This espresso macchiato at the Regina Palace Hotel in Stresa was the best cup of coffee I have had outside of home since, well, since the last time I’ve been to Italy.
🍿 Weapons (2025) brought me back hope that Americans still know how to make movies. It is a simple story well told, which trusts the audience to make the appropriate inferences — important for a competent horror — and has an overarching point to make on the bias towards normalcy. Will re-watch!
There isn’t one, because we still don’t know how acetaminophen works.
Aspirin has been in use for thousands of years and what it does to the body was a mystery for 90% of that time. But no more: ibuprofen, diclofenac and other NSAIDs all use the same mechanism, inhibition of two enzymes that promote inflammation, cause platelets to be sticky, but also destroy your stomach lining. We tried to get cute and selectively inhibit only one of those enzymes because the other caused gastritis, but that didn’t go well. That part of the aspirin family tree was cut short. There is, however, a whole separate branch that builds on aspirin’s effect on platelets. The more we know the more we don’t know, and at the edges of our knowledge lie new drugs.
The acetaminophen family tree is a stump. On one hand this isn’t a surprise: we have only known about it for 150 or so years. But then pure aspirin was synthesized around the same time — it was just willow bark extract Acetaminophen was derived from coal tar so it is, in fact, coal tar extract. Somewhat off-putting for something to be taken by mouth, though coal tar can do wonders for dandruff. before the late 19th century — and look at how much we have learned since then. The best we have come up with is that acetaminophen works sort of the same way as aspirin, but only in “the central nervous system”. Vagueness covering for ignorance, like The cure? Heavy cream and butter. generic life “stress” causing stomach ulcers.
Our knowledge gaps are so large that we still can’t agree on the name. Is it acetaminophen (APAP for tired interns who hand-wrote their notes) or paracetamol? Or just Tylenol? More vagueness.
Which is to say, there can be no mechanistic arguments for APAP risks and benefits as we know nothing about the mechanism: all inferences must be made empirically. And our 150 years' worth of popping coal tar pills have shown them to be safe for everything but the liver.
Still, it is worth acknowledging that APAP is a molecule extracted from coal tar whose mechanism of action is unknown but has something to do with the central nervous system. If someone described such a drug and then asked whether it could be behind some disorders of the brain, would you find the question completely whackadoodle? I would not. And would in any case practice myself and recommend to my patients via negativa, whenever possible and sensible.
The number of ways in which one can spend money for biomedical science is infinite. America has sunk trillions into genetics research, with a few important wins to show for it but not nearly as many as hoped for in the early 2000s. For those too young to remember, this is the time when media were full of headlines about scientists finding the gene for x, where x was everything from hypertension to obesity to being gay. None of them panned out. Would a fraction of that being allocated to figuring out how one of the most widely-used drugs actually works be such a waste?
This espresso macchiato at the Regina Palace Hotel in Stresa was the best cup of coffee I have had outside of home since, well, since the last time I’ve been to Italy.
Last year, writer Robin Sloan published a brief essay in his newsletter, and one part in particular has stuck with me since:
“You could extinguish a star,” but you never will, because that power is occupied by the task of living.
I was reminded of it talking to a colleague a few days ago who was of a similar (which is to say, middle) age as myself. She noted that we are getting into that not-so-pleasant space in between the hammer of having young children and the anvil of parents who are starting to need some extra care themselves. But of course, I commented, our parents had the same issues and we as children were protected from feeling any effects.
Except now I am having second thoughts, as I do think we have it significantly worse than our parents.
To start with, children require more maintenance than we ever did. Toddler age onward, we act as our progeny’s administrative assistants-slash-social secretaries, scheduling playdates, RSVP’ing to birthday invitations, filling out the afterschool activity calendar. School are no longer send-them-and-forget-them affairs. Parental participation is strongly encouraged and often required. Every day brings a new newsletter from the school district, the school itself, one or more teachers, the PTO, the separately-arranged (and paid for) aftercare, each with a new set of dates to track, tasks to complete, ideas to consider. This is all good! But also exhausting.
Parents live longer, with more chronic conditions and with an ever-growing list of medications. Even those who are healthy have to contend with the modern digital services that have supplanted a 30-minute queuing session at the post office, for which they need technical support. The only apps they can use seemingly without support are those for social media, which they use to spam us with the latest pixelated meme or — if you are not as lucky — AI slop that was reshared in their group.
And then there are our own administrative tasks: separate logins for all utilities, each now requiring 2-factor authentication; mortgage and car payments to keep track of; the ever-growing number of things to repair in the household; all those incantations to chant to get the AV system working (or is that just me?)
So yes, our lives have gotten more complex and if it weren’t for them we’d be busting lots of stars.
If you liked Ted Gioia’s reminiscence of David Foster Wallace that I linked to yesterday, you will love Gioia’s follow-up post with recommendations on where to start if you would like to read DFW’s work. To this I would add a plug for The End of the Tour (2015) which is now on my to-watch pile.
Quote of the week, from Adam Mastroianni:
People say “do what you love and you’ll never work a day in your life” and they’re right, because you’ll get bored and go home. If you find the job, the cause, and the partner that annoy you in exactly the right way, you’ll never know peace again.
If this weren’t true, few people would choose medicine as a calling.
Indeed.
Stresa is a tiny town just north of Milan, one of many dotting Lake Maggiore. It was for a 3-day conference with much work to do, but some observations could still be had.
Burn it.
