I was floored to discover Reddit is violating Google’s Auth TOS! Check this out:
1. Log in using your Google account.
2. Log out of reddit.
3. Clear your Reddit cookies.
4. Visit Reddit again.
You’ll be automatically logged in..!! This is nuts, shady, and a violation of the Google TOS. You can’t keep users’ auth tokens, secretly, and then log them back in when you feel like it. A user clicking “log out” means you expire the auth token.
In large dense American cities there are risks with even going outside on a walk. There are stories of people who didn’t leave their homes except on walks but caught COVID-19. There was a NYT columnist who got it and hadn’t done anything except go on walks in NYC. That seems statistically odd to me, because there can’t be that many NYT columnists.
Consider that to go outside, many in a large city must leave their flat, walk down a shared hallway, walk past other people’s front doors, use an elevator, etc.
There’s also a lot of people on the sidewalk, many without masks, who will walk right past you, often talking loudly on a cell phone. It’s often not possible to avoid walking close to these people due to small sidewalks and busy city streets.
Obviously the risk is lower than other activities but it’s not the same as going outside in the suburbs or driving somewhere. In my city, on a 40 minute walk I pass several hundred people. In my building here, none of the other residents wear masks and to enter and exit I must walk past their front doors.
So I would say it’s quite safe. But it’s not quite as safe in big, dense American city as in the suburbs.
None of the items were life or death essentials. These were things like protein cookies, pet-themed gifts, exercise equipment, etc. I wouldn’t have bought them if I never saw the ads.
But wanting and needing are different things. I wouldn’t consider it manipulation to show me something I might be interested in that I wouldn’t have known about otherwise. For instance, I just discovered (via ads) the galaxy night light trend and I’m now thinking it might be fun to get one.
I might be one of the few, but I like the ads I see on Instagram and have purchased lots of things via IG ads. I can’t think of any other app/site where the ads have sucked me in.
I realize this is besides the point, but I thought it was worth sharing in terms of how they might be doing personalization. For me, it’s so good that it actually works.
The problem I see with this trial is that it’s open-label, small n, and has subjective endpoints (ICU admission as the primary outcome). The study is underpowered to detect mortality. Given the open-label nature of the trial, the subjective outcome with the small n makes this result less strong.
Why is this the case? Well, for this trial the physicians treating patients knew who got the Vitamin D and who didn’t, and thus they may have been more likely to admit those who didn’t to the ICU (subjective). Something like mortality is not as subjective, but there are too few study participants to detect a mortality signal in this trial.
If I had been conducting this small open label trial I would have picked some less subjective outcomes, like maybe P/F Ratio.
ARBs upregulate ACE2 but within normal physiological limit (see other comment). My understanding is it is the Ang II activation of AT2R that drives the increase in ACE2 expression. In this case, we would expect children and women (estrogen upregulates AT2R, downregulates AT1R) to have higher ACE2 in the presence of increased Ang II. I think children may have more AT2R. https://twitter.com/__philipn__/status/1233569567512772609?s... but this may be beside the point.
Other coronaviruses that use more common receptors are not as lethal. Even if the virus has a higher probability of cell entry, does that make it more lethal?
Proportion of reduction of ACE2 correlates with disease severity.
Check out figure 1
“Differences in clinical outcomes did not correlate with differences in viral replication efficiencies.”
Compare C and D. Viral replication basically the same between young and old mice. But old had severe disease.
So I’m not sure it’s as simple as increased replication (a proxy for cell entry?) that drives severity.
Edit: just re read your final sentence. Great point. But in the case of ARB usage, while ACE2 may be upregulated and the cell may have another ACE2 cleaved by the virus, if AT1R blockade was occurring then maybe the lung damage would not happen.
Is the cell itself worse off with more than one copy of the virus inside of it? Or would the damage be the increased loss of ACE2?
If damage from increased loss, then I can see the ARB approach helping.
If more than one copy of virus in cell is really bad, then sounds like this could be more complicated. But I do wonder about other viruses which have lots of receptors available, and why this one is so serious in some, but not most, people.
Just a little clarification. These renin-angiotensin terms are totally confusing (due to how similar they all are!) and from my correspondence with physicians, many of them even get them mixed up!
Virus binds to and downregulates ACE2. ACE2 converts Ang II to Ang 1-7. Ang II binds to AT1R and AT2R receptors:
When there’s less ACE2, and in general due to immune response, there will be more Ang II to bind to AT1R. This AT1R binding may create the lung injury seen with the virus.
The idea is that by blocking AT1R with an ARB type drug you don’t stop the virus from entering a cell, but you instead stop the body’s pathological response to the virus. After all, most viruses don’t kill us, and our immune system - if it doesn’t over react - will usually kill a thing if it has enough time and the virus isn’t “special” like HIV or herpes (that’s my general, non expert understanding!)
While it seems smart to try and inhibit ACE2 directly, there are a couple problems with this I see:
1. It may be pathological. More Ang II to bind to AT1R, you might end up way worse off. ACE2 is the “good” ACE, and all the evidence we have seems to suggest that a reduction in the ACE2:ACE ratio will make tissue fibrosis, death, etc worse. This happens in the heart and lungs in mouse models.
2. Small molecule ACE2 inhibitors bind to the C shaped area of the ACE2 enzyme, while the virus attaches to the back. So they likely may not inhibit cell entry:
If you’re a funder, VC and you’re reading this: The scientist at John Hopkins who’s developing ACE2-fc is looking for funding. He’s working with Chinese biotech firms now to do the testing. Please comment here and I will connect you.
As far as I can tell, there are no studies showing a higher ACE2 causes more severe disease. Sure, it could, but the pathophysiological models and animal data suggest that it is the loss of ACE2 that may drive disease severity.
There is a contradictory preprint (that hasn’t passed peer review) on ACE2 mRNA expression in smokers’ lungs being higher than non-smokers; but there is data saying the opposite happens in animal models of mice exposed to smoke:
Relative ace2 reduction correlates w disease severity; viral load growth the same between groups - check out study!
Chinese paper discusses this as well:
They reason that 1) ARB doesn’t increase ACE2 past normal human baseline anyway, just to normal status 2) Younger have higher ACE2, older women more than older men; both groups more protected so disease severity unlikely from higher ACE2.
ACE2-fc being developed- will both stop AT1R activation and neutralize virus:
They won’t block ACE2 but as indicated in the article they may prevent the lung damage associated with SARS by blocking AT1R which is the receptor that may mediate lung damage.
There’s lots of discussion and papers collected here:
This wasn’t in a petri dish actually, this was an in vivo study using mice. Other in vivo studies show similar.
There are actually no known trials with ARBs and SARS-CoV-2, which is really weird. There should be. One reason why is because most of the non-crazy (eg Chinese medicine) drugs being trailed were selected by semi-brute force from in vitro type testing. ARBs wouldn’t work in vitro AFAICT, which is a reason they haven’t been tested; the drug won’t stop the virus from entering cells the same way other drugs might, but instead may stop some or all of the major damage the virus does to the body.
There’s lots of discussion and papers collected here on this subject:
Excessive unrelated business income causes a loss of public charity status due to failing the public support test. In this case it’s moot because ISOC is giving up on their status regardless. I was wrong saying 501(c)3 status is lost- instead, the organization becomes a private foundation with accompanying restrictions and regulations (e.g. disbursement requirements).
In the case of ICANN, I can see the IRS dropping 501(c)3 status. While the final purchase price of the .org asset may or may not have been at fair market value (as you note, having GS involved gives credibility), it’s undeniable that ICANN made it possible by lifting price hikes. I don’t see how it isn’t self-dealing, unless ICANN truly had absolutely no idea their former CEO was going to acquire .org. I think it’s more likely that they were convinced to lift the price hikes by their former CEO.
In this case, ISOC should almost certainly lose their 501(c)3 status, as the transaction is unrelated business income, and may or may not have been sold at fair market value (I don’t believe it was). In either of these cases, the penalty is at minimum the removal of their 501(c)3 status.
I believe they may be preempting this by converting themselves to a “B Corp.”
The case of ICANN is more interesting. I believe they knew what was going on here, and facilitated this transaction to their former CEO. In this case, the IRS has good reason to revoke ICANN’s 501(c)3 status, as this transaction was self-dealing.
The mass complaints work very well when backed by an organized effort to lobby, press attention, etc. There are people vulnerable to political and social pressure who make decisions based on this stuff, e.g. the CA attorney general (in the case of ICANN)
ICANN, by lifting the price restriction, was likely “in” on this deal.
When a nonprofit does something to greatly enrich a former CEO, that’s likely self dealing and illegal in the IRS’ eyes. The CA attorney general should also take action (ICANN is CA based).
I don’t understand how this “sale” is legal in the first place.
PIR is a legal 501(c)3 nonprofit. You can’t really sell a nonprofit to a for-profit company except in unusual and rare circumstances.
In California, I know you need a letter from the state Attorney General to do so.
There are also federal restrictions on sales like this, particularly around self-dealing transactions. This transaction was obviously self dealing.
Someone seriously needs to dig into this. The PIR board members could be in big legal trouble. And also ICANN, which is a 501(c)3 nonprofit as well and is subject to self-dealing restrictions.
This is obvious, plain as day corruption. In the business world, not much can be done. But these are two nonprofits (PIR and ICANN), so something can and should be done. These kind of transactions aren’t normally legal.
Like, just read the examples of what an illegal self dealing transaction is in the eyes of the IRS:
“Keep Our City Beautiful, a membership organization, plants a city alley with elaborate flowering bushes. The alley is not heavily traveled but the decorations increase the attractiveness of the city’s main restaurant whose owner is a member of the organization.”
ICANN clearly engaged in an illegal self dealing transaction by allowing their former CEO to enrich himself with a deal that would otherwise not be possible.