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#142 - 📑 Journal Club 55

Hello friends 👋

We have a new episode of journal club ready for you. This week we discuss how maternal hemoglobin levels can impact neonatal outcomes, whether it is okay to feed babies during therapeutic hypothermia, new advances in GBS vaccination and what are the outcomes of BPD babies undergoing high altitude testing.

Have a good Sunday!


The articles covered on today’s episode of the podcast can be found here 👇

Association between maternal haemoglobin concentrations and maternal and neonatal outcomes: the prospective, observational, multinational, INTERBIO-21st fetal study.

Ohuma EO, Jabin N, Young MF, Epie T, Martorell R, Peña-Rosas JP, Garcia-Casal MN; INTERBIO-21st Consortium; Papageorghiou AT, Kennedy SH, Villar J.Lancet Haematol. 2023 Sep;10(9):e756-e766. doi: 10.1016/S2352-3026(23)00170-9. Epub 2023 Jul 20.PMID: 37482061 Free article.

To feed or not to feed during therapeutic hypothermia in asphyxiated neonates: a systematic review and meta-analysis.

Kumar J, Anne RP, Meena J, Sundaram V, Dutta S, Kumar P.Eur J Pediatr. 2023 Jun;182(6):2759-2773. doi: 10.1007/s00431-023-04950-0. Epub 2023 Apr 4.PMID: 37014443

Potential for Maternally Administered Vaccine for Infant Group B Streptococcus.

Madhi SA, Anderson AS, Absalon J, Radley D, Simon R, Jongihlati B, Strehlau R, van Niekerk AM, Izu A, Naidoo N, Kwatra G, Ramsamy Y, Said M, Jones S, Jose L, Fairlie L, Barnabas SL, Newton R, Munson S, Jefferies Z, Pavliakova D, Silmon de Monerri NC, Gomme E, Perez JL, Scott DA, Gruber WC, Jansen KU.N Engl J Med. 2023 Jul 20;389(3):215-227. doi: 10.1056/NEJMoa2116045.PMID: 37467497 Clinical Trial.

Pre-Flight Hypoxemia Challenge Testing in Bronchopulmonary Dysplasia.

Levin JC, Sheils CA, Hayden LP.Pediatrics. 2023 Aug 1;152(2):e2022061001. doi: 10.1542/peds.2022-061001.PMID: 37503557 ----

Find some of our notes here 👇

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The transcript of today's episode can be found below 👇

[00:00:00] Ben: Hello, everybody. Welcome back to the incubator podcast. It is Sunday. Journal club is upon us. We have Daphna and most notably Priya

[00:01:10] Ben: in the studio.

[00:01:11] Ben: how you?

[00:01:11] Priya: Good. How are you

[00:01:12] Ben: Priya, are

[00:01:13] Ben: It's

[00:01:13] Ben: good. Good to have you back.

[00:01:15] Priya: I'm excited to be back.

[00:01:17] Ben: Yeah. Daphna, how are you?

[00:01:19] Daphna: Same old.

[00:01:20] Ben: Same old. That's not true though, but that's okay.

[00:01:23] Daphna: Why?

[00:01:24] Ben: It's not the same way. It feels like you're doing a million things.

[00:01:28] Daphna: You're one to talk.

[00:01:29] Priya: I was going to say, aren't you both always? Come on now.

[00:01:33] Ben: Mine were very administrative types of tasks. If you if you guys haven't checked out the videos from Delphi and from the TED event that we put together, they're available on YouTube. We're going to link some of the TED videos on our Twitter and social media. But. They're on the tedx website.

[00:01:50] Ben: So like they're on the official ted website So you can actually go on the tedx new river, which is our tedx event and you can see them on that page there but[00:02:00] but yeah, they were That was quite good. We're going to keep posting to a week. I think this week This week we just released it. This past week we released the talk from mary cofflin and from leaf neal and were

[00:02:11] Daphna: They were both so good. And people should subscribe, right? Because then they'll get up, they'll get alerts when

[00:02:18] Ben: Yeah, you can subscribe and you can do, I don't know, what does Mr. Beast say? You have to do the bell and the subscription. It supposedly help. I don't know.

[00:02:28] Daphna: What does the bell do?

[00:02:29] Ben: I have no idea, but all the YouTubers

[00:02:32] Daphna: what the

[00:02:33] Ben: Said if you do the notification, it helps them. I'm assuming that if you guys do it, it would help us as well.

[00:02:38] Daphna: But we don't know how.

[00:02:40] Ben: we don't know how we're not making money off YouTube. We're still too small to even monetize the YouTube channel. So I don't know, but maybe the algorithm there's everybody talks about the YouTube algorithm as if it's like a beast, its own little organism. So maybe

[00:02:55] Daphna: thought you would know.

[00:02:57] Ben: I don't, I sound like I know [00:03:00] everything.

[00:03:00] Ben: And I know

[00:03:00] Daphna: we'll learn, we'll all learn together,

[00:03:02] Ben: that's right. I know very little. Okay. So I'm going to, if you guys don't mind, I'm going to get us started today. There's this interesting paper that came out in the Lancet called association. We're going to do a there's going to be a lot of maternal papers this week but they're big papers.

[00:03:23] Ben: So we have to review them. This one is called association between maternal hemoglobin concentration and maternal observational multinational inter bio 21st fetal study. It's a long

[00:03:37] Daphna: What a name. But what a good study. How often do we go over to Huddle and they're like, This mother has significant anemia.

[00:03:45] Ben: Oh, boy

[00:03:46] Daphna: Oh, boy.

[00:03:47] Ben: the pen Pandora's box right there. Hold on. Eric Ohuma is the first author. And it's like a very international group of of investigators. So no specific countries. So the background I [00:04:00] think is very interesting. And I, I. wrote down a few things from the background.

[00:04:04] Ben: Number one, that anemia in pregnancy, you primarily to iron or fully deficiency is associated with an increased risk of both maternal mortality, having a C section adverse outcomes, including preterm labor, preterm birth, small for gestational status and perinatal and neonatal mortality. Now, if you're using a cutoff of 11 grams per deciliter for your hemoglobin, the prevalence of maternal anemia in 2019 was estimated to be about 36% worldwide.

[00:04:32] Ben: That's huge. How often, like you said, how often do we see anemia when we go to LND? Now the CDC has developed these cutoffs for the different trimesters. So they're saying that the cutoff for anemia in trimester one is 11, trimester two is 10. 5, and it's again, 11 in trimester three, but. It remains very unclear whether these cutoffs predict any health risk or provide any protection for either the mother or the child.

[00:04:59] Ben: [00:05:00] Sorry. Didn't move my phone this time around. The other thing that's concerning is that these cutoffs are mostly derived from expert technical consultation and not really from prospective studies. Also these are country specific studies that even the non prospective studies that these cutoffs are based on, they're mostly conducted in the U.

[00:05:19] Ben: S. and don't really involve the rest of the world. What's happening is that in truth, both low and high hemoglobin concentration have been associated with increased risk of adverse maternal and neonatal outcome. However, There's little that is known about gestational age specific hemoglobin what these thresholds should be in terms of predicting health risk or protection for both mother and their infants.

[00:05:40] Ben: So what these, this, the, this group of authors tried to answer was that Can we create a longitudinal study linking hemoglobin values during pregnancy to longer term maternal and child outcomes? And so one of the reasons we're reviewing this paper is because the effects on the newborn are quite impressive [00:06:00] and I think people will be interested to hear that.

[00:06:02] Ben: So this is a prospective observational study. It's called the interbio 21st study. It was conducted between February 2012 and November 2019 in six cities. In pelotas in brazil in nairobi in kenya in karachi in pakistan In soweto in south africa in my sought in thailand. I think i'm mispronouncing that and in oxford in the uk Now, patients were considered eligible if they sought to initiate antenatal care before 14 weeks of gestation the gestational age determined by an ultrasound irrespective of their pregnancy risk profile for adverse maternal or neonatal outcome.

[00:06:43] Ben: They were followed for the duration of their pregnancy at an interval of about five weeks until the time of delivery. Now the mothers had to be at least 18 years old. They had to have a BMI less than 35 They had to have a natural conception. So no IVF pregnancy and it had [00:07:00] to be a singleton pregnancy Now the health growth and the development of the children were monitored up until two years of age, which is why?

[00:07:09] Ben: The recruitment period really ends in 2019. That's because there was a significant follow up They obviously collected hemoglobin levels from the mother This was done from a venus sample and they looked at several outcomes both mother and baby So the maternal outcomes consisted of pregnancy induced hypertension defined as a blood pressure of 140 over 90 blood pressure more than 140 over 90 without proteinuria.

[00:07:36] Ben: They looked at gestational diabetes defined as any degree of glucose intolerance with onset of first recognition during the pregnancy. And they looked at preterm premature rupture membrane. When it talking about neonates, they looked at preterm birth. They looked at acute respiratory distress syndrome defined as clinical features with abnormal chest X ray requiring oxygen at six hours of life [00:08:00] and the continued need of respiratory support and surfactant therapy within.

[00:08:04] Ben: The first days of life, they looked at growth status, large for gestational age and small for gestational age. There's more stuff in the methods, but I would like, there's a lot of results for us to go over. So I'm going to go, I'm going to go to that now. So the analysis was based on 2069 women who had at least one hemoglobin concentration measured between week 14 to week 40 of gestation. They contributed these Approximately 2, 000 women contributed to 4, 600 hemoglobin measures with a median of three hemoglobin measure per woman. The median gestational age at delivery was 39. 1 weeks. The median number of hemoglobin measurement, as we said was three and the median hemoglobin value was 12 gram per deciliter.

[00:08:52] Ben: I'm going to give you the hemoglobin measurement in gram per deciliter. It's in gram per liter. So it's like 120 in the paper, but obviously it's, you divide by [00:09:00] 10. That I made a clarification for you pre I know that the pharmacist probably cares about the units okay. So a very interesting result the risk of preterm birth and acute respiratory distress syndrome Increased by more than 50 percent for hemoglobin concentrations of 8.

[00:09:19] Ben: 5 And the risk was approximately twofold higher for hemoglobin concentrations of seven For preterm birth when compared to a standard hemoglobin of 11 So very interesting that a low hemoglobin had such a dramatic impact on preterm birth and acute respiratory distress syndrome. Now what was very interesting is that hemoglobin concentration of 14.

[00:09:44] Ben: 5. Not anemia, but obviously a much higher hemoglobin. For preterm birth and acute respiratory syndrome, acute respiratory distress syndrome were also associated with an increased risk, and there was more than a twofold increased risk for hemoglobin concentration of 16. 5 [00:10:00] for preterm birth and acute respiratory distress syndrome compared to a reference hemoglobin of 11.

[00:10:06] Ben: Now, what was interesting is that then what we find in the graphs, which are quite impressive, is that the risk of preterm birth and acute respiratory distress syndrome follows then like a U shape. curve continuously across gestational ages and higher risks were observed higher or lower than the reference hemoglobin value of 11.

[00:10:27] Ben: So it's not just anemia, but even a higher hemoglobin was found to be a problem. Now, when it came to SGA, they did not find any significant association with hemoglobin concentrations. Now, Looking at things by trimester in the second trimester compared with the hemoglobin concentrations of 10. 5 were not associated with an increased risk of SGA or acute respiratory distress syndrome.

[00:10:54] Ben: A hemoglobin of less than 9. 5 was also not significantly associated with an increased risk of [00:11:00] preterm birth. However, the risk of preterm birth increased by more than 70% for a hemoglobin concentration of 16. 5. So in the second trimester. higher hemoglobin could be a problem. In the third trimester, the risk of preterm birth and acute respiratory distress syndrome increased by more than 65% for hemoglobin concentrations of 8.

[00:11:20] Ben: 5, and there was a more than twofold increase for preterm birth and acute respiratory distress syndrome when the hemoglobin concentrations were 7. 5 when compared with the reference hemoglobin of 11. A few maternal outcomes that were interesting. There was a 50% higher risk of pregnancy induced hypertension for hemoglobin concentrations higher than 16 grams per deciliter.

[00:11:44] Ben: And the risk was more than twofold for a hemoglobin concentration higher than 17. There was a reduced risk of pregnancy induced hypertension at a hemoglobin concentration of 10. 5. And there was an overall reduction of the risk of gestational diabetes at a hemoglobin [00:12:00] concentration of 12. And in the third trimester I'm sorry, 12 in the third trimester and 12.

[00:12:04] Ben: 5 in the second trimester. Overall, no statistically significant association for PPROM, but in the second trimester, the risk of PPROM increased by more than twofold with hemoglobin concentration of 16. And so what began as a paper that really we, I thought was going to focus on anemia, turns out to really cover both ends of the spectrum. The last piece of information that's interesting is that after adjusting for iron supplementation, they didn't find any difference in their results. And so the summary of the study is that in this multinational longitudinal study they've described an association pattern between maternal hemoglobin concentration in pregnancy And adverse maternal and neonatal health outcomes.

[00:12:42] Ben: Now, the finding of risks relative to hemoglobin concentration suggests that the clinical and the public health benefit might arise from using an optimal range. A little bit like, almost like a caffeine, where if you stick within a therapeutic range, you have decreased complication. And that seems to be in point throughout the pregnancy as [00:13:00] it is associated with lower risk of either maternal and neonatal outcomes.

[00:13:05] Ben: Thoughts?

[00:13:08] Daphna: I guess that makes sense.

[00:13:09] Priya: yeah, it does. I was going to clarify. So are there different recommendations then for each trimester or is it always the same range of, I miss this on the hemoglobin.

[00:13:23] Ben: Yeah, so they, they do report the data based on the different trimesters. And I think based on the complication that they are looking at, different results where in the second trimester, it really seems that the higher hemoglobin really is an issue. For example, for preterm birth, where they saw like a 70% increase in preterm birth.

[00:13:40] Ben: If your hemoglobin concentration was 16. 5, this are less complications. If you were. Considered anemic in the second trimester. And then when you get to the third trimester, it looks like being anemic is really an issue with a twofold increase in the risk of preterm birth and acute respiratory distress when the hemoglobin goes to 7. 5. But that's again, when they're looking at it from [00:14:00] that's again, when they're looking at it from the trimester, but even Looking at, you could look at it from the entire duration of the pregnancy or by trimester. And I suggest that people look at the different graphs because they have they have a good number of graphs, figure two, which is the association between overall hemoglobin concentration in pregnancy and the neonatal outcomes. But if you go to figure three, You actually get the same kind of data. In the second and third trimester of pregnancy for for pregnancy and neonatal outcomes.

[00:14:27] Ben: So you can actually see what the effects are based on the different

[00:14:33] Daphna: And you said that iron supplementation didn't change the findings. Yeah, that's the unfortunate part. So what do we do about it?

[00:14:42] Ben: That's something that I was wondering, I think from our standpoint I think it's going to help me when I go to a console to figure out exactly what kind of risks we're dealing with. What I will be curious about is that I think this really is a paper that is addressed for our OB colleagues.

[00:14:58] Ben: And so I'll be curious to see how [00:15:00] that. May change their approach to anemia during pregnancy and that I don't know and that I don't know again what kind of Iron supplementation we're talking about whether it is just like you taking The daily iron supplement versus actually being treated with IV iron, for example.

[00:15:16] Ben: I don't know. But that will

[00:15:18] Ben: the next step

[00:15:19] Daphna: The end question is then does preconception supplementation moderate any of that?

[00:15:27] Daphna: I

[00:15:27] Ben: You're asking me questions I do

[00:15:28] Daphna: I know.

[00:15:28] Ben: answer to

[00:15:29] Daphna: thinking. I'm just thinking. But I, it just is such a good example of us neonatologists, we like that the baby doesn't have a lot of PHI, right? Like past, BMH, past medical history, right?

[00:15:41] Daphna: That part of our soap note is very short. But like they do. All of the mom's history is the baby's history and we don't always write it down, all those little things.

[00:15:54] Ben: Yeah. And usually even, when I go to a prenatal consult. Unless I have to come through the records, if I [00:16:00] want to find out what the hemoglobin was in the second trimester

[00:16:02] Daphna: for sure. That's if you have access to all the medical records.

[00:16:06] Ben: don't get me started. We have a lot of venting that Daphne and I need to do about access to our medical records, but anyway,

[00:16:16] Daphna: Okay. I had this paper to feed neonates, a systematic review and meta analysis. The lead author Joginder Kumar, this is in the European Journal of Pediatrics and it was a meta analysis. And the question was really whether enteral feeding during the cooling phase of therapeutic hypothermia increases the risk of severe neck, and they're using stage 2, 3 of of the Bell staging criteria in neonates with perinatal asphyxia, obviously undergoing cooling.

[00:16:49] Daphna: The prime, it's such a good question, right? There have been many smalls and not many. There have been a few small studies who looked at that question.[00:17:00] The primary outcome was the incidence of NEC greater than equal to stage two according to the Bell staging. They had a variety of secondary outcomes they wanted to look at.

[00:17:11] Daphna: They wanted to look at the incidence of any stage NAC, all cause mortality, culture positive sepsis feed, feeding intolerance, time to reach full enteral feeds, which they define as greater than or equal to 120 mls per kilo per day, time to achieve full oral feeds. Designated by removal of the oral or nasogastric tube, time to breastfeed, time to regain birth weight, rate of weight gain, time to discharge, number of days of TPN, and number of days of central venous catheter use.

[00:17:43] Daphna: And then they wanted to look at some anthropometric parameters, and they had, they intended to look at neurodevelopmental outcomes at 18 to 24 months. They used in total, six studies the reasons for removal of other [00:18:00] studies screened included duplicates, that they were purely animal studies, that they were biomarker or lab studies, the intervention was incorrect study design, study protocol, incorrect control group, or insufficient information.

[00:18:14] Daphna: In general, they included 3, 693 infants in those six studies. And all the studies enrolled infants greater than or equal to 35 weeks with moderate to severe HIE who underwent therapeutic hypothermia. For the study breakdown two of the six studies were randomized controlled trials. The remaining four were non randomized studies.

[00:18:37] Daphna: Three were retrospective and one was a mixed analysis. And, obviously, with meta analysis the data can sometimes be complicated. Three of the six studies used minimal enteral nutrition, like 10 to 20 mLs per kilo per day during therapeutic hypothermia, and they stayed at that rate during the duration.

[00:18:57] Daphna: Two gradually advanced feeds in the [00:19:00] intervention group, as per their standard unit protocol, and one did not provide any information on the feeding protocol. propagation. And notably, the type of feed intake, formula, or breast milk varied considerably across studies. And I think that's something that we will have to look at more closely in the future.

[00:19:18] Daphna: There was one study also in particular one of the larger studies that looked at cohorts from Sweden, which were quote unquote enterally fed and cohort, a cohort from the UK, which was, quote unquote not fed. However, in the study, one third of the enrolled infants in the control group in the UK who were not to be fed still received some feeds, five mls every four hours, so 30 mls.

[00:19:42] Daphna: Per day at the clinician's discretion. So some of the control groups still got fed a little bit. Though most infants were kept, N p O, the office did not provide this kind of separate population. And then in terms of risk among randomized controlled trials, one study had some [00:20:00] concerns in four domains.

[00:20:00] Daphna: It was considered a high risk of bias. The other was at low risk in all domains and among the non The non randomized studies, one had a serious risk of bias and the remaining three had a moderate risk. So the first question was next stage two or three, the primary outcome. And in general there were fewer than 25 cases among the 3, 691 participants.

[00:20:25] Daphna: The largest study reported data on 3, 236 infants receiving therapeutic hypothermia had reported severe neck in less than five infants. Therefore, the overall incidence of seeing severe neck was approximately 0. 5%. 6. And then 5 studies, 2 randomized controlled trials and 3 non randomized trials involving 455 babies compared data for the primary outcome.

[00:20:50] Daphna: And there was no statistically significant difference in the incidence of severe neck between the 2 groups in the randomized controlled trials [00:21:00] or the non randomized. Groups. The one large, the largest study had, like I said, fewer than five cases in the entire cohort. And this was not statistically significant between the two groups.

[00:21:16] Daphna: So then they looked at the secondary outcomes. The overall instance of any stage of neck across the cohort was 1.27%, and the analysis revealed no significant difference between enteral feeding and no feeding groups in the non And the non randomized trials, infants in the enteral feeding group had significantly lower sepsis rates than those in the control group, however, this was not seen in the randomized control trial.

[00:21:41] Daphna: The incidence of culture positive sepsis did not differ significantly between the groups. And in the meta analysis of just the non randomized trials, infants in the NRL feeding group had a significantly lower incidence of all cause mortality than those in the control group. There was no statistically significant difference in [00:22:00] mortality in the randomized control trials.

[00:22:02] Daphna: In terms of the feeding outcomes for the studies, with close to 400 participants reported the time to full enteral feeding, and there was wide variability in the definition of full enteral feeding. But in all four studies, irrespective of the threshold used, the enteral feeding group achieved full enteral feeds earlier than the no feeding group.

[00:22:21] Daphna: And this was consistent for the randomized control trials and the non randomized studies. Infants in the enteral feeding group received parental nutrition for a shorter duration in both the randomized and non randomized studies and required a central venous catheter for significantly fewer days. This was only reported in one study.

[00:22:40] Daphna: In addition, the enteral feeding group had higher breastfeeding and breast milk feeding rates at discharge. This was studied in the non randomized groups, and there was no significant difference in oral feeding rates at discharge or time to full oral feeding. Early enteral feeding did not appear to increase the risk of hypoglycemia or feeding [00:23:00] intolerance.

[00:23:01] Daphna: Two of the studies reported data on weight at discharge and found no significant differences between the groups. One study reported on daily weight gain and time to regain birth weight with no differences. And the last major outcome, six studies reported data on the duration of the hospital stay.

[00:23:17] Daphna: And infants in the NRL feeding group had a significantly shorter hospital stay than those in the control group. And this was seen in both the randomized control trials and the non randomized trial. There's only one trial of 100 participants that reported data on neurologic exams at discharge, not a long term neurologic exam.

[00:23:37] Daphna: And they didn't really talk about what the examination method was. But in that study, there was no significant difference in the infants with quote unquote normal neurologic exams at discharge. They did do a subgroup analysis, looked at feeding volume. Again, they wanted to see did it matter if babies were on the minimal enteral nutrition, so 10 to 20 mLs per kilo per [00:24:00] day, or full feeding from day one.

[00:24:04] Daphna: They wanted to look at time of initiation of feeds and speed of advancement. So none of the studies looked at their none of the studies achieved Their units, quote unquote full enteral feeds, so the baby not needing any IV fluids from the first day of life, which makes sense. Three studies looked at infants on minimum enteral nutrition during the period and two studies gradually advanced feeds to reach full feeds per their unit.

[00:24:28] Daphna: Pro per some unit protocol, but not necessarily the protocol that's typically used. And. So they included finally four studies three with the minimal enteral nutrition and one with gradually advancing feeds. And there was no significant subgroup differences between the minimally minimal enteral nutrition and advancing to full feeds groups, except the time to full enteral feeding and breastfeeding rates at discharge were lower in the in the [00:25:00] groups that had, that worked up on feeding faster.

[00:25:04] Daphna: In general, positive results of this meta analysis in terms of feeding during therapeutic hypothermia.

[00:25:12] Ben: It is a very interesting study because it's always a question, right? Where that we should start feeding. I think. There's still this question that's lingering about when should you begin feeding? I think there's always this question of the diving reflex where maybe in the first 24 hours, if there's any degree of hypoxic injury or lack of oxygen to the body in general, do you need to let the gut rest for 24 hours?

[00:25:35] Ben: I don't know if this paper really answers that question, but you still have 48 hours when you're on therapeutic hypothermia after that, where you can actually start feeding if you're feeding at the 24 hour mark. So it's quite It's quite interesting and I think it makes me feel much better about starting enteral feeds because These outcomes are quite impressive.

[00:25:54] Ben: Especially when it comes to sepsis they have all cause mortality rates of sepsis this is [00:26:00] fascinating even I think there's only one of the studies that actually looked at also feeding intolerance And the kids who were started had actually less feeding intolerance than and the ones who weren't so

[00:26:10] Daphna: this is, this makes sense given what we know about the studies of NAC, right? That, that, feeding can be protective. And actually some of the early studies, they, for example, my friend Lily Chang, who wanted to look at inflammation of babies who were being fed during therapeutic hypothermia, They actually found less inflammation, so there's things happening on a cellular level that we don't even really understand yet.

[00:26:35] Ben: Yeah, it would have been very, now we become more demanding, but I'm very interested to see how these outcomes differ between breast milk versus non breast, non human milk type of feeds. But But this is fascinating and I have to say it might change the way I practice because I might be reluctant to start feedings even at 24 hours after birth because I'm always afraid about what's going on, what are the outcomes going to be like, and this [00:27:00] is actually this is actually great data. And the studies that,

[00:27:04] Daphna: feed.

[00:27:06] Ben: yeah but even then even when you do feed I've done it before. It's not like I keep them NPO for 72 hours, but you always like am I gonna, am I going to pay the price for me pushing feeds and to see this data presented in this manner is quite, it's quite impressive.

[00:27:20] Ben: And the, by the way the trials that they're pulling, as you mentioned from the RCT, number one are all published after 20, 2010. So they're recent. And then. There's two RCTs. There's like maybe three retrospective studies. And the other one is a prospective study with a historical cohort.

[00:27:38] Ben: So these are good data. It's good. Thank you for presenting them.

[00:27:43] Daphna: My pleasure.

[00:27:46] Ben: Priya, where are you taking us

[00:27:47] Ben: next?

[00:27:48] Priya: right, I'm going to take you into the world of GBS. So the article that I'm reviewing here is The Potential for Maternally Administered Vaccine for Infant Group B Streptococcus. The first [00:28:00] author is Shabbir Mahdi and this was published in New England Journal of Medicine, and this group comes from South Africa, so it's one thing to keep in mind as we go through all of this.

[00:28:09] Priya: It was, All of these patients were in South Africa. So as everyone is familiar, GBS is common cause of sepsis and meningitis in newborns through 89 days of age. And the primary risk factor of course, is that maternal recto vaginal GBS colonization during delivery. So exposure to the infant to that. And while we in high income countries do a great job screening in the third trimester, and then we have the prophylaxis with interpart, Part of antibiotics, it's really only effective for the early onset.

[00:28:41] Priya: So they call that zero to six days. It's 80% effective, but not really effective in late disease. So past the first week of life. And so obviously a maternal vaccine has the benefit to potentially prevent this late onset disease and mitigate the use of antibiotics, right? Who doesn't want to decrease the risk for [00:29:00] antimicrobial resistance and disruption to the development of the infant microbiome.

[00:29:04] Priya: And of course, in these Source limited community settings where they're not screening and they don't do antibiotics. This could be a big therapy. So there are 10 serotypes of G B s that have been defined causing approximately 98% of the invasive disease in infants worldwide. There's already been a lot of studies to show the association between the serotype specific anti.

[00:29:26] Priya: capsular polysaccharide, which they called anti CPS, IgG, and the reduction of invasive GBS. But we're not really sure of the specific concentrations, and there's never been a large enough study with more than 80, 000 participants to be able to do this sort of analysis. Quite possibly do due to low incidence.

[00:29:48] Priya: So the questions that these authors are trying to understand are what are the results of GBS 6? So six of these serotypes in pregnant women and [00:30:00] examining of the transfer of anti CPS antibodies to their newborn infants. And can you relate induced antibody concentrations to potential protection by evaluating IgG thresholds that are associated with the reduction?

[00:30:14] Priya: Thank of the risk of invasive GBS among infants through 89 days. And I will say there's two different studies going on here. So there's two different study designs. The first is a zero epidemiologic study. And then the second is a phase two vaccine trial that was funded by Pfizer and the Bill and Melinda Gates Foundation.

[00:30:37] Priya: So firstly, we're talking about the case control longitudinal observational cohort study that was performed in South Africa. They were looking at these anti CPS IGG concentrations through the cord blood serum samples in case patients, so those with disease, so infants with evasive disease, and controls, infants without invasive [00:31:00] disease, who were born to mothers with GBS in the prospective cohort.

[00:31:04] Priya: And these serum samples were obtained at the time of infection from the infants that were born. enrolled retrospectively within 72 hours after lab confirmation. Vaginal and rectal swabs were taken at the time of delivery in a subgroup of the maternal participants. And then there was this exact matching.

[00:31:22] Priya: So case patients were matched to controls according to the same serotype of group B strep and similar gestational age at the end. of the infant at birth. So that was our first part of the study. And then the second piece here is the phase two vaccine trial. So this is a three stage trial and this reports the results of just The second stage of this trial, it's a randomized placebo controlled trial at three research centers in South Africa.

[00:31:50] Priya: Healthy pregnant women aged 18 to 40 were assigned to receive a dose of 5, 10, or 20 micrograms per serotype of [00:32:00] GBS 6 with or without aluminum phosphate. or placebo. Serum samples in mom and infant were taken at specific time points to assess for anti CPS IgG, and then safety was assessed in mom and baby.

[00:32:14] Priya: Mom kept an electronic diary. She recorded local and systemic events for the first seven days after vaccine, and then unsolicited events through month one after vaccination. Of course, serious AEs medically attended adverse events and OB complications were recorded for 12 months after delivery. And then for the infants, unsolicited adverse events recorded from birth to six weeks and then serious adverse events of special interest and medically attended adverse events were recorded through the first year, 12 months of age.

[00:32:47] Priya: What I found was interesting here is that, this is a randomized placebo controlled trial, and it's stage two, but there was no formal statistical analysis on the vaccine trial. So there was no statistics that were [00:33:00] performed on the vaccine trial. So when we talk about the results we have the first part, the seroepidemiologic Study was run through March 2019 through June 2020.

[00:33:12] Priya: I think the article does a really nice job of the flow chart, which is figure one, showing you where all these patients land, but there are 24, 000 pregnant women that were screened, and then 17, 752 were included in this prospective study. Rectal were taken at delivery in about 3, 000 patients women, showing that 26% of these women were carriers of GBS.

[00:33:40] Priya: From that 26% There were 28 cases of invasive GBS in newborns that were followed prospectively. Now remember, there's a prospective part, but there was also a retrospective part. And so there were 90 infants enrolled retrospectively within the 72 hours after lab confirmation. And so [00:34:00] what we really found here was the incidents per 1000 live births in this prospective cohort was 0. 72 for early onset and 0. 83 for late onset. And in those graphs, you'll see that they break it out by gestational age. And of course this incidence is much higher in those that are less than 34 weeks gestational age than those that are greater than 34 weeks. And when they talk about the six, different serotypes.

[00:34:25] Priya: The most prevalent serotype 58% had that, and then serotype 1A, 23% had that. And then looking again in the study, I think they also do a really great job. Figure 2 is the curves, and it shows the distribution of the serotype specific anti CPS IgG antibodies In infant case patients, and then their match controls.

[00:34:49] Priya: And then they also have this risk concentration curve on the right side that shows the probability of invasive GBS, according to that antibody concentration. [00:35:00] And so the authors note that the IgG threshold of 0. 184. to 0. 827 mics per milliliter was associated with a 75 to 95 percent reduction in disease.

[00:35:14] Priya: Now talking a bit about the vaccine trial, this was from July 2019 to August 2020. There were 360 patients enrolled and they were randomly assigned to one of six Different vaccine formulation. So again, three different doses with or without aluminum phosphate, so there's 40 in each of those arms, and then 120 patients got placebo.

[00:35:37] Priya: Two patients withdrew, and one patient had a stillbirth, which was unrelated to the study. So safety was only reported on 357 patients. Local reactions were common in patients receiving the vaccine and the solicited systemic effects were similar between treatment and placebo. The severe systemic effects reported in four [00:36:00] patients in the treatment and four patients.

[00:36:02] Priya: in the placebo. So those were similar too. And then for unsolicited events, there's 45 to 75% in the treatment arm and 61% in the placebo arm. And they broke those out, but they're in the supplement, I believe, but they were looking at pregnancy related and they found that the most common was fetal distress syndrome.

[00:36:23] Priya: Again, there was one stillbirth that was not related to When they looked at the infant's adverse events that occurred, those occurred in 62 to 75 percent of the treatment group and 74 percent in the placebo group. There were three infant deaths, one in the treatment and two in the placebos. Those were also unrelated to the study as deemed by the investigators and there were no adverse events in infants that were deemed to be related to the trial vaccine.

[00:36:51] Priya: And keeping in mind they followed them for up to a year, but of course these were These were reported events there was a discussion there [00:37:00] on immunogenicity, and so they looked at the induction of maternal anti CPS IgG antibodies against all serotypes seen after immunization with any form Of the vaccine.

[00:37:14] Priya: The one a was the highest that was was targeted and it was in the highest dose of the 20 microgram dose without the aluminum phosphate table to analyzes the dose with the serotypes, the percent of infants with anti C. P. S. I. G. concentrations that reached the threshold associated with 75% the threshold associated with 75% risk reduction of birth ranged by serotype.

[00:37:39] Priya: So 57 to 97% there. And so really in conclusion, this GBS 6 elicited anti CPS antibodies against GBS in pregnant women that were transferred to infants at levels associated with a reduced risk of invasive transmission. Thank you. GBS. Again, I have to highlight [00:38:00] here, this was studied in a low and middle income region with a really high incidence of disease.

[00:38:05] Priya: And then the use of seroepidemiology, I cannot say it, seroepidemiologic studies to identify quantitative immune correlates for invasive bacterial pathogens has in many cases correctly identified both the protective nature of the target vaccine antigen and the associated protective antibody level, which was also reported in the study.

[00:38:31] Priya: But as with others as with most studies, further studies are still needed to better define these immunologic relationships especially with high income countries. And then also one big. The other factor that they didn't account for is concurrent infections, malaria, HIV, those can have an effect too on how you're going to respond to this type of vaccine.

[00:38:52] Priya: I think it's a great start. I'd be curious to see, where this goes in the phase three of the vaccine trial. But I [00:39:00] think it's a great start for looking at this type of indication and these patients.

[00:39:05] Ben: I'm going to let Daphna give her thoughts.

[00:39:07] Daphna: I was going to let you give your thoughts. And it's moving in the right direction is as all I can say, like we, I think this would be great. I wonder, we need more information, but I wonder if it was available, how it would change the antibiotic situation, would we not give it at all to these moms if they were Is still GBS positive or do we expect them to be GBS negative after, we don't know.

[00:39:37] Daphna: I don't know how any of that, how does that change

[00:39:39] Daphna: our clinical practice,

[00:39:41] Priya: And it may not in these high income countries for maybe this is just where they don't screen and they're not giving antibiotics like we do. So I think it's, you got to start somewhere, but I do have some hesitations here

[00:39:55] Ben: I think that, I think first and foremost for the low and middle income countries [00:40:00] where GBS sepsis is early onset sepsis is an issue. I think without a doubt, if this can prevent neonatal deaths, I think this is a huge step, but to go back to your point, I'm wondering if as we try to find the best QI project rights to reduce antibiotic usage in the NICU. And we have, and we had a whole board review week on GBS. If you, if people are subscribed and we talked to Karen Popolo about this, how we screen these infants and how we determine whether they'll need antibiotic prophylaxis after birth. GBS status is a huge component of that. And so I am wondering if being able to vaccinate for GBS is going to reduce how much mPengent we use in the NICU.

[00:40:42] Ben: I think we're, I think there's still a bit of an ocean to cross when it comes to, from this paper to us reducing our use of Amp and Gent. But that's what gets me excited about this paper, which is. Man, are we going to stop doing EOS risk calculators? And are we just going to is AMP and GEN going to be reserved for a very select few?

[00:40:58] Ben: And are we going to be able to [00:41:00] reduce the rate of multi drug resistant organism because we're able to control GBS a little bit better on the prenatal end of the spectrum?

[00:41:09] Daphna: And obviously, this was done in pregnant people, but I wonder what the feasibility, again, would be in a preconception model where you got this even before pregnancy and how does that change? the efficacy. I don't know.

[00:41:28] Priya: That's a good question.

[00:41:30] Daphna: I also think there's a lot of hesitancy in getting the already recommended vaccinations during pregnancy. So maybe we can get bigger groups to study.

[00:41:42] [00:42:00]

[00:42:00] Ben: Okay. I guess I'm next. I'm

[00:42:02] Ben: I'm going to review a paper that caught my eye that I think is interesting and answers a very interesting question. Published in pediatrics. It's from a first author Jonathan Levine and the title of the paper is pre flight hypoxemia challenge testing and bronchopulmonary dysplasia.

[00:42:19] Ben: I think we too frequently, we get asked by parents can my baby take the plane? And I think sometimes that's a relatively easy answer if you have a very healthy baby, but when you have a former preemie Maybe even who has BPD, that could be that could be a difficult

[00:42:38] Daphna: And this happens to us all the time in South Florida where

[00:42:41] Ben: the time.

[00:42:42] Daphna: people are trying to go back somewhere else. So it happens

[00:42:46] Ben: Daphna's curiosity. There you go

[00:42:48] Ben: First first level

[00:42:49] Ben: unlocked.

[00:42:50] Daphna: We had a, I'm thinking of a

[00:42:52] Daphna: specific case. Anyways.

[00:42:54] Ben: So the background is actually very interesting, right? Because it goes into some trivia kind [00:43:00] of details about flight and altitude. So preterm infants obviously are at an increased risk of hypoxemia during air travel with the greatest risk in those who have BPD. Now commercial, the background, all this information is in the background.

[00:43:13] Ben: So I'm just quoting, but commercial air travel occurs at 9, 000 to 13, 000 meters with cabin pressurized From to from 1530 to 2, 440 To meter. So at 8, 000 feet, the reduced oxygen tension is approximately 108 millimeters of mercury compared with 148, 148 millimeters of mercury at sea level, which is the equivalent of breathing approximately FIO two of 15% at sea level.

[00:43:44] Ben: So that gives you already an idea of what altitude does. Now there's a small, although there's a small decrease in oxygen saturation in healthy individuals during air travel, this can be pathologic for those with lung disease. And so multiple studies have shown that preterm infants with BPD are likely to [00:44:00] fail what's referred into the paper.

[00:44:02] Ben: commonly as HAST, H A S T, which stands for high altitude simulation testing. And that happens beyond their estimated date of delivery. Now, the British Thoracic Society guidelines suggest that infants under the age of one year with a history of neonatal chronic disease should have their high altitude simulation testing performed.

[00:44:22] Ben: So the question they're asking is what is the likelihood of developing hypoxemia during the high altitude simulation testing? over time and to identify specific neonatal risk factors that are going to predispose you to developing hypoxemia. They hypothesize that children with more severe neonatal courses, including those with longer duration of respiratory support, greater support at 36 weeks, permanent hypertension, will be at the greater risk of developing hypoxemia during high altitude testing through two years of age.

[00:44:54] Ben: So what did they do? It was the They took BPD patients who completed a high [00:45:00] altitude simulation testing from the preterm long patient registry at Boston Children's Hospital. And this study included preterm infants who were born before, at or before 34 weeks of gestation between 2008 and 2019.

[00:45:17] Ben: They excluded children with congenital cardiac disease, pulmonary diagnoses other than BPD, congenital and genetic anomalies that contribute to their respiratory disease. They collected demographic and NICU history from enrollment questionnaire and from their discharge summary. Obviously the important question to answer here is what kind of BPD definition they were using.

[00:45:38] Ben: They were using the job, Benkel RE 2001 BPD definition. So what is high altitude simulation testing? Because I must admit that this is not something I'm super familiar with, but. It's fairly straightforward. So it's ordered basically by the pulmonary provider So it's not something that seems to be driven by the neonatology team [00:46:00] But what they do is that they have baseline that is collected in ambient air or for subjects who are on supplemental oxygen on their baseline level of support, then high altitude simulation testing was performed via the administration of 15% O2 blended with 85% nitrogen at 15 liter per minute via face mask up to 15 minutes.

[00:46:24] Ben: And they, during that time they recorded Saturations in a continuous fashion and what they detected were the lowest. O2 saturation, and what was the ending O2 saturation? Now, to standardize the outcomes for this specific study, a subject was considered to have passed the high altitude simulation testing if its lowest and ending SATs were 90% or more.

[00:46:49] Ben: And in the case of patients who had pulmonary hypertension on their most recent echocardiography, the cutoff used was 94% or more. [00:47:00] So far, so good. So looking at some of the data, they had 63 subjects that were included in the study. The median birth weight was 735 gram. The median gestational age was 26 weeks and six days, 7% of that population actually had a tracheostomy and.

[00:47:20] Ben: What the breakdown was in terms of BPD. They had about 22% of the babies with mild BPD, 17% with moderate and 60% with what's considered severe 38% of the population. 24 babies had pulmonary hypertension at 36 weeks corrected or after now. In total some of these subjects repeated testing. So they ended up having 94 high altitude testing studies to include in the analysis.

[00:47:47] Ben: And the reason, so how many, 32% of the subjects had actually more than one studies done. Now the studies occurred at a median age of about 14 months. Now during the challenge at FIO2 of [00:48:00] 15%, the median change in O2 saturation was about 8% from baseline. And I think that's quite interesting. 37% developed hypoxemia during testing.

[00:48:14] Ben: The question that's interesting based on the data is what was the probability of really passing the high altitude test? So on the cumulative distribution function curve that they're showing, the probability of passing the high altitude test at three months corrected was 50%. At six months, it was 67%. At 12 months, 72%.

[00:48:33] Ben: At 18 months, it was again, 72%. months, it was only 85%. And I think that's very interesting. Now, Obviously, you have to remember that. on the testing. Cause that's one of the questions I had when I was reading the paper, like they're not switching the oxygen support to 15% to 15% oxygen. You're still having your cannula on.

[00:48:57] Ben: You're still having whatever you're on. If you're on baseline [00:49:00] oxygen supplementation, but the air that's surrounding your cannula that could be entrained or anything that's going to be 15%. So they're changing your environment, not really changing your amount of support. Cause I don't think that would be.

[00:49:12] Ben: ethical. Now, the time to pass the high altitude test was significantly different for history of tracheostomy, for having needed postnatal corticosteroid, and for the type of respiratory support you are on at the time of NICU discharge. In the multivariable analysis with the Cox proportional hazards, the Ventilation for more than 14 days, postnatal steroids, respiratory support at 36 weeks PMA and severe BPD after controlling for gestational age, birth weight, and sex had a hazard ratios that suggested significantly lower proportional odds of passing the high altitude test at any time point.

[00:49:51] Ben: Having pulmonary hypertension after 36 weeks also had hazard ratio, suggesting lower proportion of passing the high altitude test. Now, [00:50:00] the time to pass the high altitude test curves were used to calculate basically the probability of you passing the high altitude test at 6, 12, 18 and 24 months corrected gestational age based on neonatal risk factors.

[00:50:14] Ben: I don't know if you guys are looking at the paper, I'm going to share my screen because you got to see this because this is such a useful table, basically table three in the paper. Gives you based on some of the risk factors in the left hand side of the column You have the different rows you have the different risk factors and then you have four columns Which basically you ask give you when you're doing the high altitude testing 6 12 months 18 months and 24 months And it basically gives you your risk of passing your chance of passing the high altitude test I think that is such a great table to have in your back pocket when that question ever comes up So I clipped it I saved it and i'm sure i'll make use of it very soon Now the infants who were on, who were no longer on respiratory support at 36 weeks, [00:51:00] postmenstrual age had a likelihood over 90% of passing the high altitude test at each time point.

[00:51:06] Ben: I think that's a good reminder, obviously, that the less severe the respiratory disease, the more likely they were to pass. At 18 months, infants who had not required postnatal steroids had a high likelihood of passing the high altitude test. At 24 months, infants with pulmonary hypertension or who had been discharged on respiratory support were the least likely to have passed the high altitude test, which is obviously very concerning because you would think that by 24 months, these families would be able to travel and so on.

[00:51:33] Ben: So the fact that it extends up until that point is quite, it's quite staggering. Now, When they only they did a sub analysis where they only included the 50 children who actually passed the high altitude test because some babies some children actually never really passed. At nine months corrected gestational age, the there was a 90% probability of passing in that sample among the two Children with a [00:52:00] tracheostomy who ever passed the high altitude test.

[00:52:02] Ben: The ages at first past were 103 months and 38 months. So having a tracheostomy is doesn't bode well for passing the high altitude test. And then finally, the last piece of data is that among the babies who did pass among the 18 children that passed the high altitude test that had a history of pulmonary hypertension at any point after 36 weeks, the median age to pass was actually 42 months.

[00:52:30] Ben: And the probability of passing did not reach 90% until they were eight years old. So I think it's a fascinating study that gives us a great insight into something that we don't commonly see in the neonatal literature. The conclusion from the group is that children with. post prematurity respiratory distress post prematurity respiratory disease have high rates of hypoxemia during high altitude simulation testing, particularly when they're under 24 months corrected for gestational age.

[00:52:59] Ben: [00:53:00] Children who were not on respiratory support at 36 weeks PMA are less likely to develop hypoxemia during high altitude testing, whereas factors associated with premature lung disease severity, including having history of pulmonary hypertension, receiving postnatal steroids, or who were discharged from the NICU on respiratory support, we're most likely to develop hypoxemia during high altitude testing through two years of age.

[00:53:24] Ben: These, this has implication for consideration of fitness to fly and ongoing hypoxemia in stress condition in children born prematurely. I love that study.

[00:53:35] Daphna: I think it's terrifying. I

[00:53:36] Ben: I know.

[00:53:37] Daphna: think, my takeaway one, it's a great thing. We should, of course, we should test. We should be able to give the most predictive information. So I love the test. I think that's a slam dunk. It is reassuring to me that if you can come off of oxygen before 36 weeks then that is reassuring.

[00:53:58] Daphna: But I guess any [00:54:00] kid on oxygen is really at risk.

[00:54:02] Ben: Yeah, no, I was thinking about that from

[00:54:04] Ben: the standpoint of my patients and I'm thinking like if a baby,

[00:54:06] Daphna: guidance.

[00:54:07] Ben: yeah, and if a baby has a bit of pulmonary hypertension or goes home on some oxygen and the parents asked me, would he be able to fly by age three? I would have said 100% of course three years. It's so far down.

[00:54:19] Ben: He'll be so much better and it's not that clear

[00:54:22] Daphna: And most of them are looking to travel before age

[00:54:25] Daphna: three.

[00:54:25] Ben: 100 i

[00:54:27] Ben: i took my daughter on the plane We took my daughter from france to the us

[00:54:30] Ben: when she was two weeks old

[00:54:31] Priya: Oh, Ben!

[00:54:33] Daphna: don't even tell me that.

[00:54:34] Ben: Yeah, the needs for visas and green cards were definitely very important for us. But so yes, I can I empathize with parents who would like to travel to see family or to show the baby to family members who were

[00:54:46] Daphna: Or yeah, you never know. Emergencies happen and people are,

[00:54:49] Ben: Or they want to take the kid to Disney world for the first time. I was like, can you imagine? This is baffling. So it's a great paper. I love that table three with all the risk factors [00:55:00] and telling you what is your chance of passing. There's some very interesting data there. Obviously like they have different gestational ages, but yeah, the chance of, if you have severe BPD, the chance of passing the test at six months, 53%, good luck with that.

[00:55:14] Ben: Six months. That's so bad. Anyway, a very interesting paper.

[00:55:19] Daphna: Very interesting paper.

[00:55:21] Priya: Maybe this justifies the cause that you can't take

[00:55:23] Priya: your kids to Disney until they're, what is it, eight years old? Is that where they said?

[00:55:27] Ben: Maybe that's what will trigger Disney to invest billions of dollars to solve BPD so that actually kids can actually make it to Disney World.

[00:55:35] Priya: you go. There you go.

[00:55:37] Daphna: Man, what if Disney solved BPD?

[00:55:41] Ben: The money,

[00:55:44] Daphna: Oh gosh I had one more paper but we're already at the hour. What would you like to do?

[00:55:49] Ben: it's up to you. You can save it for next time if if if you'd like. Give you an excuse.

[00:55:56] Daphna: it's 4.

[00:55:57] Ben: It's 4. 15, I have to go to call. And they will give you an excuse not to [00:56:00] procrastinate the last, the next time.

[00:56:01] Daphna: That's true. Okay,

[00:56:03] Daphna: I'll let you go relieve our colleague.

[00:56:06] Ben: All right, that sounds good. Thank you guys for making the time. This was a fun journal club.

[00:56:11] Priya: Thanks to you both.

[00:56:12] Ben: By the way one more one thing that we need to mention. The Recently approved fda the recently fda approved vaccine for rsv is something that people are talking about There was a an important paper in the new england about this and we reviewed it on the podcast when it came out So if you guys have questions about that, it's in the episode.

[00:56:31] Ben: I think we said episode 48

[00:56:33] Ben: And not too long ago in the past few weeks, we reviewed the other New England Journal that reviewed the administration of the vaccine to pregnant mothers. So we've reviewed all these papers. It's quite exciting. We'll see what the recommendations from the AP will look like when it comes to this vaccine, but yeah, check out this episode if you want to review the latest evidence.

[00:56:50] Priya: And I'll say that to my pharmacy friends who just posted

[00:56:53] Priya: on the listserv about this. Listen in to those episodes. We'll help you. Talk

[00:56:57] Ben: Absolutely. Absolutely. I think I [00:57:00] definitely know that the I definitely know that we reviewed the RSV vaccine for term and late preterm infants on episode 48. And I know that we reviewed the I know that we reviewed the. The vaccine for pregnant mothers, in the in a very recent journal club if you give me If you give me a few minutes, I actually I will be able to Yeah, 125 episode 125.

[00:57:25] Ben: There you go done

[00:57:27] Ben: Recently. All right See you guys later

[00:57:31] Daphna: Bye, have a good night.

[00:57:32] Ben: Thanks

[00:57:38] [00:58:00]

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