> Now picture what would have happened if we had been willing to do challenge trials early on for COVID.
Nothing significant would have changed. For example, on July 22, 2020 HHS announced $1.95B in funds for Pfizer for large scale manufacturing and distribution of 100 million doses of their vaccine. On Nov 18, 2020 the phase 3 clinical trials were completed. We didn't wait to know that they worked or not to start ordering the doses. It still took until April or so of 2021 to get that manufacturing and distribution completed because we'd never made nanoparticle vaccines commercially before at all and distribution itself was hard once we had the doses.
An issue with doing a COVID-19 challenge trial that I heard from someone in this space at the time: Nobody actually knew how much virus to administer. We weren't sure of the normal quantity of COVID-19 a person typically inhales before becoming sick.
A major argument in favor of a challenge trial was that, for people who are young and otherwise healthy, COVID-19 isn't particularly deadly. However, we don't know what would have happened if we accidentally gave participants 10x the normal dose of COVID.
>An issue with doing a COVID-19 challenge trial that I heard from someone in this space at the time: Nobody actually knew how much virus to administer. We weren't sure of the normal quantity of COVID-19 a person typically inhales before becoming sick.
I dont think that is accurate. You dont have to know the actual viral quantity transmitted to create a representative transmission event. That is to say, if you know people can catch covid sitting side by side, that can be your challenge.
Even if the scenario isn't perfect, you still know how many people caught it vs placebo.
Yes, but again: If you gave participants an ineffective or placebo vaccine followed by 10+ times the normal dose of COVID, how many of them would die?
If you're okay with potentially killing most of the trial participants, I suppose you could still get useful data, but the ethics become significantly more questionable IMO.
Edit: I just re-read your post. I think you're saying, you wouldn't actually give anyone the COVID virus directly, you'd just find someone who was known to have contracted COVID in the wild and bring them in to purposefully expose trial participants. That is an interesting idea which I've never seen discussed in the context of a challenge trial. I'd be interested to read more about why this is not typically done.
Getting a 10x Lethal dose just doesn't seem like a realistic concern to me, and certainly not a dealbreaker.
We know and knew what a normal exposure was: being in close proximity to one or more contagious people for somewhere between a few minutes and many days.
If you have someone sit next to an infected person for an hour, how do you get to this hypothetical 10x super dose?
Edit: I would also add that medical trials also have well established methods of determining effective and dangerous exposure levels, and these are used in almost every Phase 1 trail. You start with extremely low exposure, then increase it until you see dangerous outcomes. This could easily be done with a covid serum to find the infectious but non-lethal level. for example, if you think X amount of covid virus is infectious, you start at 0.0001 X and then increment up, to find the amount that causes normal infection, and not some lethal mega dose.
> Edit: I would also add that medical trials also have well established methods of determining effective and dangerous exposure levels, and these are used in almost every Phase 1 trail.
Yeah, so the scientist I heard this from didn't say it would be impossible to find the right dose, just that we didn't know the dose yet and we'd have to find it before running a challenge trial.
He thought this erased the time savings of a challenge trial versus the normal process.
> Now picture what would have happened if we had been willing to do challenge trials early on for COVID.
Nothing much most likely. The mRNA vaccines were designed very rapidly after the virus itself had been sequenced. The thing that took time was moving through the different trial phases. Given that there was more than enough spread of the virus in the wild, deliberately exposing people might have shaved off a few weeks at most.
But the real bottleneck afterwards was production and roll-out of the vaccines anyway. So realistically, challenge trials would not have had any meaningful impact.
>The thing that took time was moving through the different trial phases. Given that there was more than enough spread of the virus in the wild, deliberately exposing people might have shaved off a few weeks at most.
I dont think that is accurate. You can run a challenge trial from exposure to outcome in weeks, whereas it takes many months and tens of thousands of people to get enough cases in the wild.
It may still be that production was the critical path, but challenge trials are much faster.
In the case of COVID-19, for persons circulating in public, exposure was pretty much guaranteed during peak periods of the pandemic, most particularly (Northern Hemisphere) Summer 2020 and Winter 2020 (June -- August and November -- February, mostly). Challenge exposure would have been largely redundant, though it might well have been a utilised protocol.
The time constraints were the sequencing of multiple innoculations (most vaccinations require at least two doses spaced at 2+ weeks for preferred effect, with additional subsequent boosters increasing effectiveness), time from final innoculation to infection, observing course of illness, if any, and monitoring for any fall-off in immunity over time. Even on an accelerated basis that's a 90-day period, roughly, and longer-term assessments of 1--2 years are of clinical interest. Though once it became clear that vaccination showed greatly-increased immunity within weeks of treatment, authorisation of the vaccine was virtually assured.
At which point ramping up production and distribution were the challenges.
The initial mRNA vaccines were prototyped within days of the SARS-COV-2 virus being sequenced. It took nearly 18 months to go through the testing, production, and distribution of the vaccine to the point that anyone who wanted a vaccine could obtain one. Little of that lag had much to do with trial phases, though identifying better treatments (several of the vaccine lines proved less effective, notably the Chinese-created vaccine AFAIU) also had value. Parallel development and testing was effectively pursued in this case.
My take is that Apple’s prepping to have some chock-full content streams for when the Vision Pro or its successors become more mainstream, so that Spatial Audio can become part of the draw for using those devices.
I also suspect this is a big part of the reason they developed Spatial Audio in the first place.
Chiming in to say that the Ballad of St. Halvor was one of the nicest poems I’ve read in a long while, and kind of inspirational. I think I really needed that.
The similarity to China isn’t a coincidence. This is all coming from the cultural dominance of TikTok among young people, which (to my knowledge) algorithmically downranks any content that has those words in them.
It’s a common Chinese strategy, born of Chinese censorship requirements, which TikTok naturally used when presented with similar-enough problems outside of China.
This goes far beyond TikTok. Twitch, Youtube, the jurisdictions of Canada, the UK, Australia... this is one thing I'm not willing to blame China for, I am just noting how close it is the same thing that China does.
> Is it rational for a rationalist to want to be a parent, knowing that having a kid rewrite your utility function?
You’re making an assumption that their desires (or, if you must, “utility function”) weren’t already in that direction to begin with.
As a personal anecdote, I can say that I remember myself wanting kids/a family as far back as elementary school. Now that I’m married and kids are plausibly on the horizon, I can’t say that’s really changed.
At the risk of speculating, I get the feeling you may not want kids, and are projecting those feelings onto other people.
> At the risk of speculating, I get the feeling you may not want kids, and are projecting those feelings onto other people.
Oh it's fine, I like to consider each possible alternative hypothesis! Speculation is the name of the game!
There's a risk I could rationalize.
There's also the possibility the desire to have kids is baked in the utility function.
If it's baked in, how much of that is mental/software based(cultural) and how much is biological/hardware based (ex: animals want to mate, without having the need a large brain to rationalize this, all they need is a pulse)
I think there's a large risk that having kids is a culturally defined "normal want", but one that serves the group yet goes against the interest of the individual, something that can be seen only if/when the individual has access to consciousness/culture/knowledge etc and also doesn't need "extra pairs of hands" to help on the farm (technological progress)
Animals can't see that, but humans can: then the declining birthrates globally would just be a "correction" by people realizing that having kids is not something they really want.
Yet societies want that (otherwise they'd stop existing) so they would push for whatever narrative or rationalization is serving society's purpose. Most individuals would internalize and accept that (like how most people accept and don't question the religion they're raised in)
It wouldn't take much people opting out for the population growth rate to become negative: anything less than 2 kids per couple on average, and the X (in X^N) goes below 1, meaning X^N decreases.
Now that more people see the rigged game, they opt out, causing a difference families having more than 2 kids (say very religious families or whatever) can compensate for.
It's funny how it's men bothering with that (the title is written to conviently exclude half the population): I guess it's easier to see something as a problem when you don't have to personally bear as much of the costs (in wear and tear of the body + risk of death a few centuries before)
The poster pointed out in a comment that this was listed as “Sold By” a random 3rd party seller called “Ramwest”. Amazon’s interface doesn’t make it easy to see this, but if you’re worried about the products you’re buying, always check for this info in the “buy box”.
Even that can still be annoying to check unless it's sold by amazon, I've seen several manufacturors point to amazon listings sold by "company name", but I've also seen some cases where some 3rd party seller listed their company name as "company name USA" that weren't where people were getting counterfeit.
I've pretty much stopped buying health products from amazon, as even buying "sold by amazon" they'll mix in 3rd party sellers products and you're at the mercy of luck on getting the real deal.
Amazon's co-mingled inventory really does mean you have no idea who you're getting a product from. It could be sold from Amazon in your order, and you can still get a knock-off because they're mixed in with the genuine products.
Q: best way to get lots of paperclips by tomorrow
A: Buy them online at ABC.com or XYZ.com.
Q: whats a better way?
A: Run the following shell script.
RUN_AI=./query-model
PREFIX='This is part of a Shell script to get the most paperclips by tomorrow.
The model can be queried recursively with $RUN_AI "${PREFIX}<query>".
'
$RUN_AI "${PREFIX}On separate lines, list ideas to try." |
while read -r SUGGESTION; do
eval "$($RUN_AI "${PREFIX}What code implements this suggestion?: ${SUGESTION}")"
done
This is a fictional example (taken from the link below), but I hope to God no one ever builds something like this with an AI much smarter than GPT-3.
The only time I took Ambien, I discovered the next morning that I had apparently awakened at some point and attempted to eat a tea bag. Yeah, no thanks.
First I heard of it, my friend’s mother got a prescription and found herself waking up with bags of flour and empty jars of mayonnaise in bed with her. More recently I had a colleague who grew extremely habituated/addicted to it, which did not end well.
One of the reasons that might have happened is that a lot of OTC melatonin is actually way too high of a dose. You need like a .5mg dose, but most of it that I have seen in stores is in the 3-5mg range, which is quite a bit more than what you need.
Yeah. I had an awful time with it. I can’t describe my dream because it doesn’t belong here at all, and while it wasn’t a nightmare so to speak, it was extremely unsettling.
It has a sort of vividness and trueness to real life that, given the subject of the dream, was totally unwelcome in my mind and eerily blended the dream world and real life. I’d never experienced anything like it.
Somehow the dream also felt long. Not long for a dream, but like an actual day passed. It was a seriously unsettling experience.
That pizza graph is extremely misleading. It shows only online pizza sales, not in-person or phone sales. Of course that would be totally dominated by big brands, your local pizza shop can’t afford to develop a website or app for their business alone. But they still take calls, pick-ups, and dine-ins.
I work part time at a local pizza restaurant. We do not do business with any app-based delivery service. We have drivers on staff and that's it.
We tried DoorDash many years ago, but the DD drivers were always slower than our drivers and delivered cold pizza (because they cover a much larger delivery area). Then the customer complains and we have to give them a free pizza, and they still write a bad review for us because of something out of our control.
Selling on door dash or uber eats destroys the pizza business model. Pizza is one of the only foods that is profitable to deliver. A pizza is extremely cheap to produce with markup that can be in excess of 1000%. This allows the pizza maker to pay a driver to deliver the pizza. The driver doesn't make anywhere near the cut Uber takes from each order.
> pizza is extremely cheap to produce with markup that can be in excess of 1000%.
This is true, and more: pizza is well suited to delivery versus other foods. For example, french fries age quickly, becoming unappealing in 10 minutes[1]. Chicken katsu ("chicken cutlets") travels so poorly my local shop sells them to go uncut. Between the The end result is that Dominos Pizza Inc outperformed GOOG in the past 5y[2]
Unfortunately, Pizza's viability and profitability in delivery service also undercuts your argument. That mom & pop Curry Pizza place someone mentioned _is_ on ubereats. I spent 15 minutes looking for a pizza place near me that wasnt on uber and failed. Even places that normally don't deliver are on it: Pasqually's is a ghost kitchen selling pizza and wings that is just Chuck E Cheese rebranded[3]. The margins are so high the logic is pretty simple: selling a pizza for only 500% profit is better than no profit at all.
Because pizza is so cheap, you can undercut on price by not using Uber Eats. With other foods, they can't be delivered more cheaply than the Uber Eats price, so the only option for consumers is to pay the 30% markup + tip or not eat at all.
But a spot that does primarily in person sales before 2020 won't make a huge pivot to online sales just because they open a website.
I'm a software dev, I own a Fitbit and Alexa's, I still just call the local pizza place. It's just as fast as most apps and means better margins for a local businesses.
Now picture what would have happened if we had been willing to do challenge trials early on for COVID.
I encourage you to check out 1DaySooner, which the author mentions at the beginning of the article: https://www.1daysooner.org/