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Dexamethasone for Coronavirus Infection

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News came yesterday from the Recovery trial effort in the UK that they had seen positive results from dexamethasone treatment in severely ill COVID-19 patients (news article from Science here). This set off a number of headlines that everyone has since been trying to deal with, unfortunately, so I thought I should try to do my part, too.

Let me start off by echoing journalist Kai Kupferschmidt here, and pointing out that – as has been too damn often the case in the last few months – we don’t have the real data on this yet. What we have is basically a press release, with the most impressive top-line numbers in it, and that makes interpretation and context a lot harder. We saw this with the initial remdesivir numbers, with Moderna’s human data on their vaccine, and all over the place during the hydroxychloroquine story. Under normal conditions this wouldn’t be acceptable – and this “new normal” shouldn’t be different. Make your headlines when you release your data, folks.

So here’s what we have: 2104 patients, either on ventilation or receiving supplemental oxygen, were given 6mg dexamethasone (oral or i.v.) daily for ten days. Comparing them with 4321 patients on standard-of-care, the death rates definitely decreased with dexamethasone: the 28-day mortality for patients on ventilation with standard of care was 41%, and dex treatment decreased that to 27%. For patients receiving supplemental oxygen, the 28-day mortality was 25%, which decreased to 20%. And the 28-day mortality for patients who needed no respiratory intervention, the 28-day mortality was 13%, and dexamethasone had no effect on that whatsoever. p-values for these numbers and confidence intervals were very good indeed, as one would hope from the large number of patients – these look like very solid results, from what we can see so far.

Now, the headlines have all been about “first drug to show reduction in deaths”, but while that’s true for intentional RCT data, it ignores the recent observational study on tocilizumab, which showed similar effects. There are a lot of key similarities in these results – you’ll note that such treatment really only seems to have an effect on the sickest patients, and that is almost surely because those patients are in trouble because of the “cytokine storm” immune response. That, in fact, is where I think we can expect the real improvements in clinical outcome, because we have far more options to modulate something like that than we do to treat the viral infection itself. The good news here is that dexamethasone is far, far cheaper and more widely available than the anti IL-6-receptor antibody.

Are they doing the same thing? There’s probably a great deal of overlap. Dexamethasone itself is of course a steroid derivative, a corticosteroid that is used to damp down inflammation and immune response.Such compounds have a huge number of downstream effects in cells and in organ systems (among them a decrease in IL-6 signaling). It’s administered in a wide variety of situations, everything from severe poison ivy through arthritis, Crohn’s disease, asthma, lymphoma, Addison’s disease, multiple sclerosis, and many more. It’s an extremely useful drug, but has to be used with care and generally for a short period, because it’s so powerful – the number of potential side effects with high or prolonged dosing is impressive indeed. The dosage in this study was not particularly high, which is a good thing to see.

A point that I think should be made with all of these therapies is that they’re not actually “drug repurposing” per se. What they are is a new use for a drug’s intended mechanism. Dexamethasone is given to lower inflammation and immune response, and that’s exactly what it’s doing here (and exactly why it was put into the Recovery trial in the first place – it’s clearly something that you would want to investigate). I’m very glad that it’s worked out, because there are never any guarantees – this sort of thing was tried, for example, during SARS and in the H1N1 epidemic, with unclear results.

Another key point, which others have emphasized as well during the pandemic, is that it’s become increasingly obvious that therapy for coronavirus patients needs to be biphasic. In the early part of the infection, you would want to have something with antiviral activity – slow or shut down viral entry and replication. Now, we don’t have much in that line – remdesivir is about it at the moment, possibly faviparivir (another broadly acting RNA polymerase inhibitor) – their effects are real, but not as big as one would like. If a patient later goes on to severe respiratory problems, that usually seems to be caused or exacerbated by the overactive immune response, which has to be treated as a separate issue. And the drugs used to treat that would be a bad idea earlier in the infection, since you need all the immune function you can get at that stage. Note that dexamethasone did nothing in this study for patients who weren’t in respiratory distress – that’s exactly what you’d expect. This also means, of course, that such compounds are completely useless as prophylactics, and would likely be outright harmful. It’s a good thing that dexamethasone is a prescription drug, because that last thing you want is a bunch of people running out and taking it in hopes that it will protect them from the coronavirus. It’ll probably do the opposite, and cause all sorts of side effects besides if people aren’t careful.

The other thing to emphasize, as Kai Kupferschmidt did yesterday, is that none of these drugs directly alter the pandemic itself. They will save more lives when people get infected, but we really need to try to keep more people from getting infected in the first place, especially now that it’s become more apparent that social distancing and as trivial a thing as public use of face masks can help. We could be mitigating this pandemic with such measures in this country, but in too many regions we don’t seem to be doing that. Eventually, though, what makes this disease go away will be a vaccine.

The people (a minority, but a loud one) ranting about how such masks are an infringement on their liberties can go to hell, in my considered view of the situation, and I only wish that they could do that without taking other innocent people with them. Of course, some of those same never-wearing-a-mask people are also publicly swearing never to take a vaccine. Idiots. Loud, dangerous idiots who are endangering all our lives and our livelihoods.

 

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rclatterbuck
16 days ago
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Eventual Consistency

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Later I'm going to get a head start on the heat bath.
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rclatterbuck
30 days ago
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alt_text_bot
30 days ago
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Later I'm going to get a head start on the heat bath.

The Joke at the End of this Comic

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rclatterbuck
31 days ago
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mbmbam

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Hello and welcome to Millibar Millibarn Attometer, an advice show for the Planck era.
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rclatterbuck
36 days ago
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4 public comments
hannahdraper
36 days ago
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In a math theory class I took for fun in high school (shut up), one of my friends and I submitted all of our answers in base -3. Our teacher gave us a pass because we did the calculations correctly.
Washington, DC
duerig
36 days ago
My favorite bases are -1 + i and balanced ternary. There is just something lovely about being able to represent all integers (or complex integers) without the sloppy random 'negative' sign at the front. https://en.wikipedia.org/wiki/Complex-base_system#Base_%E2%88%921_%C2%B1_i https://en.wikipedia.org/wiki/Balanced_ternary
pavel_lishin
37 days ago
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My dad used to force his students to convert their answers into arbitrary units, just to make sure they understood both the problem, and conversions.
New York, NY
cjheinz
37 days ago
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"Units are weird".
Dimensional analysis is one of the best multitools in Physics.
alt_text_bot
37 days ago
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Hello and welcome to Millibar Millibarn Attometer, an advice show for the Planck era.

Two huge blobs in Earth’s mantle are fighting it out over our magnetic pole

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If you have a very sensitive compass, a predilection for graphing, and a lot of patience, you may have noticed that the Earth's magnetic pole has been hightailing it toward Siberia recently. It wanders all the time, actually, but in 1990 suddenly accelerated rapidly toward Siberia. A few fringe folks (as they are wont to do) have predicted doom and gloom over this, but in fact it's a natural and geologically common event… and scientists now think they know why.

The Earth is like a giant bar magnet, with a donut-shaped field that has a north and south magnetic pole (not to be confused with Earth's geographic poles, where its spin axis intersects the surface in the Arctic and Antarctic). The field is generated deep inside the Earth, in the outer core. The inner core is solid iron, but the outer core, where pressures are lower, is liquid metal, so the iron flows.

The Earth’s overall magnetic field is similar to a bar magnet, with a north and south pole (not to be confused with the geographic poles). Credit: Peter Reid, The University of Edinburgh via NASA

When it flows it generates an electric current. The Earth's rotation sweeps this around in a circle, creating a stable magnetic field. Well, relatively stable: The flow in the core isn't smooth, so that changes the field, and also the Earth's mantle (the hot rock above the core and below the crust) also affects the field generated, too. Blobs of material in the mantle can interact with the magnetic field, altering it.

The magnetic pole is defined as where the magnetic field is perpendicular to the Earth's surface. Because the Earth's spin in part powers this, the magnetic poles are near the geographic ones. The north pole was first measured in 1831 using compasses, but this is a pretty difficult thing to do, especially if it happens to be over water (plus the way the Earth's upper atmosphere interacts with the magnetic field can affect compasses too; it's a mess).

Nowadays we do this by using satellites. For example, ESA's Swarm satellites measure the local components of the magnetic field above the Earth, and these are used as inputs into a physical model of the magnetic field. From there, the pole's position can be measured pretty accurately.

The Earth’s magnetic pole wanders as forces deep underground interact. Models show the predicted position after 2019 (the diverging white lines at the top). Credit: Livermore et al.

From about 1840 to 1990, the north magnetic pole wandered over northern Canada, moving at a rate of up to 15 kilometers per year. But then, in 1990, it suddenly accelerated, topping out at 60 km/year! It's been making a beeline for Siberia, passing about 390 kilometers south of the geographic pole and crossing the International Date Line in October 2017.

Scientists found that there are two huge blobs of material deep within the mantle near the core/mantle boundary. One is under Canada, the other under Siberia. These blobs each create a bump in the magnetic field with a trough between them, like two mountains with a saddle pass, with the magnetic pole situated in that trough. As they slowly strengthen and weaken, the pole moves between them.

The magnetic blob under Canada and another under Siberia fight it out for the location of the Earth’s geomagnetic pole. In 1999 (left) the one under Canada started to lengthen radially (contracting across Earth’s surface), weakening it, and by 2019 (right) the pole wandered more rapidly toward Siberia. Credit: ESA/ Livermore et al.

But in 1990 things changed. Scientists think a flow of material in the mantle deep under North America moved around the Canada blob, altering its shape, elongating it radially (that is, stretching it up toward the crust and down toward the core). This weakened its affect on the surface quite a bit. That gave the Siberian blob the upper hand, and the pole started shifting much more rapidly in that direction.

What does this mean? Well, for example for us it means scientists have to update magnetic maps a lot more often, since many phones use this info for navigation. As for people freaking out that it means the Earth's magnetic field is about to collapse or flip over, that seems unlikely. This sudden movement has happened before historically a couple of times in the past 7000 years or so, but the last flip in the magnetic field was 800,000 years ago, so it's safe to assume they aren't directly related.

Models of the magnetic field indicate it's liable to keep moving toward Siberia, probably another 390 to 660 km. After that it's hard to say; the models aren't reliable more than a few decades in the future. But over the past 7000 years it's wandered all over that area, and hasn't moved too far away from the geographic pole. It's just as likely to turn around and head back to Canada after that, since the movement is fairly sensitive to changes down there at the core/mantle boundary.

Short of getting Aaron Eckhart and Stanley Tucci to detonate nukes down there, there's not much we can do anyway. Happily, we need not worry, this is just the Earth doing what the Earth does. It's been doing this for 4.55 billion years, give or take, and I figure we have things on the surface to worry about more anyway.



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rclatterbuck
46 days ago
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I had it more or less stuck in my head that the north magnetic pole was somewhere in Canada. I knew it moved around, but I didn't think it moved quite that fast. I'll have to update my mental models and look up the proper declination correction next time I use a magnetic compass for orienteering (i.e. never)
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I happened upon these cute TNG tops while visiting an island in...

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I happened upon these cute TNG tops while visiting an island in Animal Crossing today! She has engineering and science if you look up her creator code! 😍😍

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rclatterbuck
48 days ago
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I'm sure someone would like to know about this!
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