Ebola

Not much new. Continuing to count down to the official end of the Guinea outbreak, with no new confirmed cases in the last week.

Hantavirus

–Yes, we have a new exotic way to die in the news this week! Had a reader reach out about the headlines regarding a patient in Michigan diagnosed with Hantavirus. Hantavirus is a family of RNA viruses that live in rodents. Most cases in the US are sporadic, and appear to be contact with aerosolized rodent droppings. Rarely a bite. The case in Michigan is reported to have been working on a vacant property that had a rat problem, so at least it was reading the textbooks. Human to human transmission is rare if it happens at all, and the rodent you got it from determines which hantavirus you catch, as each member of the family is specific to the rodent that carries it. Most cases in the world are actually in rural China and coincide with the planting cycle (and thus contact with rodents at different points in that cycle). The “old world” forms of hantavirus found in Europe and Asia can cause a hemorrhagic fever. The kind of hantaviruses found in North and South America can cause hantavirus cardiopulmonary syndrome, which I have seen abbreviated as both HPS and HCPS. In short, what happens is you come across rodent poop somehow, which turns out to be carrying a hantavirus. You catch the hantavirus. Two to three weeks later (median 14-17 days) you get flu-like symptoms, including fever, chills and muscle pain. The muscle pains can be quite severe. GI symptoms often follow soon, which can include severe GI pain. Then the HPS/HCPS sets in, usually with a dry cough. This is because your lungs are spontaneously filling with fluid as the capillaries in them all start leaking like crazy–all of them, all at once.

As most hantavirus is caught in a rural setting, the speed at which this happens kills, as the patient can deteriorate quickly before hantavirus has been suspected from the otherwise not-terribly-specific symptoms, and before you can get them to a bona fide ICU. One of the biggest tips is actually the platelet count, which drop like a rock as they are consumed trying to plug all the leaks in the lungs. Coupled with a bunch of immature white cells entering the blood stream (as your immune system calls in the reserves in massive numbers), this is the “diagnostic triad” that hantavirus experienced facilities will use to trigger transfers to the ICU. Rapid ELISA and PCR tests are available to confirm the diagnosis.

Ribavirin has shown itself helpful; steroids do nothing. Otherwise, treatment is focused on maintaining oxygen exchange.

That said, the reason hantavirus makes the news is that full blown HCPS has a mortality of 10-50% depending on the exact hantavirus (Sin Nombre is the worst in the Americas) and how severe the fluid shift into the lungs is. You basically drown in that fluid that’s leaking out of your lungs.

Interestingly, HPS and HCPS can reverse themselves just quickly–sometimes within 24-48 hours of onset.

Since hantavirus spread is almost exclusive to contact with rodents, with little chance of person to person spread (only really proven for the Andes hantavirus), this will NOT be a pandemic, and we’ll only update as events warrant.

In the interim, avoid the temptation to play with rat poop.

Coronavirus

–First, as a reminder (and a good short explainer of differences among the variants of concern) I am going to blatantly lift @erictopol’s chart.

You should read “Immune Evasiveness” as “amount of antibodies (either vaccine or natural infection produced) required to control the virus in a petri dish”. Also as a refresher, Beta was first id’d in South Africa, while Delta is the variant first id’d in India.

–Fair amount to cover. Around the horn, cases in the US continue to fall. Some scare headlines about Delta. This is in part because the UK is starting to climb another wave, with rapid spread of Delta in particular, and among young adult patients in particular. Part of that may be because vaccination among the young adult set has been a little slower on the uptake coupled with Delta’s expected “highly contagious to take advantage of increasingly rare opportunities. However, Delta also needs the high antibody titer to stop it in petri dishes that only two vaccine doses (and sometimes natural infection plus a vaccine “booster”) seem to provide sufficiently often. The most recent data from the UK show that two doses of the mRNA vaccines are 88% effective against symptomatic COVID (vs. 93% against the Alpha strain). However, they are only 33% effective against Delta if you have just one dose of the mRNA vaccines. Two doses of the AZ vaccine were 60% effective against symptomatic Delta COVID, versus 66% against the Alpha strain.

It’s not clear to me though if that’s one vaccine and recovered from previous infection (where I think you may be higher than the 33% quoted), or one vaccine only and were completely naive to SARS-CoV-2. The NHS did not break the data down in that much detail.

Regardless, if you never had PCR proven COVID (and don’t count “pretty sure I had it based on symptoms”–it’s “your PCR was positive for COVID” or bust), and you have only 1 or zero doses of vaccine on board, no time like the present. Get your second dose on board.

Don’t be that guy who screws up the 4th of July for everyone by contributing to a minor Delta wave that gets all the headlines and all the masks going again. Don’t be that guy!

South Africa cases continue to climb as well–again, appears to be mostly the unvaccinated there, with no reports of vaccine breakthrough still.

–Otherwise, latest data from the CDC on the “real world” effectiveness of the vaccines suggests two doses are 91% effective against COVID, and the rare “breakthrough” cases have mild, shorter disease with less chance to spread it to others.

The FDA is monitoring rare cases of inflammation around the heart (myocarditis and pericarditis) after mRNA vaccinations, especially in young adult and adolescent patients. These have typically been within a few days of the second dose, with acute chest pain, shortness of breath, and palpitations. They have generally responded well to treatment. Thus far, they appear rare like the heparin-induced thrombocytopenia like clotting of the non-mRNA vaccines.

–In other Delta news, some scare headlines sent in by a reader suggesting Delta may be “causing” diabetes in many patients in India. This is accompanied by an outbreak of mucormycosis, a severe fungal infection that is most common in immunocompromised patients (including diabetics with uncontrolled diabetes). Mucormycosis is a surgical emergency when found–they have to cut as much of fungus out as fast as possible. Since it likes the sinuses, it’s not far from the brain, hence the emergency (once the fungus it’s the brain, it’s usually game over). So yes, “likes the sinuses” means that the emergency radical surgery to cut the fungus out is happening on your face.

Avoid the temptation to Google “mucormycosis” or “black fungus” and “surgery” and just trust me that reconstructive plastic surgery after recovery is a pretty common request.

Now, as for Delta “causing” diabetes and the mucormycosis outbreak, the best evidence, including recently published papers from India, is that this complication is still lottery-level, one in a million type stuff. There were just a lot of people in India infected in a short time. That includes many who did not know they had diabetes (they were not feeling sick, a common gripe of many pre- and early diabetics), but caught COVID, came into the hospital for it, and low and behold, “by the way, you also have diabetes–which may explain why your COVID was severe enough to put you in the hospital here.” Diabetes is not exactly rare in India–only China has more people with diabetes, and as many as 1 in every 6 diabetics in the world are Indian.

For the record, this is because India and China both have a lot of people. In diabetics measured as a percentage of the population, the US is still way “ahead.”

Those on the ground in India and publishing have found that the mucormycosis outbreak after COVID is most strongly correlated to those with diabetes, or who got lots of steroids (as part of treating severe COVID) and/or were in the ICU for awhile. There is little to suggest that Delta is causing diabetes or predisposing mucormycosis, other than bringing people into the hospitals (which were getting overcrowded rapidly lately) who had risk factors for mucormycosis, or developed risk factors as part of treatment for severe COVID.

Delta is NOT likely to give you diabetes, or clear the way for some fungal friends (unless you wind up on high dose steroids and in the ICU for awhile, but any condition that puts you on high dose steroids or in the ICU for awhile will increase the chances of this rare fungal infection).

So more media “hype” if you run across those headlines around Delta or have run into them.

–Of course, fallout from the Fauci Files remains big in the news all week. One story that deserves some comment was an Op-Ed in the Wall Street Journal about the “CGGCGG” hypothesis.

This may be a challenge to simplify in way that makes sense, and I did a little dive on this, since, frankly, I have not been paying much attention to work on potential origins of SARS-CoV-2 since last year.

Again, knowing from whence it came does not help with the more immediate problem of making it go away, and was a little more focused on the latter…

Regardless, the key paper to keep in mind is this one:  https://www.nature.com/articles/s41564-021-00908-w  This shows that SARS-CoV-2 has a furin cleavage site in the spike protein that is associated with higher infectiousness, particularly in the lung. 

“The hell is a furin cleavage site?” I hear you ask, Hypothetical Reader.

Well, a furin cleavage site is a spot in the SARS-CoV-2 spike protein that can be cut (cleaved) by other proteins—some of which happen to be in high concentration in the lungs.  Cutting the spike protein at that spot may help processing and packaging of the virus, and make it more infectious in the lungs as a result (as the authors in that Nature article suggest).  That said, the furin cleavage site is NOT where the spike protein directly binds the ACE2 receptor to get the virus into the cell—those are the amino acids that effective antibodies from treatments or vaccines tend to target.  Block the amino acids that the spike protein uses to grab the ACE2 receptor and you block the virus from binding the ACE2 receptor.  Those amino acids are found in the “RBD”, or “receptor binding domain”, of the spike protein. A useful diagram is here:

This is a busy diagram, but it shows a lot of useful things. That block above the top (above the S1 and S2 lines) is the SARS-CoV-2 spike protein. You can see the “RBD”, or “receptor binding domain”, up there. The furin cleavage site is just a little bit further along from the RBD, and this is the section of the protein that is “magnified” as all the letters and numbers down below. Over on the left hand side, starting with a red asterisk, is “2019-nCov”. This is SARS-CoV-2, and all those letters to the right of “2019-nCoV” are the amino acids that are making up this furin cleavage site region. Listed below are several bat coronaviruses for comparison, as well as several human coronaviruses, including MERS-CoV (the MERS virus), which also has a red asterisk next to it. You’ll notice that the bat coronaviruses, in particular, have dots instead of letters at several spots in this region–that simply means they have NO amino acid there. Otherwise, you’ll see slight changes in the letters between all the virus’ spike protein amino acids in this region–that means that each virus uses slightly different combinations of amino acids in this part of the spike protein. That’s normal and expected variation among these close relatives.

Are we following that diagram so far? I hope so…

Alright, the furin cleavage site has a very specific sequence. In that diagram, there is a box around it next to the “2019-nCov” that starts right under the “680”. Found it? Inside that box are the letters SPRR. They continue on to form SPRRAR. A furin cleavage site is “RXXR”–where you have two “R” amino acids at the flanks, with any other amino acid combination between them. So the SARS-CoV-2 furin cleavage site is the “RRAR” at the end of that “SPRRAR” starting under just under 680 in the diagram above.

Still with me?

Okay. Now, go straight down that list for close relative coronaviruses, from that 680 in the diagram on down. You will notice all of the viruses marked with an asterisk ALSO have furin cleavage site in this region–including human coronaviruses MERS-CoV, HKU1 (a major cause of the common cold), and HCoV-OC43. For example, MERS-CoV’s furin cleavage site is RKRR in this same region. As it turns out, a LOT of coronaviruses develop this furin cleavage site here, and they use a lot of different nucleotide sequences to do it.

That said, you will also notice that NONE of the bat coronaviruses listed have a furin cleavage site sequence here. Only the human infectious coronaviruses do.

Further, to tell a ribosome to make the spike protein with the first two “Rs” in its furin cleavage site sequence RRAR, SARS-CoV-2 uses the nucleotide sequence “CGGCGG”.

For you non science majors, you use “CGG” in the DNA, which becomes “CGG” in the mRNA, which tells a ribosome that the amino acid arginine (which we short hand “R”) is to be added to the protein at that spot.

So the current crux of the “LAB VIRUS!” argument, and what the Wall Street Journal opinion piece was highlighting as an example, breaks down as follows:

1). SARS-CoV-2 has a furin cleavage site in the spike protein

2). It uses CGGCGG to code for the first two Rs in its furin cleavage site, RRAR.

3). The bat coronaviruses relatives that SARS-CoV-2 is closest to do NOT have a furin cleavage site in this part of their spike proteins. (BUT!!! Other human infectious coronaviruses often do…that is worth mentioning).

4). While other coronaviruses have a furin cleavage site there, NONE of them are RRAR, and none of them use “CGGCGG” specifically as a code for the two Rs where a “swap of nature” is a likely explanation.

5). In addition, that overall sequence ALSO creates a restriction enzyme site, which is a “science” way of saying there is a spot there a sophomore biology student with some genetics 101 lab experience could use to cut that section out of the virus and “paste” it into another one. (BUT!!!!! There are a bazillion restriction enyzmes, and it’s not impossible for the changes in this region to have matched some by coincidence–in fact, it’s almost probable based on how many restriction enzymes there are that we know about).

“PROOF!!!  PROOOOOOOF!”, I hear you, Hypothetical Reader, now claiming. 

Well, not quite so fast. 

The argument, especially in the Wall Street Journal piece, is that the “CGGCGG” is not the usual coding sequence for similar sequences in other viruses, where a cross over event (two viruses meet in the wild, swap some coding sequences, SARS-CoV-2 results) is likely. 

But, it’s not impossible either. CGGCGG is a VERY short sequence of DNA/RNA, and you only have 4 letters to “choose” from in DNA/RNA, limiting the possible combinations of those 6 nucleotides. If you are wondering, there are 1,296 ways to arrange the 4 nucleotides in a 6 “letter” sequence. So the chance of CGGCGG occurring randomly is 1 in 1,296 off the bat. That sounds like a long shot, but remember, genomes are hundreds of millions to billions of nucleotides long. Running into “CGGCGG” by chance alone somewhere in the genome is pretty high. For example, just the the FMR1 gene in humans contains 5-40 “CGG”s in a row (which sometimes blow up to much higher than 40 through a “copying” error, causing Fragile X syndrome). To be specific for a particular gene target, PCR primers and probes are typically 20-25 nucelotides (letters) long. Anything shorter, and you run into the -high- probability that your PCR assay will be amplifying your target AND something else–either another gene in the same species, or will be positive across similar species where that gene sequence is likely also present.

So when I say that “CGGCGG” is awfully short to be smoking gun specific, that’s why. 1:1296 odds are nothing to nature when it comes to DNA/RNA sequences.

And the odds aren’t even actually 1:1296. Remember, we’re talking specifically about a furin cleavage site, which is arginine-something-something-arginine (RXXR) in the protein. There are only 6 ways to arrange DNA/RNA nucleotides to get a ribosome to spit out the arrrrrrrginine you need at the beginning and the end. They are:

CGG

CGC

CGA

CGT

AGG

AGA

Note that once you have that first “CG”, you, my friend, are getting an arginine out of that ribosome no matter which of the 4 nucleotides you choose to end the codon (the three nucleotides in a row that are the “code” for an amino acid like arginine). “AGG”, another way to get arginine, is also only one “choice” away from “CGG”, and so not a huge evolutionary leap. So the “CG” at the very beginning of CGGCGG is probable. What we’re really quibbling over is the probability of the other 4 nucleotides being “GCGG” in CGGCGG by chance alone.

The odds are not so improbable to exclude “chance alone”, and so are not exactly a smoking gun. Nature could VERY easily have landed on CGGCGG here for SARS-CoV-2 without any help, at all, from Chinese or other scientists. Many coronaviruses, especially ones good at infecting humans, wind up with some form of furin cleavage site here, which takes many different amino acid forms, and thus many different nucleotide sequences.

In short, this is nowhere near definitive proof of a lab created virus. It does point out a key difference from bat coronaviruses, though, which are SARS-CoV-2’s closest overall cousins. However, finding a way to get a furin cleavage site may be what gave SARS-CoV-2 the ability to leap from bats to humans to begin with. This is the change we would expect in a bat virus that did that. Is it possible to have helped SARS-CoV-2 along with that, popping a furin cleavage site in as a gain of function mutation? That’s what the writers in the Wall Street Journal allege. But again, many coronaviruses have landed on a furin cleavage site here, and in a multitude of different ways. Just because SARS-CoV-2 didn’t steal some other coronavirus’ furin cleavage site outright doesn’t mean there wasn’t some crossover that nature then tinkered with, hammered into a CGGCGG that became RRAR in the protein and suddenly SARS-CoV-2 was off to the races. Is that crossover easier, does nature get a big assist, in a lab that is working with lots of bat coronaviruses and human coronaviruses that have a furin cleavage site? Yeah, it absolutely would be. Hence, I still think a lab accident is a little more probable than not. But this is not “beyond a reasonable doubt” evidence that SARS-CoV-2 was deliberately modified, let alone weaponized. And the swap could also have happened outside the lab, completely in nature too. Worth mentioning that.

It really just comes down to the probability you want to assign to each of those options at this point. Now, if there is a lab notebook somewhere in Wuhan that says “we inserted this specific furin cleavage site into this otherwise mild mannered bat coronavirus and holy shit y’all”, I’m more a believer. But absent that kind of hard, human evidence, there simply is no smoking gun for any of the possibilities–gain of function, lab accident crossing, or “met in nature and totally natural”. Just slight modifications to the probability of each explanation, without a satisfactory answer at this point.

Again, don’t expect the human evidence, if it exists, ever existed or still exists, to out in our lifetimes.

–You want a conspiracy theory of my own creation though? What is most interesting is that the Biden Administration is not only suddenly increasing chatter about possible lab origin of SARS-CoV-2 in Wuhan, is not only leaking things from unnamed intelligence sources like “several Wuhan lab employees were hospitalized with respiratory symptoms in early November”, has Dr. Anthony “Clearly, I Will Say Whatever Anyone Above Me Needs Me To Say No Matter What I Might Actually Believe or Know” Fauci doing some “needs more investigation” saber rattling, you have it coming from mouthpieces of both of the ideological divides in America. When possible lab release, and “China needs to provide more answers” comes from both the Biden Administration AND the op-ed pages of the Wall Street Journal, that gets my attention.

Why I think this continuation of pressure on China is happening? One guess is Taiwan.

It’s no secret the Chinese Communist Party wants to fully re-unify China by re-integrating Taiwan. They are not afraid to do so by force. Xi would consider it a major capstone in his career, cementing his legacy as a hero of China. Don’t underestimate either how galling it is to the Middle Kingdom (because only China is between heaven and earth, and thus the society that is slightly elevated above the rest of us rabble) that foreign influence keeps them from finishing the Mao-era Chinese civil war and re-integrating all the democracy supporters who fled to Taiwan. Lifting the humiliation of “special governance zones” enforced by non-Asian powers, like the hand over of Hong Kong back to China recently at the end of the lease treaty with the UK, proves the CCP has the Mandate of Heaven.

They want Taiwan. But the US backs Taiwan, and that is a sticky wicket for the CCP.

If they try to take Taiwan by force, their best window for the early half of this century is sooner rather than later. The One Child Policy in China makes their demographics a mess, starting now and getting worse for several decades. If they are only fighting Taiwan, well, their chances are good. If they are fighting the US (+/- allies) AND Taiwan, outcomes for China are less clear. So the best outcome for China is a US that is too distracted internally to care enough about Taiwan, so that if the reunification happens by massive amphibious assault, the reaction from the US is “meh.”

No one is happier that the divide between red and blue America is as stark as it is right now than China. And yes, Virginia, they DO have a lot of incentive to try to make that worse, with oh, say, massive farms of social media bots to amplify more divisive messages…

If you’re China, you’ll get another nice distraction of the US population in the midterm elections coming up next year.

However, I think there is broad agreement that Taiwan should be allowed to choose its own way, and broad agreement by the US and regional allies in the China-Taiwan neighborhood that the CCP does not deserve nice things. The EU membership of the G-7 has been unusually pointed towards China this week as well.

So if they invade Taiwan, and the US answers the bell, you have a pretty significant war in the Pacific. That will be a war to the pain. That’s because the best way to win the war and defend Taiwan is not what you think (which is most likely “have the Marines storm the other side of Taiwan and meet China head on in the middle”). The way to win the war with China is to close the strait of Malacca. A huge chunk of China’s oil comes by tanker through that strait, and they cannot replace that volume of oil quickly or easily. China does have some pipeline agreements via Burma and along the New Silk Road they are trying to build (this is part of the reason they are trying to build it). But not enough that they can make up what they would lose if the strait of Malacca is closed to them. That China has also been trying to aggressively pivot away from oil to power things like cars and trucks should now be less of a surprise to you. The US has the deep water navy to stand at a distance, well beyond the Chinese navy, air force, or its missiles, and still sink any oil tanker or other ship headed to China through the strait of Malacca–or any of the ways around the strait. Our allies in the area, certainly the pirates in the area, would also be more than happy to pick off oil tankers headed to China if all bets were suddenly off.

Without oil, the Chinese economy grinds to a halt, and that will be a major test of the CCP’s will and ability to continue the fight, if not a test of the will and ability of the Chinese people to put up with the asshats in the CCP. The Chinese, although trying to modernize and build rapidly, do not have the deep water navy that can take on the US Navy with high expectation of success (let alone the Japanese Navy, the #2 most capable deep ocean navy in the world right now, who also have some beef with China). They cannot rely on their navy being enough to get their tankers through that strait if the missiles start flying.

China knows this, and they have two probable asymmetric options to counter that strategy. The first is massive cyberattack. GPS, computer assisted targeting, satellites, and internet based communications are what make the US Navy so formidable (besides the massive amount of boats and missiles). Take those out by taking out the internet, and the US Navy might have to fight close enough to the strait itself that China can bring their Air Force and land based missiles into better range. China will also try to make life so miserable for US citizens by blowing up the internet infrastructure everything seems to run on these days that, sons and daughters of decadent capitalism that they are, they give up quickly on Taiwan to get their Netflix back. The second is space. No accident that Space Force, despite the snickering when announced, has not gone away. A missile from a satellite is much closer to the US Navy in the Pacific than its ground based version is if the satellite is hovering overhead the aircraft carriers. China has been putting a lot of satellites up. Think all of them are harmless weather trackers?

So as I mentioned, it becomes a race to the pain. Can the US make the loss of oil to fuel China real enough and long enough that China gives up? Or can China make cyberattacks and space attacks (including on GPS and other internet satellites, not just ships) painful enough for the US that the US gives up first?

And of course, both the US and China are also nuclear armed.

Ideally, everyone avoids this war. The best way to do that is to convince China that the US will defend Taiwan if they get froggy. China’s CCP makes hundred year plans. If the time isn’t perfect despite the chance that it might be in the run up to the 2022 US mid terms, cooler heads in China may convince Xi that they can continue to build until China’s chances are assured, even if that is many decades from now, and despite any legacy cementing objections he might have to deferring “reunification” with Taiwan. How do you convince China that the US will rise up as a unified whole to defend Taiwan though?

Put out publicly, from mouthpieces of both sides of the ideologic divide in the US, that there are common reasons for both sides of that divide to not like China much right now. Like, maybe China’s to blame for the misery of 2020 both sides just went through?

If China thinks both ideological sides in the US dislike China, and all a Taiwan attack will do is this in the US:

…their calculus may change enough that they take a hard pass at “reunifying” Taiwan right now.

That’s at least a “conspiracy” about the sudden (re)interest in COVID-19 origins from China that makes sense. Especially with all the “everyone is upset with China” rhetoric seemingly coming from everywhere all of a sudden.

–That said, COVID origins may just be piling on the propaganda in the new Cold War, and that explanation is just as likely, if not more, to immediately ice my own “conspiracy theory” : )

–Finally, a couple on social issues.

First, stumbled across this earlier in the week, and it’s worth meditating on:

“In fact our personalities and wellbeing depend on the correctness of our beliefs. This is an age of ego. Ego-investments are beliefs we associated with, and internalize, so strongly that they literally become elements of our personalities. So to challenge that belief is to literally attack the personality of the person with that ego-investment. It would make no difference how empirical your evidence to the contrary of that belief might be. You attack the belief and you attack the person. Religion, racism, political affiliation, gender dynamics, social dynamics, world view, all find their roots in individual ego-investments in those beliefs. We don’t build a belief set on the results of multiple peer-reviewed, independently funded meta-analyses of research papers–we create them based on emotion, lived experience and what extrinsic sources feel for us. So our innate tribalism flares up. Our red team is better than your blue team irrespective of any factor that might be contrary to our truth. So long as my team wins and your team loses my ego-investments remain valid and I don’t need to change anything about myself based on objective truth that would make me unhappy. It becomes a clash of whose ego-investments get validated. Any value the others’ might have had are never acknowledged. And we certainly don’t want any truth forced upon us that we don’t come to on our own. We want to be right.” –R.T. (the author uses a pen name)

Lastly, Epsilon Theory on why remote work is looking like the new normal: https://www.epsilontheory.com/a-working-narrative/?utm_source=ET+Newsletter&utm_medium=Email&utm_campaign=website

–Your chances of catching hantavirus are equivalent to the chances you play with rat poop routinely.

–Your chances of catching Ebola are equivalent to the chances you (or I) expected this update to be quite so epic in length this week…

–Your chances of catching Coronavirus, in most places in the world, are equivalent to the chances that you should check out the highlights of the US-Mexico men’s soccer game this past week, if you haven’t already. Little bit of everything in that one…

<Paladin>