Posts in: medicine

My friend and fellow oncologist Timothée Olivier has just started a YouTube channel called Primum Non Nocere — yay for Latin — and the first video, about reading clinical papers, is well worth 40 minutes of your time.

The recent conversation between Peter Attia and Russ Roberts on cancer screening and longevity has left a good impression, so in case you rushed out to buy his new book, Outlive, here is some thoughtful criticism. Biennial colonoscopies and whole-body MRIs at any frequency are indeed unreasonable.

October lectures of note

The first one is tomorrow, and it’s a good one!

Sometimes, the Tartars do show up

The 2023 Nobel Prize in Medicine went to Katalin Karikó and Drew Weissman, and deservedly so. I do not look forward to the re-writing of history that will inevitably come about the role that the NIH, University of Pennsylvania, and academia in general had in their work. As a reminder:

“Every night I was working: grant, grant, grant,” Karikó remembered, referring to her efforts to obtain funding. “And it came back always no, no, no.”

By 1995, after six years on the faculty at the University of Pennsylvania, Karikó got demoted. She had been on the path to full professorship, but with no money coming in to support her work on mRNA, her bosses saw no point in pressing on.

She was back to the lower rungs of the scientific academy.

“Usually, at that point, people just say goodbye and leave because it’s so horrible,” Karikó said.

She didn’t quit. But even when the breakthrough came, the leading journal saw it as “incremental”:

“The breakthrough, as you put it, we first sent to a Nature journal, and within 24 h, they rejected it as an incremental contribution. I started learning English only at university, so I had to look up the meaning of the word incremental! Anyway, we then sent it to Immunity, and they accepted it (3). We literally did all the work ourselves, Drew and I. Even at the age of 58, I didn’t have much help or funding to perform the experiments, so I did them with my own hands. It took us a while to publish the follow-up paper in Molecular Therapy in 2008, where we presented data on the superior translation of the pseudouridine-containing mRNA and the lack of immune activation in mice.”

The story gets more tangled from there: Karikó and Weissman co-founded a company that failed, then joined BioNTech, and in parallel Moderna started working on their own modified RNA platform, and none of it would have mattered an iota if SARS-CoV-2 hadn’t provided the unfortunate opportunity for mRNA vaccines to shine. For all of our (deserved!) ex post glorification of everyone involved, no Covid-19 — no glory.

Which reminds me very much of The Tartare Steppe’s lonely soldier Drogo who wastes away his life guarding a fortress from the barbarian hordes that don’t arrive until it is too late for him to shine in battle. How lucky for us all that humanity has enough Drogos, and how lucky for this particular pair of soldiers that their Tartars showed up on time.

Everything is hi-tech and no one is happy

Emily Fridenmaker, who is a pulmonary disease and critical care physician, writes on X:

Everything is so complex.

Logging into things is complex, placing orders is complex, figuring out who to page is complex, getting notes sent to other doctors is complex, insurance is complex, etc etc. But we just keep doing it.

At what point is all this just too much to ask?

There are a few more posts in that thread, and I encourage you to read all of it to get a sampling of why doctors feel burnt out. Whether you are in medicine, science, or education, your professional interactions have slowly — They Live-style — been replaced by a series of fragile Rube Goldberg machines that worked great in the minds of their technocratic developers, but break, stutter, stammer, and grind to a halt as soon as they encounter another one of their brethren. Which is all the time!

Too much of our professional lives has been spent playing around with a series of Rube Goldberg nesting dolls, Before reading I Am a Strange Loop I would have apologized for mixing metaphors, but this is how our brains think and it doesn’t have to make sense in the physical world to be useful, so apology rescinded. 2FA inside a 2FA, and if Apple is wondering why people are taking more and more time to replace their aging iPhones, I bet a good chunk of them dread doing it because they don’t even know how many different authenticating services, email clients, education portals, virtual machines — and all other needless detritus sold to management by professional salespeople — they would need to log back into.

Don’t get me wrong: Rube Goldberg machines are fun to play with — The Incredible Machine was one of my first gaming memories — and they can even be useful for individual workflows. But mandating that others use your string-and-pulley concoction that will break at first unexpected interaction is sadistic. Just this Monday we had yet another AV failure at a weekly lecture held at a high-tech newly-opened campus. I knew there would be trouble the moment I saw that the only way to interact with any AV equipment was via a touchscreen that had no physical buttons and no way to remove the power cord, which was welded to the screen on one end, and went into a closed cabinet on the other. Lo and behold the trouble came not two weeks later: we couldn’t get past the screensaver logo. We ended up asking students to look at their own screens while guest lecturers were speaking — and nowadays everyone carries at least two screens with them to school — which was too bad, because I was looking forward to using the whiteboard which is as far from Rube Goldberg as it gets.

Me from 20 years ago would have salivated for that much technology in my everyday life, but I’m hoping it was a function of the time, not of my age, and that kids-these-days know better. My own kids' experience with the great remote un-learning of 2020–2021 makes me hopeful that they will be more cautious about introducing technological complexity into their lives.

There was a major update today in the Maintenance of Certification saga: the president of ASH (American Society of Hematology, which, oh what a coincidence, I mentioned just yesterday) wrote an open letter to the CEO of ABIM requesting to end MOC as we know it. In what is I am sure a completely unrelated announcement, the CEO of ABIM said he would step down in September 2024. He may want to reconsider that timeline.

I don’t hide my disdain for Eric Topol, and of course one has to wonder whether professional jealousy plays a role; he is, after all, a high-profile doctor with thoughts about technology. But this morning I found an excellent counterfactual in Peter Attia who is slightly closer to me in age, moves in high-profile circles, and spends time “creating content” about what I think is a bit of a time-waster for rich people: prolonging lifespan healthspan. In other words, he carries the perfect confluence of properties to create even more disdain on my part; and yet, I think that overall he is an upstanding guy who is smart, no-nonsense, and great at communicating complex ideas.

This was a long-winded intro to my recommendation for today’s episode of EconTalk, which has confirmed my priors and reminded me that it’s never too early in the week to call Topol a hack. Him and Attia are so similar on paper, so different in reality.

The Nobel committee hits and misses

While assembling slides for the UMBC clinical trials course I’m helping with, I was reminded that Richard Doll and A. Bradford Hill never received the Nobel Prize for medicine despite conclusively showing by the way of a new-fangled method called a prospective cohort study — it was the late 1950s — that tobacco kills. They both did the work in their early middle age and lived into their 90s, so it’s not like they didn’t make it to see their work validated (like, say, Oppenheimer not being there for the confirmation of his black hole theory). Of course, the committee is not infallible — they did hand out the prize to a lobotomist — but the errors of omission are so much worse.

My same slide deck also mentions Barry Marshall and Robin Warren who (deservedly!) won the medical Nobel for another disease pathogenesis discovery: they showed that the helicobacter pylori bacterium — and not stressful living, bad thoughts, lack of dietary milk and butter, or whatnot — is responsible for gastritis. Marshall conclusively proved this by ingesting the bacteria himself back in 1985; the Nobel Committee was impressed enough by this feat of IRB avoidance to hand him and Warren the prize — in 2005, the year of Dr. Doll’s death!

He died in July and the prize was announced in October so I shall refrain from making any inferrences about the cause of death.

Doing more is the American way, but you have to do more of the right thing

Patrick McKenzie on X:

I hate to sound intellectually vacuous but choose to get more done. At the relevant margins, get more done. Life : culture / peers will routinely tell you it is OK to get less done and you should politely insist on getting more done. The amount of doneness you get is not fixed.

I have been thinking along these lines ever since reading, some dozen years ago, an article about a particularly successful cystic fibrosis center, whose outcomes were an order of magnitude better than average. This was before any new drugs or promising trials were available, and the only reason why they were so much better was that they did more of everything: more frequent follow-up, more intensive manual therapy, more changes to treatment regimen with subtle changes in condition, less complacency.

Nowhere is this more evident than on the inpatient service. It is incredibly easy to coast with reflexive and defensive medicine, putting out small fires like hospital-acquired infections or patient falls, passing on the buck to the next team, shrugging your shoulders about that 60-year-old with questionable CHF (or is it COPD/asthma) exacerbation who is not following the script and doesn’t seem to be getting any better despite being treated for everything. Patients hang around a bit longer, suffer a bit more iatrogenesis, die a bit sooner, not enough for it to be obvious in any particular case but just enough for the outcomes to be worse in aggregate.

Make no mistake: this is how many (most?) American hospitals operate, for the simple reason that there simply aren’t enough doctors and nurses around for the level of attention sick patients with many active complex disorders deserve. But doing more is the American ethos (see the X-post above); not being able to provide more focused care, we dig into the seemingly infinite supply of more drugs, more procedures, more iatrogenesis to which to expose patients, making their condition all the more complex.

Outside of medicine, this is also the difference you can see in “good” and “bad” (for collaboration) institutions: good ones throw water at embers before they become a fire, communicate more frequently and openly, do not leave documents for review “for after the long weekend”. They do more; or rather, each individual there does more and does not pass on the buck to forces unknown which are beyond their control (and the bigger the institution is, the more numerous and more complacent those forces are; incredible how that works). The not-so-good institutions also do more: of emailing, usually, to tell you that something can’t be done.

So yes, choose to get more done, and also make sure you are doing more of the right thing.

Some Friday afternoon drug price whataboutism

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.