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.
A second anecdote. I live in NYC. I've been going on walks, hanging out in the park, going out to eat, stayed in a couple of cabins over the weekend, taken ride shares, dined inside, and traveled on airplanes twice. I don't have the antibodies and I've never tested positive.
My wife goes to work in an office every single day. Doesn't have antibodies, never tested positive.
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.
Would you have bought these items otherwise?
If the answer is no, then you were "sucked in".
Google AdWords was great, you search for product X you definitely wanted to buy X, that's reasonable personalization.
Now they want to know who you are, so they can
optimize manipulatating you to want X even if you didn't before you saw their ad.
There's a big difference between the two type of advertising, although they're both personalized. One is aligning stake holders interest, the other forms an adversarial dynamics.
Of course, in reality, these are the two ends of a spectrum, I dichotomized it to make my point clearer.
I question the words "sucked in." Influenced is more appropriate.
Before VisiCalc was invented by Frankston and Bricklin, nobody wanted it. Many people had the problem it solved, but nobody knew it existed, so they didn't go looking to buy it.
Advertising and public relations (see PG's essay "the Submarine") influenced people to buy it. A lot of those folks were people whose businesses improved after buying it, which is why "spreadsheets" went on to become one of the most important product categories of its age.
I think the difference between "influenced" and "manipulated" has to do with informed consent. An ad, clearly marked as such, influences. Advertorials masquerading as independent opinion, paying influencers to use a product to generate faux social proof, manipulating social media algorithms to make it appear as if a preponderance of people you know share a particular viewpoint...
That's all manipulation because the recipient is either completely unaware of what is going on, or dark patterns are used to make it difficult for them to discover what is going on.
But using keywords to target people and then giving them an ad that is clearly labeled as an ad? I think that's just influence.
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.
It does annoy me that this isn't mentioned more often. Apple aren't taking this away, they're enabling the user to opt-out.
That these are almost constantly being stated as the same thing, only shows that the vast majority of users do not want to be tracked, and the vast majority of adtech has no respect for the user's wishes. If neither of these were true, having the option would not be an issue.
From my experience, I don't enjoy relentless targeted pressure to give up my money for goods I don't really need. I don't like wasting precious time consuming adverts, each braying for my attention in one way or another. I don't think it's ethical treatment of impulsive types and folks who are less aware of what's really happening them. Interestingly, I have felt less pressure to buy anything since installing advert blockers and ignoring TV. I remember feeling strong sensations that I needed to buy a new phone, that I needed to upgrade my PC. Now I've had the same phone for four years and a PC for even longer. Those pressures and sensations are gone and my wallet thanks me.
A strong case could be made that little would be lost to the world if we banned advertising outright. Also consider, it would be better if we could be recommended goods and services by those who don't have a financial incentive from the providers of goods and services.
Even worse, advertising incentivizes business models whose primary goal is to create addictive behavior, because the side effect is that you see more ads. So, for example, social media companies will do anything they can to increase “engagement”, even if it means spreading conspiracy theories and inflaming politics. Advertising is the root of this problem, because it is the funding mechanism.
I agree - I (and at least one friend) feel the same way. There’s some great stuff being made for nerds like us and IG/FB ads have been a fun way to discover.
That being said - why doesn’t someone just cut out all the BS and just design a system that lets me give you my preferences - “show my interesting new products and services related to tech, cooking, coffee, and bicycling” - and then just show me the ads! I’d actually browse that if the ads were as good as IG/FB.
Would save everyone a ton of effort and hand-wringing.
Sure, but the ideal framing here is that Apple is not going to assume that on your behalf. It is very welcome to have someone in the space who is willing to say that my phone isn't necessarily a platform built for advertisers.
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.
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.
you should stop taking losartan if directed to do so by your doctor.
this thread is descended from a conversation about recent discoveries and lead considerations that are not yet perfected and very probably not completely understood.
I get the idea that its tempting to try and find a physiological sweet spot where you can evade the virus,
but virus has a number of tools that work in concert to manipulate the host physiology into a working environment and exploit molecular machinery.
this ACE2 related pathology is likely multiprong so disruption of one aspect will not be sure to reduce harm.
on the flipside blood pressure modulators can be a problem with incorrect dosage. Your doctor has a better scoop on your health status then i could have in any short time so thats where you should ask about changing dosage, and getting some idea of just how much risk you might have if your exposed to the virus.
Although I suspect someone who's already taking Losartan and has a blood pressure increase due to covid19, a small increase in Losartan dosage is likely a low-risk effort that looks like it might be beneficial.
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:
there would be an upper concentration of ACE2 receptor per unit of cell membrane that would elicit increased probability of receptor and viral peplomer interaction. once that concentration is reached, further increase of the docking probability would not occur.
there is a dynamic here as the virus, in sufficient titre encounters the receptor, binds enters the cell and typically disrupts normal translatory events in the cytoplasm.
the effect is to exclude further infection of the cell with increased copy number of virions, thus replication occurs instead of immediate cell apoptosis
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.
the physiological cascade that occurs due to disruption of a homeostatic feedback system is the most probable cause of direct lethality. The setpoint and the relative concentrations of the elements in these systems are genetically dictated functions.
There is probably some correlate between predisposition to morbidity/mortality and how far ones setpoints deviate from population setpoints.
there are 2 prongs to this attack, one is the disruption of angiotensin based signalling and effectation
the other is the viral entry to the cell. the virus must do a dance on the head of a pin in a sense to replicate but not hijack somuch of the cells basic metabolism that apoptosis occurs. a virus that allows its host cell to remain viable wins the lottery for natural selection.
the problem is that the virus occupies the expression machinery that creates ACE2, in an indiscriminant fashion many other protiens as well.
so this means the virus has caused damage by entry
the entry damage causes errent feedback which causes further physiological perturberance
a secondary round of disruption occurs when ACE2 expression is inhibited thus interfereing with replenishment of ACE2 that has been damaged as well as disrupting the regular recycling of ACE2 and for that matter disrupts expression of the ATI and ATII receptors
---I am not a founder or funder but simply a concerned professional
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:
