown in the bottom graphs, the administration of Ppx at the satoc nerve and the intersecule space produced maximal sensory block, but the animals did not develop the maximal motor block. This means that Ppx produced effective sensory anesthesia but without affecting the motor nerves. Our direct toxicity of conventional local anesthetics is mediated in part by inhibition of NAB 1.5, which is a voltage gated sodium channel that's predominantly located on cardiac muscle and HERG, which is a cardiac potassium channel. We then foredeceded to examine the effect that Ppx has on these channels. We found that Republican led to a 4-6-fold higher inhibition of her occurrence compared to Ppx, and Republican led to the same or two-fold higher inhibition of NAB 1.5 currents compared to Ppx. This suggests that Ppx could have less cardiac toxicity than clinically used conventional local anesthetics. We previously demonstrated that the LD50 of Republican in our animal model is 56 milligrams per kilogram. The administration of a considerably higher dose of Ppx, which would be universally fatal if it was the pivoting over a pivoting, did not cause respiratory distress, contralateral latency, seizures, or mortality in any of our animals. Finally, we assessed the tichetoxicity. At the muscle level, there was minimal inflammation in mild muscle injury, which is very comparable to Republican. There was no injury at the sciatic nerve or at the spinal cord. In conclusion, Ppx holds great promise for achieving sensory selective local and nerve-axial anesthesia. It has a more benign local tissue reaction and much less systemic cardiac and neurologic toxicity than the clinically used conventional local anesthetics. Finally, Dr. Dickie's expertise has allowed me to delve into the world of pediatric colorectal surgery. Now, very briefly discuss the design and validation of an anorectal amalgamation surgical simulator. Inorectal amalgamation's ARMs are one of the very congenital anomalies that are seen by pediatric surgeons, which require complex surgical reconstruction. However, the average number of ARM repairs that are done by pediatric surgical fellows and attending scanulae is actually quite low. We therefore aim to design an easy to use high fidelity ARM simulator. We designed a simulator using digital modeling software practice. The simulator was then fabricated using a combination of 3D printing and sculpting and multi-stage silicone injection molding techniques. We show you a brief clip of what this looks like in action. We start with the evaluation of the urethra, vagina, and the recto-bustibular fistula in the introidus. This is followed by dividing the sphincter complex and very sagittal fibers in midline and separating the anterior recto-loaf and posterior vaginal wall. Of note, the common wall in the simulator is quite thin to 2 millimeters. Recto-length is then gained. Procedures continued with a perinobladi repair, backing of the posterior recto-wall, and finally anoplasty enclosure of the posterior saddle wound. Now, today for simulator, we performed a cross-sectional observation study at IPEG 2022, recruiting 27 surgeons with varying levels of experience with performing a PCR. Experienced PCRs were self-reported. Experienced participants had done 10 or more novices less than 10. Each participant performed a PCR after viewing a short demonstration video on the model and receiving an instructional guide based on the Delphi consensus methods for PCR steps. Each session of the simulation was recorded and independently assessed by three expert pediatric colorectal surgeons from different institutions. They were blinded to operator identity and experience level and utilized both standardized general skills and a PCR steps to the big assessment tool. In summary, we found that the simulator's realism, anatomic representation, and the ability to perform the PCR steps were rated very highly. Performance of a PCR on the model could distinguish between experts and novices. Overall, I gave a support to the use of the simulator for training and maintenance of skill. I cannot adequately express in words my deep appreciation and gratitude for my phenomenal mentors that their fisherman Dr. Diggie, Dr. Cahoney, and Dr. Colihan. This work is a testament to your great support and mentorship these last three years. Thanks to the Department of Surgery for all of your education and teaching during Wednesday activities and the ORA and during and console call. A special thank you to the back and CPMC team is for welcoming me with open arms to their teams and all of their teaching. Thank you to the Cahoney lab for being the chemistry masterminds and thank you to the white cement and rapport families for their financial support. And last but not least, thank you to my husband Malik and my little baby Amateo who are watching from Zoom from home for the tremendous support these last three years. Thank you. Wow, I think we can all see as we saw at the last session that the future pediatric surgery is incredibly bright. We are so fortunate to have so many talented research fellows amongst us. The bad news about that is with 10 minutes left. It's an impossible to ask all the questions of people who have and and they call it comments as many colleagues, friends, and mentors and family in the room who I'm sure all of the comments are welcome to all of you who are joining us on Zoom. I think we'll start with comments from mentors who might want to speak and see if there's time for questions thereafter. It was certainly a pleasure to work clinically with all of you but Nicola want to give you a special shout out and thank you and thank you to the people from the ICU team that let me borrow you for a couple of years. You presented so beautifully in representing our institution in all different capacities in CDH internationally. So thank you very much for that. And a special shout out for your tenacity. You made some of the obstacles in our projects and retrospect look like little tiny bumps along the way. So I really appreciate your passion, your integrity, and just for being a wonderful team member through the last couple of years. I couldn't be more grateful. Thank you. Emily, I just like to thank you for a fantastic job. Really when one looks at the arc of your career here at Boston Children's getting your ICU fellowship and then getting your boards and doing a MPH and global health and really acquiring a tremendous expertise and intestinal failure. And now combining those and I know your husband's interests still line with yours of going really to Africa and trying to bring PN to Africa is just an absolutely remarkable concept and I really wish you well. I think you're going to make a fantastic contribution. I want to thank all the fellows that we've worked with. I mean both groups from last two weeks ago, this week, it's been a real pleasure working with you. I want to thank Tom. Brian is right. My lab can be a little challenging. But Tom, I have to say, is an amazing team player. I heat established collaborations between Mass Eye and Air Mass General, Brigham, BI, Children's and Stanford. He set a record, I think, for experiments. I did a kind of a calculation. He did over 2,000 procedures and well over 20,000 doses of medications to the animals and I just want to say appreciate that. I want to thank Emma as we can say for sharing them with our group. Where I know I speak for Dan and myself when I say watching you develop into a scientist during this fellowship has been our pleasure. Keeping four mentors happy is no easy task and she did it with ease. You walked into the laboratory and you learned an entirely new field of medicine, nano medicine and you did it effectively, efficiently and your output was tremendous. You developed a new way to treat humanist malformations and no big deal she just developed a sensory selective local anesthetic which is the holy grail of that entire field. You just submitted a first author manuscript to nature communications. You are exceptional. Your accomplishments, papers, patents, presentations, awards. I look forward to all you will do for your field. Your field is very lucky. Thank you. I just want to congratulate all four of you and especially Emily and Nicole for the CERTAGAL critical care year and Nicole for carrying out as you could see really taking what the questions she had from that CERTAGAL critical care year and expanding them through retrospective studies, prospective studies looking at another project she didn't talk about but basic science with looking at platelets and platelet transfusion with Dr. Solavisner and the NICU and just did everything so graciously. Represented us well nationally and internationally at many meetings and just doing all this with a smile. It's been a pleasure for the last three years and I thank you for all the hard work and look forward to your future. I had the pleasure of working for with most of you on call but mostly Claire and Nicole much more closely with their research and I echo everyone else's thoughts. I think the two of you both have represented our institution, our department, our research fabulously at both national international meetings both your view of both well-poised to be a successful pediatric CERTAGAL. Well I can't speak as eloquently as Dr. Claim did about Claire and we'll try. When she says that you managed to keep forement us happy you came into a situation knowing that you were going to have to be a little bit self-directed and being a sort of to be successful and I don't think she kept forement us happy. I think she made forement us happy. Ryan and his introduction said that the Vascoe Omni-Senateen is going to miss her and wondering about the function. He was politely saying that it's been pretty well advertised that they're pretty sure that I'm going to have trouble functioning without her because she's basically replaced me and that's a fault of her credit. I think that the accomplishments of these four individuals in combination with the four we saw last time is truly extraordinary and it's a a bellwether for the future but it's also a challenge for us as a department as faculty mentors to make sure that we provide all of these individuals and their successors with the best of mentorship and the best for their future careers and for the field that they're advancing. I think we have an enormous amount to be proud of and certainly all of you and your family who are here and on Zoom and your supporters have much to be proud of. There is several people mentioned this in trouble since the collegiality that happens in general in our research group but I think it's particularly true in this current era. One of them can be given easily if they've made life friends, sort of like you think about some of high school friends or college friends or medical school friends or as a family they've made lifelong friends and I think that's likely to prove true so congratulations to all of you, congratulations to the mentors who supported them and we're extremely proud as the department people would do so. Thank you all so much.
Click "Show Transcript" to view the full transcription (53683 characters)
Comments