Coronavirus thread

[JHC]

Knowing how to look for stuff like this and even just knowing to look for stuff like this at all is one of the benefits of a formal education in a subject. I'm all for self education, but training does matter.

OMG do I love this. In our niche community if someone expounds on tactics without world class training and even better flesh and blood experience, we know the score. Then in topics that touch on public policy, although they may be equally or more technical . . . do the math. I had a friend last Spring resisting the warnings of the infectious disease SME's and epidemiologists sending me links to rants from Fox News pundits. Jesus that conversation went south hard. LOL

[Nephrology]

When I clicked on each individual trial, all of them seem to be negative for HCQ benefits. You should double check that but I think I am right. So it seems like those dudes took five negative trials, reanalyzed them into one positive meta-analysis, and now publish everywhere quoting themselves.

My hot take:

Meta analyses are the Instagram of the research world. Seems impressive, means nothing at all.

Every clinical research study is like a fish tank: all you can describe are your fish, and your tank. If this is well done, it will give you the information that you really need.

A meta-analysis will describe 5 fish tanks: 4 bowls full of gold fish and a shark tank from the local aquarium, and discuss them together as if they were an accurate representation of the ocean.

In my opinion if you're not going to embrace reductivism and truly compare like versus like, you're wasting a lot of paper. Just my $0.02 as a salty, very over grad school, MSTP trainee.

You keep doing this, to the point where even to somebody that celebrates independent thought and research and thinks it's essential is getting annoyed. So how about this. You can go back in the thread to May/June and watch me and Nephrology get in a big internet fight about a study that showed HCQ had a negative effect on outcomes. Maybe that will raise my credibility in your eyes. If you won't take it from someone who went to medical school, maybe you will from another independent thinker.

Think about this:

1. At this point in the pandemic, there is too much money at stake for medical establishment inertia to block an effective treatment. Money talks. Bureaucracy and hidebound establishments can do a lot of harm, but money will move mountains and has.

2. This is a virus with a very wide range of outcomes across every conceivable age range, pre-existing condition status and comorbidity. That makes it extremely difficult to conduct an effective study on a prophylactic.

3. HCQ has very well established side effects. It has been in use for decades and those side effects are not up for debate. The data is widely available and easily analyzed.

4. Using HCQ/Zinc as a prophylactic at the scale you are suggesting would cause more negative outcomes than positive ones. That data wasn't available in May/June but it is now.

5. There's nothing wrong with being excited about the potential research into HCQ/Chloroquine having an effect on virus replication. The developments in mRNA vaccines are exciting but any novel virus is going to have a major effect even with a quicker pathway to an effective vaccine. The fact that nobody knows how it works is a good thing. It means there may be something to learn, and something good may come of it.

6. You can't say the majority of doctors are full of shit then use the fact that the people that support your point of view are doctors as a talking point. If the majority of doctors/medical professionals are full of shit, your doctors might be too.

I want to go out of my way and thank you sincerely for being open to changing your mind, and to apologize publicly for my rudeness in the past.

Not so much because you may/may not hold the same opinions I do on this topic, but because it takes a great spirit to see past the confrontational way that I approached our earlier conversation and to consider the merits of my argument nonetheless. Sincerely, thank you.

[MickAK]

I want to go out of my way and thank you sincerely for being open to changing your mind, and to apologize publicly for my rudeness in the past.

Not so much because you may/may not hold the same opinions I do on this topic, but because it takes a great spirit to see past the confrontational way that I approached our earlier conversation and to consider the merits of my argument nonetheless. Sincerely, thank you.

No problem. Having undergone medical treatment the last 3 months the irony of going 'Pffft. Experts.' earlier in the year then 'Plz sav experts' a few months later is not lost on me.

[Caballoflaco]

No problem. Having undergone medical treatment the last 3 months the irony of going 'Pffft. Experts.' earlier in the year then 'Plz sav experts' a few months later is not lost on me.

By the way, how’s the leg doing?

[MickAK]

By the way, how’s the leg doing?

Not bad. Hyperbaric oxygen therapy is amazing stuff.

[pangloss]

So, my genetics classes were decades before modern generic engineering...

It it the case that the vaccine contains X amount of mRNA, that gets taken into N cells which then display the relevant proteins, but no additional mRNA is produced in the body? I.e. only the original N cells ever contain the mRNA? And does the immune system then attack the cells that synthesized and are now displaying the relevant proteins?

My googling didn't find more than superficial answers...

A lot depends on which cells take up the vaccine. I'm not sure which populations that is, but dendritic cells and macrophages is a pretty safe bet (though there are a myriad of subtypes of each of those). My understand (possibly wrong) is that most of the antigen is secreted, which is mostly for the benefit of the B cells. Some of the antigen is not secreted, and that will be processed and presented to T cells. Like Bio said, the body doesn't make more copies of the vaccine RNA. What you get is what you get.

Sorry for the delayed reply - had an important committee meeting this AM that has occupied my time until just now...


The problem with hydroxychloroquine and COVID-19 is that there has never been a persuasive mechanistic hypothesis. Ever. I would challenge you to find one, but you will not be able to. If you can find persuasive evidence to the contrary, I am open to listening to it, but I know that it does not exist because I've looked for it and what I've found is deeply lacking. I've covered this before in this thread and won't re-hash this now, but will cover this again if you desire more specifics.

This closes part one of my argument...

I hope the committee meeting went well!

Getting to mechanism, part of my initial attraction to hydroxychloroquine was that I had an immediate hypothesis for mechanism of action. Chroroquine inhibits lysosomal acidification, which is a key step for some viruses. (Search histidine switch for more info.) The data have clearly shown that this doesn't work for SARS-CoV-2, but I thought it was an attractive idea--more likely because that's at the very very edge of my expertise (or just beyond it) rather than a good idea from the middle. Regardless, when everyone was grasping at straws, that straw looked pretty good to me. I'm sure you've heard this before, but the great tragedy of science is the beautiful hypothesis that was killed by the ugly little fact.

[scw2]

I'm behind on this thread and should have just done a multi-quote response, but this should be my last catch up post for the night.

Regarding the immunology, you get vaccinated in the arm, and the vaccine drains through the lymph vessels to the nearby lymph nodes. Once in the lymph node, antigen presenting cells process the vaccine and present it to T lymphocytes. Simultaneously, B cell recognize the vaccine and are activated and start to make IgM. In the case of the mRNA vaccines, cell in the body have to take up the vaccine, make the protein, and then eventually the T cells and B cells each get to see it. After 3-4 days, the T cells that recognize the vaccine have multiplied and are recirculating to other parts of the body. By about day 7 many of the responding B cells have become plasmablasts are also recirculating. At this point some B cells are making IgG and are in germinal centers in the draining lymph nodes where they basically figure out how to make better antibodies. Some of these B cells go on to become long-lived plasma cells that live in the bone marrow and spleen. The antibodies made by these plasma cells are what will protect people months to years after vaccination. When a person is vaccinated via injection, you usually don't see much of a mucosal (e.g. nose/respiratory) immune response, which would be IgA. There are some experimental injectable vaccines in animals that manage to stimulate IgA production in the respiratory tract, but I don't know what these SARS-CoV-2 mRNA vaccines will do. Regardless, if you have good IgG levels, that will protect the lung against COVID pneumonia even if it doesn't protect against mild upper respiratory infection. You'd still probably be a risk to others, but the amount of viral shedding and the duration of shedding would likely be less. Consequently, the window of time in which you could transmit infection would likely be lower.

Thanks, this is helpful in better understanding the risks if I manage to get the vaccine but higher risk family or friends have not gotten around to it yet!

[Nephrology]

I hope the committee meeting went well!.

Far better than expected. Whole committee will be quite pleased to send me back to clinic ahead of schedule in April.

]
Getting to mechanism, part of my initial attraction to hydroxychloroquine was that I had an immediate hypothesis for mechanism of action. Chroroquine inhibits lysosomal acidification, which is a key step for some viruses. (Search histidine switch for more info.) The data have clearly shown that this doesn't work for SARS-CoV-2, but I thought it was an attractive idea--more likely because that's at the very very edge of my expertise (or just beyond it) rather than a good idea from the middle. Regardless, when everyone was grasping at straws, that straw looked pretty good to me. I'm sure you've heard this before, but the great tragedy of science is the beautiful hypothesis that was killed by the ugly little fact.

So to get into the weeds with you on this, I did see the proposed mechanism (lysosomal acidification) plus a few early in vitro studies (one in PLoS pathogens IIRC) looking at its role in viral replication, but my recollection is that viral fusion/exit from the endosome required endosomal acidification - quite the opposite from being deleterious (vs malaria where it directly targets the parasite's digestive vacuole, iirc).

[Caballoflaco]

So to get into the weeds with you on this, I did see the proposed mechanism (lysosomal acidification) plus a few early in vitro studies (one in PLoS pathogens IIRC) looking at its role in viral replication, but my recollection is that viral fusion/exit from the endosome required endosomal acidification - quite the opposite from being deleterious (vs malaria where it directly targets the parasite's digestive vacuole, iirc).

It’s been a while, but weren’t the effective concentrations of HCL in the vitro studies greater than LD for living patients? Or am I remembering that wrong.

[Nephrology]

It’s been a while, but weren’t the effective concentrations of HCL in the vitro studies greater than LD for living patients? Or am I remembering that wrong.

That does sound familiar to me too, but it's been a long while since I looked at any of that stuff so I can't recall specifically.