ice9 Profile picture
I do quantitative things. Sometimes I think about society and economics.
Daniel Bilar Profile picture Melissa Andersen Profile picture Jediphone Profile picture hotelzululima-OPEN_COVID19_VAX_2ALL_NOW-BOFH guild Profile picture Crystal Profile picture 9 added to My Authors
19 Jan
GABA administration protects mice from death by mouse hepatitis virus (MHV) infection, another coronavirus often used in animal experiments.

Ivermectin activates GABAAR (GABA is used in e.g. leukocytes, not just CNS).

OTC GABA supplements are safe for brief use and inexpensive.
L-glutamine (a GABA precursor) was studied clinically for COVID-19, but the study was poorly designed and results were rather weak. I expect little benefit from glutamine in COVID-19.

ncbi.nlm.nih.gov/pmc/articles/P…

Effect on GABA levels appears limited.

pubmed.ncbi.nlm.nih.gov/17218538/ ImageImageImage
Typical serum GABA: 75-225nM.

nature.com/articles/s4200…

Typical overall serum GABA-equivalent compounds: 200-800nM.

pubmed.ncbi.nlm.nih.gov/6137647/

So a proportional increase does not count for much. This is likely why glutamine was unhelpful.
Read 6 tweets
6 Jan
One request--

If you work in COVID-19 critical care, please consider the following:

We know, with certainty, that plasma *free 5-HT* is highly elevated. Always.

We know, with certainty, that this is *causal* for pulmonary vasoconstriction, thrombosis.

We know the 5-HT2A receptor activates platelets, and the 5-HT2B receptor promotes fibrosis. This is basic physiology.

We know that 5-HT2 antagonists have been proven repeatedly to block these processes in many related contexts: cyproheptadine is one.

Given this:

How could you possibly justify refusing to treat *known, universally* elevated plasma 5-HT, in an often-lethal disease state that is *defined* in part by *frank, known symptoms of elevated plasma 5-HT*?
Read 7 tweets
4 Jan
@coolnidal @farid__jalali First off:

Because Zaid et al. already directly demonstrated that plasma serotonin is indeed greatly elevated in hospitalized moderate to severe COVID-19.



Therefore, this is no longer a theory, but rather an established fact about the disease process.
@coolnidal @farid__jalali Second:

Because the excess plasma serotonin has obvious and serious ramifications for clinical symptoms and management.

It is a miserable condition to be in for even hours, much less weeks.



People thrashing, hallucinating, clawing at tubes: here's why.
@coolnidal @farid__jalali Journalists like videos and media, right?

Here's what it looks like.

Click this post, scroll up by one for the video.



Imagine if this were your father or uncle or grandfather.

Just weeks like that.

We can do something about this. It can be blocked.
Read 7 tweets
4 Jan
More autoimmune exacerbation in COVID-19:

Fatal cases have higher levels of autoantibodies to Annexin A2, vs. non-fatal severe cases and non-severe cases.

Inhibiting Annexin A2 promotes thrombosis and pulmonary edema.

Similar to Abs against β2GPI in antiphospholipid syndrome.
Interestingly, antibodies to SARS-CoV-2 S2 are also somewhat cross-reactive to Annexin A2.

Not relevant to vaccines using stabilized Spike.

Relevance unclear for natural infection.

May matter during the exaggerated antibody response in severe COVID-19.

Anti-S2 antibodies do not appear to be neutralizing either. Overall, this is arguably a form of ADE.

stm.sciencemag.org/content/12/550…

Note again this can only arise during a COVID-19 case, 'natural infection'.

All leading vaccines use stabilized Spike, so the vaccines cannot do this.
Read 5 tweets
3 Jan
Excessive plasma serotonin levels contribute to lymphopenia.

This may partly explain the relative lymphopenia seen in some severe COVID-19 cases and its poor prognostic implications.

H2 antagonists (e.g. famotidine) and cyproheptadine block the effect.

sciencedirect.com/science/articl…
More on the effect of excessive plasma serotonin levels in suppressing T cell activity:

tandfonline.com/doi/abs/10.310…

@farid__jalali
Elevated plasma serotonin also promotes B cell activation and antibody secretion.

nature.com/articles/s4159…

ncbi.nlm.nih.gov/pmc/articles/P…

Severe COVID-19 often includes useless or harmful antibody production-- against the viral N protein, other CoVs, other viruses, human tissue, etc.
Read 6 tweets
3 Jan
@ianbirrell Comprehensive.

Only a few flaws.

The first is the 'missing researcher'-- she left years earlier, irrelevant.

The second is that you missed the EcoHealth Alliance grant, and Daszak explicitly confirmed recombinant CoV testing in humanized mice Nov 2019.

Read 4 tweets
3 Jan
What to expect in a COVID-19 case that progresses to the severe phase and ICU admission-- in terms of typical patient experiences.

Note this thread is 14 posts long.
The things we are discussing about 5-HT2 antagonists and plasma serotonin, about attempting to halt progression in the early severe stage, are relevant *during* these events.

Rates of PTSD following survival from severe COVID-19 exceed 30%, ditto anxiety and depression.
The ventilator settings required to keep these patients alive tend to permit blood CO2 levels to rise somewhat, in avoiding excessive mechanical damage to the lungs.

This has been repeatedly demonstrated to cause severe anxiety and promote PTSD.

Read 5 tweets
2 Jan
Cyproheptadine prevents pulmonary platelet trapping in endotoxin shocked or severely beaten dogs.

osti.gov/biblio/5502933…

Further evidence for potential efficacy against development of ARDS via pulmonary microthrombosis-- explicitly discussed.

@farid__jalali ImageImageImageImage
@cameronks @pathdoc3 @icedoc61 @Jopo_dr @Acute_Pulmo_Med @ZaidYounes9 @Geurys7 @MARYau_MCU_PH @DrBrandon55 @VectorSting @Crashcart

Interesting earlier result on cyproheptadine and pulmonary platelets.
Just found this one for pulmonary fibrosis as well-- another success for cyproheptadine in earlier animal experiments:

Read 4 tweets
30 Dec 20
For anyone interested in the Baric interview on synthetic recombinant SARS-like CoVs earlier, see around 38:00 into this video.

There is also some interesting preliminary discussion starting around 36:30 or so, mostly in English.
This provides the video that went missing when a few accounts I had quoted earlier were suspended.

Here are the translations of the transcript of the Baric interview, reference via @TheSeeker268

Read 4 tweets
29 Dec 20
@HenkPoley Yes, am familiar with the issue.

I will see if I can locate my earlier findings on this.

So far I have only located some notes from earlier, but not the actual citation yet.

@HenkPoley This paper indicated that a single exposure to 70% ethanol largely preserved filtration efficacy, comparable to dry heat or UV sanitizing. However, further exposure events gradually worsened filtration efficacy.

medrxiv.org/content/10.110…
Read 6 tweets
29 Dec 20
To date, anecdotal reports from dual entry inhibition in mild acute COVID-19 remain excellent.

Recovery within 48 hours appears typical, absent significant complications (e.g. secondary infection).

Dual entry inhibition means blocking both:
- TMPRSS2/13/11
- endosomal entry
Dual entry inhibition was tested in the Ansarin et al. RCT, adding bromhexine 8mg t.i.d. to a baseline of HCQ 200mg q.d.

Mortality in hospitalized moderate COVID-19 patients fell to zero.

This remains one of the best results of any COVID-19 RCT to date.

Theoretical justification arises from the fact that endosomal entry is of only secondary importance for SARS-CoV-2 replication in the respiratory tract.

Both TMPRSS (proteases at the cell membrane) and cathepsins (proteases in endosomes) must be blocked.

Read 15 tweets
25 Dec 20
Continuing to hear extremely favorable case reports informally for cyproheptadine even in severe COVID-19.

Publications forthcoming, but worth highlighting now given magnitude of improvement-- extubation within days, reversal of renal failure, stark decline in D-dimer, etc.
Try it for 48 hours and see. It's just an old allergy medication. Side effects are minor and it is already known to be effective in serotonin syndrome.

It blocks 5-HT2A (platelet activation) and 5-HT2B (cardiac remodeling, pulmonary fibrosis).

The potential benefit-to-risk ratio is immense.

Cyproheptadine is one of only a handful of drugs for which I have seen decent evidence for large mortality reductions in severe/critical COVID-19.

In combination with standard of care, it appears to be halting and reversing MODS.
Read 10 tweets
3 Dec 20
More evidence that endothelial cells are not directly vulnerable to infection by SARS-CoV-2.

Endothelial dysfunction in COVID-19 is entirely indirect. Image
Discussion thread on pericytes, nearby susceptible cells strongly suspected to mediate some of the damage.

Discussion on infection of pulmonary megakaryocytes, i.e. platelet-forming cells, also strongly suspected of involvement.

Read 6 tweets
3 Dec 20
People want ironclad proof for everything. It doesn't exist. It never will. Even the best trials only apply to a certain stage of the disease in a certain set of the population at a certain dose with a certain baseline standard of care.
One must weigh evidence and combine signals in a safe way. That is all.
"First, the only certainty is that there is no certainty. Second, every decision, as a consequence, is a matter of weighing probabilities. Third, despite uncertainty we must decide and we must act."
Read 4 tweets
1 Dec 20
More evidence inflammasome activation predicts severe COVID-19, and acts as a major driver of disease progression.

They release IL-1β, which summons neutrophils and promotes (highly pro-thrombotic) NETosis, plus IL-18, which prompts IFNγ secretion (very inflammatory, apoptotic).
In layman's terms:

Certain virally infected or antigen-swamped white blood cells smash their emergency self-destruct button, explode, and release huge amounts of signaling molecules that summon exploding neutrophils and tell other classes of WBCs to order nearby cells to die.
This strongly contributes to the severe lung clotting and often serious broader lung tissue damage that define the state we call "severe COVID-19."
Read 4 tweets
1 Dec 20
@Deadly_Statins it's pretty nasty. the systemic inflammatory response is intense and can hit hard and fast. not a cold or flu at all. not like anything I've ever caught before. glad I was able to abort it.
@Deadly_Statins trying very hard not to catch it again. basically just hiding out in my residence as much as possible.
@Deadly_Statins the percentage of people with active infections out in public right now is obscene; it would be apocalyptic if IFR were higher.

unfortunately because there are so many of them, hospitals are turning people away and IFR *is* getting higher, slowly, inexorably.
Read 4 tweets
28 Nov 20
So far, N=5 cytokine panels from post-acute COVID-19 patients with persistent inflammatory sequelae all show the same basic pattern:

- TNFα ⬇️
- IL-4 ⏫
- IL-13 ⬇️
- IL-2 ⬆️
- GM-CSF ⏬✨
- CCL3 ⏫
- IL-6 ⏫
- IL-10 ⏫
- IFN-γ ⏫✨
- CCL4 ⬇️
Sorting a bit differently:

- TNFα ⬇️
- IFN-γ ⏫✨
- IL-2 ⬆️
- IL-4 ⏫
- IL-6 ⏫
- IL-10 ⏫
- IL-13 ⬇️
- CCL3 ⏫
- CCL4 ⬇️
- GM-CSF ⏬✨

One discussion on the subject:


Last image that didn't fit above:
Read 4 tweets
22 Nov 20
@drakchaurasia @poiThePoi @GephenS @youyanggu @mattparlmer A combination of quercetin, bromelain, and vitamin C succeeded in an antiviral prophylactic RCT. This surprised me.

Ivermectin works in antiviral prophylaxis RCTs, likely by enhancing T cell response.

Aspirin is effective for thromboprophylaxis in general. Dipyridamole too.
@drakchaurasia @poiThePoi @GephenS @youyanggu @mattparlmer Arbidol (umifenovir) 200mg t.i.d. succeeded in a Chinese antiviral prophylactic study.

Interferon alpha nasal and pharyngeal spray succeeded in another Chinese prophylactic study.

Hydroxychloroquine shows limited impact for post-exposure prophylaxis, partial for pre-exposure.
@drakchaurasia @poiThePoi @GephenS @youyanggu @mattparlmer Combining ambroxol/bromhexine with hydroxychloroquine is extremely likely to be effective in pre- or post-exposure prophylaxis.

Note long-term ambroxol/bromhexine use is known to be safe in e.g. COPD.

Unfortunately they must be used 2-3 times per day, much like Arbidol or IFN.
Read 9 tweets
22 Nov 20
One of various ways in which COVID-19 is indeed not 'just the flu.'
... and here, if so inclined, one can see physically what that actually looks like--

Some other autopsy studies, organizing these links to keep the imagery limited to those indeed so inclined.

Read 4 tweets
22 Nov 20
Summary note on staging for COVID-19.

This list is not definitive. Just heuristics.

Many authors draw the mild/moderate division around where the patient will soon need oxygen support, SpO2 nearing 90-92% on room air.

Others take a less aggressive stance.

I use the former.
The less aggressive usually draw the moderate/severe line based on need for oxygen support. However, this labels most hospital cases severe, losing granularity. Some add a 'critical' category to compensate, but this is an overloaded term.
In discussions here, I draw the moderate/severe line around onset of hypoxemia on high-flow oxygen, often onset of pulmonary microthrombosis and soon rising D-dimer, with a high risk of ARDS and DAD but not quite there yet. This matches my reading of the literature.
Read 4 tweets
22 Nov 20
@poiThePoi @GephenS @youyanggu @mattparlmer No. But keep in mind 30% is the highest reported figure. Vast majority of counties are lower. So it could make sense roughly given that.

At this point they are just letting it rip. Not enough people cared soon enough with enough coordination.
@poiThePoi @GephenS @youyanggu @mattparlmer Although tbf the average visually at least does appear to be about 20% as you assumed. I agree with that reading of the map colors.

Either something is off, or... the delayed impact from positive test to hospitalization is going to go entirely unmanaged. They are full already.
@poiThePoi @GephenS @youyanggu @mattparlmer If this model is accurate, which it may indeed be, then Iowa CFR is likely to increase materially within the next 2 weeks as staffing ratios fall and admission refusals cut deeper into the scale of severity in spite of overflow capacity.
Read 4 tweets