Taking a look! It appears as of two days ago that the gov is officially looking into it https://www.youtube.com/watch?v=_q74khGSSi8 - but other than this I haven't seen any new developments beyond the Pfizer email statement to WaPo.
Pfizer's unsubstantiated claims have really flooded the coverage of the issue in the last few days. I continue to have my money on there being no "actual rebound" in the placebo group.
Great article!! As Modern Discontent said, many of these media articles are repackagings of our substack articles, pretending to be original thoughts and using the same references.
Also "Eric Feigl Ding" seems to be bringing strangely coincidental graphs and thoughts
Interesting. The plot continues to thicken I suppose! Honestly Brian I wouldn't be surprised if those in the media are scoping out Substacks for information. I did find it quite ironic that I sat through the entire Molnupiravir press briefing and reported on some of the concerning remarks, only for the NYT to mention more than a week later "hey, this might be dangerous for pregnant women!", or maybe I'm just being conspiratorial- I always make sure to keep some Reynold's wrap around (I kid, I'm sure they didn't get it from me, but then again I don't discount that the media is turning to Substacks to find what to write).
I think this really just indicates why such a rushed approach to approval has seriously "glossed" over so many things that should have otherwise not been "glossed" over.
I'm imagining them staring at a substack page in incomprehension, literally not able to make out the words until someone puts a blue check over them. Thought-stealing via rays might be more plausible. In reality MSM science journos seem to just trawl twitter and then email-spam their expert contacts to see which ones can hash out some copy with only a few hours notice before a post. And I haaaaaaaaaaaate the way the information comes out all jumbled around as a result.
Yeah and this especially pronounced in so-called "fact checks" which are really "we called an 'expert' and asked them to approve of our stance". They usually don't provide anything else of substance but to say someone big say no and therefore it is no.
It's actually funny, because for Molnupiravir all they said is that it targets viral replication. Of course if that is all you mention in a post when it later comes out that it may have mutagenic properties everyone gets all up in a tizzy. Wouldn't you think that these reporters should have known that?
They also just cite one another. There's a reason no one every cites the actual study- they just use strange ambiguities that refer to a school rather than the actual article. It's all just a really hot mess that doesn't state anything!
That Michael Charness preprint discloses that he has ownership of some Pfizer shares. It also discloses Gupta as someone who has owned Pfizer stock in the past.
I also thought it was interesting that Charness seems to suggest that instead of 5 days of Paxlovid, patients should maybe get it for 10 days? Am I reading that right? IDK.
Right, it was an interesting detail that Gupta was a Pfizer rep on loan for another matter. That’s the suggestion. I think that’s inflexible, “everything is like antibiotics” thinking. It could be better to take a shorter course, get the benefit vs severe outcomes but without pointlessly delaying the rebound and eventual clearance. I suggested 3 days in Pt 3 but maybe just 1 or 2 is enough.
"Vaccination and boosters provide only modest protection against symptomatic infection with the omicron variant (4); hence, the development of natural immunity to unique omicron epitopes may be necessary to clear omicron virus, even in vaccinated persons."
Right, it's purely a product of the Paxlovid mechanism because the "pause" is illusory within the cell and occurs at exactly the moment where interception / destruction of the infected cell is least likely, as described in the extra text added in today's update to Pt 1.
Longer course might solve the issue, but that's a big "might." It could in fact be the case (really, I think it probably is) that the virus is successfully replicating, going from cell to cell, at a low rate even during treatment (once the Orf1 polyprotein gets unpacked in any "unpaused" cell, Pax isn't going to do anything to stop the rest of the viral replication process), which means two things are possible: Because Paxlovid is still only "pausing" the virus each time it enters a new cell, the only way to avoid letting the infection play out at the end of treatment (for whatever % of patients was going to have a rebound anyway) is taking Paxlovid forever; prolonged treatment will create a backlog of infected cells with unknown negative effects (seems unlikely since there wasn't any big problem with starting Paxlovid in the midst of high viral loads).
The problem could also simply be that real-life use is intervening even faster than the trial, which did not start until at least 1 symptom onset, and probably never same day as same. If it can be shown in the trial data that the rebounders were all early-post-onset-treated, then there's the solution: start treatment a bit later, no change to the 5-day course needed. This could all be figured out already if the raw data was available as should be standard practice for any drug.
Nsp1, which is released before Paxlovid pauses/slows breakdown of the Orf1 polyproteins, silences host cell gene expression in general (this is also further discussed in the Pt 1 updates added today). So even though the virus is not inside the nucleus it has, by the time of the pause, effectively taken the reins as far as what the cell will be doing. That should make mitosis unlikely since the G2 checkpoint would need to be carried out, involving lots of gene expression.
There could be a scenario where cells recover, clear out the virus's mess, and then start G2 and division as normal; and further a scenario where LINE-1 has grabbed all or part of the viral RNA molecule and taken it into the nucleus, and one of the daughter cells therefor goes on to have some SARS-CoV-2 genes in some random spot. However, this could already be happening in normal cases of successfully aborted cellular infection all the time for all we know, without any real meaningful consequence. So Paxlovid itself doesn't drive this possibility on a theoretical level nor is it easy to guess if it would increase or decrease how often that happens.
That's the fun of biology, it's above everybody's paygrade, and no one has more than the thinnest grasp.
If spike (or the S2 base, after the S1 part breaks off) is staying on the cell membrane (as opposed to being secreted in some manner) then I think it would pretty much be a 50/50 split. If spike is going into the nucleus and disrupting DNA repair, that could also have all sorts of weird effects (though the nucleus disappears during division anyway), however, I am not strongly convinced by that study. So it's a can of worms. This relates to my cancer theory from October, which I still stand by (https://unglossed.substack.com/p/liquid-cancer). To frame it in terms that match my prior comment, with the mRNA transfections it's like "no one" has the reins. The cell is receiving this input that is making it engage in a metabolically intensive process for an unknown duration, how does it respond to that? It's not like with a virus, where the whole set of genes is harmoniously geared toward controlling what the cell does; it's not like with microRNAs received from other host cells, where cells are communicating and collaborating in a particular context. It's just this total ? mark that the cell has to decide what to make of.
My tweet with a picture of Reddit post highlighted
https://twitter.com/TotallyCanc3l3d/status/1520605702158397441
reddit post
https://www.reddit.com/r/COVID19positive/comments/ufl6a8/two_paxlovid_rebounds_in_one_household/
Looks like the wife got infected by the husband from his rebound.
Taking a look! It appears as of two days ago that the gov is officially looking into it https://www.youtube.com/watch?v=_q74khGSSi8 - but other than this I haven't seen any new developments beyond the Pfizer email statement to WaPo.
Yeah, Pfizer said that Paxlovid not working is the patients fault
The govt refused to look at more data and said "it is rare" haha
Pfizer's unsubstantiated claims have really flooded the coverage of the issue in the last few days. I continue to have my money on there being no "actual rebound" in the placebo group.
Note that the recent bloomberg article seems to include a reference to "severe rebound," but this might be a total misquote - "Pfizer said it has found no link between certain patient characteristics and the recurrence of severe symptoms after finishing the treatment. " (same I linked in comments at your post, https://www.bloomberg.com/news/articles/2022-05-03/pfizer-says-patients-who-relapse-after-covid-pill-can-take-more)
Today is about when Harris should "definitely not rebound, because it's so rare." We'll see.
Great article!! As Modern Discontent said, many of these media articles are repackagings of our substack articles, pretending to be original thoughts and using the same references.
Also "Eric Feigl Ding" seems to be bringing strangely coincidental graphs and thoughts
https://twitter.com/search?q=from%3A%40drericding%20paxlovid&src=typed_query&f=live
That's not great but better than total silence. Thank you for staying on the case.
What's going on on Substack gives me a lot of hope for the future.
Imagine what life would be like with no gatekeepers at all!
Interesting. The plot continues to thicken I suppose! Honestly Brian I wouldn't be surprised if those in the media are scoping out Substacks for information. I did find it quite ironic that I sat through the entire Molnupiravir press briefing and reported on some of the concerning remarks, only for the NYT to mention more than a week later "hey, this might be dangerous for pregnant women!", or maybe I'm just being conspiratorial- I always make sure to keep some Reynold's wrap around (I kid, I'm sure they didn't get it from me, but then again I don't discount that the media is turning to Substacks to find what to write).
I think this really just indicates why such a rushed approach to approval has seriously "glossed" over so many things that should have otherwise not been "glossed" over.
I'm imagining them staring at a substack page in incomprehension, literally not able to make out the words until someone puts a blue check over them. Thought-stealing via rays might be more plausible. In reality MSM science journos seem to just trawl twitter and then email-spam their expert contacts to see which ones can hash out some copy with only a few hours notice before a post. And I haaaaaaaaaaaate the way the information comes out all jumbled around as a result.
Yeah and this especially pronounced in so-called "fact checks" which are really "we called an 'expert' and asked them to approve of our stance". They usually don't provide anything else of substance but to say someone big say no and therefore it is no.
It's actually funny, because for Molnupiravir all they said is that it targets viral replication. Of course if that is all you mention in a post when it later comes out that it may have mutagenic properties everyone gets all up in a tizzy. Wouldn't you think that these reporters should have known that?
They also just cite one another. There's a reason no one every cites the actual study- they just use strange ambiguities that refer to a school rather than the actual article. It's all just a really hot mess that doesn't state anything!
"New research from a big green building with the windows says..."
Honestly, even mentioning the color of the building might be adding too much detail..
That Michael Charness preprint discloses that he has ownership of some Pfizer shares. It also discloses Gupta as someone who has owned Pfizer stock in the past.
I also thought it was interesting that Charness seems to suggest that instead of 5 days of Paxlovid, patients should maybe get it for 10 days? Am I reading that right? IDK.
Right, it was an interesting detail that Gupta was a Pfizer rep on loan for another matter. That’s the suggestion. I think that’s inflexible, “everything is like antibiotics” thinking. It could be better to take a shorter course, get the benefit vs severe outcomes but without pointlessly delaying the rebound and eventual clearance. I suggested 3 days in Pt 3 but maybe just 1 or 2 is enough.
Extra points for "feisty pot shots".
"Vaccination and boosters provide only modest protection against symptomatic infection with the omicron variant (4); hence, the development of natural immunity to unique omicron epitopes may be necessary to clear omicron virus, even in vaccinated persons."
Har. Take that, vaxxers.
Somebody call an exorcist!
Right, it's purely a product of the Paxlovid mechanism because the "pause" is illusory within the cell and occurs at exactly the moment where interception / destruction of the infected cell is least likely, as described in the extra text added in today's update to Pt 1.
Longer course might solve the issue, but that's a big "might." It could in fact be the case (really, I think it probably is) that the virus is successfully replicating, going from cell to cell, at a low rate even during treatment (once the Orf1 polyprotein gets unpacked in any "unpaused" cell, Pax isn't going to do anything to stop the rest of the viral replication process), which means two things are possible: Because Paxlovid is still only "pausing" the virus each time it enters a new cell, the only way to avoid letting the infection play out at the end of treatment (for whatever % of patients was going to have a rebound anyway) is taking Paxlovid forever; prolonged treatment will create a backlog of infected cells with unknown negative effects (seems unlikely since there wasn't any big problem with starting Paxlovid in the midst of high viral loads).
The problem could also simply be that real-life use is intervening even faster than the trial, which did not start until at least 1 symptom onset, and probably never same day as same. If it can be shown in the trial data that the rebounders were all early-post-onset-treated, then there's the solution: start treatment a bit later, no change to the 5-day course needed. This could all be figured out already if the raw data was available as should be standard practice for any drug.
Nsp1, which is released before Paxlovid pauses/slows breakdown of the Orf1 polyproteins, silences host cell gene expression in general (this is also further discussed in the Pt 1 updates added today). So even though the virus is not inside the nucleus it has, by the time of the pause, effectively taken the reins as far as what the cell will be doing. That should make mitosis unlikely since the G2 checkpoint would need to be carried out, involving lots of gene expression.
There could be a scenario where cells recover, clear out the virus's mess, and then start G2 and division as normal; and further a scenario where LINE-1 has grabbed all or part of the viral RNA molecule and taken it into the nucleus, and one of the daughter cells therefor goes on to have some SARS-CoV-2 genes in some random spot. However, this could already be happening in normal cases of successfully aborted cellular infection all the time for all we know, without any real meaningful consequence. So Paxlovid itself doesn't drive this possibility on a theoretical level nor is it easy to guess if it would increase or decrease how often that happens.
That's the fun of biology, it's above everybody's paygrade, and no one has more than the thinnest grasp.
If spike (or the S2 base, after the S1 part breaks off) is staying on the cell membrane (as opposed to being secreted in some manner) then I think it would pretty much be a 50/50 split. If spike is going into the nucleus and disrupting DNA repair, that could also have all sorts of weird effects (though the nucleus disappears during division anyway), however, I am not strongly convinced by that study. So it's a can of worms. This relates to my cancer theory from October, which I still stand by (https://unglossed.substack.com/p/liquid-cancer). To frame it in terms that match my prior comment, with the mRNA transfections it's like "no one" has the reins. The cell is receiving this input that is making it engage in a metabolically intensive process for an unknown duration, how does it respond to that? It's not like with a virus, where the whole set of genes is harmoniously geared toward controlling what the cell does; it's not like with microRNAs received from other host cells, where cells are communicating and collaborating in a particular context. It's just this total ? mark that the cell has to decide what to make of.