The Interview: Dr. Kuppermann and Dr. Burstein On The Study That Will Change Everything (for Febrile Infants)

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Hot Off the Press! Last week, JAMA published a new study titled “Prediction of Bacteremia and Bacterial Meningitis Among Febrile Infants Aged 28 Days or Younger.” The study evaluated whether the PECARN Febrile Infant Prediction Rule (you know the one – negative urine, serum procalcitonin ≤0.5 ng/mL, and ANC ≤4000/mm3) can be applied to infants ≤28 days.
The biggest takeaway? The PECARN rule, applied in more than 1500 infants across 6 countries, missed ZERO cases of bacterial meningitis.
I spoke with Dr. Nate Kuppermann and Dr. Brett Burstein, authors of the study, to unpack what the findings mean and how they may reshape the care of young febrile infants.
Check out the video interview below!

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Audio Transcript (Generated by ChatGPT):

Dr. Joshua Belfer (00:00)
Nate and Brett, the article published in JAMA, Prediction of Bacteremia and Bacterial Meningitis among Febrile Infants age 28 days or younger. Before we get into the meat of the paper, I want to help provide some context for the study. Nate, when we think about the landmark studies in our field, many of which you were involved in, do you think this study already belongs in that conversation?

Nate Kuppermann (00:21)
Well, Josh, that’s an interesting question. And my answer to that would be we always need a little bit of tincture of time. I do think that this addresses a very, very fundamental issue, not only in pediatric emergency care, but also in pediatrics in general. So I do think this study has the potential to greatly change care. But what I think when one considers what is a landmark article versus not is how it does or does not change practice. And with that, we’re going to need time to see.

Dr. Joshua Belfer (00:58)
And Brett, to my understanding, this international collaboration was not originally planned. Can you give us a little insight into the origin story?

Dr. Brett Burstein (01:05)
Yeah, Josh, thanks for having us both here to talk about this study. As you know, the management of febrile young infants has evaded clinicians and researchers for over 40 years, and international guidelines still recommend a very cautious approach for infants in the first month of life, and groups really all over the world have been really trying to study this. This study that we’re discussing right now builds on some of the landmark work from the PECARN network.

The study was originally for serious bacterial infections. And to address the question of the infections we care the most about, the most dangerous infections, so invasive bacterial infections, that is bacteremia and bacterial meningitis, it really required more infants. Now the PECARN group aren’t the only ones that have studied this. There’s groups from around the world that have also developed strategies, but really to address this question and know for certain whether this rule could be applied in a broad generalizable sample, we reached out to international collaborators to be able to collaborate and pool our data. And that’s where this study comes from. It’s a pooled analysis from groups really all around the world.

Nate Kuppermann (02:16)
Josh, let me add to that one thing that’s important, you know, following on to what Brett said is that as Brett implied, there’s been, you know, 40-plus years of study of the febrile infant dating from Rochester in the 80s and before. And each time we make incremental gains. That’s how research works. It’s rare that you have just an epiphany that nobody has ever thought of before. You know, it’s all yours. No, no, how we typically work as researchers we build on the shoulders of those who have come before us. And it started really in that three month, the 24-month-old febrile infant, because they were at risk for occult pneumococcal bacteremia and developing meningitis. Well, that got resolved, fortunately, with the introduction of these miracle vaccines, the conjugate H. flu vaccine and the pneumococcal vaccine.

So then investigators were investigating, we moved to the first three months of life. And with PECARN and our partners in Spain and Britain, Canada, and other places, we got to really a good place, I think, in the second month of life where we kind of came to an agreement based on the good data that we could use good biomarkers to avoid lumbar punctures and empirical antibiotics in a lot of febrile infants in the second month of life. But the first month of life was left as this big unknown, and the reason was, even though, for example, in PECARN, the article that Brett discussed, by the way, I’m gonna give you the official name, the Pediatric Emergency Care Applied Research Network, but we had studied all the way down to the first month of life, and lo and behold, the prediction rule that Brett and I studied, it actually worked in that first month of life, but there just were not enough infants. That is, two-thirds of the infants that we studied were in the second month of life.

Not enough in the first month. So we were not ready to say, apply this in the first month, just because even though we didn’t miss any infant with bacterial meningitis in that first month, the precision around that estimate was narrow. So we went into the AAP guidelines with those data and whatnot, and we just didn’t have enough data. And then Brett really kind of helped spearhead the notion as, okay, well, now we’re in 2025. Now there are enough data, it’s just that it’s not in PECARN, it’s all over the globe. And so that is why we had to go and pool. It was really to get the precision around the risk in that first month of life. We needed more babies, hence this study.

Dr. Joshua Belfer (05:01)
So what I’m hearing, and my next question was going to be, was there an aha moment? Looking at the data, is there a 2 AM call between Brett and Nate? We have something here. What I’m hearing is that you had a sense that maybe this is where it was heading, and we just didn’t have the data yet.

Nate Kuppermann (05:16)
So let me just answer that alternative, Brett. So, you know, we in the PECARN rule, we knew the data worked in the first month of life. But as I said, we were not ready to push that. And it went into the AAP guidelines, also with a sense of people there. Those guidelines were 12 years in the making. And the data stopped being collected probably around 2019-ish. But then I’ll pass it to Brett, because Brett had the aha moment. I’ll let Brett tell that aha moment.

Dr. Brett Burstein (05:48)
Josh, I like this story very much. The PECARN data was very compelling and I was on the, I led the guideline committee for the Canadian Pediatric Society for the management of febrile infants. When I saw Nate present the work in a validation cohort, so after the original 2019 study, he presented the validation work and that was published in Pediatrics in 2021. I asked Nate, this data is quite compelling. Why did this not end up impacting the AAP guideline. And as he just told you, they just didn’t feel comfortable enough with the number of infants, but we had now developed our cohort and we had seen that it had been effective in identifying low-risk infants who could safely be managed without lumbar puncture. Really by that point, we had three, four years of institutional data. And I had reached out to international partners and saw in their data as well that there was no misses in their cohort either.

On our guideline committee, we had other pragmatic considerations. Our guideline was developed in 2013 and we had to make some decisions around where lumbar punctures are performed and the transport of infants across vast distances. And our guideline looked, you know, we were really compelled with the PECARN data. So our guideline actually recommended that for low-risk infants, a lumbar puncture could be deferred with shared decision-making with families. But really, to be able to say that with even greater precision, the level of precision that the AAP wanted, it was gonna take a bigger collaboration. So I approached Nate after that conference and said, you know, Nate, this is compelling data. I really think we should pool our data. We now have a large cohort and we’ve got collaborators to work with. And our guideline really said, the main premise we wanted to put forward in our guideline was there are several rules out there and we’d like clinicians to pick a rule and go with it. There are several high-performing rules. And our guideline was rather rule agnostic. So it’s not about one rule or another, but the PECARN rule was the rule that we could mutually all study together that had all the components that could be studied. And that’s really where the genesis of this idea came from.

Nate Kuppermann (07:59)
Yeah, you know, and Josh, let me just tag on because it’s important. I’m echoing what Brett said because people have asked, well, why didn’t we not look at CRP, for example, in this first month of life? It’s to Brett’s point is that we weren’t trying to prove the PECARN rule versus a step-by-step rule, whatever. We just, and Brett and I have always been totally aligned in this. We want people to use data and let the data help augment your judgment. And the data that we had available in this first month of life around the world was that happened to be the PECARN rule. And I’ll just quickly add on, Josh, is that people ask, well, in PECARN, why didn’t you study CRP? And the answer is we were studying little babies. The primary goal of the PECARN study was looking at microRNA and looking at RNA transcriptomics and whatnot. To see how they could work. So once we drew the blood for RNA and we got PCT, we just didn’t have enough blood left over for CRP.

Dr. Joshua Belfer (09:04)
Brian, let’s get into it. I’ll give you the floor. Walk us through the core findings of the study, the take-home results, the things that matter most to clinicians.

Dr. Brett Burstein (09:11)
All right, so I probably the most important thing is really the performance and diagnostic accuracy of the PECARN rule among infants in the first month of life. We were able to study over 2,500 infants in total. And among those 2,500 infants, the rule performed with a negative predictive value of 99.6% for all IBIs.

And importantly, didn’t miss any of the bacterial meningitis cases. So what we were able to do is use the test characteristics to estimate the negative predictive value now for bacterial meningitis specifically. Now, when you miss none, you have to make an estimate. And the statistical estimate tells us that it has a negative predictive value of 99.95%. So to put that in context, when we think about other landmark work from the PECARN group, think about, for example, blunt head trauma in the CT rule from the PECARN group. I like to use that as a comparison because it also carries a 99.95% negative predictive value for children to have major consequences, death, ICU, neurosurgery. So when we have that level of precision and that level of negative predictive value, you know that in that situation, we don’t do imaging. We can reassure families and we can send them home. And those are

Those are major consequences that we worry about missing. So this is similar. Here the idea would be if we have that level of negative predictive value with precision, we can now confidently not do the investigations that were as invasive as we were previously. Now, if you look at the Canadian guideline and perhaps an alternative, we mentioned this in the article as well, it’s not to send these families home directly and then back into the wild.

What we recommend is observation of these infants. So admission without antibiotics. And in that strategy, you know, ultimately I would say that even if one case were to occur, now there are no nevers, there is no never in medicine as you obviously know, right? So I think that’s why it’s important still to be cautious, admit these patients. And I don’t think that’s really called a missed diagnosis. I think that could be called perhaps a delayed diagnosis.

But the reality is that we didn’t see any in this cohort. And if you look at the confidence interval, they range from about 400 to infinity. So the negative predictive value tells us that the number needed to test would be about 2,000 infants by lumbar puncture to find one case of bacterial meningitis, but it could actually be as high as infinity. So right now, what we recommend based on these findings, could be a strategy of shared decision-making with families. You have to be able to talk to them and tell them what some of the consequences are. And we know that it’s not benign. That’s the first thing. Lumbar punctures are not benign. There’s risks involved in everything we do. And we know that this matters the most to families. Of all the interventions, of everything related to the care of febrile young infants, anyone that has been at the bedside with families knows how important it would be to avoid lumbar punctures.

Nate Kuppermann (12:27)
Let me add, Josh, and this is so important because even in, and we’ve been getting, of course, a lot of press and attention about this article because it does have this great potential to impact care, but we actually got a comment on one of the news wires by a critical care physician who said, but if you have a lethargic baby, you have to do the LP regardless of what the rule says. But again, it’s all about conveying and reading the article well, conveying the message well. We do not include lethargic babies in this data set. This is a data set of non-ill-appearing infants. And that’s when you use prediction rules, whether it’s for febrile infants, whether it’s for CT after minor head trauma.

Of course, if you have a sick-looking febrile infant, you don’t use a rule. You just use your judgment and do the full evaluation for sepsis and admit to the hospital. So to be really clear to your listeners, because even physicians who have commented on this can be confused. What these prediction rules are meant for is to not replace your judgment, to augment your judgment. So again, the power of this rule in the well-appearing febrile infant is that now, for the first time, we can go into a family and say, hey, this is the overall risk of bacterial meningitis in a very well-appearing infant with a negative PECARN rule, which is, as you know, a negative urine, negative ANC below 4,000, and a procalcitonin below 0.5. And here are the risks of bacterial meningitis.

Now you can have a really informed decision. If the risks were 1 in 50 of having bacterial meningitis, you don’t have that conversation. You just do the LP and do your thing. But now we’re in the realm of putting the precision around a number that is tight enough to really being able to inform the family and come to an educated consensus decision.

Dr. Joshua Belfer (14:33)
So I want to clarify, Brett, something you said from a practical standpoint, applying the findings of your study. So you’re envisioning then for low-risk infants under this framework, admission for observation without an LP and off of antibiotics, no antibiotics for them.

Dr. Brett Burstein (14:49)
Yeah, that’s the recommendation that our Canadian Guideline Committee came up with. We’re not the only ones to make that recommendation. In fact, there’s a group in the US as well. The Intermountain Group in Utah have a guideline that’s available online as well, and that is the recommended strategy, what they call the preferred strategy for low-risk infants in the first month of life. So that’s sort of the management that we propose in the Canadian guideline, and I think one of the main questions that’s being asked in the US is how to reconcile this finding with AAP guidelines. And I think Nate is more well positioned to comment on that.

Nate Kuppermann (15:24)
Yeah, thanks Brett. Let me just say that if you look at the AAP guidelines for infants in the fourth week of life, that is days 22 to 28, one of the recommendations in there is if you’re negative by the PECARN rule, no antibiotics, no LP, admit and observe. What I would say how to reconcile this with AAP guidelines, what Brett and I feel comfortable with is extending those recommendations of the AAP guidelines to the very start of their guidelines. So rather than starting at 22 days, based on the data that Brett and I have accumulated and published, we’d be comfortable making that same recommendation down to the very start of the AAP guidelines. Again, to Brett’s point, importantly, we’re not saying do nothing. Of course, do the blood and urine, those are cultures, of course, in addition to the screening labs, admit, observe. And fortunately, we’re in an era that, you know, when I was a resident, you’d get one blood culture reading a day. That’s not how blood cultures are read in the modern day. It’s a continuous colorimetric and other technologies to identify positive blood cultures as soon as they happen. And more than 90% of positive blood cultures happen in the first 24 hours. So the infant is still there in the hospital.

Dr. Joshua Belfer (16:51)
And I want to talk more about adoption in a second, but a good segue in terms of thinking about the blood cultures. So one of the other things that came in this data is five low-risk infants that had bacteremia identified, some of which represented or may represent contaminants. Brett, can you walk us through those cases and how clinicians should interpret them in the context of this rule?

Dr. Brett Burstein (17:13)
Yeah, so as you point out, there were five, so that brings a negative predictive value of any IBI. It was 99.6, as you mentioned. And the concern for delayed diagnosis of bacteremia is not quite as significant as the concern for delayed diagnosis for bacterial meningitis. It’s not trivial, but as Nate mentions, there are rapid blood culture detection systems. So what that means is that it would allow us to identify those infants who have any positive blood culture. And at that point, we would recommend to complete the workup with a lumbar puncture and initiate antibiotics rapidly. Now, what I would just comment on, there’s sort of two points to this. The first is that blood culture, especially true positives, will result sometimes generally between 12 and 18 hours. We have families that present in the first place longer than that, many will present even above 24 hours. So the question of delayed diagnosis of bacteremia is one that evidently there’s sort of empirical evidence that it is not as time sensitive. That’s the first thing I would point out.

The second thing I would point out is that what I really think the data is telling us is that this idea of infants under 28 days, given the current efficacy of biomarkers, the combination of biomarkers that we have today, and the infectious organisms, that combination, I think now the data is suggestive that age is really not the primary determinant of risk. And we see that because every statistically derived study that looks at modern biomarkers, so either the PECARN rule with procalcitonin or we’ve done some work also looking at what happens when you’re using a different combination in CRP, age does not get selected into that model as a predictor. It doesn’t add predictive value above what we get from these modern biomarkers. So I think there’s several lines of evidence that suggests that a delayed diagnosis of bacteremia is probably one, not related to age, and number two, probably not going to make a difference in this window of 12 to plus hours when we can still detect it with rapid detection systems. Not only that, but point number three is it’s not common. Even then it is still not common among infants who are found to be low risk.

Nate Kuppermann (19:37)
Josh, let me speak to the actual organisms that was actually quite interesting. So there were five infants that had what we call bacteremia because we, the important thing in research, you define what constitutes bacteremia and then you call it like you see it. There were two patients who had Staph aureus bacteremia. Now, interestingly, one of the two had a UTI with E. coli. And it does raise the question. I don’t want to negate Staph aureus. Staph aureus certainly can be a pathogen, but could also be a contaminant. So it is what it is. A third infant had H. flu. Wow. That is a really strange pathogen in the first month of life. Hard to know what to make out of that. And then two patients had E. coli. So those two patients, the E. coli are not surprising. The others are, you know, add some confusion, but we’re very conservative, of course, on how we call it, and we call it as we see it.

Dr. Brett Burstein (20:39)
And to Nate’s point, even just the removal of one of those missed cases, if anything, if there is a contaminant there, if we question those cases at all, that would only increase our negative predictive value. It would only improve the diagnostic accuracy more even than what we report in the study itself.

Dr. Joshua Belfer (20:59)
And thinking about when the AAP guidelines a few years ago were released, you know, big practice change, you know, clinicians are going to come similarly to this study with very different training backgrounds. Some have performed hundreds, thousands of LPs in febrile infants. Others have rarely seen bacterial meningitis. How do you think those different experiences are going to shape how people interpret the study and then how they apply it to their practice?

Nate Kuppermann (21:21)
Yeah, if I could mention something, Brett, first, that I think what is one of the really powerful benefits of this study is that we know that the vast majority of children in this country who present for emergency care do not present at the Montreal Children’s or Children’s National DC or the CHOPs of the world. They present out in the community, sometimes very small community hospitals, where the expertise around doing the LPs is not great. However, the predictors in the PECARN model are very objective. You know, the urine, ANC, procalcitonin. Now, of course, it does rely on your ability to pick out an ill-appearing infant. But just to be clear, there’s even a little bit of leeway in that because in the PECARN rule, you know, strictly defined, and we defined ill appearance by the Yale observational score. And strictly defined, a score of six is a perfect score of 10 and less is non-ill-appearing and more than 10 was ill-appearing. There were, I mean the vast majority of infants in the PECARN data had scores of less than 10, but there were some that were above that. But the bottom line is we do need people to pick out the ill-appearing infant, but that’s clinical judgment. You have to be able to do that.

Once you can do that, the beauty is that this rule will allow us to mitigate probably up to half of the LPs in that first month of life. And so for those that do not feel comfortable with the procedure, it’s a procedure you don’t have to do if you’re negative for the rule. That I think is very powerful besides all of the downstream risks. And I just want to point out this was, you know, one of a landmark study was Cathy DeAngelis, I think it was 1983. She was the editor-in-chief at JAMA at one point. She talked about all the iatrogenic risks of hospitalized infants of doing too much testing, et cetera. LPs can be difficult to perform at that age. Bloody LPs lead to antibiotics and admission. Missed LPs, they cause pain, of course. And actually, the holding of the infant, even the positioning of the infant can cause some complications that we won’t even go into. So there’s lots of reasons. There’s no perfectly safe test. I don’t want to overstate it, but there are few perfectly safe tests in medicine, even with the false-positive and false-negative rates. So that I think is just a potent thing. And I would just say about this issue, and we’ve raised this about not being cavalier. I wouldn’t be cavalier about it at a children’s hospital, nor should somebody in a community hospital. What we’re saying here is that if you don’t do the LP, the baby still gets admitted to the hospital. Brett, I don’t know, you want to add to that?

Dr. Brett Burstein (24:14)
Yeah, I like to, I think that’s a good point to lead into. LPs are necessary sometimes. Josh, you know that, of course, and we’ve alluded to it with the infants that are not well appearing. LPs are indicated for some infants, and we wouldn’t want families to say, I heard there’s some study and we don’t need to have an LP. There are certainly cases where they are definitely indicated, and especially among those unwell-appearing infants. But there’s another factor that we should discuss, it’s the exclusion criteria and it’s the other groups of infants. Now, the majority of febrile infants, as you know, present well appearing and are previously healthy. And so this applies to a vast number of infants. Probably the estimation is probably a quarter million of these presentations a year in the US alone to emergency departments.

The infants who, you know, we still have to be very careful are those who have risk factors for invasive bacterial infections. We certainly know that infants who are, you know, preterm, immunocompromised, have chronic medical conditions, those infants haven’t been studied. They’ve not been included in any of these studies. So we really don’t know the applicability or how well these biomarkers perform in that group. So if there are infants with known risk factors or who are not well appearing, it’s important to recognize that this study does not apply to those infants.

Dr. Joshua Belfer (25:46)
And as we start to wind down here, there’s going to be a lot of people reading your study and hopefully listening to this discussion that are on their institution’s guideline pathway committees. You know, do they need to call an emergency meeting? We need to change our pathway next week or, you know, what are the next steps? How are they supposed to approach this paper?

Nate Kuppermann (26:05)
You know, what I would say to that, Josh, is that there’s no emergency here. That is, you know, this has taken decades to get this far. However, however, you know what? Every unnecessary LP is another unnecessary LP that inflicts pain, has the potential for harm, et cetera. So I think the wise recommendation is that now that Brett and I have kind of compiled with our collaborators and we received data very graciously from all these different networks as Brett implied. But I think it’s a good time for hospital committees to regroup now that these data are available to reassess their guidelines to see if they can liberalize a bit. The indications for LP, as Brett alluded to, Primary Children’s of Utah, even before these data were out there, their guidelines basically recommended what Brett and I are saying here. And as Brett pointed out, that already existed in the Canadian Pediatric Society.

Dr. Brett Burstein (27:16)
I would just add also, you know, we work in a sort of a small community of researchers in this area and we’ve had the pleasure of, you know, having communications with the lead authors of the AAP guideline. That guideline is coming due for an update in 2026. They’ve told us that it’s reasonable to tell listeners that they can expect an update in the 2026 clinical practice guideline revision. So that’ll be probably coming in 2026 and that’ll reflect this study as well.

Nate Kuppermann (27:50)
But in the meantime, Josh, to your point, I think what the AAP guidelines and the Canadian Pediatric Society guidelines, they’re obviously important pieces of work, but I think that local hospital committees, they can take the guidelines already as written and assess the work that Brett and I have done to see if these things can be incorporated because the process of creating these big society-type guidelines takes a lot of time. Again, the AAP guidelines, I can tell you it was 12 or 13 years. I know I wasn’t the lead author, but I was one of the authors. I was the only pediatric emergency medicine author of those guidelines. They take a long time. So I think it’s a good time for folks to regroup and meet with their experts at their hospitals to see how these can be incorporated.

Dr. Joshua Belfer (28:42)
And to close, if you’re both amenable, I want to do a little bit of role playing. I’m a parent. Tomorrow I bring my 12-day-old well-appearing infant into the ER with a fever. You’re my ER doctor. Sort of what are you telling me about risks now that we have this new data in this paper? What workup are you doing? If, you know, traditionally those parents that are more hesitant to, you know, consent to an LP, are you having different discussions with them now than you would have several weeks ago?

Dr. Brett Burstein (29:10)
Yeah, I’m happy to share with you how I approach this. With families, we conducted a study with nearly 500 families and we surveyed them all. All families of febrile infants and we did seven focus groups with families as well. So I’ve heard what it is that stresses them and in our publication, we know that 85, 90% of families, when they come to the emergency department, they know that fever in a newborn is an emergency and they expect blood work.

A few less of them know about the need for urine testing, but only about 15% know anything about an LP at all, okay, or that there may be a need for one. And when they hear, they have not only a low expectation, but it is their greatest stressor. That’s what they’ve told us as well. So the way this has changed my conversation with families is that when we start with the tests that they’re expecting and we have results, I tell them your baby is low risk. And what that means is that we’re gonna for the interest of safety, we’re keeping you in the hospital until, so these, I tell them that these are all preliminary results and that we wait for a final result, which of course is our culture results. And then meantime, we have to be careful still for these young babies who are vulnerable. Now, I tell them that historically, we’ve also had a worry for bacterial meningitis, but our current data tells us that when infants meet low-risk criteria, and if their baby is low risk, that we can, safely admit for observation.

However, that can change. And if their baby’s appearance changes, or we get new information based on the tests that are still ongoing, that that might change. And that’s the way I have this conversation with families. We talk about the risks and benefits. The conversation doesn’t take very long with families. Most are LP-averse. When I talk to them about the risks, it doesn’t take much, even if I told them it was safe. They don’t love the idea of their baby having an LP. I think that’s intuitive. So they know they have a natural disposition away from LPs. When I go through risks with them, we do that to be complete. But I tell them if it’s gonna be necessary, we may still need to do one.

Nate Kuppermann (31:34)
Josh, I have nothing to add. I think Brett summarized that very nicely.

Dr. Joshua Belfer (31:39)
Great. Well, thank you both for your time. Like has been stated a few times, we encourage people to go to the study and read it. And I think this certainly will be practice changing. Thank you both for your time.



Dr. Joshua Belfer, MD, is a Pediatric Emergency Medicine physician at the Children’s Hospital of Philadelphia, and is the Founder and Editor-in-Chief of HipPEMcrates. He can be reached at HipPEMcrates@gmail.com.

3 thoughts on “The Interview: Dr. Kuppermann and Dr. Burstein On The Study That Will Change Everything (for Febrile Infants)”

  1. I am really curious how this can be applied to incidentally found hypothermia in the first week of life. I feel like there are still a lot of hospital protocols that full workup these infants and if the PECARN data can help adjust those workups.

  2. Pingback: Febrile Neonates Under 28 Days – Is PECARN Rule Safe? - JournalFeed

  3. Pingback: January 2026 – JournalFeed Top 10 - JournalFeed

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