Research Roundup – June 2026

Perhaps more real trials this month than usual, but don’t worry, if you read to the end you can learn about Neanderthal dentistry circa 59,000 years ago. 

The nail in the paxlovid coffin?

Butler CC, Pinto AD, Harris V, Holmes J, Rahman NM, Cureton L, Hayward G, Richards DB, Lowe DM, Standing JF, Breuer J, Hood K, Png ME, Petrou S, Dorward J, Patel MG, Thomas NPB, Evans P, Hart ND, Jani BD, Hosseini B, Murthy S, McBrien K, Condon A, McDonald EG, Daley P, Greiver M, da Costa BR, Selby P, Jüni P, Lee TC, Shi H, Detry MA, Saunders CT, Fitzgerald M, Berry NS, Saville BR, Khoo SH, Nguyen-Van-Tam JS, Hobbs FDR, Yu LM, Little P; PANORAMIC Trial and CanTreatCOVID Trial Collaborative Groups. Oral Nirmatrelvir-Ritonavir for Covid-19 in Higher-Risk Outpatients. N Engl J Med. 2026 Apr 23;394(16):1583-1594. doi: 10.1056/NEJMoa2502457. PMID: 42019019

Personally, I sort of thought this was a boring topic. I thought no one was interested in Paxlovid anymore. I thought there was no controversy. However, weekly blog traffic begs to differ:

Based on the comments section, there are still a huge number of people who love this drug, or at least who are searching for a reason to use it. This paper actually describes two separate open-label adaptive platform RCTs: PANORAMIC out of the UK and CanTreatCOVID out of Canada. The trials are pretty similar. If you want the full details you can read the blog post, but essentially they both took vaccinated adult patients with some high risk features and randomized them to paxlovid or usual care, and both trials were negative (no benefit in terms of mortality or hospital admission). This fits with my impression of the early paxlovid trials. The numbers were somewhat better in the initial trials, but interpretation had to be tempered by the significant financial conflict of interest. There is ongoing debate about whether we should adjust our scientific standards during a pandemic. Given that most experimental interventions fail in medicine, there is always harm of intervening, and the fact that our current scientific process uses a lax statistical standard that results in a lot of false positive research, I am against changing standards just because there is a pandemic. Skipping science will result in harm, and COVID proved pretty definitively that we can run massive RCTs quickly if we really want to. 

Bottom line: There is really no reason to consider using paxlovid at this point. I hope governments don’t continue to waste money stock-piling this like they have with tamiflu.

Minocycline, for stroke??!!

Lu Y, Guan L, Wu J, Yang Q, Zhang M, Zhou D, Yang H, Pan Y, Wang L, Qiu B, Liu C, Wang Y, Yang Y, Zhou X, Qu H, Liao X, Liu L, Zhao X, Bath PM, Johnston SC, Amarenco P, Turc G, Shi FD, Wang Y, Wang Y; EMPHASIS Investigators. Efficacy and safety of minocycline in patients with acute ischaemic stroke (EMPHASIS): a multicentre, double-blind, randomised controlled trial. Lancet. 2026 Feb 14;407(10529):679-688. doi: 10.1016/S0140-6736(25)01862-8. Epub 2026 Jan 30. PMID: 41628627

This is a really interesting trial, although I have a hard time believing that antibiotics are the missing ingredient in high quality stroke care. EMPHASIS was a prospective, multicentre, randomised, double-blind, placebo-controlled trial conducted across 58 hospitals in China. They randomized 1724 adult patients with confirmed ischemic stroke within 72 hours of symptom onset to minocycline or placebo. The primary outcome was an excellent functional outcome, defined as a modified Rankin score of 0-1, at 90 days, and was significantly improved with minocycline (53% vs 47%, aRR 1.11, 95% CI 1.03-1.20, p=0.006). Methodologically, this is a well done trial. The biggest modifying factor is probably pretest probability. Although there is a theoretical mechanism – minocycline is apparently known to reduce brain inflammation – it seems unlikely that antibiotics are going to play a huge role in decreasing disability from stroke. There are also potential concerns about generalization, as stroke phenotypes and outcomes tend to be different in China than in North America. On the other hand, harms are pretty minimal, and it’s not like there is huge money to be made off of minocycline, so COI is less than most novel interventions we see. My sense is that we want to see at least one large, high-quality replication before this becomes mainstream, but given the limited downsides, I anticipate we will start seeing this recomended.

Bottom line: In this high quality double-blind RCT, minocycline improved functional outcomes from ischemic stroke. 

They are still trying to make recombinant factor VII a thing??

Broderick JP, Naidech AM, Elm JJ, Toyoda K, Dowlatshahi D, Demchuk AM, Khatri P, Steiner T, Bath PM, Audebert HJ, Vagal A, Yoshimura S, Mayer SA, Wang LL, Sabagha N, Mocco JD, Molina C, Aviv R, Stinson E, Quadri SA, Carrozzella J, Huynh T, Phan A, Beall J, Davis I, Sakai N, Ohta T, Yokosawa M, Hara T, Sangha N, Morita K, Dominc Tse MY, Streib CD, Miyashita F, Silva Y, Nagakane Y, Gheorghiu T, Sun CH, Hirano T, Poli S, Izumo T, Fukuda-Doi M, Ihara M, Koga M, Buck B, Walsh KB, Spokovny I, Grotta JC; FASTEST Investigators. Recombinant factor VIIa versus placebo for spontaneous intracerebral haemorrhage within 2 h of symptom onset (FASTEST): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet. 2026 Feb 21;407(10530):773-783. doi: 10.1016/S0140-6736(26)00097-8. Epub 2026 Feb 4. PMID: 41653933

Recombinant factor VII had already fallen out of favour by the time I was in training, so I was surprised to see a large, double blind RCT in 2026. I was less surprised to see that the trial was stopped early for futility. This is a big multicenter multinational double blind RCT comparing recombinant factor VIIa to placebo in adult patients with spontaneous ICH. I won’t get into all the details, because the trial is pretty clearly negative, and so shouldn’t influence anyone’s practice. The primary outcome was function, measured using the modified Rankin score, at 180 days, and was basically identical between the two groups (45% vs 46% had the most favourable 0-2). Life-threatening thromboembolic complications were significantly higher with factor VIIa (1 % vs 5%, p=0.02), which is why I had thought this therapy had been abandoned a long time ago. I will note that there was less growth in the hematoma size with factor VII, but this is something that we have seen recurrently in ICH trials. Theoretically, a smaller hematoma should result in better neurologic outcomes, but it just doesn’t. A smaller hematoma is the reason many people suggest managing blood pressure in ICH, but we have large RCTs showing that real patient oriented outcomes – disability and death – are completely unchanged. I think it is pretty clear that hematoma size is a failed surrogate outcome, and shouldn’t be used.

Bottom line: I am not sure why they thought it was a good idea to drag factor VIIa back from its place in the failed history of medicine, but it clearly should not be used. Of course, that is not stopping them from running the FASTEST 2 trial, based around some subgroups here. 

Strike 2 for whole blood

Sperry JL, Guyette FX, Cotton BA, Luther JF, Utarnachitt RB, Kutcher ME, Daley BJ, Peetz AB, Patel MB, Goodman MD, Claridge JA, Patel N, Harbrecht BG, Hashmi ZG, Zarychanski R, Neal MD, Yazer MH, Martin-Gill C, Vincent LE, Harner AM, Meyer DE, Latimer AJ, Robinson BR, McKnight CL, Hinckley WR, Miller KR, Jansen JO, Martin D, Fox EE, Rosario-Rivera BL, Wisniewski SR; TOWAR Study Group. Prehospital Resuscitation with Type O Whole Blood for Trauma and Hemorrhage. N Engl J Med. 2026 May 18. doi: 10.1056/NEJMoa2602167. PMID: 42150044

I predicted that whole blood research was likely to be negative, but is it going to end up showing harm? This cluster RCT comparing 2 units of whole blood to component therapy in prehospital trauma patients was statistically negative, but there was actually a 5% increase in mortality in the whole blood group (26 vs 31%, p=0.24). The study is significantly under-powered, mostly because they based their power calculation on the completely unrealistic assumption that they would see a 10% absolute reduction in mortality with whole blood. (In other words, they think the type of blood you use will be 4 times more effective than aspirin for STEMI.) There was a reasonable amount of cross-over between the two groups, and, like the last whole blood trial we covered, the effects of 2 units in the field are likely to be quickly swamped by in-hospital blood products in patients who are actually sick enough for this to matter. That should bias the outcomes towards the null hypothesis, which makes me more concerned about the 5% increase in mortality with whole blood. However, it doesn’t look like randomization was perfect here, and the whole blood group might have been sicker at baseline, which could partially explain the results. The trial was statistically negative, so we need to be cautious in our interpretation of the point estiamte. However, whole blood is a completely unproven therapy at this point, and so the 5% increase in mortality seen here tells us pretty clearly that we should not be using whole blood clinically unless the patient is being enrolled in a clinical trial. 

Bottom line: It is not unexpected, but this cluster RCT shows no benefit from whole blood, and the point estimate is a major red flag. 

The full post is available here. 

HI PEITHO – widely misunderstood

Rosenfield K, Klok FA, Piazza G, Sharp ASP, Ní Áinle F, Jaff MR, Barco S, Goldhaber SZ, Kucher N, Lang IM, Schmidtmann I, Sterling KM, Araszkiewicz A, Arora V, Cires-Drouet R, Coghlan J, Hobohm L, Ito WD, Jacobson K, Kaiser C, Kopec G, Marx K, McElwee S, Meneveau N, Monteleone P, Montero-Cabezas JM, Olivier CB, Park J, Roik M, Sakhuja R, Tego A, Theurl M, Visveswaran G, Vos JA, Young MN, Asch FM, Konstantinides SV; HI-PEITHO Investigators. Ultrasound-Facilitated, Catheter-Directed Fibrinolysis for Acute Pulmonary Embolism. N Engl J Med. 2026 Mar 28. doi: 10.1056/NEJMoa2516567. PMID: 41910345

There are people using this paper to justify invasive therapy for intermediate-high risk PE, but I think the results clearly demonstrate that a ‘wait and see’ approach is better. (You can listen to Weingart and me argue about this on EmCrit.) HI-PEITHO randomized 544 adult patients with acute PE, signs of RV strain, and at least some marker of hemodynamic compromise to ultrasound-facilitated catheter-directed fibrinolysis with alteplase or anticoagulation alone. They use a composite outcome, and so can claim that outcomes are better with thrombolysis, but I think the composite has confused some people. There was no difference at all in PE related mortality (1.1% with intervention and 0.4% with control). PE recurrence rates were the same (1 in each group). So the only thing that changed was ‘cardiorespiratory decompensation’, which sounds like it could be important, but was the change in a couple points on the NEWS score, and clearly was not important given that real outcomes (death) were identical in the two groups. Scott was sold by a secondary outcome: a decrease in the ‘need for rescue therapy’. I think this is a mistake for a number of reasons. First, this is not an objective outcome. When one group of patients is already on thrombolysis, and the trial isn’t blinded, it is obvious you are going to add more ‘rescue therapies’ in the other group. However, even if these rescues were 100% necessary and unbiased, given that the mortality outcomes are identical, this trial basically proves that it is better to wait and see. Rather than giving 100% of patients an invasive therapy at the outset, you can wait and identify the small minority of patients who deteriorate, and just add invasive therapy at that point. If outcomes are identical at 30 days, the approach that only uses invasive therapy 5% of the time is clearly superior to the approach that uses it 100% of the time. Personally, I still think there is a subset of higher risk PE that will benefit from thrombolysis, but at this point there is absolutely no good evidence for these catheter based devices, and therefore no real reason to be using them.

Bottom line: Despite widely being discussed as a positive trial, there were no real differences between the groups, and any physician who reads through and understands these results would clearly prefer to be in the control group.

Managing post-DVT thrombotic syndrome: For now, stick to the basics

Vedantham S, Kahn SR, Marston WA, Weinberg I, Sista AK, Magnuson EA, Cohen DJ, Wasan SM, Razavi MK, Goldhaber SZ, Sanfilippo KM, Comerota AJ, Azene EM, Chaar CIO, Leung DA, Kolli KP, Kalva SP, Rostambeigi N, Desai A, Desai KR, Tafur AJ, Khalsa B, Majerus E, Wang B, Wang Y, Nieters P, Derfler MC, Oliver A, Hardy C, Bashir R, Winokur R, Weger N, Khaja MS, Sharma A, Mani N, Kavali P, Thukral S, Lake LL, Mikkelsen K, Parpia S; C-TRACT Trial Investigators. Endovascular Therapy for Post-Thrombotic Syndrome – A Randomized Trial. N Engl J Med. 2026 Apr 13:10.1056/NEJMoa2519001. doi: 10.1056/NEJMoa2519001. PMID: 41972998

I feel like post-thrombotic syndrome is under-appreciated in emergency medicine. Our primary job is identifying the initial DVT, and I think we mostly make the (perhaps bad) assumption that someone else will discuss the important non-anticoagulant interventions like compression stockings, exercise, and elevation. We sometimes see people with chronic problems, but our focus tends to shift towards misdiagnosing cellulitis in the chronically swollen leg rather than treating the underlying venous obstruction. So although this is not an emergency medicine study, there may be some value in knowing the results. They randomized 225 patients with moderate to severe post-thrombotic syndrome at least 3 months after their initial DVT to either endovascular therapy or usual care. Their primary outcome was severity of post-thrombotic syndrome symptoms, and it was significantly decreased with endovascular therapy (10 vs 8 on the VCSS tool, p=0.001). I don’t know this scale, which makes it hard to know how important a 2 point difference is. A quick google / AI search tells me that the accepted minimally important difference is 2.5 points, so this difference is probably small enough that patients won’t actually be able to tell the difference. The authors might argue otherwise, given that there was also a difference in a quality of life scale designed specifically for venous insufficiency. However, this is an unblinded trial looking at subjective outcomes, and so at very high risk of bias. Also, the intervention group had much higher use of antiplatelet agents (71% vs 21%), which might confound the data. The endovascular therapy group had significantly more bleeding (12% vs 4%), so it’s not like this is a completely free intervention. 

Bottom line: This unblinded trial shows a minimal reduction in symptom scores with endovascular therapy for post-thrombotic syndrome. There is a very high risk of bias, and even in that context it isn’t clear that benefits truly outweigh the risks, but perhaps future research will help identify subsets of patients with more significant benefit.

The dose of iodinated contrast required for a CT scan is below the toxicological threshold of concern for nephrotoxicity

Phillips A, Blumenberg A. The dose of iodinated contrast required for a CT scan is below the toxicological threshold of concern for nephrotoxicity: a toxicological perspective. JEM Rep. 2026 Jun;5(2). doi: 10.1016/j.jemrpt.2026.100220

The best evidence that we have tells us that CT contrast simply does not cause kidney injury. However, animal models suggest that contrast can be nephrotoxic, and I regularly meet nephrologists who claim to care for patients with contrast induced nephropathy. Aside from the fact that it is almost impossible to be sure of the cause of any one patient’s kidney injury, how do we reconcile these seemingly conflicting positions? This essay reviews some of the evidence, and reminds us the core principle of toxicology: the dose makes the poison. While it is possible that the 200-900 mL dose of contrast required for PCI could cause acute kidney injury, there is a mountain of evidence that the 60-120 mL dose of contrast required for a CT is absolutely safe. There are other possible explanations for why we see AKI with PCI and not with CT. The wire in the aorta could be the cause. This dose theory should presumably be testable, as there are many patients who get multiple contrast CTs within 24 hours. But I tend to agree with the general concept. I will order an initial contrast CT on any sick patient without any real concern for their baseline kidney function, but if a second or third scan seems necessary, I think carefully about the timing. 

Yes, peripheral pressors are safe

Greaves RL, Quay A, Bolot R, King J, Gibbs C. Safety of Peripheral Vasoactive Drug Administration in Prehospital and Retrieval Medicine (SPOTLESS-2): A Prospective Observational Cohort Study. Acad Emerg Med. 2026 Apr;33(4):e70271. doi: 10.1111/acem.70271. PMID: 41947342

A few years ago, this paper might have received top billing, but I think most people have now accepted that peripheral vasopressors are safe to use. This is a prospective observational dataset from a prehospital helicopter retrieval service in Queensland, Australia. They provide data on 619 adult patients transported while receiving peripheral vasopressors (either adrenaline or noradrenaline, translated as epinephrine or norepinephrine for North Americans). A few were excluded, and 70 received only push dose pressors, and so the final data set was 468 patients receiving a peripheral vasopressor infusion: 339 noradrenaline, 100 adrenaline, and 29 both. There were 0 cases of tissue complications, although they only collected data up to 24 hours. There were 4 “major complications”, but all of them were just the insertion of a central line due to physician preference, and so mean nothing. There were a number of minor complications, but essentially all kinking of the line during transport. (Using the antecubital fossa increases the risk of your link kinking if the elbow is moved). The data here is not necessarily novel, but they use higher concentration vasopressors in the prehospital setting, and so there were some added safety concerns. The fact that this can be done safely with high concentration vasopressors, with lines placed and maintained during a helicopter flight, really highlights that this is a practice that can be done safely in emergency department patients. 

Bottom line: Peripheral vasopressors are safe to use, and considering the harms of central lines, are honestly the preferred option for early resuscitation in almost all patients. 

Diagnostic accuracy of tongue coating in identifying acute appendicitis

Mori H, Yamasaki K, Saishoji Y, Torisu Y, Mori T, Nagai Y, Izumi Y. Diagnostic accuracy of tongue coating in identifying acute appendicitis: a prospective cohort study. Emerg Med J. 2025 Jul 22;42(8):519-525. doi: 10.1136/emermed-2024-214210. PMID: 40169241

Did you know that an examination of the tongue might help you diagnose appendicitis? That it has been described in the literature for over 70 years? Can we perhaps decrease our rate of CT by simply examining our patients tongues?! This is a prospective observational study evaluating the previously derived “tongue coating index”, in which the tongue is divided into 9 quadrants, and each is assigned a score of 0-2 (a score of 0 indicates no coating, 1 indicates partial coating, and 2 indicates thick coating). The tongue coating was scored by blinded raters, using photographs, who were not involved in the care of the patient. They include 145 patients, of whom 69 were ultimately diagnosed with acute appendicitis. The median tongue coating index was significantly higher in patients with appendicitis than those without (8 vs 6, p<0.05). Of course, a 2 point difference here just means a shift from partial to thick coating in 2 areas of the tongue, which sounds incredibly subjective and highly unreliable.

Here is the most important part of the paper: the tongue coating index performed just as well as the Alvarado score (AUC 0.66 vs 0.62). I will leave it up to you to decide whether that is because the tongue coating index is valuable, or because most of the clinical decision rules in existence are absolute garbage and are probably making you worse at your job.

I will buy a pint for anyone who calls a surgeon without imaging and tries to convince them that there is an acute appendicitis based primarily on your tongue exam. Please. I really want someone to try it and report back. 

Bottom line: Based on this prospective observational data, an examination of the tongue is more accurate than most of the components of the Alvarado score (white count, RLQ tenderness, rebound, fever, etc.) I bet none of you knew that, but it has been published for 70 years. Shame on all of our medical schools. 

Imagining dentistry from 59,000 years ago is the stuff of nightmares

Zubova AV, Zotkina LV, Olsen JW, Kulkov AM, Moiseyev VG, Malyutina AA, Davydov RV, Markin SV, Maksimovskiy EA, Chistyakov PV, Krivoshapkin AI, Kolobova KA. Earliest evidence for invasive mitigation of dental caries by Neanderthals. PLoS One. 2026 May 13;21(5):e0347662. doi: 10.1371/journal.pone.0347662. Erratum in: PLoS One. 2026 Jun 5;21(6):e0351227. doi: 10.1371/journal.pone.0351227. PMID: 42127021

We love to think of modern humans as uniquely intelligent (even if the politics of the last decade provides very strong evidence to the contrary). Most people tend to assume that they are dramatically smarter than humans even 5000 years ago, despite basic evolution telling us that we are working with essentially the exact same brain. Although there are a lot of technical details that are beyond the scope of this short (and ostensibly medically focused) summary, this study uses multiple lines of evidence to suggest that a Neanderthal tooth from 59,000 years ago has pretty convincing evidence of dental work (the use of some kind of stone hand drill to drill out caries). This is the first ever evidence of dental work in Neanderthals, and predates the evidence of homo sapiens dentistry by tens of thousands of years. Does this have any impact on your modern medical practice? No. But is it fascinating to think about the lives of humans and Neanderthals 10s of thousands of years ago, and consider the many ways in which they are basically like us? I hope so. 

Cheesy Joke of the Month

What did the duck say after buying a new chap stick?

Just put it on my bill

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