ptest1

Not only that, but many nonprofits must force their employees and even volunteers to use annoying time tracking software!

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.

I added “beside the point” because I believe so, yeah.

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.

I guess what I think could be possible is:

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?

Check out this paper:

https://twitter.com/__philipn__/status/1229568317167243264?s...

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:

https://twitter.com/__philipn__/status/1229607854232850432?s...

Pic for clarity.

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:

https://twitter.com/robertlkruse/status/1230577662751641601?...

The best silver bullet bet here is ACE2-fc, which isn’t a small molecule.

This is a soluble form of the ACE2 protein along with an fc. this gives it a longer half life in the body.

This would likely:

1. Stop virus cell entry by neutralizing the virus- virus binds to ACE2-fc instead of the cell ACE2.

2. Stop potential lung damage from AT1R activation.

Both 1 and 2 have been shown in some models.

It is now being tested in vitro. Next animals.

Chinese are testing non-fc form, ACE2 directly, but requires IV drip. Testing now directly in humans! 7 day trial.

See twitter for more on this:

https://twitter.com/__philipn__

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:

https://pubmed.ncbi.nlm.nih.gov/20178811-losartan-attenuates...

There is also an inaccurate preprint on ethnic groups and ACE2 expression with a low n count which also didn’t pass peer review.

ACE2 loss is probably bad, having more ACE2 probably doesn’t drive disease severity:

https://twitter.com/__philipn__/status/1229568317167243264?s...

Relative ace2 reduction correlates w disease severity; viral load growth the same between groups - check out study! Chinese paper discusses this as well:

https://pubmed.ncbi.nlm.nih.gov/32061198-inhibitors-of-ras-m...

I wrote a long comment and it got deleted, argh!

Best guess? ACE2 loss is probably bad, having more ACE2 probably doesn’t drive disease severity:

https://twitter.com/__philipn__/status/1229568317167243264?s...

Relative ace2 reduction correlates w disease severity; viral load growth the same between groups - check out study!

Chinese paper discusses this as well:

https://pubmed.ncbi.nlm.nih.gov/32061198-inhibitors-of-ras-m...

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:

https://twitter.com/robertlkruse/status/1233986542097567744?...

He is looking for funding if any funders are reading this. Comment here and I can connect.

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:

https://twitter.com/__philipn__

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:

https://twitter.com/__philipn__

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.

(I also work in the nonprofit space)

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)

The former CEO of ICANN basically started the PE firm PIR was “sold” to:

https://www.privateinternetaccess.com/blog/2019/11/isoc-pir-...

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’m doing this! Both for PIR and ICANN.

Please see my other comment on this thread. It is likely this “sale” could be considered illegal.

Here is the information for ICANN which can be used for the above form as well:

https://www.icann.org/en/system/files/files/fy18-irs-tax-for...

Remember that the founder of this PE firm was at ICANN, so this transaction is self-dealing on ICANN’s end as well.

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:

https://boardsource.org/resources/private-benefit-private-in...

“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.

Edit: please see https://news.ycombinator.com/item?id=21658324 for a “what you can do right now”

Comment deleted because this doesn’t appear to be the right place to discuss nuanced issues about Facebook.

I think accessibility is very important, but I share your worry about the future for very small startup projects. I think it’s already almost impossible.

I worry about it getting much worse, especially with the animosity the larger tech companies face from the public. What people don’t understand is that those big companies will weather any of these regulations, and that they will stop smaller startups from ever happening.

Yes, please!!

Yeah so you could do a rebase and remove all of the user’s commits, but their work would likely still remain in the subsequent history- integrated as changes in some way. It would be a real mess.

Again, the GitHub example is a good one. I have some commits in Django core from years ago. What if I “request” my data be deleted from GitHub? What are they supposed to do? If they rewrite the history it will destroy the project; and if anyone can rewrite the history in the future it leaves projects open to hostile actions.

I suppose the argument would have to be made that it’s not personal data; it’s an act of public publishing or something. So in this case it’s akin to me publishing a blog and other people quoting it years later. I can delete the original blog but not the reprints in newspapers or quotes.

Or that it stops becoming “your” data and becomes instead “the other user’s” once eg the Django project accepts the PR. So you can delete user A’s PR but not the Django project’s now-integrated copy. I think this rationale makes the most sense. After all, someone could still have the repository on their computer and push it back to GitHub again.

I realize this is an edge case that doesn’t apply to 99.9999% of companies, but as an engineer I find it interesting!

Edit: after thinking this through more, I suspect that e.g. GitHub could argue they comply as long as they delete User A’s repo. Subsequently integrated PRs, etc wouldn’t have to be deleted because they could argue they’re no longer User A’s.

I kinda feel like if language to allow this was added to the law explicitly it would be open to abuse, so I suppose this kind of thing has to remain vague and open to interpretation in e.g. the courts if someone is being nasty.

What I’m saying is that there is more work for startups / side projects to do, not that it’s impossible. It raises the barrier.

Besides the tremendous onus laws like this may place on small startups and side projects:

Does anyone know how companies are supposed to comply if “user data” literally cannot be deleted? I’m thinking in the case of blockchain type applications, where one users’ actions feed into another users’ actions, and you can’t deleted user A’s actions without deleting potentially tons of other stuff and destroying the application.

Like does this law basically ban GitHub and code collaboration too?

I believe these vaping cases are from using elicit, underground THC vaping products and not the usual e-cigarette / nicotine vaping we usually associate with the word “vaping.”

There’s some details over on Reddit:

https://www.reddit.com/r/electronic_cigarette/comments/cxov1...