The transcript of today's episode can be found 👇

SUMMARY KEYWORDS

babies, families, parents, paper, congenital anomalies, discharge, rsv, group, work, preterm, home, nicu, children, mothers, data, phenotype, number, infants, shows, fetal distress

SPEAKERS

Daphna, Ben

Ben 00:43

Okay, and we are live. Hello Daphna. How's it going?

Daphna 00:47

I'm doing great. How are you today?

Ben 00:50

I'm doing good. We've both been very busy. It's been with both sort of changed jobs. And we're both now working on this new project with Nova Southeastern University, which is very exciting. But regardless of how exciting the project is, it's been busier.

Daphna 01:04

Yeah, I think it's been a it's been a complicated year for everybody. Right. But we certainly are going through some transitions, right.

Ben 01:12

It has, it has. Okay, so today is, is our third episode, we have officially released the podcast. And I've been very encouraged by the response we've been getting from Twitter, Facebook and other platforms. So thank you to everybody who's been downloading the podcast listening in. And yes, we're ready to provide more quality content for you.

Daphna 01:37

Absolutely. I think we're excited for engaged. We want to engage with our kind of virtual community and get some feedback and hear what what what you guys want to listen to.

Ben 01:50

Yeah. So today, general Club is going to focus on I guess, two major journals. We're going to go over the latest edition of Pediatrics and the latest sort of edition of Jama peds and we're going to focus on the papers that have come out relating to neonatology obviously.

Daphna 02:11

So I guess we can get started. We are going to start with this first key paper in pediatrics, the respiratory syncytial virus bronchial eight is complicated by necrotizing enterocolitis, a case series by Dr. Arias at all. So this was an interesting case study. So they had identified some babies in their unit that were infected with RSV bronchiolitis who develop neck. And so they went ahead and did a basically chart review to evaluate other babies that had bronchitis. So they looked at 800 babies with RSV flocculated, 652 babies with non RSV bronchiolitis. And they found that in their group, they had four babies diagnosed with neck actually in the in the pinky, their pediatric ICU.

Ben 03:08

Yeah, I think that's that's what really caught my attention. Because initially, I thought pick you, okay, that doesn't really apply. But then, but then you see 34 babies were born between 34 and 39 weeks of gestation, that showed up in the PICU, a three to six weeks postnatal age, and developing NEC, I think that really got me thinking, number one, because we've been so focused on COVID, for the past year, that we sort of forgot about RSV, somehow, and, and it's coming back. I mean, I'm reading more and more posts from people on Twitter saying, Oh, I saw a case of RSV, here and there. And so it's coming back. And I think it was important for me to remind myself that yes, there's a lot of complications associated with RSV. And neck is not the one that comes to mind. First and foremost, especially at such a distance sort of age. I don't know what you thought about that.

Daphna 04:01

Certainly, I mean, any any baby who's kind of term corrected, we, you know, it's it gets farther and farther off of our, of our differential. And I think that's what really struck me about this paper. You know, anytime we, we see maybe abdominal distension, or feeding intolerance in relation to viral illness, we think, Okay, well, there's some sort of ileus I'm not surprised by that. And that's how all four babies presented. So for me, as we get into this, the takeaway point was really not to ignore kind of those early symptoms of abdominal distension.

Ben 04:38

And they had babies and they had pretty severe and you see, I mean, they documented one of them had to get a partial colectomy one of the patients actually did not make it past this admission to the PICU. So that was that was really an eye opener for me.

Daphna 04:52

Yeah, I totally agree with that. They all had X ray documentation of either Numa Numa ptosis or portal venous gas or both. He and his babies were sick. And they developed thrombocytopenia. And they all had. Well, those that were tested had elevations in the CRP, which is not something you typically see in an RSV infection in general. And so I thought that was pretty impressive. One developed real to actually developed kind of multi organ failure and shock. And in relation to their sepsis. And what I think they really clarified, it was really important to me looking through the paper was the babies didn't have the symptoms of shock, or hypotension or need for pressors until after their diagnosis, because that's what I was. That's what I was looking for. So it was it seemed to be the real deal.

Ben 05:46

Yes, yes, it was. And, and I was interested also in sort of this hypothetical framework that they developed, or that they suggested, I guess, not really developed for the pathogenesis of this RSV, and use neck and they really went through sort of four elements, saying that number one, their neonates, immature immune system is less able to control viral replication when presented with a high viral load. And number two, they wrote that immune dysregulation favoring production of proinflammatory cytokines and chemokine are associated with severe lower respiratory tract infections. Number three, this ad RSV RNA has been identified in peripheral blood and extra pulmonary manifestations may indicate systemic dissemination of RSV during severe disease. Finally, number four, they were although our patients did not exhibit signs of overt sepsis due to art, they did not exhibit those signs over sepsis due to RSV has been described. And I think it's important to remember that because I could, I could sort of see myself facing a similar situation in the NICU, where you would have a baby that would have some instability, you would maybe get a viral panel that would diagnose RSV. And if the baby had some feeding intolerance, you may be tempted to dismiss it and say, well, he's going through a viral infection. If you see some loosened sees on the KGB, you may say, Well, you know, he's just maybe a bit constipated. when in truth neck is a true entity that has to be thought through. And an age doesn't really matter. I mean, we're tend to, to remember that neck is at like, this 30 week, sort of mark. And and this paper really shows you that there's not that limited can happen in much older babies. And yeah, and it gave me a lot of food for thought definitely.

Daphna 07:22

Yeah, I also, I wonder if we looked at all babies with viral infections, and they did, they did look for epic babies with bronchodilators, that was not diagnosed as RSV, but so many other you know, viral infections that could potentially present present the same way. So just definitely something like you said, Food for Thought is gonna make me think twice about those babies who I think just have a little ileus maybe, you know, have me get the film or pay more attention to the film look, more specifically for some of those key findings.

Ben 07:56

And it's to conclude, I guess, our discussion on this paper, I think it's interesting, because when you think of the pyramid of evidence, and you think, okay, a case series, what how useful can a case series be? I think this was perfectly appropriate in terms of, hey, we're making you aware of this, of this rare, but yet possible complications of RSV. And it's one of the rare case series, I guess, where you can actually take the evidence and take it directly to the bedside and sort of think a bit differently about problem. So So I was very, I was very satisfied with that with that paper.

Daphna 08:26

Yeah, I really liked you know, they said, Oh, we have these two cases. That's interesting enough, but they really looked for what do we have more cases? And they did. So definitely something for us to keep an eye out for.

Ben 08:37

Yeah. So moving right along to another paper in this edition of of Pediatrics this month. This paper is called predicting the need for phototherapy after discharge. It is authored first author is Dr. Michael Kushner, which I hope I'm not butchering that name. This is from his associates in from California. The the purpose of the paper is really to look at total serum bilirubin around the time of discharge, especially in babies who have not really required phototherapy and come up with an algorithm or a structure that could help predict the need for phototherapy after discharge. And this was a this was a study that included a ton of babies. I mean, I think it covered 11 Kaiser Permanente Northern California facilities from 2012 to 2017. And they had about about 2623 infants that exceeded post that exceeded phototherapy threshold post discharge. So they looked back at those babies and said What were their patterns like before discharge, and they developed this model that they called delta TSB, I guess delta for change in tsp total serum bilirubin, and they were able to show that this model had an excellent ability to put addicts post discharge, barely above their phototherapy threshold. So yeah, I'm curious to hear your thoughts on that paper.

Daphna 10:08

Yeah, you know, I am. You know, Billy is something we do every single day, right. And right now, and many of our colleagues are seeing newborns in the in the newborn nursery. And, you know, we have a system, right, most of us are using the same system, it works pretty well. So I thought it was interesting that they said, like, you know, could we do something better? Could we do something different? And certainly those of us that work with trainees know that the kind of the to chart system is not that complicated, but it does create some confusion, sometimes around the time of discharge, especially if someone doesn't have a lot of experience with with working with the B, Johnny nomograms. And the risk stratification there. What do you what do you think? How often do you use the risk stratify risk stratification,

Ben 11:03

and I'm gonna, I'm going to tell you a story of when I was a resident. As a resident, our program had this policy that all the residents had to attend at least one performance improvement meeting for the hospital. So I had to attend one just to get a sense of how this hospital functions, whether they're looking at and so on, and the one I went to discussed, readmissions, and pediatrics got slammed because they said all these babies are coming back with Billy's and you guys are not improving on the rate of readmission for hyperbilirubinemia, to which my mentor said, we have no way of predicting what the Billy is going to do after discharge, we do our best, but we cannot put babies on the phototherapy. If they don't meet the threshold, and then they leave and then they meet the threshold. So they come back. So what do you want us to do? And I was totally in agreement with his retorts during that meeting. But it's true that it has been a sort of a dilemma for us even discharging babies from the NICU be like, you know, his belly is like getting so close to threshold. Should I get Should I start some phototherapy just so that when they leave, they don't have to come back? Even though there's no grounds for a starting phototherapy? So I am very happy that a group has tried at least to create some sense of how can we predict a little bit better what's going to happen after the babies do go home?

Daphna 12:18

Yeah, and I think that they're right, it certainly simplifies things just to give a little bit of kind of that data. And they said that, for example, if babies had a pre discharge Delta tsp or the difference from the phototherapy threshold,

Ben 12:38

right. So I think I think that's the important thing, the delta, their model, when I initially read the paper, I thought the model was going to be some sort of algorithm that was going to be put through sort of machine learning or artificial intelligence. But actually, it was very, very simple. And I'm not saying this in a demeaning way, I think the highest level of sophistication is simplicity. So I was very happy that with a simple sort of model, they were able to get the results they obtained. And the way they did that is by looking at the bilirubin at the time of discharge, and look at the difference between that serum bilirubin and the threshold for phototherapy. And as that threshold for phototherapy and the bilirubin were getting wider and wider apart. The need for phototherapy post discharge was lower and lower and lower

Daphna 13:20

as that like you said, as that number increases, obviously your your risk for needing phototherapy changes. And I think their discussion was very good about how can that help us and sometimes maybe even resource poor areas where how do we get the follow up doesn't really have to be tomorrow, as we're, you know, discharging babies on Friday, we're rolling into a holiday weekend, you know, what does that look like practically and logistically for families?

Ben 13:49

And I think it's exactly right. The way I was sort of thinking about how to implement this in practice was, we have to have these discussions with the families on a daily basis, saying, Hey, your baby's bilirubin level is sort of not high, but still not super low either. And here are the options. But now I feel like this data I will bring to the discussions with the families and saying, Hey, we have an option of keeping your baby maybe a bit longer and following it up or you know that you can go get a check to the pediatrician with a risk of needing readmission for therapy that is as high as 50% Within the next 48 hours. And without without forcing anything on the families. I think it will give the family so much more information to make a decision that makes sense for their babies and for their families. Like you said, if this is a single mother that has very low resources around her, maybe she'll elect to stay in the hospital one day more to follow the belly because to her going to the pediatrician potential readmissions would be extremely disruptive. Or you may have a family that has multiple children who would rather maybe go back home sooner, even if that means following up as an outpatient. So I think this is going to empower families to make a decision because every The time the parents have asked me like, What do you think the bilirubin is gonna do tomorrow? You're like, I don't know. I have no idea. So

Daphna 15:07

yeah. And I think anytime that we can create a kind of shared an opportunity for shared decision making, I think we should we should take it. I also liked and I'm sure that this resonates with you that how simple this could be integrated into our kind of EMR to do the calculation itself, further reducing any kind of errors in that and giving some sort of recommendation for follow up. I'm not sure when I'll do that, but it's certainly an opportunity for quality improvement.

Ben 15:43

Yeah. And I was also, we haven't really spoken about this, but I think the one thing that sort of popped into my head when the I was reading the paper for the first time was that, okay, there's the non Coombs positive, there's the Coombs negative babies, and there's the Coombs, neg there's becomes negative and becomes positive babies. Because I have this feeling always since residency that becomes positive babies tend to have these huge dramatic drop jump in their bill Reubens that seemed very unpredictable. And so I was very happy to see that they accounted for that and that the model does work, even in that category of babies.

Daphna 16:16

Yeah, and and we know those are the babies that are are likely to be, you know, re admitted. And so I thought that was really important, I would have liked to see or would like to see in the future. More of this, maybe the same model using the kind of Transcutaneous serum Billie's or Transcutaneous. Billy measurements, since many places are moving away from routine serum measurements. So that would be the only thing that I'd like to sort of

Ben 16:48

love. Absolutely. But yes, I still think that the simplicity of the model is what makes it so attractive. Because, again, as they said, they said it themselves. They said the simplicity of the Delta tsp model is a strength and I could not agree with them more, because it feels like it's easy to manipulate. It's easy to enhance, it feels like it's within reach of everybody. And like you said, you could easily make an Excel calculator to incorporate that into your daily practice.

Daphna 17:12

Absolutely. And I think anytime we can make our daily practice easier, less less room for error. And certainly anytime we can make the lives of parents easier, we should. I think that actually takes us to our next paper in this month's issue pediatrics regarding medical device workarounds, in providing care for children with medical complexity in the home. So this paper is by Barton at all from the union, University of Wisconsin Madison. And so I think they really invested a lot. And in doing this study, so they were doing in home interviews of caregivers whose babies are medically complex, and a part of their kind of complex care clinic. And so this this cohort, the babies to qualify just for their clinic, they need at least three body systems involved in at least three and specialists involved in their care. And so certainly some of our most vulnerable babies or children, and I think very much captures some of our medically complex NICU babies. So most of the babies had G tubes, and 30% had tracheostomy. And, of course, they had a multitude of other complications. And so they sent into researchers to meet with the families in their home, to do some one on one interviews with the caregivers, but also to evaluate their home take pictures here, what their day to day challenges are, particularly regarding their kind of medical devices, most of which, if we really think about it are built for hospital use. But as we're having greater and greater successes and sending complex babies home to be with their loved ones. We're sending hospital grade equipment home. And you know, we we commit to these families that will teach them how to use it. They'll be comfortable when they go home. They'll be safe when they go home. But I think until we you've really experienced what it's like to work with some of these things in the home environment. And it's difficult to really understand.

Ben 19:36

And we'll go into each each of the barriers that they've identified there. There wasn't that many of them. I think I highlight there was there was four main barriers. But there's a few things about the data that I thought was very interesting. Number one, I have been advocating for us to start looking differently at the way we collect data in the NICU. I think length of stay BPD all these things are good and well but we have to start looking at practical aspect Tough care. And not just in the NICU, but around in and around the NICU, including the disruption that having a baby in the NICU causes for families. And even when a baby that's medically complex does go home, how difficult it is to manage. And there were a few things to me that I highlighted in the paper. So they, like you said they collected data from 30 families, but then they looked at the caregivers were between the age of 20, and 78. And that sort of struck me as, obviously, these are the extremes. But 20 year old is extremely young and seven year eight year old is extremely old to care for a medically complex baby. And I think when you take that into account, it makes it so much more important for the devices and the medical sort of care of the baby to adapt itself around those caregivers, because these are caregivers that have that have needs. And that's that needs to be sort of catered to. But also, interestingly, is that, so the average age was 38 years old of the caregivers, they were mostly female 80% female, that was also a statistics that I was that I was interested by, because again, it shows how the dynamic of having a baby in the NICU sort of shuffles the cards in this sort of way. And I don't know if there's anything anything, anything wrong about the fact that it was 80% female, but it does, it does show the dramatic effect that having a medically complex baby enter the home has on a family, particularly mothers. Absolutely, absolutely. And and episode on that. And the and the other thing that it made me think of, and this is a leap that I don't know, if I'm allowed to make but you're thinking have these mothers sort of stopped working give up a job that they were passionate about to be able to care for their for their ill child. And, and that's that's to me, that's, that's very difficult for a family. And I feel like these, these mothers and these parents in general are being placed in these positions. And it's an it's a stress that needs to be thought about, especially from our standpoint before discharge, to try to make this transition as as best as we can make it for them. So

Daphna 22:09

yeah, and I and you, I think you really hit on something that is particularly important now in this kind of Perry COVID era where, you know, we say to parents will will, will set you up with home nursing. And that's really not always the case, we can't guaranteed full time nursing, we can't even always guarantee part time or any nursing, for families and particularly for some of our colleagues who are working in, you know, less resource rich communities or rural communities. That's really a promise that we can't make to everybody. And so, so the the burden to families is high.

Ben 22:49

And it's funny because it reminds me of when my wife and I were starting residency at the same time. And we had our daughter who was at the time like two years old and we thought should we how are we going to deal with nannies and we thought maybe we should hire a live in nanny, which was funny that we even thought about that, because we were living in New York City in a very small two bedroom apartment. And then we thought about it and we said, where's she gonna be like, where's she going to stay. And then we said, it's gonna be so crowded, and it's gonna we're gonna have this, I guess, quote unquote, stranger in the house. And we're like, you know what, we'll find a different solution. But it made it always makes me think of, of my own experience, when we say, Oh, you'll have a nurse at home as this as if this is the best, the best solution in the world. It's true, it's very good that somebody can attend to the baby. But it is a strange presence in the home. And not everybody lives in a mansion. I mean, if you live in a small apartment, you get gets crowded very quickly. And so even that, which appears to us as a very strong solution is doesn't mitigate everything.

Daphna 23:48

Yeah, and I think space is one of the major issues that actually these families had in dealing with their medical devices. So the top the top four kind of problems, I guess, barriers as they titled them, are, when you really read them, they're they're significant, right. So the first quantity and type of devices allotted do not meet family needs. And so this was really about, do they have the supplies that best fit the equipment that are most optimal for the care? And do they have enough? Or can they keep, maybe you discharge them with enough but this is a life, you know, a few months few years for some of these children's a lifelong thing. And so can they continue to get the devices, the supplies that they need?

Ben 24:39

Yeah. And their work arounds was that, that they the family said to address this barrier families described the washing and we're using single use supplies. And, and that sort of didn't make me feel too bad because it made me wonder, you know, in the United States, we have a lot of resources and sometimes things that are Here's single use are many on many other countries not single use. And is there a potential for us to reuse some of our single quote unquote single use equipment? Maybe, even though that's not optimal, but the one thing that struck me was that one family it says right in that in that paragraph one family described collecting their used syringes during a hospital stay to wash and reuse at home. And that I mean, that that was a little bit striking, because number one, I think family shouldn't have to do that. Number one, but number two, where's the communication breaking down, that the families cannot communicate with the hospital? Hey, we're out of syringes. We need more syringes without them having to sort of scavenge the syringes used in the room. And I thought, again, going back to how can we bring this to the bedside? If a patient gets readmitted, and it's a medically complex child, maybe we can ask the families? Do you have everything you need at home? Do you need extra supplies and avoid having them sort of gather all syringes in the room? Because I don't know why. Maybe they're ashamed. Maybe they don't want to ask, but this is up to us to make this to create this bridge so that they can voice their needs when it comes to the supplies of their child.

Daphna 26:16

Yeah, and to take a step further, I think when we're first discharging parents home, especially from the NICU, right, so they haven't even experienced it, and they don't, they don't actually know what they need. And for us to even think, you know, long term about okay, this is what you need for like, a week, we're discharging you home with supplies for a week, you know, what does that mean? times four times 12 months, you know, and moving forward and for our for a lot of our families, just planning ahead to get enough diapers or wipes is really a strain.

Ben 26:50

And that's where I think the families of former NICU babies who have gone home in a medically complex situation can be very helpful if a family that that was discharged can call a family that says, hey, here's, here's what my experience was, here's what you need, make sure you ask them to give you an extra circuit for X, an extra syringe for why that can be very helpful. And it could create these networks of families that support each other through their discharge and, and onward.

Daphna 27:14

Absolutely. The the second barrier device is not designed to be used in the locations families require. And I would argue that most of them aren't designed to be to be used in the home. But I think what was striking to me is especially some of the workarounds parents had to engage with to get their kids out of the house.

Ben 27:37

Yep. They did all sorts of sort of tweaks and DIY techniques using Velcro bungee cords and all sorts of things to try to make the medical device sort of fit either a wheelchair stroller or things like that. But I have heart

Daphna 27:52

Carsey

Ben 27:55

having worked significantly on ventilations, and ventilators in the VPD program at Joe DiMaggio are now and now at NOVA. What I'm seeing from a lot of the manufacturers that they're taking that into account, so the home vents are now designed to have to be much more compact. They're designed to have multiple batteries so that parents wouldn't be sort of strapped for sort of energy sources outside the house. And also the screens have now all these features that can make them sort of dimmer, and really so that they are lessened in less intrusive in the in the home environment. So hopefully, this is an issue that and from my perspective, I thought at least we're making some progress.

Daphna 28:37

Yeah, I agree. I think individual companies are trying to do the right thing they're trying to, you know, be the one that people want to want to purchase, right, or want to have on stock because it has better, you know, reviews and patient satisfaction. But unfortunately, I think parents are in the situation where they don't have just one device, they have 1234 devices, and only two hands. And so you know, how did they how do they juggle all of those that are that are individually, you know, improving, but still don't kind of adequately support the burden.

Ben 29:14

And I think I jumped onto barrier number three, where the barrier number three was device use is physically or organizationally disruptive to the home. So obviously, they talked about being noisy and physically disruptive. But in that, go ahead. You were gonna say something. Yeah,

Daphna 29:31

I mean, I think this is the one we hear most often, most most commonly.

Ben 29:36

The one that what struck me is that in the workarounds, the paper quotes a family saying family is also noted that if a device was too disruptive, they stopped using it. And and that gives you some of the magnitude of why this is important. Because yes, parents are not going to put up with disruptive equipment for ever and, and they'll they may haven't stopped using it. And so that gives us even more incentive to come up with better solutions.

Daphna 30:04

Yeah, it's hard as you know, someone who sees babies and follow up and for you to think, Well, gosh, you know, we thought your baby needed this, and you guys just stopped using it. But it's, it's, it's, it's one of those things where it's so easy for us to judge when we can't, we're not in the home. And we don't understand the magnitude of like the sleep deprivation or, you know, the machines waking up other children in the house or waking up the, you know, the patient themselves. And so, we just can't, we just can't understand that if if we've not been there. And so, you know, I bet families are just trying to do the best they can, you know, given their circumstances. So I think this is one we have to think about, we have to really provide anticipatory guidance for families, about how disruptive it can be. So they're, you know, at least not not surprised.

Ben 30:58

And it made me wonder that maybe the families will stop using it. And they may not even disclose that to the doctor, they're a bit ashamed of that. So I think it's important for us to say, hey, you know, if the, if the machine is disruptive, let us know, because there are settings in the machine that we can use to make the alarms less noisy, and there's many things that we can do so that the families know that they don't have to stop using it, but they could just bring it up at their next follow up visit. And then we can go into the sort of advanced settings of the vent or of the pump and just make sure that it doesn't alarm as loud and wakes up the other kids.

Daphna 31:29

Yeah, and at a minimum, we should know, right with what the patients are using and not using. And so kind of creating an environment of openness and say, you know, lots of families aren't, you know, are having trouble tolerating this? How's it going? You know, is there something we can do to simplify that to change that? Or, you know, to make the environment more safe, if you're not going to use it?

Ben 31:53

Barrier? Number four, was device not designed to fit the user? Again, I think there's a lot of overlap sometimes. But yeah, I, the families described the barriers related to receiving medical equipment that did not appropriately fit their child or was not conducive to optimal use by the caregiver. One of the examples that they were giving was the bed height, and they showed the work around where a parent had to create sort of sort of these risers on the bed on the beds leg so that the carrying the baby in and out of bed would not string the caregivers back. So I thought that was also a very, very important aspect of these barriers.

Daphna 32:35

Yeah, I, you know, I'm not I'm not surprised by any of these things here. I know, intuitively, that going home with a medically complex child is difficult for families. But you know, I tend to focus on kind of the emotional burden, the physical exhaustion, but this kind of these logistical challenges are, are overwhelming. And and I think, collectively, it's something we can work on, we can, you know, advocate for companies to do better to include parents in their, you know, next design, I think, I think there are ways that we can advocate for that. And I just, it's a good reminder, I always say that NICU parents are really some of the most resilient people that I have ever met. And unfortunately, this, this reminds me that they're also some of the most resourceful, you know, families of medically complex children, get the job done, you know, one way or another. And it's, it's tough.

Ben 33:38

Absolutely. And I think this, this leads into this other this other paper that was published in pediatrics this month. And I'm not sure if they specifically waited for these two papers to be published. At the same time. This paper is called mortality among parents of children with major congenital anomalies. And it was the first author is Dr. Anne fuller. And this is coming from a group out of Canada. The the background, and the objective is to really talk about the long term health of fathers and mothers of infants with major congenital anomalies, and they looked at in a population based prospective cohort study, using the Danish registry, they looked at mortality of mothers and fathers of babies who have major congenital anomalies, and compare them to parents of children who did not have major congenital anomalies. And the main result and the main conclusion of their findings was that the mortality of the parents of babies of children with major congenital anomalies was significantly higher. And, and obviously to me that that was a that that's that's a massive sort of finding. And it gave me a lot to think about what were your thoughts, Daphna?

Daphna 34:55

Yeah, I'm not I'm not surprised by the data, but I think that we're just really started To quantify the trauma and the ongoing stress of how, you know, Nicu admission, or really a life with the complex child, how that strains, parents, you know, I think I'm glad that we're paying more attention to it. There's definitely some good things that are coming from this attention. You know, I know the TPN. Group for early career neonatologist to the AAP is starting to put together some resources exactly to help providers work with families to mitigate some of the stress or at least bring attention to tau as to how it's affecting them. And so, you know, previous literature shows that, certainly, they've mostly focused on mother's and that's maybe how this paper differs a little bit, but that mothers of preterm infants are more likely to have early death. And actually, I was surprised to kind of reread some of those studies, and that the highest risk of early death was in the first 10 years after a preterm delivery. And maybe some of that has to do with the preterm complications. But I think we can't underscore how much the ongoing stress affects our cardiovascular health. And that's something that this paper touched on that, you know, most of the deaths, and again, the follow up, ranged from nine to 25 years median of 18 year, so, of course, still, most of our parents were living at the end of the study follow up period, but that most of the deaths were were cardiovascular in nature. And so it really speaks to how much our kind of stress response effects you know, the developing metabolic syndrome, and the long term effects that, you know, we can't really even adequately account for, until we until we follow all parents to, to kind of death death outcome.

Ben 37:11

It made me it made me think of the fact that this paper probably should be also co published in an adult journal, I feel like it's showing that having a child with major congenital anomalies, is now a new risk factor for mortality, and that family practitioners, internal medicine, physicians should now take that into account in how they're going to sort of follow up these parents follow up these mothers and fathers in terms of their treatment, and the routine labs and in all these different things, knowing that there's a child with major congenital anomaly in the home being a huge risk factor for increased mortality, metabolic syndromes, hypertension, and so on and so forth. The data from the paper showed that, for example, in the case of fathers, the the adjusted hazard ratio was 1.4. mortality was 1.62. For parents with no child with MCA major congenital anomalies versus 1.76, in the fathers who had the child with MCI, and then mothers in went from 1.0 to 1.2. For mothers of children with major congenital anomalies. So yeah, I think this is very important for adult colleagues to be aware of as well. And we have to disseminate this evidence to them so that they can take care of these parents appropriately, because it really falls out of our purview when it comes to managing these parents.

Daphna 38:37

You Yeah, and I think it just it touches on another point that, you know, the NICU in particular is a place that becomes very mother centric. And, you know, we want fathers to be engaged in care. And we just, we're not studying them enough, we're not good at including them in care, we're not good at, you know, monitoring a, you know, how, what the fallout is for parents, even though the data is coming out, really, I think pretty strongly for mothers, and we know that fathers are affected too. And they may be affected in a different way. But certainly the the effect is, is there. So I was glad to see this paper, I think it certainly adds to the literature. I think you're right, that, you know, the audience needs to be broadened so that we can protect these parents. And kind of my review for this I was looking at the literature to for parents who experienced the death of a child and they have 30% more likelihood to experience early mortality. And most of those deaths are also related to heart disease. And so the effect is is not insignificant and then so we need to think about how we can support the mental health which translates really to physical health and longevity of parents.

Ben 39:57

Absolutely. There was one other aspects of the Paper and I lost all my notes on this paper. Now just I don't know why my iPad is doing that. But I remember that it mentioned that the predisposing factors of these mothers of children with major congenital anomalies were different from the ones of healthy, I guess, quote unquote, healthy children. And it is paused. A question that was very interesting, which was, in their discussion, they mentioned an alternative explanation could be that infants and parents share a common genetic predisposition and environmental exposure or health behaviors that lead to both anomaly and the parental illness. And I think this was a very interesting point that I was happily surprised to see that they brought up in their discussion because it is a chicken in the egg phenomenon, which is if if the parents have any type of predisposition, or if there's any epigenetic phenomenon that is causing the baby to be born with those major congenital anomalies, could this just could the parental then increased rate of mortality be related to this initial sort of predisposition, as they mentioned, and and that's why I think this paper was so impactful, because it shows how proper health supervision and proper healthy habits are necessary before conception, and after delivery, and even after discharge. And it's sort of span such a wide timeframe. That, I mean, it really feels like the magnitude of it is sort of overwhelming. But it is true. That that it's it's it's you wonder which one is responsible? Is it is it that the child with major congenital anomalies is so disruptive to this family, that it's causing stress and eventually sort of physical sort of health issues? Or is it that parental sort of habits caused the baby to be born with, with the genetics of this genetic predisposition, cause major congenital anomalies, and then this sort of is a snowball effect that leads eventually to increase mortality of parents. It's just mind boggling to think about it and see how all these different things tying together it's it's, it's tough.

Daphna 42:03

Yeah, and I think it does point to how some of these, you know, large, national registries can help us answer some of these these questions. And, you know, in a country where we don't have that kind of a database, we will really rely on on other countries to do to do that work for us.

Ben 42:22

Yeah, yeah, absolutely. Well, yeah, that was a fascinating paper. And that logarithmic curve showing the increased mortality of mothers and fathers is very impressive. Okay, I think the last paper for Journal of for pediatrics specifically is is a paper from Dr. Moran do dassia. I hope I'm pronouncing this correctly from the Children's Hospital of Philadelphia using data from Kaiser Permanente, and the paper is called intrapartum Group B streptococcal prophylaxis and childhood allergic disorders. And this paper was interesting because it poses an interesting question, which is, Can GBS prophylaxis disrupt the microbiome of the baby such that to cause allergies later into childhood, and they conducted this retrospective studies of 14,000 children where the mothers received GBS prophylaxis using penicillin, ampicillin, Sephora, Zola and clindamycin. vancomycin, more than four hours before delivery. And they followed these children for primary outcome of asthma, eczema or food food allergies within the first five years of age. And their results was that GBS prophylaxis was not associated with increased incidence of composite outcome among infants delivered both vaginally and via C section. And so I think it was it was interesting, because I was happy that it's, I guess from my standpoint, I was happy that GBS prophylaxis doesn't cause allergic diseases into childhood. But also it posed the question I never thought of, I never thought of GBS prophylaxis as potentially disrupting the microbiome of the baby really long term. So I was happy that somebody addressed it.

Daphna 44:04

Yeah, and I think it it provides for more questions. Right, that? Well, I think when we talk about the microbiome, and you know, the theory about how microbiome affects long term health outcomes, I think there are some other, you know, questions that we could ask, I was a little bit surprised, you know, given there's kind of some controversial associations with C section delivery, and concerns about long term ATP just from, you know, being delivered C sect by C section versus vaginally and as someone who admittedly had a C section delivery, this is something you know, that I wonder about, and think about kind of in my in my own life, so I thought it was interesting that but they didn't find even in their cohort, and they didn't find a difference between the two modes of delivery. I was glad They did evaluate some of the maternal history, which I think is hard to do, especially in kind of retrospective chart review. But they did make the effort to look at maternal allergic disorders, asthma, maternal allergy, and then specifically chorioamnionitis, which we know can predict childhood asthma. So I'm glad that they covered those kind of co founders, though, again, I'm sure it was difficult to ensure that through through the chart review, but I will say and then I think one of the strengths is that in their documentation of the childhood allergy, that they you know, require recurrent documentation, they had really good follow up, and that the ICD codes were paired with a prescription. So I thought that was definitely a strength and trying to capture, what does kind of the allergic population look like? Yeah,

Ben 46:05

the group was very thorough. They looked at neonatal antibiotic use the rates of breastfeeding. So no, they they did a very good job, in my opinion, to try to mitigate all the potential co founders that would immediately pop to mind. And so they did a very good job at that. So no, it was definitely a thorough study, and know very interesting results to a very interesting question that most likely we will never be faced with as neonatologist. I'm assuming the obese are probably getting that question more. But yeah, there you go. The data is there now.

Daphna 46:33

And I think it highlighted some of the other kinds of variables and really disparities that we have in our population. Um, specifically, and this is not new information. But I think it's important to highlight that you know, the need for GBS prophylaxis. In both types of delivery, were associated with a variety of specific factors. Certainly, black or Asian maternal race, high maternal BMI, maternal history of asthma allergy, and then residents in areas of low education, and income, and specifically at those were almost the identical factors that individually predispose to allergic conditions in childhood. And so, you know, none of that is surprising, but it's a it's a good reminder. I feel like especially in our BPD population, parents are always inquiring about asthma. And, you know, I think that we we have some data to help them better predict which babies are most at risk, and certainly gives us some areas of improvement of advocacy to focus on and to try to change some of those outcomes.

Ben 47:54

Absolutely. I could not agree with you more. Before we move on to Jama peds I think we there was another paper that I think maybe the listeners would be interested in knowing about it's called trends in retinopathy of prematurity screening and treatment 2008 to 2018. The paper is from Dr. Grace procolor popcorn. And this is data from the Vermont Oxford Network that looks at sort of the trends in retinopathy screening and treatment over the past 10 years. And it showed it's a good paper because it provides data that is necessary, but it was not very surprising in any way. It showed basically looking at the data from the VA network looking at the at the trends in screening and treatment and the findings of 381,000 very low birth weight infants across 819 us NICUs showed that basically infants received more eligible infants over time received ROP screening. Among those screened overall ROP, severe ROP and retinal ablation declined. And interestingly enough anti vascular endothelial growth factor injection increased. And so yeah, so I mean, I think we didn't really, I was not really surprised by all this. And I'm curious to see if you had any insight or any thoughts about this paper?

Daphna 49:20

No, I think that even the authors felt like they weren't surprised by the data. But I think it's useful for us to have it's useful for us to see what's really changing, you know, for for some of our sub specialists, they did spend some time in discussion about how 10% of their group were actually not screened in the in the timeframe. And again, they use the gestational age less than 29 weeks, in a birth weight less than 1500 grams. And the fallout so to speak, are those babies that I think we encounter all the time. You know, maybe they don't meet both criteria, or maybe they're so close To the cut off, you know, we're not sure what to what to do with those babies. So the majority of those babies were older or only met one criteria or, you know, the weight, the weight was was close in some institutions are not using 1500 grams. So that's that's definitely, I think, a point for discussion and always, in our individual units to say, how can we avoid missing babies or, you know, make sure that our all of our screening gets done on time.

Ben 50:31

Yeah, and, and that was, that was a bit striking that 10% would be sort of falling through the cracks. The other thing that might change over time, I think it's the use of anti vascular endothelial growth factor injections. I think this is something that was extremely promising about 10 years ago. And as the data about long term neurodevelopmental outcomes of babies who undergone who have undergone some of these injections compared to laser is showing that there's a detrimental effect of these endothelial growth factor injections of these endovascular endothelial growth factor injections, well, it makes you wonder if that trend is going to get reversed in the next 10 years. So I'm curious to see what the follow up paper is going to show.

Daphna 51:11

Yeah, and I think there's still some, you know, debate debate in the literature, I think, you know, we're still waiting on some of the long term, follow up data. So I think it will direct care for sure.

Ben 51:23

And I think like everything in neonatology, it's going to boil down to there's going to be some criteria that are going to be published that says, well, for this specific group of patients, Avastin works really well for this group of patients, laser works better. And I think it's going to be depending on ROP stages and the zones, specifically, whether you're in Zone One versus zone two, and three. So every year, I think it's going to end up being a bit more granular. And it's going to be a bit more sophisticated in how we approach the different treatment modalities that are now available to us.

Daphna 51:53

What I mean, I think that's the key, right, just working towards individualizing medicine, and really kind of hammering out the data about, you know, splitting babies into into groups, the right group and and deciding what works best. And I actually think that that takes us into our JAMA article for this month, the association between preterm birth phenotype and differential morbidity, growth and neurodevelopment at age two years. And so I thought this was a fascinating paper, I really care about, you know, good anticipatory guidance and

Ben 52:35

so, so for the people who haven't read the paper, this was I know yours. I know that you have a lot to say about this. So hold your horses and I'm going to I'm going to just give the listeners a quick summary It was published. first author is Dr. Jose Vilar, and this is from a group out of the United Kingdom. The objective of the paper was to examine the association between specific preterm birth phenotypes and clinical growth and neurodevelopmental differences among preterm newborns compared with turn newborns to age two years. The main outcomes were infant size, health, nutrition, W H. O motor development milestones assessed at ages one and two years neurodevelopment evaluated at age two years using the integrative 21st neurodevelopmental assessment tool, were their findings. So they were able to identify the studied the study that they included in their analysis about 7000 babies, and they were able to identify eight phenotypes that they and they are defined as follows no maternal fetal or placental condition detected, I guess, completely normal, then there's infections. Then there's preeclampsia, fetal distress, IUGR, severe maternal disease, bleeding and congenital anomalies. And then in their conclusions, their results show that compared with term newborns, the highest risk for scoring lower than the 10th percentile on the inter NDAA normative values was observed was observed in the fine motor development domain among newborns with the fetal distress phenotype. They're saying that these results suggest that phenotypic classification may provide better understanding of the etiologic factors and mechanisms associated with preterm birth, than continuing to consider it an exclusively timed time based entity. So go ahead, Daphna. Tell us your thoughts about this.

Daphna 54:28

Well, I mean, first to credit the group. I mean, they had babies from all across the world basically included, which I thought was impressive Kenya, South Africa, Thailand, Brazil, Pakistan, and of course, the largest group there in the UK. They did take babies from 23 weeks gestation to 37 weeks gestation, though their mean gestational age was 34 weeks. So I think that if we maybe even had a group of more preterm babies said that the data I imagined would be pretty similar. But like you said, we could get a little bit more granular. They had, I think, excellent follow up. So they had almost 80% Follow that one year and up to 70% Follow up at two years. And so I, you know, I think that they gave us some really good data to work with. Some of the other findings are that the, you know, you talked about the neurodevelopmental findings that fine motor delay was high among all phenotypes. So you know, that really shows that just prematurity and in and of itself without any comorbidities affects development, particularly in fine motor. The babies who had the highest mortality, were the babies in the bleeding infections and congenital anomaly groups, independent of gestational age, that babies that had the highest risk of neurologic disorders were in the bleeding IUGR and fetal distress groups. And then the highest risk of like you said, severe clinical conditions IUGR bleeding, and congenital anomaly, I thought, you know, that this is something that we really need to start paying attention to so much of the maternal history or pregnancy history, we write down in the HMP, and we used in the first maybe 72 hours to make decisions about antibiotics are about feeding progression. But we're not really using it as part of our prognosis for parents. And this, this is almost kind of reminiscent of the discussion we had in our first episode about MRI, you know, findings and ultrasound findings, and how can we really counsel parents and give them the best information about their long term prognosis? And so I think this is so important to, you know, one reducing some of the burden mental burden associated with prematurity by by being able to give parents kind of more information, and, and to ensuring that we get the best developmental follow up for the babies who are at most risk. And so I hope we see more papers like this. I hope that we are using it, at least preliminarily to talk about with some of these additional risk factors. Like, you know, IUGR, the babies who had a perinatal infection, and then I think it really gives me more pause about those babies born for fetal distress. And we don't know why they were born for fetal distress, you know, or what was the cause of fetal distress? And there are so many causes of fetal distress. But certainly we know that things like you know, hypoxia are a big predisposing factor to fetal distress certainly could predict kind of some neurodevelopmental outcomes.

Ben 58:08

Absolutely, I think I completely echo your sentiment that it shows us how we should be thinking about these preterm babies. And that starting to think about them in terms of their phenotype based on their clinical course, before delivery makes a huge difference. I also completely agree with you that right now, this paper is looking at a few items, infant size, nutrition, and some neurodevelopmental milestones. But I'm very curious to see a broad spectrum sort of study looking at short term morbidities and mortalities associated with different phenotypes. But I also think this paper is the is the product of where our field is going. Overall, I think until now, it was all about let's get some premiers to survive. And they were all bundled together. And we've become over the past 2030 years really good at saving 2627 2829 weekers, maybe less. So below 25 weeks, it's still remaining a big challenge in many places. But for those babies, I feel like since our technology and our knowledge has become so strong, it is now time to tease apart all these different babies and stop bundling them as like these ELB W's they're not just Joby W's anymore, and we have to see who they are, why they were born early. And, and again, always creating the link between the baby and the mother. We tend to feel like once the baby is born, it's like a hand of poker, you know, we've been dealt a few cars and we just have to play those cards. But no, it's the baby is directly connected to the mother even after delivery. And it's interesting that the phenotype of preeclampsia is there as well, severe maternal disease, bleeding, all these things that you would think well, these are maternal issues. And so the baby is quote unquote, fine. Well, that's not the case. And that needs to be looked at more intense intensively. I know There's a lot of data looking at outcomes of preeclampsia, for example, but I'm just very happy about the development of a new approach to the thinking of prematurity. So yeah, this paper got me really excited about thinking about things a bit different. Yeah,

Daphna 1:00:15

I think it's gonna force us to adapt our algorithms, you know, that we can't just have these kinds of sweeping protocols for all of our tiny babies that that we will have to use, like you said, play play to the strengths of the babies, but certainly be aware of some of the additional complications that are not just a factor of gestational age.

Ben 1:00:39

And practically speaking, I think when you're admitting a patient to the NICU, and you're putting in their list of diagnoses, you would never put preeclampsia, for example, but now it makes you wonder, should we put some of these maternal conditions in the baby's chart so that we are reminded of the phenotype that this baby belongs to, in order to anticipate some of the complications that we now know are associated with them? Something to think about?

Daphna 1:01:01

Well, I think we'll start doing that, won't we? At least?

Ben 1:01:08

Yeah. So I guess we're running out of time. We're now but it's okay. I mean, we have one more paper that was interesting that recently came out in JAMA peds and this paper is called fortification of breast milk with preterm formula powder versus human milk fortifier. In preterm neonates, a randomized non inferiority trial. The trial was conducted by first author, Dr. Chen, Japan, and this is data coming out of India. The objective of the paper was to demonstrate that fortification of EBM by preterm formula powder is not inferior to fortification by HMF in term in terms of short term weight gain in V. LBW neonates, this was an open label non inferiority randomized trial conducted between 2017 and 2019. At a level three unit in India, the neonates were randomized to either this, this powdered formula called PTF, or HMF. And the main outcomes were weight gain until discharge from the hospital or 40 weeks postmenstrual postmenstrual Age whichever was earlier. And their main conclusion was that fortification with preterm formula powder is not inferior to fortification, which human milk fortifier in preterm neonates, given the possible reduction in food intolerance and lower costs, preterm formula might be a better option for fortification, especially in resource restricted settings. And what they're referring to was that they did notice a few in terms of their outcomes. They didn't notice less intolerance to powdered formula supplementation, they noted a little bit less any See, even though that was not really statistically significant. And so the number the proportion of times in whom fortification had to be withheld was lower also in the powdered formula. So they did find some advantages as well. When it came to differences in sepsis, culture, mortality, culture, positive sepsis, metabolic bone disease, ivh PDA ROP BPD, that was sort of similar between the two groups. So I'm curious to see what your thoughts were on that.

Daphna 1:03:21

Yeah. And I think, importantly, one of the one of their outcomes that they didn't find any difference in the longitudinal postnatal growth, and either in height or weight, even given the the difference in protein between the two products. So I gotta say, I was surprised by, by the by some of the findings, and it was 120 infants, they were randomly assigned almost. exactly in half to, to either group. I, I'd love to see a bigger trial, I think, just to see somebody, you know, how would some of those other factors that didn't reach a significance would would play out?

Ben 1:04:04

But I think I would be I would be interested in this. This was done in India, which is which which they described themselves as sort of a, a low to middle resources sort of area, but I'm thinking even in a in a high resource area, looking at the different fortification, the Similac HMF, versus regulation versus poor lacto versus powdered formula, all these things, I think, would be very beneficial even for us.

Daphna 1:04:29

Well, and I think we've almost gotten to a point where in some places, it's it's hard to do this type of study, because we kind of have this bias that we've selected one and we think that's the safest thing for for babies. So it actually has kind of eliminated some of the research opportunities in this area, but I think it certainly gives us something to think about about you know, doing a study like you said with kind of more arms made me thinking twice about, again, the individual baby and what's right for that specific baby? Do we, you know, in our units that we're using HMF until a certain gestational age threshold and the baby's not growing well on on what we're doing. Could we try a different product? Could we try a different formulation? Could we try?

Ben 1:05:22

Right? So there's there's two things that I noticed from this study that I think are to take with a grain of salt, not because they were bad, but because it impacts how generalizable the data is. Number one, their babies were quite old in terms of gestation. The mean gestational age was 30.5 weeks with a standard deviation of 2.2 weeks in the preterm formula fortification group, and 29.9 in the human milk fortifier group. So they were not 23 weekers. That's number one. The other factor that I thought was a bit different from how I'm used, at least to practice is that their target feed volumes reached consistently 180 mL per kilo per day, which I don't think is bad. I just I'm just saying that this is something that I'm not used to doing. And I'm wondering if in terms of growth, specifically, if this would change if suddenly, we had a lower target volume. So if you're targeting our usual 151 67 135 and BPD patients, would that impact the amount of proteins that these babies would be receiving vitamin D and things like that? I don't know. However, what I think is very useful about this study is that yes, it's testings, something that may not appear to be a problem to us. But I have encountered so many families that have questions about using HMF. And looking for alternatives. And like you said, because we're used to doing something one way and not really entertaining other alternatives, it's hard for us to give options to these families. And so I feel like if a family is saying, Hey, I don't want to get my baby hmm, is there any other options? Well, if they elect to go for preterm formula, supplementation, well, now at least I have data to say, you know, what, it's not going to impact the baby's growth and complications are not going to be significantly impacted. So I feel like, even for us, in the US, this may serve a specific group of parents who have questions about the use of human milk fortified

Daphna 1:07:10

well, and I think they touch on to some some, you know, some kind of biological plausibility to some of their findings. And, and a big one was about the total osmolality of the formulas and, and that matters, right, and in different formulations of the same type of fortifier. The that changes. And so, you know, it's something we definitely need to think about and for there HMF product, the osmolality was 464 versus a preterm formula of 357, which is no no small difference, you know, in his right there along the, the, you know, threshold for what we think of for the extremely preterm infant. The other thing that, you know, it really, it really is a good reminder about

Ben 1:08:05

how exactly what's I know exactly what you're going to talk about now, go ahead, but we'll see,

Daphna 1:08:09

we'll see about how some of the other additives impact, you know, the overall feeding progress. And for some of our babies, if we look at the list of medications that they're on, and the additives that we're, you know, reacting to their vitamin D levels, their anemia, you know, when you really take take a look at the how much that that tiny preterm intestine has to tolerate, it's really incredible that we can ever feed babies to be perfectly.

Ben 1:08:42

Yeah, that's true. That's true. And it's and it also at the end of the day, I'm really appreciative of the group putting costs in the equation. I think, as doctors, thankfully, we don't think too much about costs, because it shouldn't be driving how we practice medicine, we have to give babies what the best treatments possible, and whatever's the best treatment available. But it is true that cost is an issue. And we have to be mindful of how much resources we're consuming, especially when alternatives are available, that might be sort of less of a burden on both parents in the US because parents have to short shoulder the bill and in other sort of socialized countries where the state has to really pick up the tab at the end of hospitalization. So I think always thinking in terms of cost analysis really, is something that is valuable. Okay, so we tried to look at some of the articles in the New England Journal of Medicine, there was not really anything particular. Regarding neonatology. There were two interesting clinical images. One of them have a closed gastroschisis and another one of visual peristalsis in a newborn preterm infant, I invite you to go check them out. They're kind of cool pictures and videos. But other than that, I think that's it For our second journal club and episode number three, any any other final thoughts Daphna?

Daphna 1:10:06

No, we're just welcoming more listeners. And thanks for everybody for kind of hanging in with us today as we went a little bit long, Ben, it's a pleasure is all No, but

Ben 1:10:17

it was it was fun. It was fun. And we have and we have a lot of cool episodes scheduled with a lot of interesting collaborations between us and, and other people and organizations. So this is going to be a lot of great content coming, coming your way. So yeah, subscribe and and we'll see you next week. Daphna. Thank you very much as always, have a good one. Bye. Bye. Thank you for listening to this week's episode of the incubator. If you liked this episode, please leave us a review on Apple podcast or the Apple podcast website. You can find other episodes of the show on Apple podcasts, Spotify, Google podcasts, or the podcast app of your choice. We would love to hear from you. So feel free to send us questions, comments or suggestions to our email address NICU podcast@gmail.com. You can also message the show on Instagram or Twitter at NICU podcast. Personally, I am on Twitter at Dr. Nikhil spelled Dr. NICU. And Daphna is at Dr. Duffner MD. Thanks again for listening and see you next time. This podcast is intended to be purely for entertainment and informational purposes and should not be construed as medical advice. If you have any medical concerns, please see your primary care practitioner. Thank you