Hello Friends 👋
We are back after a week of absence. COVID has wrecked its way through our team and has caused us to fall behind on recording and releases. With this out of the way, we have an interesting journal club this week to share with you. We talk about Sildenafil for pulmonary hypertension and review a study out of India 🇮🇳 looking at the differences between IV vs PO sildenafil. We review a paper from Iran 🇮🇷 assessing the effects of head positioning in preterm infants on Near Infrared Spectroscopy (NIRS) parameters. We also talk about something that was new to us: Presepsin. This marker was reviewed in a meta-analysis in JAMA Peds and appears to be a good marker for early onset sepsis. We have a lot more article this week, so check out the episode and have a good week!
The articles covered on today’s episode of the podcast can be found here 👇
James J. Cummings, Arun K. Pramanik; COMMITTEE ON FETUS AND NEWBORN, Postnatal Corticosteroids to Prevent or Treat Chronic Lung Disease Following Preterm Birth. Pediatrics 2022; e2022057530. 10.1542/peds.2022-057530
Initiation and duration of skin-to-skin contact for extremely and very preterm infants: A register study. Linnér A, Lilliesköld S, Jonas W, Skiöld B.Acta Paediatr. 2022 Sep;111(9):1715-1721. doi: 10.1111/apa.16433. Epub 2022 Jun 10.
Oral versus intravenous sildenafil for pulmonary hypertension in neonates: a randomized trial. Chetan C, Suryawanshi P, Patnaik S, Soni NB, Rath C, Pareek P, Gupta B, Garegrat R, Verma A, Singh Y.BMC Pediatr. 2022 May 27;22(1):311. doi: 10.1186/s12887-022-03366-3.
The effect of head positioning on brain tissue oxygenation in preterm infants: a randomized clinical trial study. Mohamammadie ZR, Ramezani M, Heidarzadeh M, Sezavar M, Saki A.J Perinatol. 2022 May;42(5):660-666. doi: 10.1038/s41372-022-01366-w. Epub 2022 Mar 24.
Presepsin for the Diagnosis of Neonatal Early-Onset Sepsis: A Systematic Review and Meta-analysis. Poggi C, Lucenteforte E, Petri D, De Masi S, Dani C.JAMA Pediatr. 2022 Aug 1;176(8):750-758. doi: 10.1001/jamapediatrics.2022.1647.
Sodium supply from administered blood products was associated with severe intraventricular haemorrhage in extremely preterm infants. Späth C, Stoltz Sjöström E, Ågren J, Ahlsson F, Domellöf M.Acta Paediatr. 2022 Sep;111(9):1701-1708. doi: 10.1111/apa.16423. Epub 2022 Jun 10.
Thrombocytopenia and insufficient thrombopoietin production in human small-for-gestational-age infants. Takeshita S, Kakita H, Asai S, Asai T, Mori M, Ueda H, Aoki H, Aoyama M, Yamada Y.Pediatr Res. 2023 Feb;93(3):619-624. doi: 10.1038/s41390-022-02107-7. Epub 2022 May 14.
The 5-minute Apgar score and childhood school outcomes.Selvaratnam RJ, Wallace EM, Davis PG, Rolnik DL, Fahey M, Davey MA.Acta Paediatr. 2022 Oct;111(10):1878-1884. doi: 10.1111/apa.16443. Epub 2022 Jun 14.
Longitudinal changes in lung function in very prematurely born young people receiving high-frequency oscillation or conventional ventilation from birth. Bisquera A, Harris C, Lunt A, Zivanovic S, Marlow N, Calvert S, Greenough A, Peacock JL.Pediatr Pulmonol. 2022 Jun;57(6):1489-1496. doi: 10.1002/ppul.25918. Epub 2022 Apr 18.
Dextrose Gel for Neonates at Risk With Asymptomatic Hypoglycemia: A Randomized Clinical Trial. Gupta K, Amboiram P, Balakrishnan U, C A, Abiramalatha T, Devi U.Pediatrics. 2022 Jun 1;149(6):e2021050733. doi: 10.1542/peds.2021-050733.
Detection and impact of genetic disease in a level IV neonatal intensive care unit. Hagen L, Khattar D, Whitehead K, He H, Swarr DT, Suhrie K.J Perinatol. 2022 May;42(5):580-588. doi: 10.1038/s41372-022-01338-0. Epub 2022 Feb 18.
The transcript of today's episode can be found below 👇
Welcome Hello, everybody. Welcome back to the podcast. It's Sunday. We are back. We're back. How are you? How are you? It's good
to be back.
Yeah, it's so. So we took a week off, because I was ill with COVID the past week. And so I know, there was there was no way to get anything. Nothing of quality out. And so the so yeah, so there was no point. So that's, that's why we were Mia, for a week. But we are back with Journal Club. We're very excited to be back. And there's a few things that that thankfully, I mean, definitely you announced on Twitter handle this week, that we should probably remind our audience number one. Probably next week, we'll have our first Spanish episodes of journal club released. We recorded the first one, it was very, very cool. So that yeah, so that will be done. Next week, we have our first episode of Tech Tuesday, which again, had to be postponed because of just me being completely out of commission. And then finally, for the people who have joined the neonatal network, the first set of grant applications is out and you have a few weeks to apply for grants. It's exciting.
Yeah, we're really excited about that. And it's, it's more than a few weeks. Right. So
yeah, I wanted to apply some pressure. There's some.
That's fair. That's fair.
So that's, these are the announcements. And without further ado, I think we should get into Journal Club. Sounds good. Should I start?
Yeah, you start?
Okay. So the first, I guess, I guess that's the first paper. The first paper I'll be talking about today was published in BMC. Pediatrics. It's called oral versus intravenous sildenafil for pulmonary hypertension. In neonates a randomized trial. first author is Shin may shaitaan. And this is a paper coming out of India. It's an interesting, it's a very interesting discussion, right? I mean, they're making the case that in India, which, based on lower resources, they're saying, we don't have access readily to nitric oxide. And we relies heavily on sildenafil. And
we, I mean, nitric oxide, even here in the States is so expensive.
Your your time and for the people who are listening from abroad, we have to do very frequently peer to peer, which is that the insurance company has some random doctor call us to say, Hey, you're using nitric oxide? Can you walk me through why you're doing that? And if you don't convince that peer, that the nitric oxide is warranted, they they refuse treatment. And I think nitric oxide is is something that they bill by the hour. So for the people who don't know, and that's maybe a I love these low fun facts. But if you look on your nitric oxide, tanks, people, there's a meter on the tank, which means that as you open it, it calculates time. And that gets built to the patient. So that's how they know how much nitric you've used is. Yeah,
I mean, it is any other medication. I don't know of any medication.
So this is not one day, I asked one of the wrestlers like why is there a meter on the tank and that I get, that's how we know how much you guys are using. It's by the time you leave the tank open. So anyway, so Dr. Shaytan makes the group there makes the ask the question, how do we know the difference in efficacy and side effects between the two forms of benefit whether it is pure or IV? And I think this is a very interesting question because we tend personally I tend to use a V sub NFL when Pio no longer is an option meaning the BBS either in an in and around an operation or something like that, but I never really knew whether the two were equally in terms of efficacy and if there's any difference that I should be aware of. So this was an open labeled parallel randomized trial that was designed and conducted in a single center at level three units in urban and urban academic medical center in Pune, India, Pune, Pune, India. I'm probably mispronouncing I don't know. They looked at, I don't know. Yeah, I'm doing my best here. It was the children that were studied were enrolled between February 2019 and December 2020. They were randomized One to One either to PO or IV sub NFL. Now, they looked at late preterm infants, which I think is the proper population and term infants. So anybody above 34 weeks, and these babies had pulmonary hypertension, which was defined as having a pulmonary arterial pressure above 25 millimeters of mercury on echocardiogram within 72 hours of birth. The excluded anybody with congenital heart disease, congenital diaphragmatic, hernia, lethal congenital anomalies, any contraindication for oral or IV sub NFL, whether it was systemic hypotension, necrotizing, enterocolitis, GI bleed, and any babies that did get nitric oxide was also not included, obviously, because it was it was compounding. So a few questions that I was wondering that are interesting from a design standpoint is how did they obviously diagnose PPHN. So all late preterm interim infants that were admitted to the NICU on nasal oxygen, non invasive support or invasive support, were screened for pulmonary hypertension with an echo every 24 hours for the first 72 hours after birth. And they measured the pulmonary pressures through tricuspid. regurgitation velocity. They didn't really have a breakdown as to what they defined as mild, moderate to severe. That's that's all the information that we have. And then in terms of the medications, the oral sildenafil group was started on a SKU six hours, one milligram per kilo per dose regimen, and the babies and the IV group, were given a loading dose of point four milligram per kilo over three hours followed by an infusion. That was 1.6 milligram per kilo per day. So the outcomes that they were looking at were the time it would take for the pulmonary pressures to go below 25 millimeters of mercury. And after they basically how did they figure this out is they started the medication and they did functional echocardiography every 12 hours until it was until the pressures were below 25. They looked at some other secondary outcomes time. Time for the Oli the oxygenation index decreased by 25%. The days of ventilation duration of hospital stay some outcomes, failure of treatment, meaning they had to recourse to something else to treat the permanent hypotension, complications and time to reach for feeds. So, alright, let's get into some of the results. They were able to enroll 40 neonates out of 2400 neonates above the age of 34 weeks that were admitted to the NICU. And those 40 neonates were diagnosed with mild to moderate PPHN. The median gestational age and birth weight was about 38 weeks and 2800 grams. And the baseline characteristics were pretty much the same except and not not, it's not non significant the they had, or the oral sildenafil group had worse Apgar scores at both one and five minutes. I think it was like five versus seven and seven versus nine. They had a bunch of reasons for these kids having pulmonary hypertension, it included mostly meconium aspiration syndrome, pneumonia, birth asphyxia. There was some sepsis, very few Waititi nrds, and three cases in the oral group that were, quote, unquote, idiopathic. So let's take a look. The self benefit could be tapered in 85% of the neonates receiving oral sildenafil and 75%. In the IV group, the difference was not significant. 15% of the neonates in the oral group and 25% in the IV group had to be started on some form of other pulmonary vasodilators, again, not a not a significant difference considering that the numbers were were low.
So in terms of the primary outcome, they were able to taper the oral sildenafil and the IV sildenafil at about 48 hours of life. And the IQR is a bit different, the inter quartile range, the interquartile range is a bit different between the two but it's still 48 hours so there was no real significance. After tapering so beneficial three neonates had a rebound increase in pulmonary arterial pressure in the oral group and five had a rebound in the IV group. The only thing that was interesting and that was actually statistically significant were some of the complications associated with the treatments. And these involve the hypertension which was the son no cases of hypertension in the oral sub NFL group, but saw four cases out of 20 in the IV group, and then one baby in the IV group had poor cardiac contractility. None were find in the IV group. So the conclusion of the studies this study is that both routes of administration of Sudan and elsewhere pointed hypotension in neonates are beneficial. And, but there's caution regarding the close monitoring for hypertension and cardiac contractility using IV, the IV formulation. So I don't know if this paper really answers fully the question because it's a small study, but it's data nonetheless. And I thought that was interesting. Any any thoughts?
Yeah, no, I mean, it's important to know, because we see, it's not uncommon to have to switch back and forth. So or to use one or the other, you know, is a primary intention.
Yeah, absolutely. Absolutely. And I mean, for us, babies who are usually very sick tend to be started on nitric oxide. But the question always, I always wonder, like, should I start IVs of benefit instead? And would that just work? But I'm afraid to deal with pharmacy? So
yeah, at this point in our facility, it's easier to it's easier
to get my trick, of course, it's been the same like this everywhere. I've worked anyway.
And it's faster. Right. So sometimes, when you need it, you need it. Yeah.
That's yeah. Us to next
let's see, I had this paper entitled The effect of head positioning on brain tissue oxygenation and preterm infants a randomized clinical trial study, lead author, Zeinab, Mo hum. Ma mowdy.
I even practice that one before we start.
It feels like it should be easy to pronounce Mohammed Yeah, no,
it's I think it's like, spelt, it's a nice name. This isn't a journal Perinatology. And so the question really is, does head positioning change brain tissue oxygenation? And so obviously, this is an ongoing area of debate. You know, because a lot of the ivh bundles use it midline, head positioning, with or without some sort of incline. And the data is not really robust on whether or not this actually helps prevent intraventricular hemorrhage. So this study did not try to answer that question specifically, but was looking at brain tissue oxygenation, using nears. To say does it does it change brain tissue oxygenation? Or I guess, does it change our nears measurements? We can answer. So the study design is it's a it's a cohort study. The inclusion criteria was all preterm infants less than 32 weeks and less than 50 nanograms admitted to this NICU, in this hospital in Mashad, the infants,
and that's an Iran Correct? Yes, I think that's kind of cool. That was one thing that I was thought was kind of cool. Like it's a it's a nursing, I'm assuming it's a nurse because the first author is from the School of Nursing and Midwifery. So it's kind of neat. I love to have variety of groups from all around the world. So that's kind of I thought that was cool.
The babies needed to have no ivh they had Apgar inclusions at girl greater than five at one minute and greater than seven at five minutes, which I thought was good, really good for babies wasn't 32 weeks. And they needed to have a hemoglobin greater than 12 and a map quote unquote, normal. But they didn't give us what their parameters were. exclusion criteria was any baby that had known IV or is found to have ivh AND, and OR need for blood transfusion. So the intervention was the use of six combinations of head positions, and I'll talk about what those are. They have 39 and fence that underwent head positioning within the first 48 hours of life. So, infants were served as their own control group because they were placed on the nears monitor to evaluate brain tissue oxygenation at baseline, quote, unquote, which didn't describe any particular head positioning. And then, over the course of 12 hours, they cycled through the six positions by changing position every two hours and measurements were recorded in those positions in addition to vital signs And, like the pulse ox, the peripheral arterial oxygen saturation. So I'll tell you the positions, the first position was head and midline with the bed at zero degrees, so no incline position to the head rotates 45 to 60 degrees from the midline to the left at zero degree incline, then into the third position, the head rotates, basically, the opposite 45 to 60 degrees from midline to the right, but the head at zero degrees incline. The fourth position then is just midline with the head inclined 15 to 30 degrees. position five is basically a combination. So head rotated to the left with inclined position six head rotated to the right, with incline. So they wanted to look at the differences between those positions, baseline characteristics, the mean age enrollment was 30 hours, and none of the demographic criteria collected was significant. And in regards to the baseline oxygen saturation. So the primary outcome was what was what were the measurements and in each of these positions, and I'm not sure it's totally that useful if I just read these out loud. They're pretty similar. But there were some significant differences. So it was significantly lower in the third position compared to baseline.
So I think for the people who need to have who are driving like, yeah, the first three are like head is head is down, and it's either midline, right or left. And then they had I don't understand why they would have a head at an incline, like almost like as if they had put a pillow underneath the baby's head, right?
Yes. So there are lots of there are lots of hospitals that that are using head inclined,
right, so and then. And then in the last three positions, whether it is positioned for five or six to head is at an incline, and is either an insulator midline at position four, right or left position five and six. So
I don't think it's like a pillow. I think it's like most people are doing it.
Like the whole, like the whole bed is just Yeah, Tilton but I mean, it does look like on the diagrams, it looks like the rest of the body. Like because they have the bed, the bed remains straight, and they just have this incline for the head. So it's almost like they have I don't, I'm just trying to give people a visual representation. I'm not
sure. But that's an interesting point. Because that would be
different, right? Because it doesn't like on the on the diagrams that they have. It doesn't seem like the angle of the bed on which the baby drawn is resting is moving, that stays at zero degrees. They just are introducing something right before the shoulders where the head is moved up and down. Yeah, it does
look like that doesn't Mm hmm. While I think that's important to note, because then that is a you know,
yeah, just so people can can decide if that's something that they should change on their way to work today. Right,
great. Okay, so what I'll tell you is it was significantly lower in the third position, which is a reminder is the head rotated to the right with the bed at zero degrees as compared to baseline. And in that same position head to the right with no incline compared to the first position, which is midline, no incline and the fourth position, which is midline, with an incline. So it was significantly lower with the head to the right. And in addition, it was lower in the second position, which is head to the left with no incline compared to the first which is had midline midline. But there were no statistically significant differences between the other two positions. Okay. And in addition, there were no differences in respiratory rate by position in map mean arterial pressure by position or in the arterial oxygen, ox oxygen saturation, and in terms of heart rate, the fourth position, which is head midline, with an incline actually had higher heart rates than the first and sixth position. Sure. midline, no incline, and six is to the right with an incline. Okay, and there were higher heart rate It's in the sixth position, which was head to the right with an incline. Significantly higher than almost all of the other positions first, second, third, and fifth. So it was only not higher than midline with elevation and no turn of the head. So, the study takeaways were that in this study, the head mid line with the head of the bed elevated to 15 to 30 degrees had the most tissue oxygenation. And that the third position, which was head rotated to the right, soccer, and had the lowest had the lowest saturation. So I'm not I don't know what to make of this information. So I think there is probably I think there probably is something about head positioning, we just we just don't have enough data. The studies are too small. And was this the right? Was this the right measurement? I don't think you know, we don't even we still don't know is is nears was nears and this fractional excretion of oxygen? Is that equivalent to you know, brain saturation?
You're absolutely right, I think because the evidence is so scant on this topic. And I feel like this is something that I don't have a long career. But every institution I've been at that question comes up, and no one has. And so I think as a from from from us in an editorial role at the podcast, we have to keep bringing up these these studies as they come out, especially when the evidence goes back and forth. Because I feel like I cannot quote you the paper. But I feel like the last paper we read said that the head positioning didn't matter when it came to ivh. I think the outcome was ivh. And now this is saying
that there have been two Cochrane Reviews in 2020 and 2017, who they just they didn't even necessarily say their difference, just that there wasn't enough data
now, for the people. Okay, so now let's leave the discussion out. There's one thing I really like about this paper. And if you scroll all the way down in the implications of the paper, the first bullet point is that it says, and I quote, nurses should consider the importance of head positioning to improve brain oxygenation of preterm infants in the NICU. And we discussed that this is most likely a paper written by nurses in Iran. And to me, it was a great reminder, because Daphna and I are actually having discussions within our unit about neuro protection, the neuro protection bundles and all that stuff that we have to look at again. And to me, it's interesting that you read this and that you realize that, for whatever reason, this falls on the nurses in Iran. Right. And, and it made me feel that
there's an R unit to in most units. Right, right.
But I did feel like it almost seems that the nurse makes the decision, right? It almost feels like it's it's a it's a public service announcement that they're these nurses are making, saying, Hey, if you're a NICU nurse, you should pay attention to head positioning, which made me feel very fortunate that we have the luxury of time to actually look at this as a multidisciplinary group in our team, right. We have nurses, we have physicians looking at this. So that's kind of neat, to see how other countries are functioning. I'm always very curious to see how other places do things. And I thought that was a nice little peek into the life of a NICU nurse in Iran who has to worry about these things, because I guess, maybe the doctors because of staffing because of resources, I don't know are preoccupied with other issues. And so this falls on the nurses. I don't know. But this is very interesting to me that this was in the implications. Yes. Okay, um, next, I guess. So. So then it felt we talked about
let me see. Is there Oh, okay, so the next paper I wanted to talk about, I'm going to do it quickly. But this is another paper that from an editorial standpoint, I felt like we needed to mention to the audience, and it's a paper published in JAMA peds and it's called the precepts in, like the name of the molecule is called precepts and for the diagnosis of neonatal early onset sepsis, a systematic review and meta analysis. For starters, Chiara podi, and it's a paper out of Italy. The idea is that there's this this marker called precepts, and it's the it's from the cleavage of city 14 by circulating bacterial proteases during sepsis. And the paper looks at whether we could use this marker to diagnose early onset sepsis. Obviously They're making a strong case for why this would be useful in early onset sepsis, we don't really have good inflammatory markers, CRP protocol are usually very, very high. This with non infectious like this spike in non with reaction to non infective stimuli in the first 48 hours. So then babies in the getting worked up for sepsis sometimes even get empiric antibiotics. So having a marker that could help us make a decision would be very much welcome. Now, this is a meta analysis. So there's been studies on this on this on this compound on this on this marker, which to be honest with the I was not aware of. But if there's a meta analysis on this in JAMA peasley, you got my attention. So they're they're also mentioning that there's not a lot of studies that have looked at early onset alone, some studies have looked at early onset and late onset. We'll talk about that in a second. So the aim of the study was of the analysis was to assess whether precepts and its accuracy for the diagnosis of neonatal early onset sepsis. They included studies based on the following criteria, the studies that included newborns either term or preterm. Number two studies with a diagnosis of early onset sepsis as the evaluated outcome defined either as culture proven sepsis, and that was used for their primary analysis, or as a clinical or culture proven sepsis. Meaning like, if the clinician didn't have a positive culture, but determined that this was a sepsis, then that was also considered an outcome. And that was used the studies that use this as a as an outcome was were used as for the secondary analysis. And third, that's important,
right? I mean, we've talked about this, so many times our definitions of disease in research, matter, right.
And, and studies that use precepts and values during the initial workup for suspected us exclusion criteria studies that did not include us studies that lacked data on sensitivity and specificity studies that were case reports, commentaries or reviews. So let's talk a little bit about the results. A total of 12 studies met inclusion criteria for the primary analysis, and then a total of 23 studies. So in addition, 11 met inclusion criteria for the secondary analysis, and the primary analysis among the 12 studies, which included 828 newborns, of any gestational age, pulled sensitivity and specificity. Were point nine, three and point nine one respectively. So pretty impressive, the pulled diagnostic odds ratio was 131.7. The diagnostic odds ratio for people who I mean, I have to look these things up every single time and I'm thinking maybe you guys would benefit from reviewing it with me. Yeah, the diagnostic odds ratio is the odds of a positive test in those with the disease relative to the odds of a positive test in those without the disease. So, so yeah, so that's the diagnostic odds ratio, and in this case, it was 131.7. subgroup analysis showed that precepts and specificity was associated with the inclusion of only EOS or all neonatal sepsis, precepts and precepts and accuracy was not associated with gestational age. And, but about that, I want to I want to make a little clarification. So when you go into the results, even though the gestational age as a continuum was not really associated with the accuracy, they found no differences in precepts and accuracy between studies enrolling only term infants versus only preterm newborns, whereas studies enrolling term and preterm newborns showed significantly lower specificity in comparison to those enrolling only term newborns, but not significantly different sensitivity, or the or diagnostic odds ratio. So it seems to work pretty well on term and a bit less when you include the premiers in there. But I feel like that's kind of good, because the question usually that arises is mostly for the term babies that I mean, it's really separation from the parents. And so yeah, studies enrolling only newborns with EOS should have higher specificity compared with those enrolling a mixed population of us and LS late onset sepsis, but not a significantly different sensitivity, or Dr. Diagnostic odds ratio. So in terms of the conclusion, the conclusion of the systematic review and meta analysis suggests that precept seven is an accurate biomarker for us, but at clinical trials are warranted to assess its usefulness and safety to reduce early antibiotic exposure, especially in the case of preterm infants. So if somebody mentions precepts and now you know, now, you know, you know what this is I yeah, I
mean, I, I didn't know either well, so we know
Yeah. So and it would feel useful in addition to the US calculator, maybe we'll we'll get better at triaging those kids.
Okay, well, we're all looking for some test. This next paper is entitled initiation and duration of skin to skin contact for extremely and very preterm infants or register study, lead author Agnes Lunaire, the Journal of ACTA paediatrica, and this is done in a unit in Sweden. So, what's the question? The study sought to describe how skin to skin contact in the extremely very preterm infant and their parents is practiced in Swedish neonatal units. So the study designed it's an observational cohort study, I'm using the Swedish National Quality registry which collects data for infants. They were looking at infants born less than 32 weeks. So the inclusion criteria was the extremely preterm infant, less than 28 weeks, and the very preterm and vent less than 32 weeks born between January 1 2020 and October 19 2021. And they wanted to really look at the rates of skin to skin care in the first day of life, and in the first week of life, and then looking at hours of skin to skin per day. And they also did a kind of a subgroup analysis to look at infants who had skin to skin care data, and in 2019, to evaluate if there was like a difference because of the COVID 19 pandemic. So, so for baseline characteristics there 1483 infants registered in the registry, eight excluded for lack of skin to skin data in the first week. The mean gestational age was 28 weeks, but they had a range of 22 to 31. And I mean birth weight was 12 105 grams range 360 to 2810. So the primary outcome, they looked at time to first skin to skin and they had 782 infants that had information about when was the time to first skin the skin. The mean gestational age of this subset was 28 weeks, and the mean birth weight was 11 175 grams. And for these infants, the overall mean skin to skin care initiation time, was 32 hours of age but varied from 88 hours for the extremely preterm infants and 14 hours for the very preterm infant, which is, I think, quite good. Initiation times vary significantly between gestational ages and between regions. And, and then of the 539, extremely preterm infants who had data on the time to first skin to skin and it said that 5% had skin to skin care initiated during the first postnatal day, and I'll talk more specifically about that in a second, compared to 34%, in the nearly 1000, very preterm infants who had again 34% In the first postnatal day, duration of skin to skin care in the first week. So for extremely preterm infants in median daily skin, the skin care durations, they looked at, again, the first postnatal day during the first three days and the first seven days. So this was interesting because I told you that they had 5% had skin to skin care initiated in the extremely preterm, but for all comers, the total hours, for the first day were zero, the first three days were zero, then these are averages, right, because the interquartile range, there's obviously some data here. And then the first seven days were point seven, and then the remainder the NICU stay, were 3.7 hours for the very preterm so that less than 32 weeks the corresponding journey durations were zero hours in the first day 1.7, the first three days 2.4 hours a day in the first week and 4.9 hours for the remainder of this day. This varied by region. And then when they looked at the different factors, obviously time to skin the skin and the first three days was significantly lower by lower gestational age by C section, multiple birth and Umbilical Catheter. All of those make a lot of sense during their manner this de shorter duration was statistically associated with gestational age and multiple births. I told you they were going to look at the 2019 data to see if there's an impact of pandemic but actually the This did not reach statistical significance. Crazy. Yeah. Good for them. Either interesting results, they looked at some of these medical interventions. So of the extremely preterm and very preterm infants with Umbilical Catheter 20% had skin to skin care on the first page natal day, whereas those who did not have an Umbilical Catheter, it was 28%. This corresponded to an adjusted odds ratio of point three, three of infants who were intubated 7% had skin to skin on that first day. And of those receiving non invasive ventilation 28% had skin to skin on the first day, this corresponds to an adjusted odds ratio of point five, four. So the one thing I wanted to mention is that if you really look at their granular data, they have these nice tables by gestational age. I mean, when you talk about the first postnatal day in the first three days, and that first week, they were doing skin to skin care on not many, but Psalm 22, weekers, 23 weekers, for 25, weekers and 43% of 31 weekers. So, the study takeaways for that they had that they wrote were that few, few, extremely preterm infants and very preterm infants were given the opportunity of skin to skin care with their parents on that first postnatal day. I think their data is much more babies, I think, than we do here in the States. One of the other things they wanted to talk about is what is like the median time to skin to skin compared with, like historical papers. And they were disappointed to say that that hadn't changed much in the last decade, again, compared to historical reports. But compared to most of the units that I have practiced in, I think this is tremendous work for skin, the skin in the very small babies. Yeah,
yeah, I think I were going to post that that graph where we look where they look at the time to first skin to skin by gestational age and weeks. It's very nice. It's a very nice graph. I was looking at this table that you mentioned as well. And I think it's it basically gives you the gestational age and week from 22 weeks to 31 weeks, and it gives you on the second column any skin to skin care on the first postnatal day. And it's funny because to me, your your first tendency is to look at the 22 weekers. Right, it's like, how many, how many are they getting to do skin to skin, and it's an it's not an impressive number, I think, in this table, the 22 weekers were like one out of 39, which was 2.6%.
But but they did do 122 weaker,
right? I'm saying whether but that's the thing is that whether this kid was was I don't know if this what the palliative care situation was like, and what context that just doesn't matter. What I'm trying to say is, don't look at those go to the 2928, weaker, the 30 weekers, the one that we sort of preemptively don't let the parents do skin to skin on the first day because they're still technically like maybe in the neuro protection bundle, or this or that. And then you look at these babies, 28 weeks, 29 weeks, 30 weeks. And like It's like hundreds of kids that they're letting do skin to skin on the first 50%. And I think this is where to me, I'm taking a big takeaway, which is the 22 weaker, I mean, it's a case to case by case basis, depending on the parents expectations, but the 30 weaker, where they get 105 out of 255 infants to do skin to skin on the first day. That to me is a lesson. And then I was thinking to myself, Okay, like they're so good with skin to skin, their ivh rate is going to be horrible. They're not. So you look in table for supplements to and the ivh, grade three to four, they're less than 10%. I mean, they're basically for the entire cohort, it's 7%. So it really isn't a case of oh, they're sacrificing one for the one for the other. So to me, that was again, the Swedes are I mean, there are
some schools of thought that it may help prevent it. Oh,
I'm a I'm a, I'm a romantic when it comes to that. I do think that the synchrony between the mom and the baby definitely would help prevent IVF more than anything, but I mean, it's, it's, it's this data that we have to present to, to our quality improvement meetings, you know, because this is this is so good. So fascinating. All right, what else you got? I got one more and then I have like a grab bag of papers that I just want to mention to the audience because they weren't they were fun, but maybe yeah, so The next paper I have is in ACTA paediatrica. And it's it's a bit of a bit of paper that freaks you out the title is sodium supply from administered blood products was associated with severe intraventricular hemorrhage in extremely preterm infants. First of all, there is Cornelius Spath from umiya in Sweden, like I said Acta paediatrica. So what's what's the what's the rationale here? They're they're saying that sodium imbalances such as hypernatremia, and large fluctuation in serum or plasma sodium have also have been suggested as risk factors for ivh. They've previously shown this group that 21% of infants in the extremely preterm infants in Sweden study the Express study had a plasma sodium concentration superior to 150 millimoles per liter, during the first postnatal week most frequently appearing at postnatal postnatal days to for the supply of sodium and not fluid volume was the main determinant of plasma sodium concentration and the risk of hypernatremia in that cohort. So where they're wondering is, the aim of the study is to investigate the associations between severe ivh and sodium imbalances as well as sodium supply and fluid volume in extremely preterm infants. And they hypothesize that a higher early postnatal sodium supply contributes to sodium imbalances and thus contributes to the pathogenesis of ivh. And this is something that to me is fascinating because if you are managing small babies, right, if you are having micro preemies and your units, their sodium fluctuates tremendously, and whether you fluid restrict them, where you give them more fluid, how much sodium you give them. It's a topic of what our early discussions definitely I mean, between those fluids left and right. So this was a very compelling study to me. So the study design is that they used data from the extremely preterm infants in Sweden study the Express study that consists of infant born at 22 to 26 gestational weeks during 2014 2007. And they can talk conducted a nested case control study. So for every infant with severe ivh, which was defined as grade three or higher or Pdl, one ivh free control infant with the birthday closest to the case infant and matched for hospital sex, gestational age, and birth weight was selected. And this was an n of 70 babies. And they included all life born extremely preterm infants with a gestational age of 22 weeks to 26 weeks. I mean, 26 plus six, between 2004 in 2007. In Sweden, they included all infants who survived the first 24 hours, they excluded babies with major congenital or chromosomal anomalies, infants who were missing cranial ultrasounds, and infants with missing plasma sodium concentration on postnatal days two and three. So how do they do the study practically so data from for the sodium supply and fluid volume on the day of birth day one and day two, the first obtained plasma or serum sodium concentration on each day, as well as the first obtain hemoglobin level on each day between the day of birth and day three, were retrospectively retrieved from hospital records, the total supply of sodium and fluid included in parenteral and enteral, fluids, flush solutions and transfuse blood products. And the content of these products, including the transfusion was calculated based on manufacturer's information and published values. And the reason I'm mentioning this, obviously, is that this was not a prospective study where they went in each case and computed everything prospectively, right, they had to do some retrospective stuff. And, and obviously, that has some pitfalls that I just, I just want to make sure that we're aware of before we we get into the results. So of the 533 Extremely preterm infants 72, which is 13.5 percents developed severe ivh. compared to controls, infants with severe ivh had a higher crib score, and were more likely to receive sustained mechanical ventilation, kind of not really surprising. Other potential confounding and matching factors were similar between between the cord the risk of developing severe ivh was significantly increased with higher total sodium supply, and with higher total fluid volume administered to the infant until postnatal day two and that to me is a huge result. We are careful in the sodium supply obviously, and that's something that we can work on but there's more and more data especially coming from groups looking at hemodynamics where higher total fluid volume gets get really cranked up right? In the first few days of life and I'm doing it as well. But so that way that this can this this result is a bit concerning. And now this is the one that is crazy when when they excluded the amount of sodium the infant received from transfused blood products from the calculation of sodium supply and fluid volume, respectively, the results did not remain significant. So they were able to identify that if they removed the transfused blood products from the calculations, those results lost significance. Infants with severe ivh received 45% of their total sodium intake from transfusions. erythrocyte and plasma transfusion accounted for the vast majority of sodium exposure will post the graph I mean, it's pretty impressive. The sodium supply from the from the blood products, one of the seven University Hospitals included in the study had more strict transfusion guidelines resulting in infants receiving less mean daily transfusion volume between birth and day two. And this was I mean, I mean, so the ml per day with difference was 2.2 versus 10.1. So I mean, that's that's a lot of transfusion in the first few days. In the hospital with the more strict guidelines 8% of the infants developed severe ivh compared to 15%. In the rest of the Express cohort, the incidence of hyponatremia and the magnitude of fluctuation or peak concentrations of sodium did not differ significantly between cases and control. High plasma sodium concentration or large sodium fluctuations were not associated with severe IBS, which is also something that sometimes you're like, when we see these changes in right, what is it called? In the in the we have to know this for pediatric boards, right? Cerebral Fontein Milo Gnosis right, when you when you when you mess up, listen, it's
that, you know, it's one of the things I'm totally worried about.
But there's, there's really not much data. So that's kind of interesting to see that that large fluctuations are not responsible for severe ivh. I mean, yeah, again, right. We've had this discussion, because it's like, they don't have much, which,
you know, I think there's previous data that I think, argues that that there is there is concern for fluctuations, the theoretical
discussion is like, they don't have myelin, they're so small. So what's the big deal, right, and then, but there's not much data out there. So in conclusion, the results suggest that there's a relationship between sodium rich transfusion of blood products and severe ivh. In extremely preterm infants, it is unclear whether this is an effect of sodium load volume load, or some other transfusion related factor. So the takeaways for me is that it reinforces my thinking that we should maybe try to get some Ico in these kids, as soon as possible try to reduce the amount of blood transfusions. And I guess this is not something that I mean, I feel like for us, we tend to take into account the fluid volume that we are giving with the transfusion. So you're giving what 10 To 15 mL per kilo per day, we're trying to account into our total fluid volume for the day so that we don't overload the babies. But we never looked at how much sodium does that account for. So that's interesting, especially on day two, where your TPN may start to have a little bit of sodium where you may be infusing some sodium somewhere, whether it's a sodium acetate sideboard, or something. So it's a fast Yeah, where
I trained the sodium load was a huge point of debate and discussion. And yet, we knew we were not including the sodium load from transfusions. So that
but it's interesting because we don't transfuse I don't think. I mean, I don't know. I'm talking about our group now. But like, I don't think we transfuse that many kids on day one from day two. But
well, it begs the question, right, if you're transfusing if you're needing to transfuse a lot, and those first few days, I mean, there's bleeding happening, right?
So, yeah, as you're saying, Is it a chicken or the egg? And on that note, we'll move on to another paper. Given enough skepticism,
okay, so you had some other papers you wanted to just alert us to?
Yeah, I think there's some very cool papers that didn't really make it to the podcast. And I feel like if we, if we had reviewed them thoroughly, we would have said it next time, and they would have never made it to next time. So I'm just gonna go quickly over.
There's so many papers coming out that we don't want. We don't want to miss right now, at least that way. You guys know that they're out there.
So there's this study called thrombocytopenia and insufficient thrombopoietin production and human small for gestational age infants, first authors Oturu Takeshita from Japan. This is a study that basically looks at SGA infants compared to non SGA infants and is looking at the platelet count the thrombocytopenia and wants to know is there any relationship between the immature platelet And the thrombopoietin in these infants. So the image of platelets are basically it's a useful marker of thrombo predict activity. They're basically large platelets released by the in circulation by the by the bone marrow. And they're kind of analogous to the reticular sites in the red blood cells. And the thrombopoietin is like Erythropoietin, right, so glycoprotein hormone made by the liver and the kidneys, which basically regulates platelet production. So this was a prospective study of 202 infants with a gestational age less than 37 weeks. 30 of them were SGA and 172, were non SGA. thrombocytopenia was seen in 17, out of the 30, SGA infants and 40 of the 172, non SGA infants. And they looked at the lowest possible hemoglobin and platelet level within the first 72 hours how they did that exactly, I'm not exactly sure they don't really describe how often in blood. But the results were interesting. The platelet count was significantly lower in SGA infants than non SGA infants at the time of the lowest platelet count within 72 hours after birth, in SGA. It was 150. And the non SGA was 233,000. But not after seven days of age. So this was really transitory. When they looked the platelet count and the immature platelet factor were negatively correlated in non SGA infants, but not in SGA infants. So let me explain that to you. So you have and this was the same for the thrombopoietin. So as your platelet count is lower, you're expecting your image replated fraction to be higher. And they show that in the graph, right? It's it's basically a downward slope. Because if your platelets are low, you should be making you should be actively trying to replace whatever you don't have. Same thing with thrombopoietin. But when they compare that to the SGA kids, you look at their curves, and it's like flat, meaning no matter what their platelet count is, there's almost like no response to decreasing platelet count.
And like a decrease sensitivity.
Yeah. And so they're what they're saying is, immature platelet factor increased with thrombocytopenia to promote platelet production and non SGA infants due to increasing thrombopoietin. But not in SGA infants, this study found an association between insufficient TPO thrombopoietin production and thrombocytopenia in SGA infants. In addition, this study is important for understanding the etiology of thrombocytopenia in SGA. And so I thought that was very interesting, because I mean, we know these kids are thrombocytopenic, we just never really know why. So I thought that was that was great.
And it's just so neat, because it's the opposite with EBO. Right? So the SGA babies have more EBO they can have even polysafe anemia. Yeah.
Yeah. And so if you go into in the I think it's figure three, C and D, that are not the best to look at, but they're the ones telling the picture. Okay, but another paper that you're going to like is called longitudinal changes in lung function. In theory, prematurely born young people receiving high frequency oscillation, or conventional ventilation from birth. first author is Alessandra Scarah. This is from London, UK. So
I especially like that they call them young people.
So this study is insane. They basically, they had this study called the high frequency, the United Kingdom oscillation study, where they had randomize these kids to high frequency oscillation at birth or conventional ventilation. And they're now assessing these kids for pulmonary function at 14 years of age and 19 years of age. And their their question is, does it make a difference whether you're on high frequency or conventional ventilation for your pulmonary function testing in young adulthood? Yeah. So I mean, not that it's going to make a difference on a day to day basis. But this was very, very interesting. So let me So number one, the babies that we're looking at, despite the fact that they're 20 years old, now, there were small, so like, mean, gestational age was 27 weeks. And then the birth weights was like 900 800 grams. So they were tiny. Let me give you some some results. So they didn't find any difference in the in the lung function, right. So there were significant changes in the mean, F E, F, 75, F 50, F, E, F 25, FEV, one FVC and DLCO Z scores within the conventional ventilation and high frequency cohort, but no significant difference in the changes between the two groups. Okay. Now, so there was no difference, but some interesting stuff, the slope of the mean trajectory for FEV, one over a VC Z score. So if you remember, if you want to read VC, it's marker where you could actually do this if if the ratio is normal, but both factors are low. It's a restrictive pattern of lung disease if FFP one is reduced, and it's an obstructive pattern. So what they found was the FEV, one of her MVCC scores differed significantly by the motor ventilation, and the z scores were much worse at 11 years of age. The conventional ventilation group minus 2.43, compared to minus 1.73, at 11 years in the high frequency group. However, when they looked at the same kids at 19 years of age they had caught up. So the mean ratio increased by point 08 Z score per year for the conventional ventilation group compared to a decrease of minus 0.01 Z score per year in the high frequency group. Despite the changes in slopes, the mean Z scores in both groups remained low with predicted values, less than minus 1.7 Z scores at 19 years of age. So, there were some difference before 19 years of age, but another interesting things is factors associated with deterioration in lung functions. Those whose lung function scores decreased from the age of 11 to 14 to 16 to 19 years old, tended to be male born to mothers of white ethnicity have lower mean gestational age lower mean birth weight received postnatal corticosteroids, and were oxygen dependent at 36 weeks postmenstrual age, motor ventilation was not associated with deterioration in lung function with the exception of FTD, one over FVC, favoring those conventionally ventilated, so that was that was very interesting.
Yeah, it's especially interesting because, you know, in, in, you know, 20, in two decades, we've come a long way in what we do see the conventional ventilator, so it's interesting.
Okay, but another paper published in pediatrics, it's called the dextrose gel for neonatal risk with asymptomatic hyperglycemia. A randomized clinical trial. first author is Qt Gupta. This is a paper out of India. So we know that if you give glucose gel, you reduce admissions to the NICU, right. But what they wanted to look at was what if we looked at a specific three cohorts of people smoke forest gestational age, or IUGR, infants of diabetic mother or, and large for gestational age and late preterm infants. And they looked at these three groups, and they looked at either babies who received extra jail followed by breastfeeding or a control group that just got breastfeeding. So they had 630, infants 46%, developed asymptomatic hyperglycemia. And then 50% in the dextrose, gel group, and 49.6%, in the just control, they were, they had a bunch of babies, right, they had 9798, and 96, infants in the SGA, UGR, idml, GA and low and late preterm categories, respectively, treatment failure in the dextrose gel group was 11%, compared to 40% in the control with a risk ratio of point two, eight, for the people who are doing this with me, the risk, the risk ratio is a measure of the risk of a certain event happening in one group compared to the same event happening in another group. And if it's one, there's no risk, if it's above one, it's an increased risk of the outcome. If it's less than one, it's a reduced risk. So in this case, it's point two, eight, treatment failure was significantly less in the dextrose group in all three categories, with a risk ratio of point two, nine and point 2.3 1.2 9.31. And point two, four respectively. The extra gel reduces the need for IV fluids and at risk neonates with asymptomatic hyperglycemia in the first 48 hours of life. So not only is extra gel good, it works even in those high risk populations. Which is
neat, because there are lots of times where you're like, well, we'll try it, we'll let's try the gel, but you know, it's probably not going to work. And it does sometimes work.
All right, next one in the grab bag, it's called, it's an act of pediatric care. It's called The Five Minute Apgar score and childhood school outcomes. This paper was freaking nuts. It's basically trying to examine the association between Apgar scores at five minutes and childhood, mental and educational outcome. So I'm going to, so I'm going to read you the thing. So they looked at babies that were born at 37 weeks or more. And basically, they use this thing called the NAPLAN, which is in Australia, it's basically a school assessment that kids go through at grades 357 and nine. So it was not like a Bailey or something like that. It was like a school assessment that they used. And what they did is that they used they looked at the Apgar scores of these kids, right. And the problem I mean, the problem, the problem is that they gave upwards of 10 to kids, so 21% of the kids had an Apgar of 10 at five minutes. I tried to give a 10 of Apgar as a resident I got yelled at. So they use this right as the reference, because and it's important for me to mention this because you'll see how the data just starts getting a little bit fishy, not fishy. You see how like the data, the outcomes start not making too much sense. Because you have to understand they're using Apgar of 10 at five minutes as the as the gold standard. And then that was 21% of their court. They didn't really look at anything clinical really Due to the NICU, right, I mean, they just looked at whether the kids were admitted to the NICU or not. And so then
well, and we know that app cars are still subject is so subjective, right? And are you on respiratory support? Are you not on respiratory support? I mean, it's a, it's a minefield.
So they say there was an inverse relationship between Apgar scores at five minutes and the proportion of infants with poor developmental and educational outcomes with the least favorable outcomes among infants with an Apgar score of zero to three. So far, I'm okay with an outdoor score of 10, but increasingly favorable outcomes seen in app with Apgar scores closer to 10. Now, why it's crazy is because if you look at the rest of the results, they right Apgar scores of 789 were all associated with poor developmental outcomes. So first, when you read that, you're like, hey, what now, like, if you have a nine at five minutes, it's bad. While Apgar scores of seven and eight were associated with poor educational outcomes at grade three, five and seven, with progression through grades three, five and seven, the extent of the difference in educational outcomes diminished, so there was some ketchup, but they're comparing to abogados of 10. So yeah, so I mean, that paper, the reason I'm mentioning it, is because you look at the title like me, and you're like, Oh, that's interesting. You read the results. And you're like, wait, because seven is poor, and it's not. Right? They don't forget, like the like, if you miss that 10 is the is the standard, you're like, wait, and burn nine is bad. And then there were two other interesting paper, which I'm just going to mention quickly, you
just couldn't help yourself.
I mean, I reviewed them. I did the work. By the way, it takes us for the people we don't know, it takes us hours to prepare for these journal clubs. So if that means let's, let's show our work a little bit. This is called detection and impact of genetic disease and a level four Intensive Care Unit. Lien Hagen is the first author from Cincinnati was very interesting. They looked at like their unit before and after they implemented the use of more readily available genetic testing. And what they found was that the cost I mean, individual genetic diagnosis had a higher mean NICU charges 723,000 versus 416, for 17,000, which are just insane numbers. But they said that they didn't, it didn't really increase the need for genetics services, but that they had a better understanding of the pathologies that were involving the babies. And I think this is something that, right, I mean, the conclusion were that the increased utilization of broad genetic testing improved the detection of genetic disease, but contributed minimally to the cost of care while bolstering the understanding of the patient's condition and prognosis. Very interesting article, you guys should really dig over the stuff that they detected. And then the final paper that I saw was called Understanding the relative contribution of prematurity and congenital anomalies to the neonatal mortality. First authors here CRN fibs. And I forget what this paper is from it's in the Journal of parasitology. But they basically looked within the states of California at state Yeah, yeah, it's like they looked at California, Missouri, Pennsylvania, South Carolina, from 2009 2011. And they looked at the contribution of preterm delivery and congenital anomalies in the neonatal mortality. And what they did is that they looked at babies by gestational age, and then they classified certain anomalies, whether they could be lethal, whether they were not lethal or whether there was no anomaly at all. And they looked at how much contributes to neonatal mortality. And the conclusion of the paper were that congenital anomalies are responsible for about 40% of neonatal death, while preterm without anomalies are responsible for over 50%. And, you know, I think it's interesting to keep an eye on the proportion of neonatal mortality and which one are associated with congenital anomalies, which one or not, which one are purely due to prematurity? Obviously, this was retrospective, this was a database study, they had to look at death certificates. It was, I mean, obviously some pitfalls there. But it was a good study, and I recommend, I recommend reading it. In total, with this, a 59% of the deaths had an ICD nine code for an anomaly. Only 43% had a potentially fatal anomaly, and only 34% had a death certificate anomaly, which means that on the death certificate, they actually mentioned right up saying, like this kid had diaphragmatic Regenesis. Right. Yeah, don't worry. I'm just trying to find something over it. preterm infants accounted for 80% of deaths, those preterm infants without a potentially fatal anomaly diagnosis comprised 53% of all neonatal deaths, which I think was interesting because again, I don't think it means they didn't have an anomaly, right? If you think about the people we just talked about, if you did genetic testing, if you did, you could have find some, maybe it's not that they're just preterm, so these papers sometimes tie in very well. But that was the Was that was uh, that's all I have for today.
You were gonna tell us about this policy statement?
I was actually i. So there's a policy statement. You see, you're keeping me honest there. So in pediatrics, the Committee on the fetus and newborn published in pediatrics, the postnatal corticosteroids to prevent or treat chronic lung disease following preterm birth.
You just didn't you didn't you didn't want to get into this.
I mean, it's a policy statement. And it goes over the different. It goes over the different steroids, dexamethasone hydrocortisone, looking at them for the treatment of chronic lung disease, looking at them for the prevention, low dose versus high dose, and it's a review basically, right. The first author is James Cummings, and our ruin Pramanik are the authors. So
we, I mean, it's a really great review. Yeah, I'm sure
they're always it's always great to look at also the, the outcomes at school age, and, and they have recommendations. Obviously, if you want, we can go over quickly over the recommendations of the of the coffin, which is that number one, the routine use of post coding, postnatal corticosteroids cannot be recommended. Obviously, it has to be a risk assessment. The decision to use steroids to prevent or treat chronic lung disease or bronchopulmonary. dysplasia should be individualized, made together with the parents, and the discussion should be documented in the patient's medical record. Point number three is that if a decision is made to administer steroids, or low dose provided for a short term predefined duration is recommended. If the infant does not show a clinical response to corticosteroids within 72 hours of initiation, continued treatment is not recommended. That's the thing that everybody talks about all the time, which is if you start them and you're not seeing a response, and they're not like the steroids responders, should you take them off. So the policy statement is that you should stop it high dose. Steroids are not recommended to prevent or treat chronic lung disease in preterm infants. And finally, in the medicine should not be used concurrently with corticosteroids. This was discovered by our friend Dr. Christy Warburg, who came on the podcast go check out this episode if you haven't listened to it yet. Did I forget anything daft? No,
no, I think I think we're all caught up now. Well, well, we went and made sure nobody missed anything. Well, we were
right. Right. And we're hoping that this is helpful. So yeah, thank you to everybody who's engaging with us on Twitter. We got some very nice feedback. And for the people who are using the website, we have a new website called that you can reach WW dot, the dash incubator, that org. The other sites are still working NICU podcast.com is still working, Nicu boy review.com is still working. But we've tried to make everything in one place so you can see all the things we're up to. Alright, that's all I have for us tonight. Definitely. Cans get ready. Alright, see you see you. See you Monday for board review.