Hello Friends 👋
This week we have the pleasure of bringing on the show Dr. Stefan Johansson from Sweden! As the founder of many startups and projects, Setfan speaks to us about how his curiosity drives his entrepeneurial "gene" and shares his advice for neonatologists interested in pursuing projects and ideas outside the clinical realm.
We hope you enjoy this episode.
Do not forget to register for our upcoming conference March 27-29 at www.delphiconference.org
Short Bio: Stefan Johansson is a Consultant Neonatologist and Associate Professor at Sachs' Children and Youth Hospital. He holds an academic appointment at the famous Karolinska Institute in Stockholm and has published extensively in the field of neonatology. He is the founder of 99nicu.org and ebneo.org. In recent years he also founded NeoBiomics a startup company dedicated to creating high quality supplements for neonates.
The transcript of today's episode can be found below 👇
Welcome Hello, everybody. Welcome back to another episode of the incubator. It is Sunday we're doing Journal Club Dafa. How are you?
I'm good. If it was really Sunday, I would be in Scottsdale. Recording pretty weekend.
But what are you're currently doing in Scottsdale even though you're not yet in Scottsdale?
Right. Well, I am thrilled to say that I will be giving two two talks at the AP Scottsdale conference. So I'm looking forward to that.
What are you talks about? Oh, you're quite interested. In one of those was gonna say I feel like people might be curious. I kind of I know what you're talking about. We spoke about it.
Yeah, I'm giving one talk on the kind of changing paradigm of neonatologist engaging on social media and then second on using communication with families like as an intervention, itself, mitigating some of the stress and trauma associated with NICU admission,
you finally get to make a cultural pride.
I'm so excited to hear her speak again at our company.
Yeah. I will be in a much less glamorous situation on Sunday. And today, I guess I am on service in the NICU.
Unknown Speaker 2:38
Taking care of the unit. So Graham
is not a busy actually. So hopefully, hopefully I get it a little bit of a break.
Unknown Speaker 2:47
it ebbs and flows, though, you know.
Thank you to everybody who registered for the conference. We're looking forward to seeing you there. spots are still available. What else did I wanted to say? I don't really have anything else to mention, I think we can really dive right in. Alright, I'm not going to ask because I know that I go first. I have a few interesting papers. And I guess the one I am going to start with is this one. It's called Let me pull up my notes. It's called. It's a paper that I saw in JAMA peds it's called the association between neonatal intensive care unit type and quality of care in moderate and late preterm infants. first author is Elizabeth Salazar. I think the data they're presenting is coming out of Vaughn, I think the team the I think the team is out of chop. And yeah, I think so let me just make sure before I assign people to divisions that they do not belong to, but that is correct. And basically, this paper is looking at moderate and late preterm infants. They start off by saying the things that we kind of know they represent a large proportion of preterm births in the US up to about like 80%, we tend to forget that sometimes. And they want it to look a little bit that the way they work, these infants who we tend to sort of shrug off and I'll have like a little essay that I want to read at the end. Maybe that will remind us not to shrug off certain things. They talk about the different levels of care that we can be provided in the different NICU. So as a reminder, the dimension the American Academy of Pediatrics, guidelines on neonatal levels of care, stating that basically level one NICUs, which are called Well, newborn nurseries really should be capable of caring for infants born between 35 and 37 weeks, and that once you have anything more immature than that Add like, you would need a special care nursery ie level two that can take care of infants born at 32 weeks of gestation, or greater now, moderate to late preterm infants are born at all different types of hospitals. And they're saying they're they're saying understanding where MLPs moderately preterm infants receive optimal care is an opportunity to improve outcomes for this population. I love that I think this is very disruptive in in in thinking and so I like the objective of the study was to evaluate the association between NICU type with the quality of care delivered to the MLPs, moderate to late preterm infants who require NICU admission compared compared with the comparison group is an interesting one with extremely and very preterm infants. So when I read the background, I guess that's, that's an interesting control group. So I'm going to I'm going to have to go through some of the things in the methods to understand how they did the study. It was a cohort study, they looked at data from January 2016, to December 2020. And they basically looked at data from the Vermont Oxford Network database. If you are not familiar, this is a volunteer database that a lot of units participate in, and they have a ton of data. They excluded from this study any babies with congenital anomalies, deaths in the delivery room or within 12 hours of NICU admission, one or more transfers, implausible values for birth weight. So that was an interesting exclusion criteria, which they basically defined as birth weight less than 200 grams, or more than four standard deviations from the mean gestational age, and sex. So then the babies were divided into two groups. So you had your MLPs, your moderately preterm infants 30 to 36 weeks gestation, primary focus of the study, and then you had your extremely and very preterm infants 25 to 29 weeks, and they were used as a reference group and national validation of previous study. The primary outcome were gestational age specific quality measures, the outcomes for extremely and very preterm infants was, was assessed by the baby measure of Neonatal Intensive Care outcome research. For moderately preterm, the outcome was MLP quality measures based on this same bait. So this is the acronym for this baby measure of Neonatal Intensive Care Outcome Research is baby monitor, that's what the the acronym is. And they basically adapted this score for the moderate to late preterm population. If you're like me, I don't know what the baby didn't know what the baby monitor score was. And I almost looked it up. But thankfully, I actually downloaded the paper, but the the author's actually gives you a brief explanation. So, the baby monitor measures, infant level process and outcomes. So, for are very preterm it means no admission, hypothermia, no healthcare associated infections, discharge on some form of human milk, administration of antenatal steroids, timely retinal examinations, survival to hospital discharge, no non surgically induced pneumothoraces. Meaning sometimes surgeons have to create a pneumothorax for I don't know, surgical interventions in and around the head and neck. So spontaneous kinds of pneumothoraces know chronic lung disease and the growth velocity, okay. Now, when they adjusted that for the moderate to late preterm, they just made minor changes, we still have no admission hyperthermia, no CLABSI, healthcare associated infection discharge on some form of human milk, survival to discharge, no non surgical induced pneumothorax, no oxygen at 28 days of life or at discharge. And then they looked at change in weight Z score, and the other one that introduced is the no extreme length of stay. Do you hear that one? No extreme end of state this will be an important one.
Unknown Speaker 9:06
Well, it seems like they're just trying to get rid of the outliers.
And they published these. So these scores, if you're interested, there's papers that you can download and read more about them. Now, how does Vaughn classify NICUs? I was not aware of that. So they have basically, three four types. They have type A, which is type A NICUs, with or without restriction for ventilation, or those that do not perform neonatal surgery and transfer infants to another center for assisted ventilation based on infant characteristics such as gestational age or duration of ventilation, then you have the same type of NICUs without ventilation restrictions, and they're the ones that just don't perform any form of neonatal surgery, but they don't have a ventilation criteria for transfer. Then you have Type B NICUs, which have no ventilation restriction, they perform neonatal surgery except cardiac. So I would say that our NICU He doesn't have a cardiac surgery program. So we would probably fall in that NICU where we have, we take care of we have every event you can imagine we have all sorts of surgeries happening all the time, but we don't really have a cardiac program. Type C is basically the highest level where there's no restriction like they do everything including cardiac, right. So type A Type, Type A without ventilation restriction, type B and type C. Okay, so on to the results. Super interesting stuff. The cord included 376 plus 1000, moderately preterm infants, and almost like 56,000, extremely and very preterm infants cared at 465 US hospitals, born between 2016 and 2020. In the cohort 6.6% received care in type A NICUs, with restriction 29%, with in type A without ventilator restriction 39% In Type B, and 24%, in type C, so it's quite quite well spread around for both moderate to late preterm infants and extremely and very preterm infants, a higher percentage received ventilation after initial resuscitation in type C NICUs. Compared with infants of the same GA at type A units. So babies who were born in the higher acuity centers were more likely to get ventilation. Does that mean that because we're so comfortable doing something for sicker babies, we end up doing it for less sick babies, God knows that's just me speculating. But that's that was a super interesting finding. The moderately preterm infants had lower school because
Unknown Speaker 11:35
you you would. Sorry, you would potentially speculate that it's the opposite.
Exactly. Yeah, I agree. The moderately preterm infants had lower my lower MLP QM, which is the baby monitor the moderate late preterm quality metric adapted score that we just talked about earlier. So they had lower scores in the Type C NICUs. Compared with all other types, extremely and very preterm infants had no significant difference in their composite score by unit type, meaning it didn't really make that much of a difference when you're looking at the extreme preterm in unadjusted and adjusted regression analysis. types in NICUs, meaning the highest level of acuity acuity NICUs, were associated with lower scores for moderately preterm infants compared with Type A with restriction type A without restriction and type B units. The higher percentage of infants born at 25 to 29 weeks gestation, was associated with decreased scores for moderate to late preterm infants, meaning the more immature babies, the unit was taking care of the worst they did on their scores for moderate to late preterm infants. No significant differences were found in extremely, very preterm infants, by NICU type, and then the last thing I wanted to mention is that in types in NICU, the highest security NICUs, moderate to late preterm infants had lower scores, specifically driven by these two factor, no extreme length of stay, which means that they stayed longer than they should have been. And the change in weight Z score, meaning their growth was not as optimal as they could have been. The conclusions of the article, and I'll let you weigh in in a minute, is that in a national cohort of premature infants, type A and B NICUs, were associated with higher care quality in moderate to late preterm infants with significant differences in no extreme length of stay and change in weight, Z score by unit type, there was no association between unit type and extremely and very preterm infant quality of care. Further identification of processes specific to units with less sub specialized cares that lead to improved ml moderately preterm infant care, quality may facilitate dissemination of these processes to other types of NICUs. We've kind of known this. And we've always said it, because when you I mean, we feel where you get where you get to the baby that comes from the level two to the level three, center, whatever. And, and we've seen this, but paper to actually articulate that finding is fascinating.
Yeah, at first, I didn't really understand what they were trying to do. But I think the data is useful. And I mean, again, for those of us who work in a who have worked in level two also, and then you're in a level three, four, or you know, the bond designation of, you know, lower acuity, you can see that those late pre terms with moderate pre terms are getting, you know, way more observation and intensive care and family updates even than they would get in a busy high acuity unit. And we know that those babies are still not the same as a term newborn who goes to the nursery and the families also still have significant distress even though the admission is quote unquote, as we say, short and the babies are, quote unquote, not that sick. But it's so it's interesting.
It's interesting. The point you're making about the late print moderate to late preterm being at more and more risk than full term is something that is that is very much mentioned throughout the paper, which we're very sorry. I was trying not to confuse anybody. But yeah, I agree with you. I mean, I think in lower acuity centers, the 33 weaker is their sickest babies, and then they're gonna watch over them. And the nurses are super dedicated to making sure that are let's just go one more ml. But when you're working in a 100 bed NICU, and you have extremely, extremely sick babies, could these moderately preterm get overlooked? And it sort of goes back to something I've been discussing with you and when you have large NICUs? Should Shouldn't we federalize the NICU is where you become sick, you break down your NICU of 100 bed into three smaller NICUs of 30 beds, right? Where you can actually have much more control with three directors and so on and so forth. Is that the way to go? Because it when we worked when I worked, at least the NICU is 100 plus beds, it's hard to get a sense of who's where like, you don't know all the patients. It's it's it's it's a it's a it's like being at a large busy airport. Like you. You have flights coming in and out?
Yeah, you know, it's like, yeah, it's like, everybody's sick all the time. And you're just putting out fires. And you and I have this experience that we're at, it's still in a very high acuity center, but just this we're at a smaller, we're in a smaller unit. And we know every patient, and when you're on call, you know, the patients and you know, what's their baseline and what's not their baseline, and you know, every family when they walk in the unit, you recognize them, you give them an update, as you're walking to the bedside, you know, it's a totally different experience.
Yeah. And I think we've seen this at Sinai out where when the census is like, I remember when the census is like, 95 100, right? And like, you're not taking sides on 100 patients, you're like, give me the sick ones. And and that's at night, obviously, right? It's not during the day, but that's the mindset. It's like talking to me about the 20 sick ones that I'm going to really have to work on tonight. And most likely, and then and then the feeder and grower, I'll look at the chart if I get called. But yeah, and so while it's not as pronounced during the day, I am sure that we try to balance the teams, you know, because we try to not have certain teams with all the acuity either. So yeah, these babies may get overlooked. Anyway, super cool paper. It's 15 minutes already. So alright, definitely Europe.
Okay, my first paper that I wanted to tell you about, see I was too busy thinking about your paper, and it was this article entitled socio demographic factors associated with tracheostomy and mortality and bronchopulmonary dysplasia, lead author Michael a Smith, senior author, Roberta L. Keller, and this is coming from the University of California in San Francisco. So basically, they've just wanted to look at what were some of the demographic factors or, or do demographic factors play a role in your risk for needing tracheostomy so they performed a retrospective multicenter cohort analysis of inpatient data from hospitals that contribute to this vizient clinical database or research manager. And it collects administrative financial and clinical outcomes data from hospital discharge records. So they queried this database for admissions from January 1 2012 to December 31 2020 of former preterm children less than 18 years old with a diagnosis of bronchopulmonary bronchopulmonary dysplasia, and then they went further, and they included only admissions with diagnosis codes for BPD and prematurity. So they were looking for babies born less than or equal to 32 weeks gestation, who developed BPD. And then the patient records were also validated for socio demographic data and other diagnoses. They also pulled some race and ethnicity data from each institution's electronic medical records. Obviously, different institutions have keep different records just right something to know especially when we're collecting race and ethnicity data, but and they mentioned that details regarding how the patient level race information was collected was not available to the study. Just something to keep in mind. And then data. Further data on the social determinants of health. were linked from the AHRQ the Agency for Healthcare Research and qualities, social determinants of health database by household zip code, and we've spoken about that, like early on in history of the podcast we did we reviewed a paper about that and Then they split the advance into three cohorts by z score. So the really the primary outcome they were looking for was tracheostomy insertion during any admission, they also wanted to look at the trends in the rate of tracheostomy insertion per year is changing. And then they wanted to look at associations between socio demographic or clinical factors, and tracheostomy insertion. So, they found over 75,000 admissions of 50 over 55,000 patients with a diagnosis of BPD. And after including only those with the ICD code indicating less than or equal to 32 weeks in 40,021 patients with BPD 4% or 1614 infants who received tracheostomy the mean postnatal age of tracheostomy insertion was 4.6 months, the interquartile range was 3.6 to 5.9 months, that's something we've discussed a few times, there's so much variability and when do we commit to placing a tree. And interestingly, tracheostomy insertion rates per BPD patients per year range from a minimum of 1.6 and 2020 to a maximum of 4.1 in 2016. So that makes you think that it decreased. But that's not what happened, there was a significant upward trend in the rate of tracheostomy insertions per year from 2012 to 2017. But in 2018 to 2020, there's a significant downward trend and tracheostomy. So that's interesting in how that changed over time. Obviously, that included the early stages of the COVID 19 pandemic. So I wonder how that influenced, you know, surgical illnesses for these babies. And there were 227 or 14% deaths in the tracheostomy cohort, and 1857 or 4.8% deaths and the non tracheostomy cohort. Sorry, so then they wanted to look at some of the other types of data so there were a greater odds of tracheostomy insertion among males and adjusted odds ratio of 1.2. There were greater odds of tracheostomy insertion in non Hispanic black patients with an adjusted odds ratio of 1.38. And in patients with Medicaid, self pay or quote unquote other insurance and adjusted odds ratio of 1.15. tracheostomy insertion was less likely in Hispanic patients adjusted odds ratio of point seven, seven. And then tracheostomy insertion was additionally associated, not surprisingly, it was gestation, a gestational age less than or equal to 26 weeks, and the comorbid diagnoses of non respiratory major neonatal morbidity, pulmonary hypertension, structural airway abnormalities and congenital heart disease. What I found fascinating and was that the tracheostomy insertion was not associated with relative neighborhood median household income neighborhood percentage with income below the poverty line or neighborhood percentage with a bachelor's is a bachelor's degree. And then they did kind of this adjusted model, so they serially added gestational age presence of a non respiratory major neonatal morbidity, and then added additional comorbidities. So associations of tracheostomy placement with race and ethnicity persisted, with still limited attenuation of the increased odds for non Hispanic black patients. So still still at increased risk for needing tracheostomy and decreased odds for Hispanic patients and in these fully adjusted models. So, in the overall multivariable analysis, there was no significant association between mortality and race and ethnicity. Nor were there associations with primary insurance provider or relative neighborhood metrics for the tracheostomy cohort and the non tracheostomy group. Hispanic ethnicity was associated with lower odds of mortality, as was higher neighborhood proportion with a bachelor's degree while public insurance and lower neighborhood household income are associated with higher odds of mortality. So I think this was interesting. I think there's potentially a threshold where babies are so sick that you know, some of those socio demographic factors may not play a role. But obviously, there's still this disparity in our the non Hispanic black infants. And they found this protective effect of these the Hispanic infants, which has been coined the Hispanic paradox witch Diana Montoya Williams has written about we've had her on the podcast numerous times. And one of my other co fellows, Carlin Diaz, so people can read about that more, if you'd like. What do you think?
Listen, I was encouraged by the results. To be honest, I think you still wonder, right? I mean, we're looking at like, you're looking at population who then delivered very prematurely. The baby in the NICU, right then had like a very sick baby who then have the sick babies, then there's the one that's so sick, that needs a trick. Yes. So you wonder like, if you have
right, you already, you already hit preterm birth, you already hit BPD, right, you already hit all the, like risk factors from
assembling standpoint, it's like it's this it's the sample of a sample of a sample of a sample. So could but but in any case, there's so many articles that are being published, where we see discrepancies, and it sort of makes you cringe a little bit, because you're like, Ah, man, why, why, why is why is it this way? And why can't we find a solution? So that actually, when we are not seeing differences, it's encouraging and makes us motivated that it because sometimes, you know, it could often seemed like an unachievable goal, if we always keep finding issues, but then when we are seeing that in certain instances, that can actually be leveled off then makes you hopeful that alright, we should keep working and, and so this is
why and I think there are always, you know, concerns about some of these babies who have low resources, right, you know, how will they manage outpatient I mean, I feel so fortunate I have every resource that I could ask for and it still seems like such such a huge task and tender taking for these families to take home these medically complex
and we've we've I mean, we're think we reviewed a paper not too long ago about like the the Jimmy regs that people have to resort to
Speaker 1 27:02
for oh my gosh, patients at home, so ative, I know
it's not the like, and to me, what fascinates me about these families is that they never sort of let their guards fall down. They're always they always like their kids, they always find a way to resource for me find a way to find a way to make it work and it can
Unknown Speaker 27:26
Yeah, these parents are amazing. Okay, your turn.
So my turn is a paper I saw today that actually was not in the folder that I added yesterday in JAMA Network open called the Association of Active postnatal care with infant survival among revival infants in the US. first author is Imani silver, it's a paper out of bits of paper that's going to look at data from across the US but the group that wrote the paper is from the University of Alabama, it includes our friend, Wally Carlo, who will be at the Delphi conference to speak. And very interesting paper, the background so articulates a few a few things that we've been talking about, actually, in our division definitely this week, how the decision of whether to initiate active care in Peri viable infants born between 22 to 25 weeks of gestation is influenced by several factors, including the fear of adverse outcomes, individual bias, local that was very brave to actually write that down, but local and national policies, medical ethics and communication between parents and caregivers. The lower threshold of viability is currently considered to be 22 weeks gestation. I think that's pretty reasonable statement to make in the US. And they're mentioning how there are regional variations in care and outcome we recently gave an unconference at University of Colorado This is one of the topics that we like to bring up how there is significant variation in care. Now, what they're saying is that is it, it is possible that regional differences in outcomes among pair variable infants in the US are associated with differences in active care, maybe you're getting different outcomes because you're not treating babies the same. So they were testing the following two hypotheses hypothesis number one is that regents with higher rates of active postnatal care among infants have the lowest positional age will have lower gestational age specific infant mortality rates. So if you resuscitate them every time, you're going to have better outcomes, less mortality. And the second hypothesis that we're testing was that were in regions where antenatal steroids and cesarean delivery have a higher incidence you will get a higher rate of survival among those babies with low transitional age. Meaning if you intervene on these on these dyads prenatally with the intent of really having a plan to actively resuscitate maybe you will have you will see these outcomes. So they use a cohort. They use the cohort word has collapsed regional level data from the US Center for Disease Control and Prevention, the CDC wide ranging online data for epidemiologic research, the wonder database, and it linked to life birth and infant death expanded database from 2017 to 2020. Now, interestingly enough, they looked at regions within the US categorized by the HHS, so you have 10 regions, right. And I'm going to give you the regions because then when they mentioned in the results, the region you're like, well, am I in that region. So Region One is CONNECTICUT, Connecticut, Maine, Massachusetts, and New Hampshire, Rhode Island and Vermont, region two with New Jersey, New York, Puerto Rico and the US Virgin Islands. region three is Delaware District of Columbia, Maryland, Pennsylvania, Virginia and West Virginia. region four is Alabama, Florida, Georgia, Kentucky, Mississippi, North Carolina, South Carolina and Tennessee. Region Five is Illinois, Indiana, Michigan, Minnesota, Ohio, and Wisconsin. Region six is Arkansas. Or Kansas or Kansas? Alright with Arkansas, Louisiana, New Mexico, Oklahoma and Texas. Region seven is Iowa, Kansas, Missouri and Nebraska. Why are you laughing? I was muted. I was muted, but you nailed it. You got it. Alright. Region eight is Colorado, Montana, North Dakota, South Dakota, Utah and Wyoming. region nine is America Samoa, Arizona, California Commonwealth of the Northern Mariana Islands, the Federated States of Micronesia, Guam, Hawaii, Nevada, the Republic of Palau and the Republic of the Marshall Islands, and region 10 is Alaska, Idaho, Oregon, and Washington. Alright, that's done. So they include the following gestational age, they looked at 2223 24 and 25 weeks, they included infants with a birth weight ranging from 400 grams to 1000 grams. There's actually good reasons why they pick that range. They said that basically, these are the extremes even for these gestational age. So like the 10th to the 90th percentile, they excluded stillbirth, any baby with a database issue. So like if things were missing, I think or if they had like inconsistencies, congenital anomalies, and those born outside of the hospitals slash birth center. So what is active postnatal care? Right? So if you're doing this database, how do you know that this was actually done? So basically, they said, we're going to consider active postnatal care if we see one or more of the following. And they basically had these proxies for intensive care and these proxies were admission to the NICU surfactant administration, ventilator and antibiotics. And they said, if you if you do one or more of these things, you're, you're you're doing you're doing intensive care. The primary outcome measure evaluated gestational age specific survival rates, by rates of active postnatal care in those 10 HHS regions. Alright, enough with the methods let's go into the results. They included 41,707, Peri variable infants 78%, of which were Singleton. The breakdown was that 14% were, that's my phone, didn't use it, I apologize. 14% were delivered at 22 weeks, 23% at 23 weeks, 30% at 24 weeks and 33% at 25 weeks of gestation. Evidence of active postnatal care was seen in 84% of the cohort. Rates of active care varied by region and by gestational age not really surprising with that's the whole point of the paper. That's why we're looking at active care intervention was more common in infants born at 25 weeks compared with those born at 22 weeks. Now, the difference is actually quite staggering. 93.5% versus 41.5%. The reason I'm bringing this up is because we have listeners from around the world, and 25 weeks. Me, me, me, me raise some eyebrows in certain areas of the world. I know that in France, there are certain corners of the country, where 25 weeks may not be considered viable. And so, so I think it's interesting, then when one of the points of the podcast is that if you're listening, you say well, if in the US 94% Maybe we should be looking at that more carefully. 25 weeks,
just Yes, certainly. Certainly there's a resource threat. Absolutely. Right. That's
why I mentioned friends because technically we should have the resources civil. Yeah. Yeah, if if anybody from the French government is listening, we should have the resources. Friends is in disarray. Right now. There's like floods of strikes and whatever. But anyway, at 25 weeks gestation, the rates of active postnatal care ranged from 1500 infants in region nine, which is about 88.1% to 97.5%, in Region eight, at 22 weeks, which is sort of what we wanted to know. It ranged the rates of active postnatal care ranged from 20% in Region eight to 56% in Region Seven. So still still a wide a wide range, Nicu admission was reported in about 12 to 13,000 infants born at 25 weeks gestation, and in 37.4% of infants who were born at 22 weeks, so less than half for the babies are 22 weeks. Overall, 62% survived infancy with survival rate approximately, of 20% for infants at 22 weeks 51% For infants at 23 weeks, and 71% for infants are 24 weeks. Finally, 82% for infants at 25 weeks, not surprising survival rate goes up with the gestational age. But now what's interesting is going to be the variation at 22 weeks survival vary by region from 8.4% in Region eight to 68%. In region two, sorry, to 23rd 28%. In Region seven, I apologize. At 23 weeks, it varied from 36% in Region eight to 57%. In Region six, at 24 weeks, it varied from 61% in Region eight to 72%. In region four, I won't remind who's region eight, but it's I felt bad for them. Survival at 25 weeks ranged from 78% in Region eight to 86%. In Region One, a few more results that are interesting. There was moderate positive correlation between regional rates of active care and survival at 22 weeks gestation, the positive correlation between regional rates of active care and survival at 23 Weeks was not significant rates of active care were not correlated with survival at 24 weeks or 25 weeks of gestation. So it's interesting how it was the correlation between active care and survival was seen for 22 weeks, but not for the other gestational ages, which goes back to show you that in this like their special category it looks like and we've
Speaker 1 37:11
reviewed other papers that are consistent, right.
Finally, the rates of cesarean delivery, varied by gestational age from 9% at 22 weeks, to 54%. At 25 weeks, regional rates of cesarean delivery were associated with survival at 23 weeks, rates of zerion were not correlated with regional survival differences at 20 to 24 or 25 weeks. So the conclusion of this study is that in this cohort of like 42,000, very valuable infants regional differences in measures of active postnatal care, including neonatal intensive care, unit admission and assisted ventilation were associated with higher survival rates at 22 weeks gestation in US regions, results should be interpreted with caution as individual patient level data, individual patient level data were not available. I recommend that you read the discussion. Fascinating, what they're basically one of the points that I wrote down in my notes that I wanted to bring up is that they're saying, you know, when we're doing, we talked about shared decision making with families, and they said, We should move away from doing this based on gestational age alone as like a single number that drives whether we recommend or not recommend. They're actually mentioning how the British Association of perinatal medicine guidelines recently recommended comfort focused care for infants with basically how do they define who should be getting comfort care, they're saying infants with greater than 90% risk of death or severe impairment, individualized care according to parent or preference with 50 to 90%, risk of death or severe impairment and active care for infants with less than 50% risk of death or severe impairment. So saying, they're saying the British Association is saying basically look at the outcomes, but not just a decision on age, but based on how did the mother receive steroids? Is there an Is there a choreo?
Well, and that's what the MA CHD calculator is for you.
And they're saying, based on what the risk of death or severe impairment is, you can make a recommendation for comfort care versus active. Now, what's the reason why the discussion is so interesting? Because then the counter argument is saying, Well, if you're using this using local data, or you're just creating the self fulfilling prophecy of like, well, we've never had good outcomes. We're not going to resuscitate your baby. So then and then it's never changes. But in any case, it's a fascinating discussion. It's a fascinating piece of study. And yeah, I really enjoyed reading it. The friends from the University of Alabama are always very productive and very strong in their work.
Speaker 1 39:45
I don't have anything to say the data speaks for itself. Sounds good.
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I would my next paper is development of a bedside tool to predict the diagnosis of cerebral palsy and term born neonates. This is different than a paper that was recently recirculating on to Twitter about, like this computer generated model of infant movements, which we we didn't review. And we missed that paper. But I think, review. That's how I read it.
I read it. Yeah, it's it's not the best paper to review in an audio format. Because,
Speaker 1 40:39
yeah, I got to see the pictures, I got to see the pictures, like
how does AI looks at a baby and then interprets, like, what does it do? And basically, if you read the paper, it shows you how it basically transforms the baby into the stick figure with nods at the joints and looks at these angles. And it's an hour of the movement. Yeah, that's why I think the podcast is great for clinical stuff and papers that lend themselves to be listened to, but this was very, very technical, and, and also not super applicable to a lot of people. I mean, what I mean, it's all tech
Unknown Speaker 41:14
tax, yet. It's coming.
And the outcomes. And the outcomes were not like staggering either. It's not like they said like oh, now we're diagnosing 100% of the of the babies either. Sure. All right. Well,
thank you for that for that brief update. Anyways, this one is coming to us from Canada. It's in JAMA Pediatrics, lead author Amira, Rue Rawabi and trailing author Mary Dunbar and this this group is the Canadian cerebral palsy registry. So, basically, they wanted to look at Kenna prognostic tool, some sort of multivariate equation be developed for the occurrence of cerebral palsy from the like, easily obtainable chart data pertaining to the pregnancy delivery and the UNI. So they pulled see cerebral palsy cases from the Canadian cerebral palsy registry, which is a prospective Canadian registry. It was established in 2003, and fullback, and it now includes pediatric centers in British Columbia, Alberta, Ontario, Newfoundland and Nova Scotia, and healthy control data was obtained from the Alberta pregnancy outcomes and nutrition Longitudinal Study, which is another prospective cohort of pregnant Alberta women. And this cohort study, again, their control collected pregnancy delivery and neonatal data. And it serves as a control for like a number of studies. They are using their evaluated babies up to three years. So the inclusion criteria for this study, it was birth between 2003 and 2007. So depending where you were from, so the babies in Quebec are being studied longer. So they started in 2003 to 2020. And then in the other provinces, babies were study from 2007 to 2020. The other inclusion criteria was that you were term birth at 37 weeks gestation or more. And the control cases were used if they had a quote unquote, normal motor development at age three years. And because they didn't want to miss any delayed presentation of cerebral palsy, or their exclusion criteria were if more than 50% of the participant data was. So the final study population consisted of 1265 children with cerebral palsy 1985 controls, then they found some premature infants, and they found participants with incomplete data. And they actually had two participants from the control groups who were later diagnosed with cerebral palsy. So total, they had 3250 included individuals 1752 were male, and the median gestational age at birth was 39 weeks. There were significantly more boys in the cerebral palsy group 57% compared with controls 52% And then they looked at the cerebral palsy severity, so they looked at which which children were ambulatory, that was 71.9% and which were non ambulatory 28.1%. And not surprisingly, neonatal encephalopathy was present in in a not enough small proportion of the group. 28% of the children had neonatal encephalopathy as a diagnosis. But but most of the children did not have neonatal encephalopathy as the diagnosis. Also interesting To the they looked at a series of models and the final model developed was using multiple imputations of these seven binary variables and they used tobacco use drug use diabetes, preeclampsia, choreo, prolonged rupture of membranes and male six. And then they had five continuous variables, number of pregnancy, number of miscarriages, five minute Apgar score, weight and gestational age and meet, I wanted to talk a little bit about some of these characteristics. Because there were significant differences in the individual kind of analysis. So for example, number of of pregnancies. So there were there tended to be a higher number of pregnancies in the children with CP group, tobacco use. So there was more tobacco use, there was more alcohol use, there was more drug use drug use is actually 15.8 as the odds ratio for the development of cerebral palsy, and there was more diabetes, and there was more preeclampsia. In addition, there was more, hold on, I want to make sure I tell you the right thing. There was actually less prolong rupture of membranes in the babies who develop cerebral palsy, I thought that was interesting. There was more chorioamnionitis they had lower median Apgar scores, lower pH more often have maternal fever more often have emergency C section. So I thought those were interesting. But using this multivariate analysis, the overall sensitivity the model was 56% with a specificity of 82%, correctly classified 70, just under 75% of infants, and they use it are using a C statistics of point seven four. So if you're not totally familiar with the C statistic, it's basically the probability that a randomly selected subject to experience the outcome will have a higher predictive probability than a randomly selected subjects who did not experience the outcome and it's related to the area under the curve of f and Roc. And then, they talked about the positive predictive value is 56%. And the negative predictive value is 82%. And then they wanted to evaluate it using CP severity. So for ambulatory MCP, the sensitivity is 54% specificity was 79% with a CS test statistic of point seven one, but for the non ambulatory CP, the sensitivity increased to 65% specificity is 86% and 80. Just under 84% were correctly classified statistic of one. They also did some data looking at the proportion with encephalopathy at various thresholds. But one of the things I really wanted to talk about was that they found that children with CB had significantly more of the modifiable risk factors than controls potentially modifiable, I'll tell you what they are. These are the five significant potentially modifiable binary risk factors tobacco use drug exposure, diabetes, preeclampsia and chorioamnionitis. Some of those, I think, you can argue are not entirely modifiable, but but something for us to look to in the future.
Koryo mean, what's going
Yeah, or preeclampsia. Right. So, but when I think was especially neat about this article was that they they took their work kind of one step further, by providing this really neat table that had recommendations for screening and follow up based on the prediction ranges, or the provider, the probability of having CPE. And this was related to the relative risk of CPE. Of course, the infants with the highest prediction range or the probability of CPE. For example, greater than point nine was expected to have much higher cases a CP, so one in eight, but this was likely to only include about point two 5% of infants. This was compared to the lowest risk group where we'd expect 70.6% of infants to fall unexpected cases or one in 1005. And then, of course, the screening recommendations for the highest risk groups is very directive that all those babies should get motor screening and evaluation. Whereas in the lowest risk group, they should get motor screening for parental concern, unable to sit at nine months is a threshold or handle asymmetry at 12 months. So I thought that was interesting. We have a plethora of nice charts into eagles.
Yeah. Isn't it fascinating that the encephalopathy didn't make it into the
right? Well, I think they talk about that in the discussion in in a number of reasons. And part of that is that they felt that babies who were flagged or diagnosed with neonatal encephalopathy should be getting motor screening anyways. So they were like a totally separate group.
That's very interesting. Yeah, I mean, this is the it's funny that we're talking about this and that we're talking about prediction models. I mean, we're trying to roll out a prediction tool for wind measurements in our NICU from a company that we'll try to bring on for Tech Tuesday, actually, so people can find out more about them and stuff. But this is the future, right? I mean, it's, it's, it's, it's kind of scary to see the risk factors. I have to be honest, because it's like, like, I mean, you may have said that they're modifiable, but there's very little things. I mean, yeah. Aside from to be honest with you, what I was looking at was like, aside from tobacco, tobacco and drugs during pregnancy, yeah, it's like, man,
and then again, you say like, as a neonatologist, with where can I, where can I make the biggest difference? But I do think that the parents are listening to us and I do think we have a role in in advocating in counseling for tobacco cessation in the NICU
100%. Yeah. Just give them better Apgar scores. I guess, five minutes I've got that's something we have control over. Okay. We're getting to the end of the show. I have two more. Two more papers I wanted to mention, one of them is like, I guess I guess I'm going to do one of them is sort of a mega paper because it's a so it's a it's an article that is published in the Archives. And it's called does donor sex influence the potential for transfusion with washed with washed packed red blood cells to limit transfusion related immune responses in preterm newborn? first author is Tara Crawford. And this is a paper that's coming out of Australia. So the background is extremely interesting. They're talking about like how originally focusing on plasma and platelet transfusion, retrospective studies report greater risk of adverse outcome and those receiving products from female donors, particularly related to transfusion related lung injury. When you go through the study, trying to understand whether sex plays a role in the effect on transfusion, they actually have published a paper last year called effective washed versus unwashed red blood cells on transfusion related immune response in preterm infants. I forget which paper it's an immunology paper, but they're talking about this transfusion related immunomodulation trim and basically trim they're saying is characterized by both by both adverse pro inflammatory and immunosuppressive response and is likely to insult process you have an initial sensitization to an inflammatory process, and it Prime's host neutrophils with subsequent exposure to biological response mediator that accumulate during PRVC storage, resulting in an amplified immune response in the recipient. Now, they were talking about how we know about pre storage, local depletion that have reduced the incidence of various morbidities. But basically, in that original paper, they were looking at whether transfusion with washed compared with unwatched, leuco depleted P RBCs. And extremely preterm infants would result in an amelioration of the pro inflammatory cytokine and endothelial activation response following transfusion. I thought that was very interesting. The, the, the results, the study was actually a randomized trial that evaluated the effect of infants who were born preterm before 29 weeks of gestation, changes in plasma cytokines and measures of endothelial activation, and recipients were analyzed after each of three consecutive transfusions like three transfusion, not like the same day obviously. And what they found was that by the third transfusion infants who received unwashed blood had an increase in interleukin 17, a to necrosis factor, whereas infants who received wash blood had a reduction in il 17, TNF, il six, il eight, il 12, and interferon gamma. The magnitude of the post transfusion increase in cytokine did not change between the first and the third transfusion in the unwashed group, but decreased in the wash group for il 12, il 17, TNF with the difference between group switching significance by the third transfusion. And what this original study concluded was that the pro inflammatory immune response to transfusion in preterm infants can be modified when PRVC is are washed prior to trends. fusion. Now, taking the same dataset, they wanted to look at whether sex could play a role, whether your blood was coming from a male or a female donor. And there's, they're talking about two prior studies that were done in preterm infants, looking at whether the impact of donor sex and PRBC transfusion related outcomes are studied. And they mentioned that these two studies have conflicting results. There's a study by Murphy and colleagues that reported higher rates of mortality, morbidity and prolonged hospital stay in those exposed to any female blood finding that was influenced by transfusion number as well. And then there's another study that was published some years ago that we reviewed on the podcast on episode 21 by Patel and colleague that showed that in very low birth weight newborns who received PRBC is exclusively from either male or female donors, exposure to female blood was associated with a lower risk of death or serious morbidity. So the question in this current study was to evaluate whether donor sex influences the immune response to PRBC exposure in very preterm infants. Now, because it was the cohort from the washed versus unwashed study, they also looked at that. And the study was done the same basically using the same cohort. So they looked at those pre and post transfusion measurements of inflammatory markers. And so let you go over the the illogical methods on your own, they were able to include a total of 153 newborn, and what they found was that by the third transfusion, the magnitude of pre transfusion to post transfusion change and cytokine. Between the groups differed for specific inflammatory markers. These were interleukin six, interleukin 12, interleukin 17, a and two necrosis factor on post hoc analysis, compared with the unwashed, any female donor group. So basically, any female donor group and red blood cells were unwashed, interleukin six, interleukin 12, and interleukin 17, were lower in the washed exclusively male donor group. And il six, il 12. And TNF were lower in the washed any female donor group. So to summarize, these findings suggest that transfusion with unwashed PRBC is from female donors is associated with an increase in recipient immune response, an effect that can be ameliorated when you're washing, washing the RBCs, which is kind of interesting, because the study that we did review on the podcast some time ago had again is it's now conflicting with the study from Patel and colleague, which were reviewed on the podcast before and in agreement more with the Murphy study that they're mentioning. So I mean, I read both of these papers. I was like, I don't know what to make of any of this. This is it seems that the data on washing red blood cells was quite interesting. And that washing PRBC is may have some immunological effect, but I'm not exactly sure it's an interesting paper. But I am not exactly sure if donor sex does influence the response on the clinical the significant level, they obviously mentioned that larger randomized control studies are needed. But I think this is it's always interesting that we're looking so granularly at what we're giving babies and considering the blood products, I think it's always probably probably a wise choice anyway.
Yeah, I mean, we're learning more and more about right balancing transfusions and risk of anemia, thrombocytopenia.
Yeah, yeah, we talked about it
this morning. Sorry, no, that's exactly right. Did you want to do your last paper or I just really wanted to bring people that I think you should finish with your so I'll go okay. I just wanted to bring people's attention in different ways that you will next but to this perspective, paper on dilemmas and Feeding Infants with intestinal failure and neonatologist perspective, it's not just any neonatologist. It's Amy hare and Misty, good, so. So it should be read. And, you know, this comes also for people who may not know, and there's a special issue in seminars in Perinatology, dedicated to necrotizing. enterocolitis has a variety of articles that are super interesting, across the gamut of neck management and research and outcomes. So highly recommend people take a look at that. But I thought we've been dealing with some patients with intestinal failure. And so I think that this is a really interesting paper. Obviously, some of this is post neck. There are other reasons that babies have intestinal failure, but I liked it because it's a really good review. It gives really good information about you know, what is The definition of intestinal failure which are the babies are the highest risk for intestinal failure. So, I mean, that helps you, I think both with your clinical expectations in your anticipatory guidance of the family. What are some good TPN nutrition standard nutrition strategies? What is the approach to Feeding Infants with intestinal failure, and they even give recommendations on like advancement. So I thought it was a really good review paper that I just wanted to highlight.
Yeah. And I think also to note, Amy Hara and Mr. Goode, who are very active on Twitter, people that you can actually, if you're interested in that area of research, I'm speaking on their behalf completely, but I am sure they will mentor you, like they will, they will literally give you whatever advice you need. They're that approachable. So yeah, yeah. 100%. Okay, so we wanted to finish with this perspective that was published this, I'm actually not sure when it was published at this point when, January 29. So it was published a few days ago. It's in the New England Journal of Medicine. It is from Dr. Amy Blake from Baystate. In Springfield, Massachusetts, we say hello to all our friends from the state. I mean, I have a few colleagues there that are very near and dear to my heart. And the perspective is called the promise. And I feel like sometimes with all the things that we have to read, we don't have time, so we're just gonna read it for you. So that if you're driving in the car, you can listen to this very nice perspective. Essay.
I'm glad that you're reading it in that me because I found it very touching.
It's it's very touching. I mean, it's, it's, it's struck a few chords with me as well. So here it goes. The last promise I made was in 2013. As a first year fellow in neonatology, I was well versed in the statistics on survival of preterm infants. When Wyatt was admitted to the neonatal intensive care unit after being born at 31 weeks of gestation, I reassured his mother, more than 98% of infants were born at 31 weeks survive, and the overwhelming majority grow into happy, healthy children. He was small around the fifth percentile for his gestational age, but he arrived screaming with strong lungs and was doing well in his first few days as why it closed in on one week of life stable and tolerating feedings his mother confessor anxiety during one of our daily updates, updates. I'm worried that she said, I just want him to be okay. I again reassured her 98% of babies like white survive, and most do well. He'll be okay. I said, I promise. She took a breath and smiled. I left feeling proud of my communication skills and confident that Wyatt would continue to do well. Two days later, I was called in from home to see another baby in the unit. While you're here, one of the nurses said, Could you look at Wyatt he's been taking Kartik and something just seems off. At why it's bedside it was clear that something was indeed very off. His heart rate was in the two hundreds high even for a premature baby. His skin was modeled and his belly distended. When I opened his diaper, I found it full of blood. An X ray confirmed the diagnosis nematocysts and test analysis a pattern of air within the bowel wall that's pathognomonic for necrotizing enterocolitis. We call this parents to come in as we do labs increased his respiratory support and started IV fluids. By the time they arrived. 30 minutes later, we had intubated Wyatt had placed an arterial line and we're starting dopamine to address his hypotension. Repeat X ray only three hours after the onset of tachycardia should extensive pneumoperitoneum his intestine had perforated I shared this information with his family and we prepare to transfer wire to the nearby children's hospital for surgery. As they left the unit, his mother gave me a hug. Thank you for everything she said. Two days later, despite maximal effort, why died of fulminant necrotizing enterocolitis. Some seven years later, I was an attending neonatologist rounding in the NICU when I received a text message from my brother. It's a boy he announced born at term after an uncomplicated pregnancy, Nick was doing well as was his mother. Only a few hours later, my brother called back concerned Nick was having trouble breathing. They were taking him to the NICU. The next 48 hours were a flurry of text messages and phone calls as I tried to interpret blood gases and chest X rays from 1500 miles away and to translate what the doctors were telling my brother into plain language. Nick Nick was moved from CPAP to a ventilator received surfactant and initially had a good response. As his oxygen requirement crept back up to 40% and 60%. I began to get uneasy. Did he have an infection, pulmonary hypertension, something less common. Maybe the neonatologist taking care of Nick tried to reassure my brother, much as I had tried to reassure why it's family years before he's doing okay. She said his blood gas is getting better and his oxygen needs are stable. My brother hoping for an answer and heavily coached by me presser is this pneumonia? Does he need an oscillator? How about a transport for ECMO? Could this be something more sinister like one of the congenital disorders of surfactant production? It's not surfactant protein be deficiencies. He said. That's the bad one. And Nick doesn't have that. I promise. As Nick continued to get sicker, he was transferred to the level four NICU across town. His oxygen requirements and ventilator support remained at near maximal levels for days, and then weeks, as each intervention helped a little and then didn't sedation paralysis, inhaled nitric oxide inotropic support, his dedicated team left no stone unturned. Just after Nick, just after Nick reached three weeks of age, the genetics report came back surfactant protein B deficiency at Red homozygous for A pathogenic mutation. My brother and his wife sat down with the team to discuss the findings, but we knew what it meant fatal without a lung transplant. Nick remained on support for several days more as his older brother and grandparents were finally able to meet him. Then, when he was just under a month old his parents with the true support, Nick died peacefully in his mother's arm. As physicians, we are frequently given the gift of implicit trust by our patients and their families. Based on years of education and experience, our words matter. A broken promise, even when broken by factors out of our control can result in not only disappointment but destruction of that trust. A recent study of parents physician communication in NICU pointed to providing hope as a key theme for good communication, the promising something that is out of our control risks providing only false hope. When I promised Wyatt's mother that he would be okay. I fully believed that he that this would be the case. With my limited experience. At that point in my training, I didn't yet understand how helpless all our knowledge or medicine, our medicines or surgeries, could be against such ruthless disease. I believe to that next first neonatologist truly believed that he couldn't have such a rare, terrible disease, and that she that she was doing her best to provide that much needed hope. promises that are within our power to keep on the other hand can strengthen the bond between physicians and parents promises to do our best to care about their child to remember the ones we couldn't save. Two years after whites died, I saw his parents again. His mother had delivered another child Bryson this time at 34 weeks, he was admitted to our NICU just down the hall from where his older brother had been when their mothers saw me. She gave me a hug. Thank you for taking care of why he said, I hugged her back thinking carefully about my words. I'll take great care of Bryce and I said, and I'll never forget Wyatt, I promise. The names and identifying details have been changed to protect the families. privacy's and the disclosure forms provided by the author are available at New England Journal of medicine.com. That org, what a great what a great letter. No, what do you think? Are you with us?
Yeah, I'm here. The you know, the takeaway is not that we shouldn't promise anything, but it's in those last few lines, that there are plenty of things we can promise families, right, that will walk with them will support them. And we'll do our very best for their babies, you know, so, but, uh, but our words, and our and our words do matter. And we should pick them carefully. You know, parents are just desperate, and they'll and they'll like, they'll like, beg you into submission, right to give you give them an answer that they're looking for. And I think there are ways that we can convey our expertise and engender trust, without making promises that we Yeah, that's not to say I haven't stepped in it before and said, you know, me made that error also.
I mean, I've been, I've been on both sides of the fence where I've, I've been too bleak, or sometimes too hopeful. But I do think that it's shining a light on a very narrow line, that we are all having the right intentions. I think we all we all know what we're supposed to say. And what's interesting to me is that and the point that that Amy is making on this paper is that nobody was really wrong in what they said, right? I mean, they were they were they were right. Yes, it's extremely unlikely. But can we then like Do not confuse things to be unlikely to then promise that things will be okay. And I think that's, that's, that's, that's such a neonatologists thing that we we demand excellence at this level of D tail, where be very careful about your choice of words. And even if there's a point 000 1% chance, there's still a chance. And and you might find yourself regretting some of the your choice of words, when all you could have done you could have provided the same comfort and with with with measured with measured words,
Mm hmm. And I think that's the complicating factor about using statistics sometimes, right? We love statistics, we love statistics. But these families don't have 100 babies, right? They have one baby in front of them. And they only care about this one baby invader, they don't have the bandwidth to care about 100 babies, right? This is their one baby. And if you're that, if you're that one, then that's all then it's 100% for that family. So, you know,
it's I always tell families that when I tell them, I give them statistics. I said, just remember, flipping a coin has a 50 50% chance of falling heads or tails. But you're flipping one coin once and right. And to you, it doesn't really matter what happens if I flip 100 coins? Because you're just gonna flip the coin only once. Yeah. And, and yeah, and so. So it's always this this thing that we were talking about on last episode and a one trials, things like that. But yeah, definitely check it out. I think it's important to circulate these these letters. They're, they're nice to read. They're definitely much nicer to read than research articles. Let me let me be honest.
First, well, I think it's one of the other aspects that we have enjoyed about the podcast, and that's hearing the stories of others, because I think sometimes this work can be isolating. And this makes it a little less isolating to see it up in print, I guess.
Absolutely. I'm gonna try to see. Because on me Blake is on Twitter, you know, but it's, it sounds like, it sounds like it's a common name. I hope. We'll see. We'll see if I find her. I'll tag her. I will try to take her tag her on that. Yeah. What were you gonna say?
Speaker 1 1:12:07
All right, buddy. No, no, I believe, I believe. I believe they are on Twitter. But
the yellow pages of Twitter is right there. Yeah. I have to go back tomorrow. Yeah, that's right. All right. Thank you very much. And see you see you next time. Bye. Bye. Thank you for listening to the incubator podcast. If you like 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 email@example.com. You can also message the show on Instagram or Twitter, at NICU podcast or through our website at WWW dot v dash incubator.org. 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 professional. Thank you
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