After a few months of intermittently kicking the tires on Dave Winer’s FeedLand, I’ve finally had the time to port over a few feeds from my preferred RSS reader. The wonderful thing about FeedLand is that you can easily follow my feed categories and read posts without having an account (which is fortunate, since new signups on Winer’s own server are on hold). The full list of feeds is here. There is even a feed of posts I liked! It’s feeds all the way down.

The Science category has your usual suspects but I had to dig deep for Medicine since many of the blogs I follow haven’t been updated in years and others have turned into HuffPost-level text mills. Fortunately, Substack enabled a resurgence of medical writing, with feeds enabled by default.

Did I mention NetNewsWire is a free, open source RSS reader available on MacOS and iOS, and can sync via iCloud? For the anti-Apple readers, Feedly is there, I guess?

Warning, it’s a press release:

Gaithersburg, MD, January 31, 2023 – Cartesian Therapeutics, a fully integrated, clinical-stage biotechnology company pioneering RNA cell therapies for autoimmune diseases and cancer, has dosed the first participant in its Phase 2b randomized controlled trial (RCT) for generalized myasthenia gravis (MG), an autoimmune disorder that causes muscle weakness and fatigue. The RCT will evaluate the efficacy and safety of the company’s lead asset, Descartes-08, a first-in-class, RNA-engineered chimeric antigen receptor T-cell therapy (rCAR-T).

To the company’s knowledge, this is the first placebo-controlled study of an engineered cell therapy, and the most advanced investigational cell therapy in clinical development for any autoimmune disease. Descartes-08 is administered over 6 weekly outpatient visits and requires no preconditioning chemotherapy.

The manuscript from the open-label study is almost done, but some of the data was presented back in September 2022 (and available on YouTube). I also talked about the study in an MGFA webinar.

RCTs FTW.

Google Scholar alerts are a quick if crude way to be up-to-date with literature. In addition to journal articles and conference abstracts it also looks at U.S. patent applications, and despite the impenetrable legalese something will ocasionally turn up that is at least amusing, if not informative.

Today was one such occasion: a patent for a combination of two already approved drugs to treat toxicity of CAR T-cell therapy, by the group which, admittedly, was the first to give CAR T-cells to humans and the first to treat their side effects.

I may be showing my ignorance of U.S. patent law here but, how is this a thing? These drugs are already commercially available and widely used for exactly this indication. How would they enforce this patent, and how exactly would the patent help with development and commercialization of two drugs which are already on the market?

After reading Steven Johnson’s Where Good Ideas Come From I realized that not everyone makes the distinction between discoveries and inventions, Which is the first website that DuckDuckGo returned, and it is servicable, but I was flabergasted by the long list of nearly identical websites with domain names all some variant of “difference between”. This is how ChatGPT destroys Google. and this may be an example of a discovery masquerading as an invention. Nothing was created — the drugs were already there — the team merely discovered that those two drugs work in a specific indication. If this is deserving of a patent, should every drug combination be patented?

To be clear, I am not a lawyer — caveat lector — but the whole patent system needs an overhaul and making a clearer distinction between discoveries and inventions should be one of the items on the long list of things that need attention.

The beginning of the year was busy enough for a short commentary I co-athored to come out without my noticing.

Briefly, the US government spent $10 billion procuring the anti-Covid drug Paxlovid after a study confirmed its efficacy in unvaccinated people exposed to the delta strain. It then proceeded to hand it out to everyone, including the vaccinated and boosted during the omicron wave, with no data on whether it is actually needed in that setting. A similar drug, molnupiravir, ended up not having any meaningful effect in those who received the vaccine despite preventing hospitalization and death in the unvaccinated.

Could those $10 billion have been better spent? We believe the answer is: yes. For a fraction of the cost, using the same network of local pharmacies as in the Test-to-Treat initiative, the federal government could have randomized the first 100,000–250,000 patients to Paxlovid, Molnupiravir, or usual care — an order of magnitude more than PANORAMIC as many in the American health care system would have been lost to follow-up. The study would have taken mere months to accrue and would have provided valuable information on the efficacy of these treatments in the U.S. population. As importantly, it would have provided an important precedent and infrastructure for more federally funded pragmatic randomized controlled trials of agents under EUA or accelerated approval. The precedent set instead was for government’s full support for use of drugs far outside of the tested indication.

You can read the whole thing here, without a paywall.

The headline: ChatGPT appears to pass medical school exams, educators rethinking assessments.

The article:

• They were mock, abbreviated exams,
• done incorrectly, ⊕ There are no open-ended questions on the real USMLE.
• which it didn’t actually pass,
• and which were reported in a pre-print. ⊕ Which isn’t a complete knock against the study per se, but even a glance at it shows that some questionable choices have been made regarding the scope — there were only 376 publicly available questions instead of more than a 1,000 on the real exams — and the methods used to ensure the publicly available questions hadn’t already been indexed by the ChatGPT training algorithm.

To be clear: this is my complaining about misleading headlines, not saying that predictive AI wouldn’t at some point be able to ace the USMLE, that point not being now, for reasons stated above. And let’s not even get into whether having a high USMLE score means anything other than the person achieving a high score being a good test-taker (it doesn’t).

Instead of setting a Yearly Theme ⊕ A CGP Gray video is where I first heard it used as a replacement for New Year’s resolutions, but I’m not entirely sure if he’s the originator. right at the outset, I let it crystalize on its own in the first few months of the year. The theme of 2022 was shelter-building — guess where that came from — and as a result we now have a whistle-clean basement ready to serve as a home gym until a nuclear strike anhilates us all.

Odds are that this year’s theme will end up being statistical shenanigans. First a brief letter to JAMA Internal Medicine we wrote received a confused commentary from a giant of cancer care that showed that even oncology giants are not immune to errors ⊕ Finding the error I will leave as an excercise for the reader; I do, however, plan to address it in a follow-up letter. Never pass an opportunity to increase your publication count! of statistical reasoning. Soon after that, working on a different — still top-secret — paper got me down a rabbit hole of the many ways we use to present clinical data. I thought these were lacking in oncology; other fields of medicine showed me that there was room for further deterioration. ⊕ Not to be so secretive about everything, but clinical data representation in this particular field will also be the subject of a commentary. And yet, the US FDA still thinks statistically illeterate doctors — present company included — are important gatekeepers of diagnostic tests, essentially banning home test kits available in other parts of the world because they are worried people are too innumerate to correctly interpret their own results.

Humans being pattern-recognition machines, I don’t doubt I will continue seeing matemathical malpractice, malfeasance, and just plain stupidity everywhere I look. It is pretty much guaranteed I will inadvertently comit some myself! I hope this yearly theme results in a few papers, at least.

Old (1999), but still good. ⊕ Even when I first wrote this, and even older now.

When I was a house officer and installing one of the first right-heart catheters, the machine that showed intrapulmonic arterial pressures was enormous and was equipped with strain gauges rather than computer chips. Making it work was difficult. After the line was in, the attending, the nurse, and I tried desperately to adjust the machine to show the pulmonary arterial pressure waves. We could not get them. The line on the screen remained flat. We manipulated toggle switches and strain gauges for about 15 minutes. Nothing. Finally, I glanced at the patient: He was dead.

The story after that is even better.

• Fractional use of vials/pills to decrease per-patient cost, because the main driver of high cost of drugs is not manufacturing (i.e. a ten times more efficient manufacturing process would not result in 10 times, or even 2 times lower prices). If you don’t believe me just look at what Sanofi did with alemtuzumab.
• Using real-world data instead of randomized controlled trials, because while retrospective, non-randomized, uncontrolled studies Now rebranded as “real-world data”. are good for generating hypotheses and maybe, maybe, detecting enormous effect sizes Think: smoking causing cancer, but not: who-knows-what new material causing lymphoma. we have learned through much trial and error that RCTs are critical for evaluating whether a medical intervention works or not. Back when personal computers were too big and expensive for mass use, the answer wasn’t to invent a story of why calculators were better — it was to make PCs so cheap and small that not having one in your pocket was a matter of personal choice, not cost. Same for RCTs.
• The Choosing Wisely initiative, which was all the rage back when I was a resident and still seems to have legs. ⊕ Not to mention that the program unintentionally promoted a dangerous frame of mind in which some doctors thought extensive testing was never indicated, thus missing some rare but life-theratening diagnoses. Money spent on producing more content for doctors to read, listen, and watch — thus taking up their time — and encouraging patients to talk to their doctors at length about questionable data behind many of the procedures — thus, again, taking up their time — may have been better spent designing and running pragmatic RCTs that would answer these questions and save both the doctors' and patients' time by reducing ambiguity. Oh well.
• Yet another health care delivery reform — this may be just my healthcare policy naiveté, but these all had the whiff of rearranging deck chairs on the Titanic. ⊕ See also: the Homer Simpson car Mandating the desired outcome instead of thinking about the right incentives is bound to increase cost through second-order effects.

Anything else?

March 7, 2020 was a Saturday. I woke up at 8am, which is as late as it gets, since the night before we watched Breathless and The Graduate back-to-back (the 1960s were a good decade for movies). Most of they was spent in visiting friends in downtown DC. They are a family of four in a tiny one-bedroom; we compared notes on where best to stash the extra flour, rice, pasta, and other staples Though not, funnily enough, toilet paper. we stocked up on expecting the inevitable. The inevitable came that night as we were heading out, when Mayor Bowser announced in a late news conference that yes indeed Washington DC had its first confirmed case of Covid-19: a man with no recent travel and no confirmed exposures, which is to say, there was already community spread. We got back to our apartment and closed the door; the next time that apartment would be empty of people again, as it usually had been on weekends and later summer afternoons before the pandemic, was more than five months later.

That was 300 days ago to the day, and as my favorite columnist and fellow millennial Janan Ganesh astutely noted, there were no grand lessons that these 300 days gave me, unless you count confirmation that humans can muddle their way through anything as a lesson. Harambe may have been killed in 2016, but 2020 was his year: a tragic, sensless event where everyone is responsible but no one is to blame — though I may be an exception in thinking this, since 2020 was the year of confirmation bias, the year of suppressing the opposing view points, the year of shaming. To complicate matters some more, it was also the year when crackpots and idiots joined into the Grand Coalition of Stoopid, expressing some points of view that maybe ought to be suppressed, and doing some things for which maybe they should be ashamed. Harambe indeed.

I finished the last year with a post about the great things that happened to me personally as the world stagnated in the 2010s. In the spirit of this year, I’ll finish with a list of failures instead, and I’ll do my best not to make it into a thinly veiled list of successes:

• I read far fewer books and watched far fewer movies than any year before.
• I wrote far fewer (medical) articles than planned.
• I wasted time on Twitter like never before (and, let’s hope, never again).
• I dropped more projects than ever before, including piano lessons, learning a new language, speed-completing the Rubik’s cube, and running in cold weather, among many others.
• I walked less than any other year since I started walking. This may be an exaggeration, but not by much.
• I commuted more by car than ever since moving to DC.
• I ordered more takeout than ever.
• And the one that hurts the most: I did not finish a single video game, or even play anything for more than 15 minutes, unless you count Good Sudoku which is truly a masterpiece of design and the highlight of the year. Yes, the highlight.

I, for one, am glad that blogs are making a comeback. Here are a few I’ve been reading for at least a few months, many of them for years, some for decades.

Applied philosophers

The only true philosophers of our time.

• Mathflaneur (by Nassim Taleb)
• Ribbonfarm (by Venkatesh Rao, who also has a newsletter of half-baked ideas he calls Ribbonfarm Studio)

The new scientists

People without major academic credentials who have interesting ideas about science.

• Alexey Guzey (also see Guzey’s Best of Twitter, and also see New Science)
• Applied Divinity Studies
• Astral Codex Ten (former Slate Star Codex)
• Fantastic Anachronism
• Gwern
• Nintil

The old scientists

People with major academic credentials and interesting ideas, something to teach, or both.

• I am Intramural (from the NIH Intramural Research Program)
• Statistical Modeling, Causal Inference, and Social Science by Andew Gelman
• Statistical Thinking by Frank Harrell
• Stephen Wolfram Writings
• The Mathematical Oncology Blog (see also This week in Mathematical Oncology)

The ludites

People against modernity of one sort or another.

• Axiom of Chance (Simon DeDeo, who does not seem to have a Twitter account)
• Patrick Rhone (who does have a Twitter account)
• Study Hacks (by Cal Newport, whose Twitter account, if real, has been abandoned years ago)
• Wrath of Gnon (who is in fact — and sadly — all Twitter)

People doing their own thing

Unclassifiable but exhilarating.

• Craig Mod (and on Twitter) who walks, makes books, and takes photos.
• Garden of Forking Paths (by Abe Callard, who watches movies)
• Rands in Repose (by Michael Lopp, who manages people)
• The Sephist (by Linus, who makes his own software tools)
• Thought Asylum (by Stephen Millard, who makes other people’s software tools more usable)

Apple enthusiasts

Some tips, a few tricks, many opinions.

• And now it’s all this
• Brett Terpstra (if you have a Mac and use it for more than just browsing the internet and answering email — not that there is anything wrong with that — Terpstra’s tools will save you days of work; he could easily have been slotted in the category above, but the Apple tag predates all and he is an Apple lifer)
• Daring Fireball (by John Gruber)
• Hypercritical (a sadly neglected blog by John Siracusa although what you should really check out is the podcast of the same name which has been out of production for years but still fun and relevant)
• Macdrifter
• Marco.org (by Marco Arment)

Finance-adjacent

Economists and investors, for the most part.

• Global Inequality (by Branko Milanović)
• Marginal Revolution (by Tyler Cowen and Alex Tabarrok who also wrote an excellent textbook in economics which I plan on reading some day, likely in retirement)
• Pseudoerasmus (the last post was in 2017 so I’m not holding out any hope, though he is on Twitter)
• The Rational Walk (see also Rational Reflections and the Twitter account)
• 10-K diver (as close to a blog that a Twitter account can get)

Journalist-cum-substackers

Former or current journalists who now earn some or all of their living by writing newsletters via Substack, which is slowly reinventing blogs (in the sense of reinventing the wheel, not actually making them better and in fact in many was making them much worse).

• Everything Studies (by John Nerst)
• Galaxy Brain (by Charlie Warzel)
• Insight (by Zeynep Tufekci, who is hands down the best journalist currently writing)
• Slow Boring (by Matthew Yglesias)

Company blogs

For when I really want to know when the next update is coming.

• Devonian Times, from the makers of my note-collecting tool of choice, DEVONthink
• The Omni Group, makers of OmniFocus (and OmniGraffle, which I don’t use often enough for it to be essential but which is fairly
• Wolfram Blog, from the makers of Mathematica