Posts in: medicine

John Carroll, the founder of Endpoints News has stage 4 Merkel cell carcinoma and quite a story to tell:

If I had stayed at Valley Baptist and been treated with chemo, I likely would have seen Merkel cell carcinoma rear back up within a few months, putting me on a statistically short path to the grave.

[…]

My case manager said that if I wanted to leave they would have to arrange a transfer. But I already had the lay of the land from the small army of assistants and nurses who kept the hospital on its rickety track. A nurse told my wife and I — sotto voce — that as we were headed into the weekend, that could take days.

You should just go, she said quietly.

My wife drove the get away car after I signed the AMA (against medical advice), and a friend in the industry helped text my way into MD Anderson as we made the six-hour trip north.

At the other end of that journey was immunotherapy, from a company that Carroll disparaged as a journalist. So it goes…

It’s been exactly 3 years since Norm Macdonald died from acute myeloid leukemia, which was itself a know. complication of treatment he received for multiple myeloma.

But none of that is important. Anwyay, here’s Norms last stand-up performance on Letterman.

Three weeks into the new school year, and we have our first sore throat. So it begins…

A few good links for the weekend:

ChatGPT, the blog expert

The latest episode of The Talk Show was with Taegan Goddard, who all the way back in 1999 founded the blog Political Wire which is apparently a continuous intravenous drip for people interested in US politics. Now, I’ve had other preocupations back then and not being an American citizen still have little to no interest, so this blog wasn’t even on my radar until listening to the episode. But now I wonder: are there any more relevant blogs I’ve missed out on, about medicine and biotechnology in particular?

ChatGPT’s first pass was mediocre. I’ll save you the verbalist padding, but here are its suggestions in response to my prompt: “Is there a website/blog like politicalwire.com or daringfireball.net but for biotechnology?”

It’s a 20% hit rate: only Derek Lowe’s In the Pipeline comes close to what I asked for. The others are all medium to big news outlets that yes, focus on biotech, but that’s not what I asked for. The second try, after I asked for more like Lowe’s, was a tad better:

That’s more like it! 80% now, and if I were feeling generous I’d give it a full 100% since In the Pipeline is, in fact, a Sci Trans Med blog. But then I asked for too much, and it hallucinated 3 more, two of which were hallucinations (BioPunk and BiotechBits, which were at least plausible names) and one was a sub-blog of Endpoints that also didn’t exist.

So, now I have two new blogs to follow (Timmerman Report and The Niche; Biotech Strategy is behind a paywall and I’ve already been following the others), and an ever-increasing urge to update the Blogroll, which has been under construction for the past five months with no end in sight.

Not one week after I first wrote about zombie medicine, this happened:

So many examples out there: icing injuries, treating mild fevers in kids, Paxlovid. Someone really ought to collect these and write a book.

Zombie medicine: it's everywhere, it's evil, and it's coming to get you (and your money)

In their excellent but unfortunately titled book Ending Medical Reversal, Adam Cifu Dr. Cifu talked to Russ Roberts recently, in one of the best episodes of EconTalk so far this year. Dr. Prasad’s interview with Russ was also quite good, though the topic was not my cup of tea. and Vinay Prasad note the practice of “medical reversals”, which is a tendency of medicine to reverse practice — or self-correct — once evidence suggests that something that was thought to work actually doesn’t. Typical examples are starting prophylactic anti-arrhythmics after a heart attack, using estrogen to treat symptoms of menopause and performing kyphoplasty to treat vertebral compression fractures. The RCTs that led to reversals are: CAST, Women’s Health Initiative and ACTRN12605000079640, and guess which one of these was done in New Zealand. For each of those, there was a randomized controlled trial that showed no benefit — or, even worse, more harm — of the intervention compared to placebo. And presto, medical reversal was official and doctors around the world stopped doing what they now knew was harmful.

Just kidding: it took years to stop those practices, and kyphoplasty/vertebroplasty is still being performed, in select cases, based on little to no evidence. There is a long tail of doctors who either don’t believe RCTs in general, or don’t know about some of those in particular, or what is most common know and believe in RCTs when they affect someone else’s practice but find a million faults in those that investigate their own bread and butter. These doctors perform what I’d like to call Zombie Medicine, a term inspired by Lisa Feldman Barret’s Zombie Ideas (↬Andrew Gelman): Incidentally, “Zombie Medicine” would have made a much better book title than “Ending Medical Reversal”. Add a subtitle (Zombie Medicine: How Doctors' Inertia and Bad Science Harm Patients and Waste Billions) and you have a best-seller. Maybe for the second edition?

Zombie ideas abound in our culture, nibbling away at the brains of their victims. The mistaken belief that vaccinations cause autism — a celebrated zombie idea — is responsible for rising rates of vaccine-preventable diseases. The belief that a person’s personality type, assessed by the Myers-Briggs Type Indicator (MBTI), predicts job performance is another zombie idea that continues to lure otherwise capable managers into making decisions that benefit neither employees nor their companies.

But inertia to a big, unexpected medical reversal isn’t even the most common type of zombie medicine. There are some undead concepts so ingrained that a million RCTs couldn’t reverse them: the belief that atelectasis (partial lung collapse, common after surgery due to immobility) causes fevers (high body temperature, common after surgery due to infection, transient bacteraemia, and general inflammation), that early cancer detection is an absolute good, that Vitamin C cures anything other than scurvy, that vitamin D prevents anything other than osteoporosis and rickets. And it’s insidious, for I bet every reader will have felt a pang for at least one of these concepts. (“Wait, why does he think this is zombie medicine when I know it’s true!?") That’s how zombie practices become undead: with a sliver of doubt, a shimmer of hope, a dollop of wishful thinking.

And on the very edge of zombification sit tempting ideas that have greater than 99% chance of being false, but that you know will never truly die: that mTOR inhibitors can prolong human life spans, that with enough sequencing we will find genetic causes of most diseases, that the gut microbiome influences anything other than gastrointestinal health and quality of stool. This kind of zombie medicine adds another item to the list of harms: opportunity cost in both money and time.

The first step in addressing a problem is to identify it, the second is to name it. Now comes the time to make lists.

Here are four good articles on this fourth day of the week:

The unintended consequences of death-delaying technologies

My boss at the NIH was in his late 80s when I started working there, early 90s when I left. There was an obvious physical decline into complete frailty during those four years, but he was as sharp, lucid and stubborn as ever. You don’t get to work into your 90s unless you have it your way, and “the way” became shorter hours in the office with prolonged nap time, sometimes during meetings, while maintaining the final word on anything that happens in the lab.

So, “the mind is willing but the flesh is weak” often came to mind, and until we develop a Futurama-style brain-in-a-box there are limits that biology imposes which can’t be overcome through force of will. You hate to see it, but we will be seeing it more and more often as the Baby Boom generation gets into its sunset years. Not because they’re any more selfish than other generations, mind you (my old boss was of the Silent generation), but rather because they are the most numerous and the biggest beneficiaries of death-delaying medical advancements.

It seems to me that the higher up the person is in the hierarchy and the longer they have worked in the field (my boss spent 60 years at the NIH), the harder it is to imagine anything other than staying on the job until an act of God intervenes. This is exactly what happened; I was gone before then, but there were many in the lab who were left scrambling for a new position, taken by complete surprise that their 90-plus-year-old chief was no longer with us.

So it goes…

Why are clinical trials expensive?

Why haven’t biologists cured cancer? asks Ruxandra Teslo in my new-favorite Substack newsletter, and answers with a lengthy analysis of biology, medicine and mathematics. Clinical trial costs inevitably come up, and I know it is a minor point in an otherwise well-reasoned argument but this paragraph stood out as wrong:

Clinical trials, the main avenue through which we can get results on whether drugs work in humans, are getting more expensive. The culprits are so numerous and so scattered across the medical world, that it’s hard to nominate just one: everything from HIPAA rules to Institutional Review Boards (IRBs) contribute to making the clinical trial machine a long and arduous slog.

What happened here is the classical question substitution, switching out a hard question (Why are clinical trials getting more and more expensive?) with an easy one (What is the most annoying issue with clinical trials?). Yes, trials involve red tape, but IRB costs pale in comparison to other payments. Ditto for costs of privacy protection.

If we are picking out likely reasons, I would single out domain-specific inflation fueled by easy zero-interest money flowing from whichever financial direction into the biotech and pharmaceutical industries, leading to many well-coined sponsors competing for a limited — and shrinking! — pool of qualified sites and investigators. It is a pure supply-and-demand mechanic at heart which is, yes, made worse by a high regulatory burden, but that burden does not directly lead to more expensive trials.

There are some indirect effects of too much regulation, and at the very least it may have contributed to more investigators quitting their jobs and decreasing supply. They also contributed to regulatory capture: part of the reason why industry has been overtaking academia for the better part of this century is that it’s better at dealing with dealing with bureaucracy. But again, these costs pale in comparison to direct clinical trial costs.

Another nit I could pick is the author’s very limited view of epigenetics: if more people read C.H. Waddington maybe we could find a better mathematical model to interrogate gene regulatory networks, which are a much more important part of the epigenetic landscape than the reductionists' methylation and the like. But I’d better stop before I get too esoteric.