• Kristen French for Nautilus: New Fathers Are Dying, and We Don’t Know Why.

Oh but we do, at least superficially: “of 130,000 men who became new fathers between 2017 and 2022, almost 800 died during that same 5-year period, and 60 percent of those deaths were from potentially preventable causes like homicide, accidental injury, and suicide” which is about what you would expect for a group of men that skews younger. The authors of the paper make a comparison between fathers who died and those that survived but a more interesting one would have been a demographically matched of childless men. Alas, all we have is all the men in Georgia and lo, for each age range the new fathers have a lower mortality and the discussion appropriately leads with “Fatherhood appeared to be associated with reduced mortality.“ ⊕ [Note: Another reason to have more children. Though, if you are going to do it solely because of a misguided belief that you yourself would live longer, then perhaps don’t? ] Methinks French — or her headline writer — were fooled by randomness.

• Derek Lowe: What Success Can Look Like, Darn It.

Vepdegestrant for breast cancer seems to be another entry in the annals of approved drugs being considered failures by Mr. Market. Let it be noted that a chemist (Lowe) writing for a prestigious peer-reviewed journal (Science) dunks on a drug while citing millions and billions of dollars exchanged or promised to various stakeholders while barely mentioning, and wrongly at that, the actual trial results. “It did not really demonstrate any advantage versus the comparison in the trial, fulvestrant” is factually incorrect: median progression free survival was 5 versus 2.1 months, which, fine, is tiny and may have been the result of statistical shenanigans; but it may also be a true and meaningful incremental improvement and if we are going to dismiss it out of hand then what are we even doing here? The rot runs deep.

• Deena Mousa: We don’t know why Malawi is poor.

It is a genuine mystery of why a mostly agrarian functional democracy with no separatist movements, demographic catastrophes, curses of resource wealth and the other usual suspects of stalled growth should completely flatline their GDP. Mousa shows compelling data and many hypotheses, though I wonder whether there is something that isn’t and can’t be measured which is keeping the country where it is. And if you are thinking that oh, GDP can’t measure happiness, I bet that at least they are happy, think again: it was the 4th least happy country last year. But then the “Happiness Report” methodology takes GDP into account (!?) so it is almost impossible for a GDP-poor country to break through in the rankings.

• Dynomight: What’s with all the slide decks?

This is about slides shared via email, never meant to be presented, but rather serving as a landscape-oriented picture book for adults. I don’t know what is behind communication-by-slide, and as a seminar-attending Tufte acolyte I abhor it. Management consultants spreading them around like a viral respiratory disease — which is the thesis of the blog post — certainly has something to do with it, but the syndrome is now bottom-up as well. My third-grader asked me just this morning why they were forced to watch and make (!?) slides at school.

The good: How an ‘Impossible’ Idea Led to a Pancreatic Cancer Breakthrough by Gina Kolata and Rebecca Robbins for The New York Times. The breakthrough discussed is the real deal, and they manage to do it in a measured tone which correctly identifies daraxonrasib as a stepping stone and not a miracle cure. It has this important note up top and not buried down at the end:

The pills, three taken daily, are not a cure — eventually, daraxonrasib stops working. Many patients do not respond. And it has side effects that can be harsh, including rash, diarrhea, fatigue, nausea and raw, split fingertips.

How refreshing — I hope Derek Thompson takes note.

The bad: The Human Body’s Hidden Pathways by Dr. Avraham Z. Cooper, who is a pulmonary/critical care physician at the Ohio State University, for The New York Times Magazine. For the life of me I can not figure out the point of this post-modern journalistic exercise.

Nominally it is about a peer-reviewed research article which came out in 2021 under the title “Evidence for continuity of interstitial spaces across tissue and organ boundaries in humans”. The NYT Magazine staff did not deem it worthy of being linked to, but here it is in its entirety. In it, the authors showed small fragments of tattoo pigment migrating into tissues — skin and colon — deeper than they expected. We are not talking about ink being injected into a bicep and showing up in someone’s rectum here, but rather a series of biopsies of tattooed skin or the lining of the colon where there is a lot of pigment up top, and much less and in smaller pieces down at the bottom of the slide, deeper in the tissue.

Let me pull out my rarely used master’s degree in histology and note that this is hardly surprising. Connections between cells are not exactly air-tight — other than maybe in the brain and the testes — so of course there is some gel-like fluid circulating in the space. Or did the original article’s authors not realize why people tend to rub their feet when they get swollen?

But that is only the introduction. The meat of the article is Dr. Cooper’s theoretizing that this has something to do with — drumroll, please — acupuncture. With no evidence, mind you, but a tingling sensation in the back of his neck or somesuch. By the time the 30th single-sentence screen scrolls by we are firmly in bullshit territory, in the formal sense of the word. Caveat lector.

The ugly: Longevity Medicine - An evidence based guide by Dr. Vinay Prasad who is out of the FDA and back making YouTube videos. And oh my, the contrast between the most recent thumbnail and the one posted just before he joined the FDA is striking. Has it only been a year? No wonder that his first topic back as an influencer is about longevity.

A sidenote here which I will put at the end: the increased interest of Silicon Valley types with longevity, and I am not thinking only about Bryan Johnson’s delusions here, reminds me of the recently quoted speech Charlie Chaplin gave at the end of The Great Dictator, the relevant quote being that “so long as men die, liberty will never perish.” Good for us that snake oil salesmen are still the longevity field’s most prevalent phenotype.

What possessed me to type x.com into the address bar I can tell you not, but there I was, staring for the first time in weeks at the “For you” tab. And there it was, in all capital letters: “THIS IS HOW WE CURE PANCREATIC CANCER”, staring back.

That was the X-crement of one Derek Thompson, writer for The Atlantic, podcaster, abundance enthusiast. It was promoting his most recent blog post which, being on Substack rather than X, had a more subdued name: “How AI Could Help Cure Pancreatic Cancer”. It is, supposedly, an interview with a co-author of a paper with an ever-less-so boastful name: “Next-generation AI for visually occult pancreatic cancer detection in a low-prevalence setting with longitudinal stability and multi-institutional generalisability”. Most of the interview, however, is behind a paywall which I shall not climb.

Above the fold is Thompson’s exuberant, hyperoptimistic speculation. He approaches the problem from the perspective of the three recent developments — one from above, the other two previously discussed — but presents the areas which they are “solving”, targeting KRAS mutations, pancreatic cancer’s immune evasiveness, difficulties with early detection, as the sole reasons why the disease is so difficult to treat.

But that is disingenuous. There are so many more reasons why it is hard: the uniquely hostile, acidic, high-pressure environment of the tumor that makes drug delivery to it nigh-impossible. It’s propensity to metastasize — spread to distant organs — no matter what size the original tumor is. A biochemical storm it stirs up in the body leading to rapid weight loss, blood clots and horrendous pain which are distinct even among other cancers. Why not highlight those three as the “3 broad reasons why pancreatic cancer is so hard to treat”, to use Thompson’s terminology? Well, no recent high-profile studies for those, are there?

I understand that he has some personal reasons to be interested in pancreatic cancer, and I am sure it is coming from the best of intentions, but please.

• Ed Zitron: Am I Meant To Be Impressed?. A detailed account of why you cannot trust anything tech companies say about the business side of AI, even in official SEC-sanctioned documents (because, of course you can’t). Note in particular how the unsuspecting public buys their narrative about big AI spending leading to increased profits hook, line, and sinker (the “profits” coming from bloated valuations of OpenAI and Anthropic). I am no fan of Apple, but it appears that they have made the right choice by staying out.
• Richard Dawkins: Is AI the next phase of evolution? ⊕ [Note: ᔥJason Kottke ] A eulogy to New Atheism.
• Lada Nuzhna: What the hell is happening in China? This is with regards to their push in biotech. All good things, I’d say.
• Isaac Greene: The Gift of Music. A delightful reframing of gift-giving.
• Derek Sivers: Geography is four-dimensional. About knowing places only at a certain time. The short essay matches my own experience of being asked what Serbia is like now. Having last truly lived there more than 15 years ago, the only correct answer is that I haven’t a clue.
• Charlie Chaplin: The Final Speech from The Great Dictator, with transcript. It gave me chills.

To those who can hear me, I say - do not despair. The misery that is now upon us is but the passing of greed - the bitterness of men who fear the way of human progress. The hate of men will pass, and dictators die, and the power they took from the people will return to the people. And so long as men die, liberty will never perish…

Soldiers! don’t give yourselves to brutes - men who despise you - enslave you - who regiment your lives - tell you what to do - what to think and what to feel! Who drill you - diet you - treat you like cattle, use you as cannon fodder. Don’t give yourselves to these unnatural men - machine men with machine minds and machine hearts! You are not machines! You are not cattle! You are men! You have the love of humanity in your hearts! You don’t hate! Only the unloved hate - the unloved and the unnatural! Soldiers! Don’t fight for slavery! Fight for liberty!

Amen.

• Bob Grant: The Mysterious Hantavirus Outbreak That Put the Virus on the Western Map. European hantavirus is what you get when mice pee all over your idyllic mountain cottage. It causes your kidneys to fail and you may need dialysis until they heal, but unless you had bad kidneys to begin with there should be no permanent damage. The (wild) west hantavirus you can get from mice and humans alike, goes for your lungs instead of the kidneys, and kills 4 out of 10 humans who get it. And now there is a cruise ship full of people who were exposed. As if I needed another reason to avoid cruises like the plague.
• Kristen French: What Your Dream Life Says About You. It tells me I wake up too early because I only remember them once every few weeks!
• Kristen French interviews Lisa Feldman Barrett: How Does Your Brain Know a Cat Is a Cat? It is about Barrett’s Nature review which is behind the paywall but at least gives out the punchline in the title: “Categorization is ‘baked’ into the brain.” Barrett’s own article in Nautilus, about emotional intelligence, is also worth a read.
• Jake Currie: The Best of NASA’s Newly Released Photos From the Artemis II Mission. An excellent source of desktop and smartphone backgrounds.
• Bob Grant, again: AI Music vs. My Parents. A sad state of affairs. Thankfully, personal experience tells me the younger generations are better at identifying saccharine “content” as slop and filtering it out.

• Virginia Postrel for Works in Progress: Engineering the disposable diaper. I, for one, am grateful that there is no more need for “the knife method” of diaper washing — one guess as to what the knife was used for. The article doesn’t mention that the technology which made baby diapers ever so thinner and easier to transport has also helped microscopy. Knowledge begets knowledge.
• Dynomight (pseud): You’re probably taking the wrong painkiller. On the benefits of acetaminophen, the blind alley of pain medicines.
• Brennan Kenneth Brown: Video Games that Secretly Teach Mathematics. Just a few week ago my wife and I were talking about the mind-bending difference in magnitude between a googol and a googolplex, and the notations described in this article would have come in handy. More to the point, even farming games not mentioned here like Stardew Valley and Animal Crossing do wonders to teach children math.
• Ted Gioia: Socrates vs. the Venture Capitalists. Look, when FT’s Janan Ganesh praised the unexamined life I don’t think he meant going about it like an amoeba. Est modus in rebus.
• Jake Currie for Nautilus: Birds Are More Afraid of Women Than of Men. Submitted without further comment.

The essay is five years old yet I have discovered it just now because the author is also the person behind Denote, a marvelous note-taking tool for Emacs. The tone is not as dry as a scholastic text ⊕ [Note: For a Substack version of a similar message I encourage you to check out Experimental History. The most recent post, for example, is a case study of one particular aspect of scientism — zombie ideas. ] but not as entertaining as something one would find on Substack. The message is unambiguous, and rather than rehash it let me quote one paragraph out of many:

Science as a career choice rather than a disposition towards learning, and an attitude of living in accordance with the principles than (sic!) enable such learning, contributes to the distancing from philosophy and to the degradation of the moral character of those involved. The practitioner who has not been in the least exposed to the rigours of a virtuous modus vivendi is likely to prioritise superficialities that obscure their own intellectual insecurities, such as social status, a growing collection of titles and certificates that are supposed to support one’s appeal to intellectuality, or the emptiness of being celebrated as a force for so-called “progress” and “rationality” among those who are believed to be unfortunate enough not to be scientists. The latter is one of those non-scientific beliefs amplified by the oligopoly of mass media that helps the philosophically deprived science stake its claim as the tutelary figure of the contemporary world, while blithely disregarding its instrumentalisation as both the apologist and militant activist of the power apparatus that enables it.

The author, who chose to drop his surname and go just by Protesilaos thereby making me break the house rule of using last names only when referring to folks, lives in a hut he built himself ⊕ [Note: A hut which brought to mind this recent essay from Joan Westenberg about people retreating from their true calling for years in order to recharge. ] in the mountains of Cyprus. Fascinating stuff, all with a large back catalogue I will be perusing in the months to come.

The last few years have been particularly tricky to tread for people who recognize the difference between science and scientism. If the entire board of the National Science Foundation is fired in one day, is it an attack on science or an attempt to curb scientism? [Note: ¿Por qué no los dos? ] When one of the “Abundance” guys — yes, that book is still on the pile — proposes an unbaked not-even-embryonic scheme for reform, is the rebuke from a seasoned scientist legitimate or just circling the wagons? [Note: Vide supra ] So yes, a retreat to the mountains does sound appealing.

Thank you, Hacker News, for promoting — if only briefly — this marvel of an article from Physics World (or is it physicsworld?) about the more scientific aspects of the final and most important step of making coffee. Funnily enough, it focused on the two methods I’ve settled on after a couple of decades of tinkering: espresso and pour-over.

Refreshingly, it is not a “well-actually” article that would use theoretical physics and/or laboratory experiments to prove coffee experts wrong. In fact, much e-ink is spent confirming practices that baristas have settled on, including the coffee-to-water ratio, steeping time, pressure used. There were, however, two things that could make me change how I’m doing things.

For espresso, theory says that using less coffee with a coarser grind would — to me, paradoxically — result in equal extraction and coffee tasting the same despite not using as many beans. With the price of coffee rising, this could be a big deal so I will check it out. Although, to me the benefit of a proper espresso is that it allows you to get a tasty liquid out of sub-par solids, so I would never go with the most expensive beans to begin with (ahem). No, the $2/oz bag is reserved for the queen of brewing, which is the pour-over.

And for the pour-over, there is but a single thing I should change: the height from which I pour, which should apparently be far higher than I’m doing now. A pretty diagram shows the reasons why 20cm is the right height from which the stream of hot — 96°C, thank you very much, so you’d better have a temperature-controlled kettle — water onto a coarsely ground pile of dreams. And there is no safe way to do it from that high up without a gooseneck kettle, so add that to your kettle requirements. Sadly, they don’t go into the quality of the filter and the differences between plain paper, Chemex and metal meshes. I am sure there is much physics involved.

Now before you start commenting that good ol’ Folgers in a hotel room drip machine will do for you, thank you very much, let me suggest a few decidedly unfussy methods of coffee making that are infinitely better than drip coffee out of a plastic tub:

• Aeropress, which used to be the main way I made coffee but abandoned as the family and the number of coffee-drinkers in the house expanded (we are currently at three; five with grandparents visiting).
• Nescafe Gold, which is probably the best instant coffee you can get and it doesn’t get any less fussy than pouring hot-ish water into a mug.
• Turkish coffee, with strong preference for Mehmet Efendi which, if not in Istanbul, you can easily get online.
• Boiling raw beans in DC tap water for about 30 minutes.

Okay, maybe not that last one.

• Cory Doctorow: The enshittification multiverse, in which Doctorow proposes a general theory of enshittification to match his initial, special theory. I enthusiastically concur.
• Anonymous on the Marginal Revolution comments section: On health care price transparency. The only non-Xified content you can find on Marginal Revolution these days is in the comments, so I am glad that Cowen highlighted this minute dissection of the madness called American medical billing. Needless to say, I concur.
• Reese Richardson: A do-or-die moment for the scientific enterprise. ⊕ [Note: ᔥAndrew Gelman, who sure loves his mile-long headlines. ] This is the author’s summary of a more detailed paper in the academic journal PNAS which points to a looming catastrophe of LLM-boosted scientific paper mills holding hands with pliant journal editors to decimate the signal-to-noise ratio of the literature. Of course I concur!
• Cory Doctorow, again: Ada Palmer’s “Inventing the Renaissance”. His review after actually reading the whole book, and yep.

Apart from looking like he has just been on the losing end of a fistfight, and having occasional bouts of nausea, Ben Sasse seems to be doing as well as someone recently diagnosed with metastatic pancreatic cancer possibly could. Both the nausea and his face peeling off are because of daraxonrasib, a new drug which targets KRAS G12 mutations which are common in many cancers but are found in most pancreatic ductal adenocarcinoma (PDAC). As a reminder, PDAC is the one that Steve Jobs did not have, the one that has the dubious distinction of being both the most common and the most lethal cancer of the pancreas.

Well, daraxonrasib seems to be doing its job and doing it well, based on a company press release. Remember, most press releases should not count as evidence for anything. This particular one, however, is worth reading because it is (1) for a randomized controlled trial with (2) a “hard” endpoint of overall survival ⊕ [Note: OK, putting my pedant hat on, the pre-specified co-primary endpoints are progression-free survival (PFS) and overall survival (OS) in the RAS G12-mutant population. What is reported in the press release is only OS in the “intent-to-treat” which is to say both G12-mutant and wild type populations, which was a secondary endpoint. A bullet point at the beginning says that all primary and key secondary endpoints were met, so why not report both? Probably because one looked better than the other, but would it not be a tad suspicious that a less targeted population did better than the more targeted one? But this is just speculation, let’s see review the actual data once they come out. ] which will (3) be presented at the ASCO annual meeting, I imagine as a plenary talk, in early June of this year. The thing to look for there will be informative censoring, in particular early censoring of frail participants — the ones more likely to die early of their disease — who were randomized to receive daraxonrasib but then withdrew due to the “manageable” toxicity of a melting face. The fact that there are no participant numbers reported at all in the release makes me suspicious, though information on the number of patients enrolled is readily available: 501. That’s a lot of patients!

The company is certainly feeling optimistic: they have already received a National Priority Voucher from the US FDA and will now submit a New Drug Application. Kudos and congrats for designing and testing a working drug without using AI, because to read both professional and lay media the past two years it is a miracle there were any drugs being discovered until Large Language Models came along.

Yes, I had to invoke AI, because it is becoming exceedingly common for people to give algorithms credit where it is not due. This is what Tyler Cowen wrote yesterday about pancreatic cancer research:

AI and the pancreatic vaccine. More testing is needed, but there is a reasonable chance that we have a good treatment for pancreatic cancer, and AI was instrumental in that. It is mRNA as well, so a double burn on the haters.

The link is to a post on X by one Rotimi Adeoye, a “contributing opinion writer @nytimes” (one guest essay as of today which is one more than I have so congratulations, I guess?) who in true X fashion superimposed a screenshot from an uncredited journal abstract over someone posting a link to an NBC news article about the updated results of a phase 1 trial of an mRNA vaccine for pancreatic cancer. ⊕ [Note: For those not keeping track, you are right now reading a blog post about a blog post about a retweet of a tweet about a news article based on a press release. You’re welcome. ] These were presented yesterday at the annual meeting of the American Association for Cancer Research but were hinted at in a press release (?) from Memorial Sloan Kettering, where the vaccine — generic name autogene cevumeran which rolls right off the tongue doesn’t it? — was being tested.

Remember how a few paragraphs above I had implied that you should ignore most press releases? Well, news on academic websites should rank even lower as no one there has to answer to the SEC. The primary study was great for what it was, a first-in-human trial with laboratory endpoints meant to test whether the participants’ immune system responded at all to the vaccine. And it seems that it did, as shown in not one but two papers in Nature published two years apart. The number of original participants, all of whom had early-stage, freshly resected and otherwise untreated PDAC upon enrollment, was 19. Three of these did not make it to the vaccine as they had progression, died, or had toxicity from adjuvant chemotherapy before being dosed. Chemotherapy? Yes, in addition to the vaccine everyone also received “adjuvant” (meaning: there to “clean up” any residual cancer after surgery) chemotherapy (FOLFIRINOX, not for the faint of heart) and immunotherapy (atezolizumab which is in comparison to the chemo a walk in the park but even that has its side effects). There was no control.

Of the 16 participants, 8 were “responders” to the vaccine as measured by some highly sophisticated laboratory tests — not that the patients would care what their blood work showed — and in 7 of those the cancer hasn’t come back for 3 years as noted in the follow-up Nature paper or for 4-6 years as noted in yesterday’s update. This compares to 2 of 8 who were “non-responders” to the vaccine.

If you don’t have your calculator handy let me do the math for you: 9 of 16 patients, or 56.25%, with newly resected PDAC who received chemotherapy, immunotherapy and the vaccine were still alive more than 3 years after treatment. You may not know this, and I didn’t until I looked it up just now as it has been a while since I have treated patients with newly diagnosed early-stage pancreatic cancer, but the median OS after (modified) FOLFIRINOX alone in a recent large, randomized Phase 3 trial was 53.5 months, with 43.2% of patients still alive 5 or more years. Did the addition of atezolizumab and the vaccine change anything? I can’t tell and neither can anyone else until there is a randomized controlled trial, which isn’t to cast shade on the investigators — kudos to them as well for a successful first-in-human study — but let’s curb our enthusiasm.

So we have some updated results from a tiny trial that didn’t really move the needle one way or another, and yet Cowen et al. feel the need to push AI into the narrative. To be clear, there is absolutely no mention of LLMs, machine learning, algorithms or artificial intelligence of any kind anywhere in the autogene cevumeran literature. Granted, it is a “personalized” vaccine, meaning that every potential participant had their tumor sequenced and up to 20 vaccine targets identified among the newly mutated proteins. I am sure there was a lot of computation involved. But not every sophisticated computer analysis is AI, let alone an LLM, so I truly don’t see how they could legitimately be brought into the conversation.

And in case you were wondering, no, the screenshotted abstract did not in fact back up Adeoye’s claim. Best as I can tell this was the paper in question, a speculative review article in an obscure journal written by a Shanghai-affiliated group of authors who had nothing to do with BioNTech whose purpose was to be a never-looked-at reference for a false claim, that “AI played a critical role in advancing the vaccine”. Anything for the clicks, am I right?

Adeoye’s behavior was regrettable but Cowen’s is detestable, especially when paired with his look-at-the-sheeple attitude towards humans. ⊕ [Note: The linked to article from Cowen is particularly wrongheaded if you realize who the Luddites really were and that the label should in fact be a positive one. ] Cory Doctorow had warned about AI companies over-promising their capabilities for a short-term gain. But they don’t really need to: there are plenty of useful fools willing to promise on their behalf, giving it credit even where there is none.