I had a bad reaction to a tweet an X-post ⊕ Let this be the last time I cross out the word “tweet” in reference to posts on X. I actually quite like calling them X-posts, since ex post philosophizing is the most common mode of discourse there.yesterday saying that:

…effective drugs suffer from the silent hero problem that Taleb wrote about in The Black Swan. Many can prevent far worse downstream outcomes (hospitalization, surgeries, chronic pain, early death), but we don’t tend to reward acts of prevention like we do acts of correction. Thus, surgeons are revered and drugs are reviled.

Why would I have a problem with a statement as obvious as that? Yes, humans overvalue procedures and neglect the importance of drugs, especially those with a delayed effect, no matter how large the effect may be. Well, the ellipsis hides the first part, which was agreement to a quoted post which is one of those newfangled blog posts disguised as an X-post so apologies for the long quote:

Drug industry’s [lack of] popularity is thanks to its own success. … If you have a disease for which there is a medicine, you don’t know anything other than the bill at the pharmacy counter.

If you have a disease without a cure, all your faith is put into the drug industry because no one else is coming to help and nothing else matters.

And if you don’t have a disease (yet), you really don’t care other than your fear of the bill you might one day get at the pharmacy counter.

The great irony here is that the pharmaceutical industry doesn’t control what you pay at the pharmacy counter: your insurance plan does.

Followed by a graph that shows plumetting public opinion of the pharmaceutical industry according to Gallup polling, from ~40% positive, 37% negative in 2014 (peak recent positivity) to 18% positive 60% negative in the most recent year, which I presume is 2023 but the image doesn’t say.

This is an example of a reverse-BS sandwich, where three interesting (and perhaps even true) observations are layered in between two nonsensical pieces of dreck.

Let’s start with the middle first. Per the second statement, if you have a disease, and there is a cure, the only thing you “know” is what you have to pay for it at the counter. I would argue that this is only half-true: as a patient, I would also know how I should take the drug (pill, self-injection, infusions at an infusion center, hospitalization, etc), how often and how easily (from a four-times-a-day horse-pill to an ocassional subcutaneous injection), how quickly it works, and what the side effects are. For any particular disease there may be several options, with more convenient and/or less toxic ones costing more; and people may be ready to pay more for the convenience and/or fewer potential side effects. The price difference may not even be that high, like in the case of four-times-daily versus once-daily antibiotics. So there is quite a bit of nuance there, but hey, it’s X: if there needs to be some simplification to make a valid point, that’s OK.

But then after reading the statement that follows I’m not sure if there is any point to be made. It’s an attempt at a dichotomy — separating diseases into those with and without… something. For there are many diseases for which there are medicines, but those medicines are not cures: the terms aren’t interchangeable. And for incurable diseases, the pharmaceutical industry is emphatically not the only place in which people put their faith: see complementary and alternative medicine, support groups, religion. There are many people of different persuasions, motivations, ambitions, and fee schedules who will happily give their support. But lest this is construed as nitpicking I will squint once again and let it pass, assuming that the preceding statement talked about cures, and not medicines in general.

The next statement is absolutely true. Healthy people in general have a hard time imagining what disease is like, and we all know what a financial nightmare American health care can be.

The first sentence is a strong statement of causation: that the pharmaceutical industry is unpopular thanks to — which I interpret as because of — making such good drugs. I’ll attempt to construct the three that follow into supporting arguments:

1. You have a disease for which there is a cure. You take the cure for granted and you don’t like the pharmaceutical industry because you have to pay for their drug.
2. You have a disease for which there is no cure. You don’t like the pharmaceutical industry because you had put all your faith in them because of their past successes (see above), and they have failed you.
3. You don’t have a disease. You don’t like the pharmaceutical industry because you are scared of what may happen to your finances if and when you do get sick.

Do get in touch if I didn’t get this right, but if I did, I’m afraid it’s bad reasoning. It does point to prices as the reason for pharmaceutical industry’s unpopularity, but neglects the price of the vast majority of medicines which are not cures, yet which people take with flimsy or no evidence because of medicalization of normal variability, use of bad surrogate endpoints, and, for terminal diseases like most metastatic cancers, lack of alternatives. The industry isn’t unpopular because it charges to much for life-saving drugs (if anything, it charges too litle), but because it puts out — pushes, even — wimpy drugs that treat nothing in particular.

Yes, if it weren’t for the “silent hero” problem people may be more appreciative of the benefits and the industry may be slightly less unpopular. But make no mistake: the industry as a whole is unpopular because it overweighed the amount of slack it would get riding the coat tails of the many truly miraculous drugs it came out with in the last 20 years, from antiretroviral therapy for HIV, to hepatitis C treatments, immune checkpoint inhibitors, SARS-CoV-2 vaccines, and, most recently, semaglutide (Ozempic).

As for the final statement, well, it’s wrong in two ways: one — the wholesale price sets a ceiling that the patient would pay. Medical insurance could not make the patient pay more for a drug than the drug actually costs. Second, many pharmaceutical companies will be all too happy to cover the entirety of your co-pay for their specialty product, since it is usually significantly less than the margin they get on the agreed-upon price for their drug.

So anyway, I hope you can now see why a simple scroll down the time line is not an easy exercise for me, or really for anyone with more than a passing knowledge of the American drug price problem. There are no purely good participants on any side (even patients, which is a bit of anathema but take a look at the average American’s overflowing medicine cabinet and compare it to that of someone from Europe), and there are very few truly evil parties anywhere (although, yes, some do come to mind). So instead of rapid-fire whataboutist replies, I write articles like this to vent. I hope you don’t mind.

A recent podcast episode and a recent blog post show how screwed up the American drug market is, and in how many different ways.

In his Healthcare Unfiltered interview focused on generic drug shortages, the FDA Commissioner Robert Califf blamed Group Purchasing Organizations for driving down the cost of generic drugs to below what’s economically feasible. The manufacturers don’t have an incentive to shore up their process, the fragile production line fails, and presto, you have a shortage. Which is fine if you are manufacturing a placebo, but in recent years the FDA’s Drug Shortages Database has been ever-growing, and as of today includes potentially currative cancer drugs like cisplatin and carboplatin, many antibiotics, and even some formulations of sugar-water. Not to be confused with placebo.

This all reminds me a bit of my childhood in Serbia back in the mid-1990s, when bread was dirt cheap and never available. But that was too much price regulation. Here, we have too efficient of a market leading to a shortage. Only, I am sure there will be hands raised wanting to tell me that — well, actually — this was a clear example of over regulation, since new factories can’t just pop up too meet the demand and make use of the temporary market inefficiency, being dependent as they are on pesky FDA regulations — like the ones about drugs being safe. If only we could price in the risk of death by sepsis, we’d be in great shape!

So, on one end we have Medicare/Medicaid paying through the nose for brand name drugs because it is forbidden by law from negotiating for a better price, and on the other private GPOs negotiating too well for generics, to the point of extinction, forcing payers to get those expensive brand name drugs. Heads, brand-name pharmaceutical industry wins, tails, payers loose.

It was encouraging to see some movement in the price negotiation area: the comically misnamed Inflation Reduction Act allows for CMS to negotiate the price of some drugs, and the list of those drugs was recently made availalbe. Ideal? Far from it — in an ideal world the federal government would not be involved in any of this; but it’s not the world we live in. This is where the blog post comes in: from Alex Tabarrok, about how we are bad at pricing drugs because of unknown externalities (true!) but also with a side-comment reframing measures the IRA takes allowing nogiation as “price controls”, linking to [a policy paper][10] which suggests yet another set of measure to mitigate the adverse effects of IRA’s proposed solutions to the drug pricing problem. ⊕ Efficient markets for me, but not for thee, as Tabarrok’s writing partner would quip. And so the measures pile up from both the pro- and anti-regulation side. Ad infinitum, I suppose.

See also: better drugs don’t cost more, and a list of a few earnest but misguided attempts at cost control.

To convince myself that I am not completely clueless in the ways of medicine, I occasionally turn to my few diagnostic successes. ⊕ To be clear: this is cherry-picking, and I make no claim for being a master diagnostician. Yes, a bunch of my colleagues had missed the first patient’s friction rub that was to me so evident; but say “friction rub” to a third-year medical student and they will know immediately the differential diagnosis and the treatment. How many friction rubs have I missed actually hearing? Plenty, I am sure! Like this one time when a 20-something year old man who languished in the hospital for days with severe but mysterious chest pain. Our first encounter was on a Saturday, when I saw him as the covering weekend resident; he was discharged Sunday, 24 hours after I started treatment for the acute pericarditis he so obviously had.

Once, during a mandatory ER rotation, I figured out that a patient who came in complaining of nausea and vomiting actually had an eye problem: bilateral acute angle closure glaucoma. I pestered the skeptical ophthalmology resident to come in on a Sunday afternoon, confirm the diagnosis, treat the glaucoma, likely save the patient’s vision, and get a case report for a conference out of it.

And I will never forget the case of the patient who was in the steaming hospital room shower whenever I saw him; he had come in for kidney failure from severe vomiting and insisted he never used drugs, illicit or otherwise. Still, it was obvious with anyone with a sense of smell that he had cannabinoid hyperemesis syndrome and would have to quit.

Superficial commonalities aside — all three were men with an acute health problem — what ties these together is that I had to use senses other than sight to figure them out: ⊕ This being the 21st century taste is no longer allowed, but I will leave to your imagination how doctors of old could tell apart the “sweet” diabetes (mellitus) from the “flavorless” one (insipidus). hearing the friction rub, feeling the rock-hard eyeballs, smelling the pungent aroma of cannabis. And all three cases came to mind when I read a tweet an X about ChatGPT’s great diagnostic acument.

I can’t embed it — and wouldn’t even if I could — but the gist of Luca Dellanna’s extended post is that he:

1. Had a “bump” on the inside of his eyelid that was misdiagnosed by three different doctors.
2. Saw the fourth doctor, who made the correct diagnosis of conjunctival lymphoma.
3. Got the same, correct diagnosis from ChatGPT on his/its first try.

A slam-dunk case for LLMs replacing doctors, right? Well, not quite: the words Luca used to describe the lesion, “a salmon-pink mass on the conjunctiva”, will give you the correct response even when using a plain old search engine. And he only got those words from the fourth doctor, who was able to convert what they saw into something they could search for, whether in their own mind palace or online.

Our mind’s ability to have seamless two-way interactions with the environment is taken for granted so much that it has become our water. This is the link to the complete audio and full text of David Foster Wallace’s commencement speech that became the “This is Water” essay, and if you haven’t read it yet, please do so now. But it is an incredibly high hurdle to jump over, and one that is in no danger of being passed just yet. It is the biggest reason I am skeptical of any high proclamations that “AI” will replace doctors, and why I question the critical reasoning skills and/or medical knowledge of the people who make them.

In fact, the last two years of American medical education could be seen as simply a way of honing this skill: to convert the physical exam findings into a recognizable pattern. A course in shark tooth-finding, if you will. This is, alarmingly, also the part of medical education that is most in danger of being replaced by courses on fine arts, behavioral psychology, business administration, medical billing, paper-pushing, box-checking, etc. But I digress.

Which is not to say that LLMs could not be a wonderful tool in the physician’s arsenal, a spellcheck for the mind. But you know what? Between UpToDate, PubMed, and just plain online search doctors already have plenty of tools. What they don’t have is time to use them, overburdened as they are with administrative BS. And that is a problem where LLMs can and will do more harm than good.

Continuing the daily cadence of one photo followed by a complaint about America’s most hated board of medicine, ABIM has once again shown its complete deafness of tone. While almost 10% of its customers — for we are not members of this private club — rebelling against its practices, it still sent out an automated extortion reminder threatening to remove certification if you don’t pay up. Well, I don’t think I shall.

The campaign to end mandatory maintenance of certification is, as of yesterday, at 20,000 signatures. This is just shy of 10% of the people affected; what are the other 90+ percent thinking? Still, it was enough to make the professional societies pay attention.

Derek Lowe writes about a recent Cancer Cell paper pitting glioblastoma cells against each other in a mouse model:

A single clonal line that hit on high Myc expression could outcompete fifteen thousand others from a standing start!

As someone who’s treated patients with Burkitt lymphoma, the Myc-dependent cancer, I can absolutely believe this.

Aaron Goodman’s petition to eliminate Maintenance of Certification requirements for ABIM-certified physicians is on track to reach 20,000 signatures, which would be just terrific. But it was at 16,000 2 weeks ago, and the pace has certainly slowed down. Do the other 200,000+ certificate holders think mandatory MOC is a good idea, on top of the state-mandated Continuing Medical Education?

Jason Snell notes that the iMac’s strongest legacy was Apple itself:

The company was close to bankruptcy when Jobs returned, and the iMac gave the company a cash infusion that allowed it to complete work on Mac OS X, rebuild the rest of the Mac product line in the iMac’s image, open Apple Stores, make the iPod, and set the tone for the next twenty five years.

I’m currently reading The Dao of Capital, which is all about the Austrian school of economics and the roundaboutness of true entrepreneurs, and this made what Apple is doing even more salient. Can you name a more roundabout tech company than Apple? ⊕ To be clear, I suspect little of this was premeditated in the long term — i.e. no, Jobs and Ive probably did not have a Vision Pro in mind as the ultimate goal when they thought of the iMac — but the ethos of seeing everything as a potential intermediary and not commoditizing it fully à la Samsung is very much the Apple way. Using the iMac as the intermediate step towards the iPod, which was itself an intermediate step towards the iPhone, which was supposedly to be an intermediate step towards the iPad but turned into something much greater, though it also did end up being an intermediate step towards Apple silicone, all the while peppering these intermediary products with technology — LiDAR, ultra-wide lenses, spatial audio — that would become the key building blogs of Vision Pro, which is itself an intermediary towards who knows what. Very Austrian.

Thinking more closely to home, I can think of a few biotech companies that may be doing something like this — maybe, if you squint — but none come close. The addiction to immediate profits that the distorted American health care market provides is much too great.(↬Daring Fireball)

Jake Seliger is a writer with an aggressive, incurable cancer, a wife — Bess — who is an ER doctor, and a blog:

We spend so much time buying, storing, corralling, searching, sorting, and thinking about stuff, and then we perish and what happens?

I mean that in a literal way: I die from that squamous cell carcinoma in my neck and lungs, and then what? What happens to Bess?

Have a tissue ready.

There was something particularly irksome about a USA Today article from a few days ago — it prompted 3, count them, three tweets posts Xs from me — and I wanted to figure out what bothered me so. Here is the headline:

Left or right arm: Choosing where to get vaccinated matters, study suggests. Here’s why

No, it’s not the typography, although they should either not have had a full sentence in their headline, or else should have finished it with a full stop. But then they would have lost the chance for the click-baity Here’s why as a prelude to an article ⊕ OK, this can get real confusing real fast since there are two articles I am writing about: the USA Today’s newspaper article, and the research article to which it refers. So, let’s use article for the newspaper, and manuscript for the research article. Because why not? about Real Science™ which — color me astonished — takes a hypothesis-generating study and presents the hypotheses it generated as the final results.

To its credit, the article starts of with a link to the manuscript and the name of the journal where it was published, which is eBioMedicine, part of the proliferating Lancet family, impact factor 11.1. ⊕ Although, you know what they say about impact factors.Good! They also invited an independent researcher to comment. And I am sure that his comments were similar to mine, although of course most of what he said (or more likely wrote in an email) didn’t make it. What ended up on the page were two blurbs about precise vaccination from the director of a Precision Vaccines program. Gasp.

But these are all side attractions. The biggest problem is this: scientists want to compare people who had a two-dose vaccine shot in the same arm to those who had it in different arms; in the manuscript, these were called ipsilateral and contralateral groups. They aren’t randomizing people to one versus the other, ⊕ What they describe as randomization isn’t really so, but that’s a rabbit hole we better not get into. but with these being generally healthy people, and with the participants not having a choice as to where they will get a vaccine, that is not too much of an issue. Then they ask them some questions about vaccine side effects and draw some blood. The questions are about side effects and the blood is to check for “the strength of the immune response”.

Note that they don’t say at the outset that the groups would be different, and how. Would the opposite arm have fewer side effects? Better immune response? If so, in what way? More antibody? Stronger antibody? A different subtype of antibody? Better or worse cellular immunity? Which cell (among dozens)? More cells, stronger cells, or different cells? Or maybe the same side would be better?

The beauty of hypothesis-generating research (for the researcher) is that it doesn’t matter. Whatever you get, you will get it published, sometimes in a double-digit impact factor publication. I’ve sat on many a lab meeting where things like this were proposed and always, always, the comment is that “the results will be interesting whatever they are”. And they are right! But you will not know — cannot know — whether the results you got are based on an underlying physiology, or occurred purely by chance. That is where confirmatory studies come in.

Neither the manuscript nor the article recognize this. Among the many things they looked at, the researchers found two things that were different between the two groups: those who had the vaccine in the same arm had “more” of a certain type of immune cell than the other, and the opposite-arm group had increased expression of a certain marker on yet another type of immune cell. “More” is in quotes because even that is more subjective than it appears — another rabbit hole — but even if true in this sample, it is at best a hypothesis that should lead to another, possibly smaller study, where you focus on these cells, with different operators counting them, and doing additional hypothesis-generating analyses on the side to figure out the why of it, which would lead into yet another confirmatory study… You get the idea.

This is not what the manuscript authors propose. Instead they take their result at face value and concoct a mechanism out of thin air that would explain the result. The journalist then takes the mechanism and presents it as the main research result, the Here’s why of that clickbait headline. There is a high bar for calling anything in science conclusive and the article does have the usual disclaimer that “more research and data is needed”. But the phrase has been repeated so much that it has lost all meaning, something you say to mark yourself as a “believer in science” while with a wink and a nudge you act as if the results were indisputable.

Fortunately, science is a strong-link problem: those who know what they are doing will adjust their beliefs accordingly, and down the line confirm or falsify these preliminary findings. Unfortunately, science doesn’t operate in a vacuum. If its covering of science is indicative, journalism, the fourth estate, is in a hole and digging deeper, taking others with them.