Hello friends 👋
Two journal club weeks back to back! Thankfully we are not short of important articles to review. This week we are reviewing some fascinating article. A study published in the Lancet from an Australian group of researchers who followed preterm infants in their mid fifties to assess for the risk of COPD! Daphna reviewed for us a short report on the effects of dexmedetomidine on cerebral activity via EEG monitoring. This paper may tame our excitement for this new medication.... you tell us. We also reviewed a paper looking at the effects of storing irradiated PRBC versus transfusing freshly irradiated PRBC, some very interesting results there too. Most notably, we reviewed a Cochrane review published a few days ago looking at COX-I for the prophylactic treatment of PDA. We are fortunate enough that the study's first author, Dr. Souvik Mitra, joins us live to breakdown the study design and the main outcomes of the meta-analysis. We reviewed a few more papers, most notably a new POC tool to assess for genetic predisposition to aminoglycoside ototoxicity. Anyway, as we said, it was a packed journal club. We hope you enjoy it and will share your feedback by joining the discussion on twitter.
The articles covered on today’s episode of the podcast can be found here 👇
Association between very to moderate preterm births, lung function deficits, and COPD at age 53 years: analysis of a prospective cohort study. Bui DS, Perret JL, Walters EH, Lodge CJ, Bowatte G, Hamilton GS, Thompson BR, Frith P, Erbas B, Thomas PS, Johns DP, Wood-Baker R, Hopper JL, Davis PG, Abramson MJ, Lowe AJ, Dharmage SC.Lancet Respir Med. 2022 May;10(5):478-484. doi: 10.1016/S2213-2600(21)00508-7. Epub 2022 Feb 18.
Effects of Freshly Irradiated vs Irradiated and Stored Red Blood Cell Transfusion on Cerebral Oxygenation in Preterm Infants: A Randomized Clinical Trial. Saito-Benz M, Bennington K, Gray CL, Murphy WG, Flanagan P, Steiner F, Atkinson G, Berry MJ.JAMA Pediatr. 2022 May 1;176(5):e220152. doi: 10.1001/jamapediatrics.2022.0152. Epub 2022 May 2.
Dexmedetomidine affects cerebral activity in preterm infants. Cortes-Ledesma C, Arruza L, Sainz-Villamayor A, Martínez-Orgado J.Arch Dis Child Fetal Neonatal Ed. 2023 May;108(3):316-318. doi: 10.1136/archdischild-2021-323411. Epub 2022 Mar 14.
Prophylactic cyclo-oxygenase inhibitor drugs for the prevention of morbidity and mortality in preterm infants: a network meta-analysis. Mitra S, Gardner CE, MacLellan A, Disher T, Styranko DM, Campbell-Yeo M, Kuhle S, Johnston BC, Dorling J.Cochrane Database Syst Rev. 2022 Apr 1;4(4):CD013846. doi: 10.1002/14651858.CD013846.pub2.
Time to positivity of blood cultures in neonatal late-onset bacteraemia. Mukhopadhyay S, Briker SM, Flannery DD, Dhudasia MB, Coggins SA, Woodford E, Walsh EM, Li S, Puopolo KM, Kuzniewicz MW.Arch Dis Child Fetal Neonatal Ed. 2022 Nov;107(6):583-588. doi: 10.1136/archdischild-2021-323416. Epub 2022 Mar 10.
Rapid Point-of-Care Genotyping to Avoid Aminoglycoside-Induced Ototoxicity in Neonatal Intensive Care. McDermott JH, Mahaveer A, James RA, Booth N, Turner M, Harvey KE, Miele G, Beaman GM, Stoddard DC, Tricker K, Corry RJ, Garlick J, Ainsworth S, Beevers T, Bruce IA, Body R, Ulph F, MacLeod R, Roberts PL, Wilson PM, Newman WG; PALOH Study Team.JAMA Pediatr. 2022 May 1;176(5):486-492. doi: 10.1001/jamapediatrics.2022.0187.
The transcript of today's episode can be found below 👇
Hello, everybody. Welcome back to the podcast, journal club. Two weeks in a row back to back.
We're making it happen.
We're making it happen. We have to catch up. We we have some logistical things going on that required us to get back on our feet when it comes to the schedule. It is what it is. We have a ton of very cool papers today. Yeah. We have a surprise guests who's going to make an appearance as well.
We'd love surprise guests.
I know. It doesn't matter.
It's our new thing.
So stay tuned for the episode and you'll get to hear who who is our who's our guest for today. Definitely anything fun happening in your life this week.
It's spring break, which is not as fun as it is not as wild as it was what it once was. But you know, hang by the pool. Traffic is better.
Traffic in Miami is so much better. Thanks. Anyway, we have a lot of cool papers. We are coming back tomorrow for the board review podcast. So if you guys haven't you guys have taken a few weeks off like we did. Good for you. But now's the time to get back in shape. And we're going over a new format. We're doing a whole new set of things that are quite interesting. So tune in to the neonatology and board review and the incubator and neonatology review podcast. It's gonna be very cool. So yeah, yes, yeah, definitely agrees.
I agree. I mean, we're working really hard on it. So I think people will really,
yeah, we're working hard. I am enjoying it tremendously. So I have, I have to share this with you. I have one rule of thumb when I'm making a presentation, is that I will be I will have an extremely low threshold to trash the entire presentation. If I'm not having a good time preparing it. And good for you. My dad used to tell me if you're bored making it there'll be bored listening to listening to it. That's true. So if I'm doing a presentation, I'm like, oh my god, like this is so long. This is so painful. It's like how do we expect to make this not long and painful to the audience? So to say to go back to the neonatology review podcast we are having I'm having a blast going through and doing this this archaeology, archaeologists work into the history of neonatal medicine. And, and listen, the people who are going to listen to the podcasts are going to kick some ass on rounds. And so um, you lose?
I think so. I think so. I mean, I'm, we're learning a lot to just putting it together.
Okay, so the first paper I want to start off with is a paper that like caught my eye, I think on your Twitter, and the title, the title is just so it's published in The Lancet and it is called association between very to moderate preterm births, long function deficits and COPD at age 53 years analysis of a prospective cohort study. So 53 year follow up, you got my attention. Amazing. The first author is probably going to not pronounce this correctly is din suey. This is coming from a group out of Australia. And this is published in The Lancet as we say. So what was the question that they were trying to answer? So the aim of the study was to investigate the potential association between varying degrees of prematurity and lung function and COPD in the six decades of life. Is this a valid question to ask? Yes or no As the author mentioned in the background, if we're looking back at the baraka hypothesis, and the fetal origins of adult diseases, it's definitely a question that is worth asking. There is some data reporting on the association between prematurity and adult onset of pulmonary disease. But as they mentioned, a lot of the data really focuses on the very preterm infants follow up length does not extend beyond the third decade in most studies. And so in light of this scarcity of this evidence, the question is about it. So what, how did they design this study? So they use the Tasmanian longitudinal health study. And this was a prospective population based cohort study in school aged children, seven years that started in 1968, in Tasmania, Australia. And the goal of this study was to study asthma in childhood. And then they talk about this about this cohort as like the proband. Right as like the first group of patients to be studied in that cohort. And so they were followed at the admin ages of 14 years, 18 years, 32 years, 45 years, 50 years and 53 years. And I mean, it's incredible. It's insane. I was imagining, I was imagining myself as a potential subject in the thing, and I have to go to this appointment. It's part of the study that I've been involved in since I was a kid forever. Yeah. imagining this 53 year old person in the most recent follow up at the age of 53 years. They invited obviously, everybody in the cohort to come for for these measurements. So what were the inclusion criteria, so they needed anybody that had a gestational age, and an assessment that 53 years and then the gestational age, they categorize them, they didn't look at it continuously, and they defined extremely preterm as younger than 28 weeks very preterm 28, to 32, moderate preterm 32 to 34, late preterm 34 to 37 and term anything 37 and above. So what was the what was some of the interventions that they did so obviously, they collected gestational age from birth records, and the participants performed pre bronchodilator and post bronchodilator spirometry. According to the American Thoracic Society and European respiratory society guidelines, spirometry was repeated 10 minutes after 300 microgram of salbutamol was administered via spacer, single breath diffusing capacity was measured according to the again to the ATS and the ers criteria. And in addition to follow up studies of preventive survey of the surviving parents was done in 2010. What kind of information that they collect, so they collected information on maternal age at birth, number of older siblings, maternal and paternal smoking was reported by the parents socioeconomic status and early life was based on the father's occupation. The lung function parameters, including FEV, one, the forced vital capacity, if we see the FEV, one over FVC ratio, the forced expiratory flow at 25 to 75% of FVC diffusing capacity for carbon monoxide, the DLCO. All those were measured at 53 years. Information on respiratory symptoms were also collected at 53 years using standard question, like the ways in shortness of breath. And any of those symptoms happening in the past. Well,
it's been a long time since I asked those questions. Yeah.
And the presence of cough phlegm without having a cold that were well defined as positive response. I had to go see a baby in the ER the ER called me the other day for a baby that from the NICU that had that had returned, maybe like a few weeks after discharge. And and when I went a sudden asking like the question I used to ask as a resident like anybody at home, it's like, Oh, my God.
That happened to be just yesterday, I had two er calls, and I was like, let's think about things that happen outside. It
was so good. It felt like I felt like a resident again. And the funny thing about it is that when I went to write to write my little consult note I signed as a resident Yes, yes. By accident.
Okay, state dependent learning.
Let's go back to the to the so what was the primary outcome of this study? The primary outcome of that study here was to look at COPD at the age of 53 years defined as the post bronchodilator FEV want to FVC ratio less than the lower limit of normal derived from the global lung function initiative reference values. Okay, easy enough. So what did they find? 1445 participants were included in the study. 51% were female gestational age ranged from 28 to 43 weeks of the 1,000th of the 14 145 participants. Less than 1% were classified as very preterm. 3% were moderately preterm 12%, late preterm, the bulk of them were considered. The bulk of them were term 85% were term. So let's look at the primary outcome of the 14 144 participants who answered the questions about smoking 46% have never smoked 39% were past smokers and 50 percents where 50% were current smokers. Obviously, you're talking about COPD, you gotta like this is a huge confounding factor. And as neonatologist we don't tend to process like What do you mean like the patient is smoking, that's not something where you still but let ya 10% of the participant had current asthma at the time of the assessment so after adjusting for sex age, adult hide maternal age at birth number of older siblings, maternal and parental and paternal smoking, socioeconomic status, very to moderate preterm birth was significantly associated with increased risk of COPD at age 53 years. Compared with Trenberth, the odds ratio were 2.9. Very to moderate preterm birth was also significantly associated with lower post bronchodilator FEV. One to FVC ratio, it was associated with lower Fe one lower DLCO and lower fVf 25 to 75%. Other interesting findings FEV one and FE want to visit ratio decline more rapidly between the ages of 45 and 53 years in the very to moderate preterm group than in the term group. That's fascinating. Older gestational ages, was older gestational age was significantly associated with a higher effigy one to a VC ratio and decreased risk of COPD for each week increase in gestational age or of point nine for each week. Increasing gestation. So that's that's, that's really impressive, right? I mean, when we say lab
when they can give us that pair of those with those ratios estimate? Yeah.
Because it gives you concrete goals. It's like one more week. Yeah, compared with term birth, no evidence existed that late preterm birth was associated with COPD, or lower FTD. You want to FVC ratio. Right. And so just to make that clear, we were talking earlier about very to moderate preterm birth. And if you don't recall what we had defined this as in the, the very preterm was 28 to 32. Moderate was 32 to 34. And then late preterm 34 to 37 and term was above 37. So, very to moderate preterm birth significantly associated with an increased risk of COPD, and then, late preterm birth, they didn't see that association when they were comparing that to turn birth. Other interesting results, they found a significant interaction between prematurity and active smoking status for the association with FTD want to FVC ratio will be surprising, to be honest, very to moderate preterm birth was significantly associated with reduced FEV want to FVC ratio among current smokers? What else did I write down the association between reduced FEV one and FVC ratio and very to moderate preterm birth was not significant among past smokers or never smoking individuals. The interaction between childhood asthma and prematurity was not significant for COPD. That's that's huge, right? Because you would say, Well, if you're right, if you're preterm and you have asthma that says you're you're toast. Yeah. So the takeaways from the study are that this is really the first study to investigate the effect of prematurity on lung function it to Lake middle age. And the data shows that very true moderate preterm is prematurity is associated with obstructive lung function deficits, including COPD, well into the six decade of life, and that this effect is compounded by personal smoking. Is this going to change anything in my practice? I don't know if parents are going to be ready to hear what things look like when their child's going to be 55 years old. But this is this is a window into a length of of follow up in prematurity that had never seen before. So kudos for these for these for this group. To, to for the study, really terrific job is very interesting results.
Yeah, and it's neat because it was not a study of preterm infants, right. They were a subgroup analysis, which I actually think is even kind of cooler. Because, you know, it just bore out in the in the data, which I thought was neat.
Okay, okay. Where are you taking us to next?
I'm going to do the article entitled, Dex metadata, Dean effects cerebral activity and preterm infants. Lead author Christina Cortez Ledesma. This is from the archives of disease in childhood. And it's coming to us from Madrid, Spain. So the question was really to determine how decks metadata and effects or precedents, the brand name affects cerebral activity and preterm infants and whether those effects would be related to ducks induced hemodynamic changes. And this was an this was an important study because there really were no studies on the effects of dexmedetomidine on subgroup cerebral activity and preterm newborns, like we have some understanding of the side effects. And they wanted also to evaluate, is it the side effects that we worry about, like hypertension or bradycardia, that might cause changes in cerebral activity? Or is it separate from that altogether? So it was a retrospective chart review. They looked at all very what they called very low birth weight infants born between January 2019, and may to 2021. Receiving Dex Dex magnetometry. And during their stay in their NICU, and we'll talk about what the birth weight criteria was, they weren't, they didn't give a clear birth weight cut off. And it may be larger than some units might consider but we'll talk about that. And then they they had information from the medical charts and basically the recordings of the amplitude integrated EEG. In all in all of these babies, they had 10 Babies total dexmedetomidine was selected as a first line sedative, there were four babies who needed deeper sedation given their clinical condition. And for those babies fentanyl was added as the fentanyl was really at the first line but they received X metadata and on top of fentanyl when the when the the anticipated level sedation was not achieved just with fentanyl. And then for each infant, they looked at two six hour periods one just before starting dexmedetomidine And then six hours after starting ducks, magnetometer and infusion and and those were the times where they looked at the amplitude Ed eg tracing, and the tracings were all assessed by a researcher that was blind to which period it was in,
but not to the EEG that would have been a problem if they were blinded to the age.
Right they were allowed to look at the input to tell a dad joke as we call them. Um, the inclusion criteria, like I said very low birth weight infants receiving decks, metadata and exclusion criteria were severe ivh PVL, non interred interpretable amplitude eg tracing because of artifacts, but they didn't have any newborns actually that met those criteria. And then the measurements they were looking at on the amplitude EEG, they were really interested in the lower limit amplitude, that interspersed interval which if you're not familiar with that, that's kind of it's the quiet period between first and in general, having a smaller interspersed interval predicts better, more, more maturation. So we see this as gestational age increases, we see smaller interspersed intervals. And then they looked at cycling like sleep wake cycling, they looked at brain regional saturation using nears. They looked at noninvasive mean blood pressure, they looked at heart rate, and they had the Transcutaneous oxygen saturation. They also took the co2 and the total hemoglobins. And they calculated the fractional tissue oxygen extraction for each infant during this time period, to the results. The mean gestational age was 26 and a half 26.5 I should say, which is interesting. And I'll talk about why I guess at the end, and the mean birth weight was 844 grams. But this included two babies greater than 1000 kilos, the biggest baby was 1100 grams. And what they found was infusion of dexmedetomidine led to changes, decreases in brain regional saturation in fractional tissue oxygen extraction, but did not modify the heart rate, the blood pressure, the oxygen saturation, the hemoglobin, or the co2 in this cohort of infants. It didn't seem to modify the lower amplitude EEG limit, but did lead to prolongation of the interpersonal interval and reduction of cycling. Interestingly, they saw sight Filling in seven babies seven out of the 10. Right before infusion. Which is interesting because some of these babies were quite young. And you know, we don't really see solid cycling until about 28 weeks. And some of these babies were younger than that. But they said that they saw it in seven of the 10 babies. And then in only one of those babies after the infusion was initiated, and that was statistically significant. The brain regional options and saturations did not correlate with the changes that they saw in the interpersonal, or was cycling. So the study takeaways, this was the first study really to look at dexmedetomidine and fusion, and how it modifies brain activity. And in these very low birth weight infants. Like I said, it led to prolongation of the interspersed interval and disappearance of cycling. So they really had a less mature amplitude EEG tracing when they were on the infusion. And the other important piece that they wanted to look at is that one of the reasons people say they don't want to use prospects, or dexmedetomidine Is this bradycardia hypotension, and they actually didn't see much of that at all. And in this study group, so they didn't feel like the changes on amplitude, EEG could be explained by any of the hemodynamic changes. And they also wanted, this is important work, because if you have a baby on amplitude, EEG and you see these changes, then you might think, Okay, well, it's related to the dexmedetomidine. And not to some change in clinical status. There were limitations to the study, obviously, it's retrospective, there were only 10 patients, there was a lot of variety in the clinical pathologies, they had other concomitant medications, that may change some of these findings, like pressors. And again, some of the babies were quite young, which, which could theoretically change their amplitude EEG tracing. So I thought it was interesting it that it'd be nice, especially as we're using art, we're broadening are the groups of babies where we use precedents to get a little bit more information.
Yeah, I think this is, this is the type of papers that I don't know if you can take the evidence directly to the bedside, you've mentioned that it's retrospective, you mentioned it's like 10 patients. So it's very, very hard. Didn't have a control group, either. Right?
Yeah. Right. It the each baby served as their own control, because they looked at the interval before and the period after.
So I think at the end of the day, it's one of the good reminders that whenever we tend to use data from other fields, whether it is even pediatrics, we can say, oh, it's safe. Let's Let's go. And we sometimes go on very weak evidence. It's good to have these papers to say maybe it may not always be as safe as you think it is. Just be careful. I think this is what I'm taking away from the paper. Just be careful. Yeah. Don't use precedents. willy nilly.
Yeah, I don't know if I'm there yet. I think, you know, like you said, we know that some of the other sedatives we do have similar Yeah, have similar findings on amplitude, EEG. So there's something about the effect of sedation. I think it's just a reminder to use the, you know, minimum necessary rule,
I guess. Yeah. What is what was the rule in medical school that they taught us first say no, meaning try to see if you could do it without the medication. Start slow, start low, go slow. And there's another thing about like discontinuing it anyway. You're up. All right. So the next paper I wanted to talk about was published in JAMA peds and let me let me pull up this paper. It is called the effects of freshly irradiated versus a freshly irradiated versus irradiated and stored red blood cell transfusion on cerebral oxygenation in preterm infant, a randomized clinical trial. first author is Dr. Is Maria Saito bends. This is coming out of NC anything on my thing out of group in New Zealand, and that was a very interesting study. So obviously, they're looking at irradiation of red blood cells and they are mentioning a lot of interesting statistics in the background. Did you know this, some infants in the NICU may receive up to 200% cumulative replacement of their total circulating volume at birth by means of transfusion
It's not even their blood anymore. Nuts
completely that's one common processing method is gamma irradiation of local reduced RBCs which basically prevent the proliferation of viable donor leukocytes, and this eliminates the risk of transfusion transfusion associated graft versus host disease in the recipient. Now, transfusion associated graft versus host disease is a rare but life threatening complication of RBC transfusion, that affects individual with established immunodeficiency. A systematic review of case report has suggested that preterm infants with image with immature immune systems may be at risk of graft versus host. So what was the question? So the aim of the trial was to examine whether transfusion of freshly irradiated red blood cells packed red blood cells comparing that to irradiated but stored improves cerebral oxygenation delivery in preterm infants with anemia. And so, is there is this is this? What about this question? Well, the reason it's an important question to ask is because in these infants right, it remains unclear whether modern pre storage local reduction alone is sufficient in preventing graft versus host. There's not many studies on the oxygen delivery capacity of irradiated and stored RBCs. And there's limited in vivo evidence to date that has highlighted the potentially detrimental effects of storage after irradiation on the ability of red blood cells to increase vital organ oxygenation. This finding in conjunction with in vitro evidence of accelerated storage li lesion formation in irradiated and stored RBCs raises the clinically relevant question, is storage really a bad thing? And should we try to not store irradiated red blood cells when we're wanting to transfuse them in preterm infants? So this study is part of the is called the Nimmo rad trial, the near infrared spectroscopy for monitoring brain oxygenation randomized control trial of freshly irradiation versus standard red cell transfusion. For anemia of prematurity, it feels like a very long title to squeezing into Nimrod, but that
is not that is a mouthful, it may be the longest study. We
will read I can I can get on board with but anyway, the Nimrod trial which was a single center, double blinded proof of concept randomized control trial conducted at the NICU of Wellington regional Regional Hospital in Wellington, New Zealand, between December 1 2017 and November 30 2018. The transfusion episodes were randomized to either the intervention group, which means that they receive the transfusion with RBCs that were freshly irradiated or irradiated on the day of transfusion or a control group. And those are infants who received a transfusion with RBCs that were irradiated and stored up in the blood bank up to 14 days. What were the inclusion criteria included preterm infants born at less than 34 weeks of gestation at birth, and they were at least 14 days of age in the in the NICU in order to be considered for inclusion. They excluded babies who had invasive respiratory support who underwent treatment with for any type of systemic infection, or who had hemodynamically significant ductus arteriosus or, or any type of edema, because obviously, they're doing near infrared spectroscopy and they didn't want to have any issue with the acquisition of, of data from the near infrared spectroscopy. So who got transfused? That's that's a sticking point of the paper. Obviously, the decision is left to the clinician and they said that they were following the pints trial, all the Enrolled infants receive the transfusion of 50 milliliters per kilo given over a three hour duration, near infrared spectroscopy was used for three hours at the following time points of the transfusion immediately before immediately after 24 hours after and 100 and 100 hours after which is five days after the transfusion was given. The RBCs use for transfusion were produced from whole blood from non donor with negative CMV antibody and collected in citrate phosphate, dextrose anticoagulant there's more there's if you're if you're a pathologist, and you want to know how they prepare the units, it's in there. And when I wrote it down, and now I'm realizing like it's it's, it may be a bit too much. What was the primary outcome of the study was it was to look at the change in cerebral regional saturation from baseline to immediately after the transfusion. And then the secondary outcomes were the pre space where they were pre specified changes in CF to E, which is tissue oxygen extraction immediately after transfusion and in the cerebral regional saturation and CFTR are 24 hours and five days. So these other time points at which they were following the baby's post transfusion. Okay, so what did they find? They enrolled 42 infants so it is a small study. But I mean, give them credit right I mean, freshly irradiated red blood cells for, it's not easy to do. But the 42 infants accounted for 64 transfusion episodes. They had some issues with a few babies infant follow up. So anyway, 61 transfusion episodes were were were considered for the study. The mean gestational age, gestational age of these babies was 26 weeks and three days, no infants received more than three transfusion and the mean age at PRBC transfusion was nine days. So let's look at the primary outcome. The main effect of treatment on cerebral regional oto saturation across all follow up time point was 2.1 percentage points. The treatment and follow up time interaction was not statistically significant, indicating a relatively consistent mean treatment effect at each follow up time points, which means that the cerebral regional saturation was better in the babies who had freshly irradiated red blood cells. Compared with infants in the control group, those in the intervention group showed a higher covariate mean regional saturation of 2.0 percentage point immediately after transfusion. So it seems to seems to matter. The confidence interval was 1.2 to 2.8. So let's look at the secondary outcomes. So compared with the control group, which remember the control group or the kids who are getting these stored, irradiated PRBC is the intervention groups sustained a post transfusion increase in covariates adjusted mean, cerebral regional saturation at 24 hours of 2.4 percentage points at five days of 2.0 percentage points, the main effect of treatment on CFTA across all follow up points were statistically significant and amounted to a reduction of point 002. Compared with control transfusion, the intervention showed a statistically significant covariate adjustment mean reduction in tissue oxygen extraction immediately after and at 120 hours. So, to summarize, the results of this trial showed that trace transfusion of freshly irradiated red blood cells conferred a small advantage in cerebral oxygenation for at least five days after transfusion compared with transfusion of irradiated and stored RBC components. Now on demand irradiation, they're very honest in the paper may be considered to optimize the oxygen delivery in the recipient, but it might be difficult to put in place. So yeah, they're realizing that this is this is a big change. Now, the limitations and the of the study, obviously, as a small study, it's a single center. And the other important factor is you they noticed changes on the nears, but like physiologically, does that make any difference? And we don't know that. And they're acknowledging all these limitations, right. I'm not critic critiquing the paper. These are limitations that they that they realize and obviously they're they're working with the best data that they can. Obviously the other consideration is that they're using the pints trial as a criteria for transfusion. Would more restrictive practices, like the ones that have been published more recently have impacted outcome? We don't know. Now, when it comes to whether this is going to change my practice? Well, I don't know if the evidence. I mean, it's very interesting data. I just think the evidence needs to move forward a little bit more before I think it's a big ask to start asking our blood bank to do on demand irradiation. And and I think the data needs probably to be a bit more robust for us to make the move. But it does swing the door wide open to have a much more full focalized discussion on whether we need to start doing this more consistently and whether that could improve outcome in the NICU?
Yeah, I mean, when you talk about end organ tissue, you know, oxygenation. I mean, that's, that's all over the body. Right. So, you know, being able to look at some of the other things we see all the time, like, neck, I think would be also really, really interesting.
Yeah, yeah, I mean, this but I think this is, this is where 60 intervention points are not enough. Whereas you want to start looking at all these other comorbidities. That's when you that's when that big sample is needed to.
Yeah, absolutely. But it was a super interesting paper, a lot of buzz on Twitter about it. So if you're, if you haven't, I'm gonna say it again. If you haven't joined As I near Twitter, maybe, maybe today's the day
Yeah, the funny thing about this paper is that it made everybody wonder like, are we doing stored or fresh? Yeah, how do we do it? Like? irradiated? Right? We know that we ordered irradiated, but it's like, I don't know if they're always fresh or if it's just everybody started liking investigating.
That's right. That's right. And, you know, not all units use or irradiated. So I mean, that's a whole nother
does this paper start from the premise that you are using irradiated? Are you just doing it fresh restored?
That's right. Okay. A different kind of study here. So I have this article time to positively blood cultures, and neonatal late onset bacteremia in the archives of diseases in childhood, coming to us out of chop, the lead author, so gory, mukha pa da. I should practice these before we
get in touch with those authors. Hi know, how do i pronounce your name?
Yeah, just you guys, let us know. Tell us out. So we could do better next time. But
Mukhopadhyay? Like you said, yeah, yeah.
Well, we'll keep working for it. Well, we will keep working to do better. And the anchoring author Michael coos knew it. But
didn't have to go with the senior author. I saw the name, I was like, she's gonna skip it and know you went to good, good, good for you.
But, obviously, doctor, pupils on the paper, so I, you know, to mention, um, so what's the question, they wanted to look at the time to positivity of blood cultures, among infants with late onset bacteremia, and predictors of time to positivity greater than 36 hours. And so the reason they looked into this is a lot of units are moving to a 36 hour empiric antibiotic course instead of a 48 hour empiric antibiotic course, while you're waiting blood cultures to reduce antibiotic exposure in neonates. And so as a lot of units are using that. And a lot of that data came from early onset sepsis. And so it's, it's really we didn't have the data to say, would the same thing be safe in late onset sepsis. So I think this is actually a really important paper. And this was a retrospective cohort study, they were comparing the median time to positivity and the interquartile ranges and the proportion of positive bacterial cultures by 24 hours, greater than 24 to 36 hours greater than 36 to 48 hours and then at greater than 48 hours. And they looked at a lot of different groups of bacterial infection. So pathogens versus contaminants, pathogens, excluding cons versus cons managed as a pathogen, gram positive, excluding cons versus gram negative pathogens, cultures obtained prior to antibiotic antibiotic administration versus pretreated cultures. And then CLABSI episodes versus non line associated infections. And then they, they did have two study sites. So they also looked at the difference between the study sites. And they looked at Kaplan Meier curves generated for each time to positivity in these groups. They looked at the probability of a culture of growing a bacterial pathogen after 36 hours. Using a formula where time to positivity is the proportion of positive blood cultures growing less than 36 hours after birth. X is the rate of positivity for blood cultures obtained greater than 72 hours after birth. So they do have that formula here. If you're interested. When you say that it's their it's their formula here, it's this big long formula about time to positivity fine, which is way more complicated than I thought time to positivity was going to be. I thought it was just the time to positivity.
Fine, I would have to
I mean, there's there's like, a numerator and a denominator and that's already too much for me.
Oh, yeah, no, it's it's a very long equation. So anyways, everybody should take a look at the formula. They also looked at a lot of associations between time to positivity greater than 36 hours, and they looked at gestational age of birth, postnatal age, when cultures obtained sex presence of central line pathogen type Study Center, and like I said, antibiotic pretreatment. So the inclusion criteria, were infants with a positive blood culture obtain greater than 72 hours after birth. I'm in 16 centers across two different healthcare systems, the primary outcome was time to positivity. Divide is a time interval from specimen collection to when a neonatal provider was notified of culture growth. Time to positivity analysis, was really looking at the first positive culture per infant and baseline characteristics. So they had a total of 10,235 blood cultures obtained from 3808 infants greater than seven to 72 hours of life. A total of 1082 blood cultures were positive, that was a 10.6 positivity rate. And then they excluded cultures that were repeat positives due to persistent bacteremia funky meow. And so that was 40 40.8% and contaminants 13.4% And so they overall found that there were 496 unique episodes of late onset onset battery Marfan anemia in these 447 infants. The mean gestational age for the cohort was 26 weeks, and the median postnatal age at the first episode of a blood culture was 14 days. And then they had data on central line available for 378 episodes, and 66% of these infections were identified as a CLABSI. So line associated gram positive organisms accounted for 58% of all pathogens cons was the predominant organism, representing 28% of all pathogens, gram negative organisms were the second most common 33% followed by fungi 6.1 and poly microbial 2.6. So the primary outcome was the time to positivity the median time to positive video is 23.5 hours, with 54% detected by 24 hours 85% detected by 36 hours and 94.9% by 48 hours. The probability of detecting a bacterial pathogen after 36 hours was 1.8%. And the probability of detecting a non Khan's pathogen after 36 hours was point 5%. Then they wanted to look at what were the risk factors for getting a positive blood culture after 36 hours and they looked at cons cons had a lower had a longer time to positivity compared with other pathogens. Excluding cons, the median time to positivity remained longer for other gram positive organisms compared to gram negative organisms. However, the proportion detected by 36 hours overall did not differ. And Cons represented 70% of organisms that were detected greater than 36 hours. However, there were 19 other organisms that were detected after 36 hours, they included Staph aureus and NF 10, E. coli and Anna for Pseudomonas and then have to enter Bactrim n of one, enter caucus and have one stenotrophomonas and have one more of the secondary outcomes central line presents antibiotic pretreatment. And like we said cons all significantly associated with time to positivity greater than 36 hours. And then the multivariable analysis cons and pretreatment of the cultures. So just to be clear about that the babies got the antibiotic before the cultures were drawn, remain significantly associate associated with time to positivity greater than 36 hours, but central line presence did not at that time. Other interesting results, so they looked at so if in this cohort, they had stopped antibiotics at 36 hours, they would have avoided 1164 antibiotic doses for gram positive coverage. That's the big point of this question. It's a it's a lot of antibiotic. And then they said well, how what would we have missed? Right? So that would have resulted in an interruption in the span of a question. It would have resulted in an interruption of antibiotic therapy for eight hours in six infants with an eventual positive culture. So I guess everybody can decide for themselves if that's how has significant that is for you. The longest time to positivity was for a culture growing equal aka 83 hours. And for this episode, a 36 empiric duration would have interrupted the 40th hour antibiotic dose and delayed a subsequent was 44 hours, whereas a 48 hour empiric duration would have interrupted the 48 hour antibiotic dose and delayed by 36 hours. However, for every case with an interruption of antibiotic therapy of greater than eight hours, 194 antibiotic doses would be avoided. And other interesting things they looked at antibiotic pretreatment was not associated with a lower median time to positivity, pre treated cultures were less likely to be positive by 36 hours compared with non pre treated cultures. So when they looked at all of the subgroups of time, the other thing they looked at, again, was between the two groups. So, one of the groups had an onsite microbiology facility, and the other group had a centralized off site facility, which makes sense. So the off site facility had longer times to positivity, obviously, because it took longer just to get the cultures set up. But it didn't change the data for the 36 hour cut offs, which I thought was cool. So I thought this was a really neat study, I think they answered a lot of questions by doing some additional statistical analysis, especially the questions like so how many babies would we miss? How much antibiotic would we prevent? And I mean, the overall takeaway is that empiric antibiotic coverage, if you're not concerned for cons, could probably be stopped at 36 hours. If you are worried that it's cons, which How do you know? And then if there's pretreatment of the antibiotic course, then that should maybe give you pause that you would want to watch the cultures for a little bit longer. And obviously, before the multivariable multivariable analysis, and even a line associated infection was was related with a longer time to positivity. The limitations were that it was retrospective. Actually, I thought the different facilities was an interesting factor. I think it may, I think it may have been easier to study all those babies at one facility. Will it change my practice? Probably not, because we actually have we really tried to stop the antibiotics already, why 36 hours, but it's nice to have the data for this late onset, except that I might be more careful about some of those factors that prolong time to positivity, like lines and pretreatment. For sure.
I think I think, I think it's, it's, it's a tough one. It's a tough one. Because what are you what are you supposed to do? And I think it doesn't mean to me that we should change our policies all across the board, and say, Hey, like, if you have a rollout sepsis, looking at late onset sepsis, 36 hours is enough in all cases. But I do think there's going to be many scenarios in which you always like it has happened to all of us that we ponder, can we stop antibiotics a bit early, like the sepsis workup? Sometimes babies have tortured us so long that we are so afraid of anything that maybe you're you pull the trigger earlier than you might have liked. I think it's nice to have the,
quote unquote, soft car, right?
Yeah. But I mean, listen, there's some babies that that have been so sick, that they start getting better. And if you see something you like, Oh, my God, I'm not gonna I don't want to miss the infection, right? sepsis, right? I think these babies, if you feel okay, then maybe there is no need. Maybe there is no need to do sepsis to, to continue antibiotics for 48 hours. And I think you have that data to support that that decision is kind of nice.
Yeah, it's hard, right? Because this, I mean, what we got from the paper was how many antibiotic doses, but we don't know what the cost of that is. And I don't mean, fiscally, financially. I mean, what is the cost right to the baby to, to all of us for, you know, antibiotic overuse? It's, we can't measure that. What is the cost to a family if you have a baby who you know, is sick and doesn't get treated, you know, and you stop the treatment early? It's, it's, it's tough. Tough to wait. I actually thought I was surprised to see how many how many, it's still the minority. But how many did present after 36? I know. And what kind of bacterial pathogens were no scary. Yeah. But But this LED coli, but again, but again, it's the minority, it's the minority of cultures for sure. I think
also, there's reasons why you do a sepsis workup. You have presenting findings that say I'm worried this baby may have such and such and and then things happen and clinically the baby looks that's very, very good. And you're like Oh, was that was that a bit of a and overall. Now you never know whether the baby looks really, really good because you're having in vivo in vivo proof that that things are getting here. Anyway,
the antibiotics are working fine. You can go round and round about this. I find
myself making the argument for against for against. Yeah, and I can't I Yeah, it's a tough one. But great job. Great job. By the
way. That was a really cool paper. Yeah. All right, your turn. We're running out of time, as usual.
So the last paper we have for you today is a big review. It is published in the Cochrane Library. It is called prophylactic cyclooxygenase inhibitor drugs for the prevention of morbidity and mortality in preterm infants. In network meta analysis, the first author is Dr. Shubik Mitra, from Canada. This this is, in my opinion, typical Dr. Mitra paper, extremely, I guess. Well designed No, like from a methodological standpoint, I was looking for the word eloquent, but it's not. It's elegant. That's the word I'm looking for. I'm sorry, very elegant. Methodologically. Right. I mean, they're him and his group, we are always thinking very carefully about what is the best way to conduct the study to really answer the question that I'm trying to answer. And if you are a young researcher, and you want to follow people who are doing research in a very, very clever and nice way I would I suggest you follow Shafiq Mitra, who is a new Twitter superstar he works for he's working with the EB Neo group as well. So yeah, I'm not reinstating the obvious here. So the question was, that they were trying to be to ask is looking at the effectiveness and the safety of prophylactic treatment for PDA? Comparing ibuprofen, indomethacin and acetaminophen. And they did this in a Bayesian network meta analysis. And the reason they thought this question was needed to be asked is obviously because nobody has really looked at all these interventions. Together. I'm going to talk a little bit about the inclusion criteria. They included studies that looked at preterm infants less than 37 weeks or low birth weight less than 2500 gram, they needed to be assessed slash treated within 72 hours after birth. Interestingly, Dafna needed no prior clinical or echocardiographic diagnosis of PDA like when they meant prophylactic, they meant and provenance. And obviously, the interventions included prophylactic administration of indomethacin, ibuprofen or acetaminophen compared with placebo or no prophylaxis, the intervention watchful waiting, watchful waiting, which which is one of the most common way of addressing these issues these days. The intervention had to be delivered within the first 72 hours. And there must be no documented clinical or echocardiographic evidence of the PDA they had. I'm going to talk about the outcomes. The primary outcome of the study was severe ivh and mortality as separate outcomes, right not not combined with severe AVH. mortality. secondary outcome was a long list of things. I'm going to read them quickly the receipt of the receipt of pharmacotherapy for symptomatic PDA, surgical or interventional PDA closure, necrotizing enterocolitis, gastrointestinal perforation, chronic lung disease oliguria ne ivh, periventricular, leukomalacia neurodevelopmental outcome at 18 to 24 months, cerebral palsy, and major neurodevelopmental disability, obviously, the paper goes into the definition of each one. We're obviously as usual, running out of time. And, you know, the paper is actually very interesting. And we're very fortunate that we have with us today, Dr. Mitra himself to actually tell us a little bit about the study the way the methods that were used to conduct the meta analysis and some of the results that they found. Should be Thank you. Thank you so much for being on with us this this this morning.
Unknown Speaker 53:58
Thanks a lot, Ben, for having me.
No. So tell us a little bit about about this, this Cochrane Review and what what do you want the audience really to take away from this data and the publication in general?
Speaker 3 54:12
Yeah, so So prophylactic use of cyclooxygenase inhibitor drugs is interesting. The neonatal community, we have generally moved away from it, including myself. For example, for indomethacin, we have concluded that it does not improve neurodevelopmental outcomes, it increases gi perforation and neck so it's bad. For ibuprofen, we believe that it does not improve any meaningful outcomes. It increases gi perforation may induce pulmonary hypertension, so it's bad. And for acetaminophen, we're all a bit unsure if it really helps as a prophylactic medication. But in this day and age when we are looking for anything that might improve clinical outcomes and extremely preterm babies, what does the randomised trial evidence, say about the cause? Reading effectiveness. And there has been a lot of head to head randomized trials over the last few years comparing the different drugs versus placebo. So, this very question prompted us to conduct a network meta analysis on the Cochrane neonatal platform, where we essentially wanted to explore the comparative effectiveness and safety of all the different prophylactic cyclooxygenase inhibitor drugs that have been used in preterm infants and have been trialed in randomized control trials.
And the great thing about this is that in the paper you mentioned, they are for intervention, right? Because you may be tempted to think it's acetaminophen, ibuprofen, in the medicine, but you add in there the fourth one, which is nothing just watching, right,
Speaker 3 55:47
absolutely. And and the fourth one is, as you rightly said, is the most commonly used intervention which is doing nothing prophylactically. And, and we've made our own judgments regarding which one is the best. Now, just just to go back a little bit into what we did, we we did a Bayesian random effects network meta analysis with non informative priors, which essentially allows us to, to combine data from different trials that have used different interventions, provided the patients enrolled in all the trials are similar, the trials are methodologically similar, only then we can combine data from the different trials as if all the patients were eligible to be enrolled in one single multicam trial. So if you think about it as one single multicam trial, that is what a network meta analysis helps you to achieve. And the other thing that we did here was we use the grid approach for network meta analysis to assess the certainty of evidence. Now, one thing that we consciously did for this review was that we defined the thresholds of meaningful benefit or harm, before we assessed the certainty of evidence, and not after, which is commonly done. And these thresholds were defined using what we call a partially contextualized approach, where we specified what do we actually mean by a small, moderate or large benefit or harm, because for a decision maker, it is it is not enough to dichotomize the evidence into this, this works versus that does not work based on this arbitrarily defined P value threshold. As a clinician, what you really want to know is, how large is the benefit or harm with this medication, and how certain you are about the degree of benefit or harm. And for the parent, when you sit down to discuss the pros and cons, they would have the exact same questions. So that is how we framed our summary of findings when you read the paper, when we presented the absolute risk differences, and their 95% credible intervals. And what you will notice that our conclusions for each outcome was based on how small or large was the absolute benefit or harm, and how certain we were about those effects, based on where the limits of the 95% credible intervals fell. So for example, what we found was that prophylactic indomethacin probably resulted in a small reduction, and severe intraventricular hemorrhage, and a moderate reduction in mortality and surgical PD occlusion. prophylactic ibuprofen probably results in a small reduction in severe ivh, and a moderate reduction in surgical TD occlusion. It may result in a moderate reduction in mortality, but our certainty was low. And the evidence so far is very uncertain about the effect of acetaminophen on any of the clinically relevant outcomes.
And that was because of lack of trials, I guess. Right? It was not so much as many studies with the same benefit as they were with the other two.
Speaker 3 59:12
Absolutely, absolutely. So, so what the big thing that comes out of here is that can we confidently ignore the benefits with respect to some of these very important outcomes, as we have been mostly doing now from the results as a clinician, all what I can say is that for indomethacin, and in some cases for ibuprofen, when the medicine is not available, it will probably be unfair, if parents are not involved in the decision making process, which I guess is not the case in any Center, where majority of the centers who do not use it, they do not involve parents in the decision making process. And in some centers who actually use it, I guess, in those centers as well that Parents are not involved in the decision making process. But if you see the results, there is some suggestion of benefit with lower certainty, which might be very important for the parents. And same same with the harm. So I think that's, that's the biggest thing that comes out of the paper.
This is fantastic. Thank you so much. Yeah, for clarifying for clarifying the data. And then the last thing I guess I wanted to ask you too, because you have these, these very beautiful sort of the bar graphs in the in with each outcome, that that are called Renko grams. And, and basically, my understanding is that this helps you classify the different medication based on the probability of actually not sure, actually, I'm not gonna say anything incorrect. But for the people who are going through the paper, when you get to these figures, how should we review these figures? Can you help us with that?
Speaker 3 1:01:04
Absolutely. So So almost there, Ben, you're right. As always, so so these are these are ranking grams, which which essentially kind of gives you the probability of an intervention, ranking in each of the possible ranks. So if I'll just give you an example, say you take any rank program, and you'll find that an intervention, C indomethacin, has a 70 or 80%, probability of ranking one, so the bar is at 84, for rank one for indomethacin. So it has an 80% Probability of ranking first. Maybe it has a 10% probability of ranking second, and none for for being the worst intervention. So that is how you interpret each of these ranking grams. So if you find that an intervention has a long bar for rank one, and almost nothing for rank two or three, then you can be fairly confident that for that particular outcome, that intervention is the best. Same goes for another intervention see it, the bar is almost nothing for rank one a little bit for rank two, and a long bar for rank three. So you can be fairly certain that for that particular outcome, that intervention is the worst. The problem that will that happens when we deal with less than number of infants and smaller number of randomised trials is that there is a bit of uncertainty. So for a lot of interventions, you would find that the bars are there for rank one, two, and a little bit and three, so. So it kind of tells you that we are not that certain that this is truly the best intervention, there's probably a 50% probability that this is the best intervention. But there's also a fairly good probability that it could rank second or third. So so the Rachael Graham's should be taken in that context. Yeah, it gives
you that that variability of of how certain is the evidence basically, right, exactly, exactly. Yeah, I get it. I get it. This is this is fantastic. Well, yeah, this is really helpful. No, I think this was really helpful. And I'm very happy that for the people who don't know, I literally texted Shauvik this morning, and said, Hey, like I'm reading the paper. Now. Can you come on the show and help us with the stats and the interpretation of the data? Because it is entirely it is important work. So I really appreciate you taking the time today. And yeah, thank you so much for this paper. That was that was really helpful. Thank you so big.
Speaker 3 1:03:52
Thanks, man. And doctor for having me. Always a pleasure. Pleasure thing.
Definitely. How cool was it to have the author on?
Yeah, I'm really liking having people come and talk about their work. I think it's really neat, I think to this study, and the way we analyze data is changing. Right. So we're looking at all of these other approaches, which obviously, I know you're, you know, 100% fan. So, you know, I think some of us are still learning. And so I think it was really nice to have that descriptive conversation.
And I have to be honest with you, I had not when I read the paper the first time around, it did not come across to me as what Dr. Mitra presented where it was, like, maybe it's time to involve the parents in the decision making of the medications, right. I mean, we barely can agree ourselves. But it is true that when when there is uncertainty, maybe it's up to the parents to make the decision for their baby. Yeah, she shared decision making decision making, but for the treatment of PDA, which is such a controversial topic is fascinating. So yeah, well thank you for that. To Mitra. And I definitely can I do one more quick paper because we're not going to do it next time? Really very quick. Very quick. Okay, I just I'm actually I'm actually going to review just the abstract. Okay, just the abstract because it's too good. Too good of a paper. It's in German,
I'm saving my paper. No, because
this paper literally will take five minutes Fine, fine. Fine was published in JAMA peds first author is John McDermott. And the title is rapid point of care genotyping to avoid aminoglycoside induced auto toxicity in neonatal intensive care. So we all know that we give a ton of aminoglycosides in the NICU, gentamicin, tobramycin, whatever, whatever you guys are using, we're using them to. And we know that they have significant side effects, most notably the aminoglycoside induced ototoxicity. Now, the paper mentioned, something I was not aware of, which is that there is a genetic variant called Mt RNR. One M dot 1555, a superior sign G, whatever.
And that, so it needs a nickname.
Yeah, I mean, I'll let them figure it out. But that variant predisposes the infant to profound aminoglycoside induced ototoxicity. And so what this group out of the UK tried to do was trying to develop a rapid point of care test for this specific variant. And the idea is, if we were able to test babies, before we start administering antibiotics, and we identify babies who are positive for this variant, we could use a different medication, and most likely reduce the rates of aminoglycoside induced ototoxicity. So they did this study prospectively, in two large neonatal intensive care units between 2020 Between January 2020, and November 2020. And the main outcome was the proportion of new units successfully tested for the variant of all the infants that they had, who were prescribing antibiotics, secondary outcome measures, whether implementation was negatively associated with routine clinical practice, and the performance of the system. So a total of 751 units were recruited median age was 2.5 days, the point of care testing was able to genotype the variant in 26 minutes. So very, very quick. The preclinical validation demonstrated a 100% sensitivity and specificity. Huge, I mean, so often we review experimental stuff, and and it's on its way, but I mean, 100% sensitivity specificity for testers is pretty mind boggling. Three participants, with the variant were identified, identified, all of whom avoided aminoglycoside antibiotics, overall, 424 infants 81%, receiving antibiotics were successfully tested for the variant, and the meantime to antibiotic was equivalent to previous practices, meaning the running of the test did not delay the administration of antibiotics. And so
which in and of itself is miraculous, right?
So the big question, the big question, this paper doesn't answer is where can we get it? But this is something that I'm terrified of gentamicin associated toxicity, just because sometimes you do a rollout sepsis, and you're not, I mean, you're doing it because you have some concern. And in my head, it's like, is it worth risking our toxic injury for that course of gentamicin and it's terrifying. So I'm very careful making sure I have gentamicin levels. And that I'm not that I'm staying within the therapeutic range. But a test like this seems like a game changer. And so I wanted to highlight the paper. It didn't take very long. I told you, great job by these authors. Yeah,
yeah. I mean, it's, it's the future, right? Even individualized medicine. One day we'll walk in and we'll get our whole panel of our, you know, yeah, I
think I think you start working with these things. And then you have like those, those PCR bio fires, and then suddenly, like, one day, you'll have like a little test that you run, and it tests for a bunch of things. You won't even know what's in there. And they will come and tell you hey, I stat
Yeah. Super cool. Yeah. I mean, it's it was neat that it didn't take long to run incredible. And I just wonder how much blood it takes to you know,
no, actually, I don't remember it's in the paper. But I I was like I told you I was reading off not of my notes. But I was reading off my
what we saw we got it in Yeah, I thought it was
for sure. I think the people who are going to be interested are going to are going to find it. And I can't seem to just when I'm skimming through my notes, I can't find the volume. It doesn't matter. Okay. It is what it is. I don't have that information is in the paper somewhere. All right, definitely. This was a fun journal. Sure. Next week, we have Dr. Christy Weinberg who comes to talk to us she recently as you all know I first authored the paper on hydrocortisone and survival without BPD. It's really neat to get all these really make the tribal trying to make the podcast more current with people who have recently published or have recently done something in neonatology. So we're very excited about that. And join us tomorrow for a brand new episode of The neonatology review podcast. We're very excited. Barry. Yeah, this will be fun, Daphna. Thank you so much. Sorry for going overtime.
That's as usual, as usual. Have a good one, everybody.