Fear and Loathing, a Rat Flu Odyssey

[oftpiste]

Just saw this posted by a former client about a former client....

https://news.illinois.edu/view/6367/...V27Y54c7Q3uLT4

[old goat]

The issue is the working poor just can't/won't take the time to vote on election day because they're working (yes, I know there are laws, but when you're working two or three jobs they don't have to coordinate time off for voting) or just flat ass exhausted. Give them a vote that they can mail in for free and weeks to complete it and now they're a voter. Many of them don't understand what an absentee ballot is, or that they could have had one. The working poor also have issues with housing security which means a steady mailing address becomes a barrier to voting as you need to show up at the correct polling place and give the address you had when you registered to vote. Seniors at the old folks home have had 40 years to figured this out, and they have a lot more time to vote, so they have it figured out. Mail in ballots add more 18-30 year olds to the electorate. The young and poor lean left.

This also cuts into the timeline for Drumph to pray a vaccine passes clinical trials so he can take credit for saving the country, as ballots could be mailed weeks earlier than Nov 3.

Mail in voting also negates the GOP strategy of closing polling places where young, poor, and minority people vote and ending or decreasing early voting.

I guess a lot of GOP leaders are worrying that Trump smearing vote by mail will drive down Republican turnout more than Democratic. Hence Trump saying it's ok for Florida to vote by mail, but not anywhere else, because we all know how honest and reliable Florida's electoral system is. (Al Gore must be rolling in his grave.)

[garyfromterrace]

What I don't understand is how mail-in voting makes it impossible for republicans to win. If they think its because people don't want them in office and won't vote for them then isn't the problem them and not the method of voting?

"In an illegal late night coup, Nevada's clubhouse Governor made it impossible for Republicans to win the state," Trump tweeted on Monday morning. "Post Office could never handle the Traffic of Mail-In Votes without preparation. Using Covid to steal the state. See you in Court!"

You are looking for logic in a party that elected the shit gibbon as their leader? Oh KQ!

[garyfromterrace]

Well, voter suppression is almost a campaign platform for the party at this point...

Exactly

[old goat]

The only area they have a polling advantage these days is the "enthusiasm gap." So the harder it is to vote the more their exuberance tilts the in their favor. Funny to see Republicans trying to get out the absentee votes now, though: they've gone so hard on this thing that now the fear is that with more people staying home some of their supporters won't vote at all. Can't even get the propaganda right, apparently.

I don't buy the enthusiasm gap. The way the polling is done--yes Trump voters are more enthusiastic about voting for Trump than Biden voters are about voting for him. (I'm not enthusiastic at all about voting for Biden). But Biden voters are extremely enthusiastic about voting against Trump and if people have to stand in long lines to do it they will.
The most worrisome thing is that in swing states currently controlled by Republicans an electoral "mistrial" could be declared and the legislature and/or governor could appoint electors, ignoring the outcome of the vote. By the time that made it through the courts the electors would already have voted for Trump and the courts would be faced with overturning the results of the Electoral College vote.

[jono]

thanks for diving deeper into what i posted. i did not dive too deeply. i've found that linsey marr will often provide science and interpretation of the science for lay-person use and understanding. however, sometimes her interpretation has some bias. for instance, a few months ago, she posted about how schools need to re-open, but it seemed that her reasoning was because he elementary-aged child was getting on her nerves.

in the field of working with children with special needs (wife's occupation), many schools and professional organizations are wishy-washy about whether a face shield is adequate w/o a mask. my wife is observing (via FB groups) that many therapists are only wearing face shield. these are adults that can potentially be super spreaders w/in a school because they migrate from class to class, sometimes working with aides, teachers, parents, the child needing therapy, and other students in the class (i.e., typically developing peers) that are part of a group session. These interactions can be dictated by a legally binding IEP that was developed over a year ago. and, of course, some therapy, like speech therapy, is very difficult to do with a child while either are wearing masks. The use of a face shield in these circumstances w/o a mask seems like a very bad idea.

I agree that would be less than ideal, and I expect they don't want to hide their faces, either, right? I think there's a solution that should be explored for that circumstance: basically "sealing" the shield to the wearer's face with a filter. PM me if you're interested in really going into the weeds on that.

[LongShortLong]

No, in concept they should be but those tests are not "cheap". They both run on proprietary instruments from each company which limits through put unless the doc's office has a machine to process them. They both require a swab, collection tube, buffer reagents, in one case freeze-dried, along with the detection reagents ( antibodies against NP protein) stabilized on a strip. They provide a positive and negative control to run along with the test.

I haven't looked at price point for either Quidel or BD test but since many of the serology lateral flow assays with very similar tech were coming in around $50/test I don't see this being a $1-2 assay without serious gov't subsidy.

I see. Too bad. Also, I don't count subsidies as discount to the price. Money is money. If the government pays the $50/test, it's still about $50 too expensive to use daily. If 300 million do a daily test, that's $15B per day. $0.45T per month, less if we don't test weekends. Seems too expensive, though it's a little cheaper than the economic hit from Corona so far.

[jono]

I don't buy the enthusiasm gap. The way the polling is done--yes Trump voters are more enthusiastic about voting for Trump than Biden voters are about voting for him. (I'm not enthusiastic at all about voting for Biden). But Biden voters are extremely enthusiastic about voting against Trump and if people have to stand in long lines to do it they will.
The most worrisome thing is that in swing states currently controlled by Republicans an electoral "mistrial" could be declared and the legislature and/or governor could appoint electors, ignoring the outcome of the vote. By the time that made it through the courts the electors would already have voted for Trump and the courts would be faced with overturning the results of the Electoral College vote.

I agree with you about the desire to vote against being stronger than the desire to vote for--definitely our present pattern. In the case of analyzing GOP tactics, though, these days hope is a plan, and they're not being led by people who want to look at that second layer.

[DBdude]

making voting easier is considered to benefit democrats because there are more registered democrats than republicans

if every democrat voted there would be far fewer or no republicans in office

[frorider]

1 in 5.

. This week, 46% of Americans know someone who has tested positive for the coronavirus – half of whom (23% of all Americans) know someone in their community who has tested positive.

Almost one in five (18%) Americans know someone who has died from the coronavirus. Black (31%) and Hispanic (28%) Americans continue to be more likely to know someone who has died of coronavirus compared to white (13%) Americans.

https://www.ipsos.com/en-us/news-pol...onavirus-index

[huckbucket]

Just saw this posted by a former client about a former client....

https://news.illinois.edu/view/6367/...V27Y54c7Q3uLT4

Thanks for posting. Wouldn't be my first choice of strategies to attack this thing for a few reasons. Producing and formulating the protein for therapeutic use could be challenging. It's a receptor which means it likes to live in cell membranes which cannot be part of the drug. So you have to produce a smaller portion of the protein that maintains comparable affinity (as the in tact receptor) for covid ... that could be very challenging. Second, if you put the decoy into humans, the possibility exists that you will bind up all the soluble angiotensin in your circulation and disrupt the intricate regulation of blood volume and pressure. Finally, the antibody therapies being developed by REGN should be every bit as effective as a decoy receptor. They will have optimized PK and a clear path for manufacturing, purification and regulatory.

[huckbucket]

Immunology lesson time folks. Expertly written for this crowd.

https://www.theatlantic.com/health/a...ystery/614956/

[Mofro261]

Thanks for posting. Wouldn't be my first choice of strategies to attack this thing for a few reasons. Producing and formulating the protein for therapeutic use could be challenging. It's a receptor which means it likes to live in cell membranes which cannot be part of the drug. So you have to produce a smaller portion of the protein that maintains comparable affinity (as the in tact receptor) for covid ... that could be very challenging. Second, if you put the decoy into humans, the possibility exists that you will bind up all the soluble angiotensin in your circulation and disrupt the intricate regulation of blood volume and pressure. Finally, the antibody therapies being developed by REGN should be every bit as effective as a decoy receptor. They will have optimized PK and a clear path for manufacturing, purification and regulatory.

Actually making the soluble ACE2 receptor proved to be dead easy, we obtained well over 300 mg/L of active materal without any expression optimization. The FL protein is ~805 aa but the membrane tether in the the C-terminal 100 aa and does not contribute to the binding site; the RBD binding site on ACE2 is also non-overlapping with the receptor's proteolytic domain for AngII cleavage. But making something functional is much easier than the path to clear regulatory for an injectable protein biological.

Soluble ACE2 has been floated as a complement to Angiotensin Receptor Blockers for ARDS as it does more than down-regulate AngII signaling, but actually promotes counter-effects mediated through Ang1-7/ATRII and MAS receptors. More than acting as a decoy for the virus, modulating the cytokine mileu may be crucial for allowing adaptive immune responses to trend toward resolution of infection instead of exacerbation.

RE: Mab's. From our own Spike-trimer immunizations, we got close to 20 Mab's clonally selected and purified that block RBD binding to ACE2 and show strong neutralization in conventional VNT assays. I would expect multiple groups putting forth Mab therapies in the next 6mos.

An assay based on ACE2/RBD blockade to measure neutralizing Ab's was just published last week in Nature Biotechnology. In their reported assay, neutralizing Ab's from SARS-1 patients were still present 17 yrs later. https://www.nature.com/articles/s41587-020-0631-z

[oftpiste]

It's all way the fuck over my head. Just was kind of a cool thing to hear about someone else I know doing the work. Keep on striving' y'all! Good job.

Thanks for posting. Wouldn't be my first choice of strategies to attack this thing for a few reasons. Producing and formulating the protein for therapeutic use could be challenging. It's a receptor which means it likes to live in cell membranes which cannot be part of the drug. So you have to produce a smaller portion of the protein that maintains comparable affinity (as the in tact receptor) for covid ... that could be very challenging. Second, if you put the decoy into humans, the possibility exists that you will bind up all the soluble angiotensin in your circulation and disrupt the intricate regulation of blood volume and pressure. Finally, the antibody therapies being developed by REGN should be every bit as effective as a decoy receptor. They will have optimized PK and a clear path for manufacturing, purification and regulatory.

[old goat]

I'm with Huckbucket. It seems to me that the potential for a decoy ACE2 receptor to wreak havoc on the renin-angiotensin system is high. I think you would have to do a lot of animal studies to prove its safety before you could begin to test in humans for efficacy. Monoclonal Ab seems a lot cleaner.

A quick Pubmed search for ARBs for ARDS seems to show maybe benefit--retrospective, mortality rates the same with and without, but after survival analysis, whatever that is, better survival in the treated group. I don't follow the statistics.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6786717/
Is there better data?

I don't see any clinical data on soluble ACE2 for ARDS.

[neufox47]

Actually making the soluble ACE2 receptor proved to be dead easy, we obtained well over 300 mg/L of active materal without any expression optimization. The FL protein is ~805 aa but the membrane tether in the the C-terminal 100 aa and does not contribute to the binding site; the RBD binding site on ACE2 is also non-overlapping with the receptor's proteolytic domain for AngII cleavage. But making something functional is much easier than the path to clear regulatory for an injectable protein biological.

Soluble ACE2 has been floated as a complement to Angiotensin Receptor Blockers for ARDS as it does more than down-regulate AngII signaling, but actually promotes counter-effects mediated through Ang1-7/ATRII and MAS receptors. More than acting as a decoy for the virus, modulating the cytokine mileu may be crucial for allowing adaptive immune responses to trend toward resolution of infection instead of exacerbation.

RE: Mab's. From our own Spike-trimer immunizations, we got close to 20 Mab's clonally selected and purified that block RBD binding to ACE2 and show strong neutralization in conventional VNT assays. I would expect multiple groups putting forth Mab therapies in the next 6mos.

An assay based on ACE2/RBD blockade to measure neutralizing Ab's was just published last week in Nature Biotechnology. In their reported assay, neutralizing Ab's from SARS-1 patients were still present 17 yrs later. https://www.nature.com/articles/s41587-020-0631-z

To think somewhere, some anti-vaxxer that lacks a highschool diploma is saying to themself, well based on my “research” this vaccine is dangerous! And I have the right to decide what I do with my body. #mybodymychoice

Thanks for what you do Mofro, Lego, Huck, and the rest of the scientists and medical community that is fighting this thing.

[Ted Striker]

To think somewhere, some anti-vaxxer that lacks a highschool diploma is saying to themself, well based on my “research” this vaccine is dangerous!

And it gets worse... at least two anti-vaxxers I know have (at least) a bachelor's of something, and a third has a doctorate. The fourth went to god college, so that doesn't count.

[old goat]

And it gets worse... at least two anti-vaxxers I know have (at least) a bachelor's of something, and a third has a doctorate. The fourth went to god college, so that doesn't count.

You have to have at least a Master's Degree in Science to understand this stuff. A PhD in comparative literature doesn't count.

[Mofro261]

I'm with Huckbucket. It seems to me that the potential for a decoy ACE2 receptor to wreak havoc on the renin-angiotensin system is high. I think you would have to do a lot of animal studies to prove its safety before you could begin to test in humans for efficacy. Monoclonal Ab seems a lot cleaner.

A quick Pubmed search for ARBs for ARDS seems to show maybe benefit--retrospective, mortality rates the same with and without, but after survival analysis, whatever that is, better survival in the treated group. I don't follow the statistics.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6786717/
Is there better data?

I don't see any clinical data on soluble ACE2 for ARDS.

It would seem that an unbalanced RAS may be an underpinning for inflammatory states.

Many animal studies have been conducted with hACE2 transgenics, and human studies per recent review, An update on ACE2 amplification and its therapeutic potential.

Human recombinant ACE2 has been evaluated in human subjects in limited clinical studies.The pharmacokinetics, pharmacodynamics, safety, and tolerability of hrACE2 were determined in healthy volunteers 71. This study was randomized, double-blind, and placebocontrolled. -In addition to showing good tolerability of hrACE2 (1-740 AA) by healthy human subjects, this study revealed a suppression of systemic Ang II levels both by single and repeated dosing of hrACE271. Since ACE2 has been implicated in animal models of acute lung injury68,72 it was postulated that administration of hrACE2 could attenuate acute lung injury in human subjects with ARDS73. In patients with acute respiratory distress syndrome (ARDS) hrACE2 (GSK2586881) was well tolerated 73. Human rACE2 caused a decrease of circulating Ang II levels 73 whereas angiotensin (1-5) and angiotensin (1-7) levels were increased and continued elevated for 48 h73. In this exploratory study registered under ClinicalTrials.gov, NCT01597635, surfactant protein D (SP-D) which is considered a beneficial biomarker contributing to normal surfactant structure and inhibition of inflammatory response was increased in hrACE2-treated subjects compared with placebo. However, hrACE2 infusions did not result in improvement in other physiological or clinical measures of ARDS in this small study and the trial was terminated early73.


Encouraging but still very preliminary findings were drawn from a recent phase IIa, open label pilot study which suggested a potential therapeutic role for hrACE2 in pulmonary arterial hypertension 74. This study found a reduced plasma ACE2 activity in subjects with PH. This was inferred, from higher plasma Ang II to Ang (1-7) ratio however, the ratio is not specific as it can potentially be affected by changes in other enzymes that affect the conversion of Ang II to Ang (1-7). At baseline in subjects with PH, increased expression in six out of nine measured cytokines as compared with controls (interleukin (IL)-10, IL-1β, tumor necrosis factor (TNF)-α, IL-13, IL-8 and IL-4) was found. Reduced plasma superoxide dismutase 2 (SOD2), which is considered an anti-oxidant enzyme, and increased oxidant stress parameters were also observed74. After hrACE2, cytokines such as IL-10, IL-1β, IL-2 and TNF-α were decreased 2 hours after administration. Human rACE2 administration was reported to also beneficially influence SOD2 levels, and reduce plasma oxidant stress. These findings were based on a limited number of subjects. Further assessment of hrACE2 as a potential therapeutic in PH certainly will require larger studies. Table 2 provides a summary of studies so far that have used human soluble recombinant ACE2.

Agree that it is unlikely to move forward ahead of Mabs in terms of inducing virus neutralization. But those same cytokines that are induced by ACE2 depletion/ AngII enhancement are the cytokines that allow disruptive t cell responses that increase disease severity and can lead to sepsis/cytokine storm. RAS is active on lymphocytes too. Still much to learn.

[hutash]

I must say immunology has changed a lot since my last formal class. Glad I only administered them.and didn't have to decouple them.

[SkiBall]

making voting easier is considered to benefit democrats because there are more registered democrats than republicans

if every democrat voted there would be far fewer or no republicans in office

It doesn’t appear from my vantage that there are many actual Republicans left in the Pub party.

[summit]

This has been a very fun page to read, thanks!

[bodywhomper]

You have to have at least a Master's Degree in Science to understand this stuff. A PhD in comparative literature doesn't count.

Just because one has an advanced degree in a science does not mean that they understand that stuff or are idiots.

There’s a “famous” immunology phd former researchers that now (mainly?) gives talks to the anti-vax folks.

A bunch of residents in Gainesville caught covid because they went to (or threw?) a house party.

[old goat]

I've been following ARDS closely since I was a resident--the condition was first recognized in Vietnam casualties and a lot of the early research was done by surgeons, including my mentor Dr. Blaisdell. What has impressed me over the years is the number of pharmacological inventions that have been tried unsuccessfully. (Dr. Blaisdell's hypothesis that the condition was caused by platelet activation and could be treated by antiplatelet therapy. It couldn't.)

The human inflammatory response is incredibly complex and simplistic interventions often have unintended consequences. The one thing we know for sure is that to treat ARDS you have to successfully treat the underlying condition--in the case of Covid 19 that obviously means controlling the viral infection. If manufactured ACE2 receptor can do that the benefit might outweigh whatever ill effects it might have on the renin angiotensin system and the inflammatory response, just as dexamethasone seems to control the inflammatory response without the negative effect on the immune system negating its benefit. Still the response to dexamethasone is far from 100% and my suspicion is that the same will be true for any other pharmacologic intervention in the inflammatory cascade.

It's still not clear to me how much of the respiratory problems of Covid 19 are viral pneumonia, excessive inflammatory response, and/or secondary bacterial pneumonia. Can someone clarify for me?

[Rasputin]

I kinda feel like it's a fit thing.

Mask is too big and people a) don't know how to adjust it b) don't care to adjust it because they think it's just the way it is given their head shape and/or c) they don't have the time/energy/money to shop around for one that fits.

Maybe we need PSA on TV about how to acheive a proper mask fit.

Honestly KQ, I think people have the intention of their mask fitting poorly, so they can get more air than when it is well sealed, flush to the face, as it should be.