Yet, strangely, these results aren’t the case if you look at long term follow up of the randomized studies. Remember unlike a “target trial” a randomized trial is actually that— a trial. Prospectively designed, where the two groups have equalized outcome distributions in the absence of therapeutic effect, and time zero is set in stone. In other words, gold standard science. Take a look here.

And as for myeloma….

What is this…. thyroid cancer is higher…

Thyroid cancer: it is notable that FDA requires a boxed warning here for a different reason… because these drugs can cause medullary thyroid cancer in animals.

The pooled effect in RCTs is confirmed by another meta-analysis I found.

Why are these results different?

Why does a recent observational study show these drugs prevent cancer, but the randomized trials don’t find that signal.

Option 1: There is not enough time in the randomized studies to see the benefit.

This can’t be the reason because the “target trial” has only a median of 2 year with IQR of 1 to 2 years of follow up. The target trial is as brief as some of the long term RCT follow up above.

Option 2: The observational “target trial” study has more power.

Maybe, but probably not a lot more power. The meta-analysis of RCTs has 90k participants, and the target trial is 80k vs 80k. I don’t have enough numerical info in the second paper to calculate power sadly. At first glance, it doesn’t look like there is a huge difference here.

Option 3: The target trial framework, like so much observational causal research, fails.

This has to be a leading possibility because even with the methods of target trial, emulations have failed to always predict randomized trials. The concordance rate is not much better than other methods. This was shown in an FDA funded project in JAMA.

Cancer takes far longer to develop than 2 years, so the overall finding in the new paper is preposterous on face value.

Option 4: The randomized data has other artifacts like control arm crossover or contamination, which biases to the null.

I searched and could not find the crossover rates. Maybe.

Overall: I think it is possible that these drugs will reduce cancer due to weight loss, but this recent annals of oncology paper is unlikely to be true.. At a minimum, the effect has not been seen in comparable randomized data.

It will take longer follow up and better data to make this case.

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ChatGPT, from Open AI, is rolling out a healthcare focused LLM among healthcare providers.

Google has deployed AI results into their search engine, and has already transformed daily searches, including those performed by doctors.

EPIC— the predominant medical record— has debuted AI tools with many more to come.

And some stragglers continue to believe that UpToDate will remain dominant.

All of this begs the question:

Who will win this race?

I can’t answer the question, but I wish to offer 6 thoughts.

1. People who think Uptodate— or any website— where you look up articles by topic and read the full essay— and/or pay a lofty subscription fee to use— will remain dominant, are delusional. They remind me of….

   

2. Controlling the electronic medical record is a remarkable advantage. (Obviously Epic owns this) If, as a doctor is typing the note, or while their phone is using an AI powered app to listen to the encounter and transcribing the summary, relevant ideas are suggested to the physician about clinical care— the doctor will be highly unlikely to look beyond those ideas, and the doctor’s attention will be captured and sated. Just as Gmail suggests email responses, an EMR that suggests you order x,y and z, and explains why, will have a huge, perhaps insurmountable, advantage. Large players interested in this space, with the right advisors, may seek to develop an AI/ EMR and dethrone Epic entirely.

3. Speed of result is the single most important factor that will govern use. Every time you ask AI a question, there is a lag time. Even if one company gains users early, the market share can be forfeited if another product is much more responsive. Doctors, like all people, have no attention span and no patience. A 600ms delay in response is a death sentence. Already google Gemini has blown my mind in terms of speed. How is it possible to return such fast AI results with perhaps a million queries made each second globally? Companies must prioritize this.

4. Doctors will want AI to speculate/ and guidelines are not based in science. I think there is a misconception that Medical AI must hew to well worn paths of knowledge and not to lead into experimental and improvisational medicine. And, don’t get me wrong, I have long been a skeptic of such improvisations, but doctors want to read both well accepted ideas, as well as ambitious and daring ideas. Doctors may not follow those courses of action, but they want an AI that is willing to suggest new hypotheses and treatment approaches.

   Second, and most importantly, AI companies must recognize that current expert guidelines are (a) not scientific, (b) highly speculative, and (c) should not be treated as gospel. A great example is the new cholesterol management guidelines. A group of like-minded individuals, laden with financial conflicts, and entrenched career biases, enters a room and produces a document that is loaded with very specific recommendations that lack randomized evidence. This document has been criticized. E.g. John Mandrola here. Adam Cifu here. Anish Koka here. And many others. The purpose of this essay is not to unpack that criticism, but to suggest to AI companies that different sets of reasonable, smart, dedicated doctors may write very different sets of guidelines. Training AI on the guidelines endorsed by professional societies when evidence is weak will result in inappropriate rigidity, and lead many doctors to bristle at AI use— particularly when the guidelines run counter to their interpretation of the evidence, and give them more work to do. Finally, note, that all the rebuttals I linked to are on platforms (Substack) that would be deprioritized by some of these Medical AI engines.

5. What students need/ what attendings want. AI companies should remember that novices and experts need and want different things. Medical trainees often don’t know where to start when it comes to processing the huge volume of medical information, and experts often simply need a quick reminder of a few details of the protocol. Current Medical AI often strikes me as a very competent 3rd year student— broad knowledge of the canonical thinking— who can do a PhD on any detail you ask about, but that’s very different than an expert physician who has synthesized all of this into a pragmatic and simple flow. AI companies should consider offering a product in medical student vs. attending mode, just like my Tesla’s auto drive can be timid or quite daring.

6. Will the advertisers control the product? Even great medical products like the New England Journal and JAMA or the major medical conferences are controlled ultimately by the advertising companies. Disagreement is curated, heavily redacted, and often dismissed. Studies are allowed to be published with massive missing data and companies are not pressed to provide it. I get it— you can only put so much pressure on your funder. Medical AI however may soon face the challenge that doctors are interested in knowing the limitations and shortcomings to therapies— that the advertisers may wish to de-emphasize. Unlike journals or conferences, there is more competition here, and as such, the focus should be on the user. I would strongly suggest they resist such pressures, and happy to elaborate on that at a future date.

Uptodate has never lived up to its name. Its articles lag new results by weeks, months or years. I loved it in medical school, but it is sadly no longer fit for purpose. Medical AI is the future of doctors and trainees learning and refreshing and refining their clinical thinking. He who controls the EHR, controls the universe. And after that, speed and creativity will dominate preferences. Technology folks and medical folks have different dispositions to new ideas, suggestions, and information— my advice for companies is to be careful that the ‘expert’ advisors you employ are not leading you astray, towards reinforcing entrenched opinions, rather than democratizing them.

From 1986 to today, a death sentence appears to be transformed. Most of the gains happened 2005 to present. Doctors online attributed the improvement to new pharmaceuticals.

Meanwhile if you look at how many people get the disease and die of it annually (adjusting for the population age structure, i.e age adjusted) it looks like this:

The blue line means each year more people get myeloma. And that is NOT because Americans are older, even though myeloma happens with age.

The figure adjusts for this— the graph means that more people get myeloma at the ages of 50, 60 and 70 (on balance) than ever before. From 5 to 8 per 100,000. A 60% increase.

The green line shows the death rate from myeloma, which is declining from peak levels. The graphic captures delaying death. In other words if new drugs extend life— even if all patients eventually still die of myeloma— that would mean more 64 year olds make it to 65, 55 years olds to 65, etc, and the graph would fall.

When it comes to the green line we see a modest decline. From 3 to 2.5 per 100k if you look at all times. A 16% reduction. From 4 to 2.5, if you take it from the peak, a 38% reduction (but why did it go up?)

Let’s look at the same figures from CML as that represents a disease that everyone agrees is a home run.

We see the same impressive PFS curves like myeloma over the last few decades

Yet incidence is more stable and death rate is more than halved. A 70-80% reduction in death rate!

Now we have two cancers, and two sets of figures.

The first figure is a tale of outcomes measured from diagnosis and the second is the population, age adjusted changes

We call outcomes from diagnosis survival and age adjusted death rates the mortality rate.

Both cancers have huge gains in the former, but different outcomes in the latter. Survival looks great for both, but CML has seen bigger gains in mortality.

What gives?

What is responsible for the reduction in deaths?

Why is myeloma incidence up while CML is stable? (Both are blood cancers)

Why does CML have a larger mortality reduction even though both have the same impressive extension in survival?

And the corollaries

—Do we just need to wait longer to see better gains in myeloma?

—are CML drugs given widely but myeloma drugs given more selectively?

Finally: Things are better in all the figures, but which is the best measure of progress?

And Bonus: why is this Substack the first you are reading about this? (You might be asking)

I will answer these questions here.

What is responsible for the gains?

The majority of the gains in CML can be attributed to just one drug imatinib, while only some of the gains in myeloma are attributable to many new drugs.

In myeloma, the major sources of gain are imids, proteosome inhibitors, cd38 abs, and bcma targeted therapy. And btw 1992-2004 auto transplant and eliminating therapeutic nihilism and giving cytotoxic chemotherapy.

Both tumors benefit from better supportive care throughout all times. Likely similarly as both are blood based tumors whose complications include infection.

Myeloma benefits more from advances in and use of radiotherapy as it can have radiosensitive lesions.

Myeloma incidence is up but cml is stable, why?

Both cancers have increased diagnoses because of more opportunistic screening. In other words, the more blood tests you run, the more you will find abnormalities that prompt diagnosis. Spoiler: docs today run more blood tests.

I suspect cml went down slightly and then up bc diagnosis shifted from white count and differential + smear to pcr for bcr abl. Incorrect diagnoses in the before period are offset by correct diagnoses (with less impressive wbc elevation) in the latter. On balance for every case you had wrongly diagnosed you pick up one rightly today. Overall things are stable.

Myeloma is way up bc of a completely different work up landscape with extensive and vigorous use of bone marrow biopsy and pet imaging. Combine this with better immunohistochemical staining, pathologists who like to up call, and you are finding way more cases. Myeloma is more subjective a diagnosis than CML as it lacks a genetic signature.

We have to also remember that the definition was changed by some doctors. Slim criteria are added, 60% plasma cells alone gets you there, etc. Changing the definition expands the incidence overnight. It also ruins the ability of survival to capture therapeutic benefit as it also captures lead time of the people diagnosed who otherwise would not be. It ruins the ability to present the first figure credibly as a scientist.

Some of increase in myeloma diagnosis means finding people who benefit from treatment who would otherwise have been missed in the past, and part of it reflects over diagnosis— finding people who don’t need therapy.

It’s worth remembering that myeloma has a massive reservoir of smoldering and mgus. Meaning many people have expansion of plasma cells that would not historically have caused discomfort or shortening of life. Some are now called myeloma.

Myeloma may yet increase when future doctors change the definition again, which I predict they will do.

Why does CML have a larger mortality reduction? (Even though both have similarly impressive survival gains)

As noted, survival is an unreliable metric of progress in myeloma because the definition has changed, and because the disease is being picked up in people whom it was otherwise ignored or missed.

The reason the mortality reduction is better in CML is because the drugs are better.

As for the corollaries: yes it is possible we will still see further gain in myeloma, but not to the extent of CML based on currently approved therapies.

It is highly unlikely that costly TKI is reaching more patients than costly myeloma therapy, but it is very likely that cml therapy works better for older people who are not included in clinical trials than myeloma therapy does. In other words CML has less efficacy-effectiveness gap— the effect of imatinib is excellent in Americans with additional medical problems, who were not in the clinical studies, whereas myeloma therapies likely have a larger gap meaning they work worse in these excludes patients.

Which is the better metric of progress?

Population age adjusted mortality rate is the correct/ only measure of progress in all diseases. This is not a new insight. It has long been known survival from diagnosis is misleading. A person can die on the same day, but you will improve survival by diagnosing them sooner. Meanwhile, mortality rate can only be affected by real increases in longevity.

Overall: There is progress in both diseases but more in CML. CML is more clearly a success story. There is much room for progress in myeloma. Myeloma is not yet curative, sadly. Presenting survival over time is misleading and masks more complicated narratives.

Why is this the first you are reading this?

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I have just four points

1. 100% of people on the experimental drug eventually progress. There is no curative subset. This is disappointing and different than other agents such as immunotherapy, where there can be cures.

2. 15% of the control arm declines treatment but only 3% of the intervention arm does not recieve therapy. A difference of 12%. These people are likely not random dropouts but the highest socioeconomic status participants with best alternatives. The drop out is patient disappointment. Thus randomization is violated. We potentially have the bottom 9/10 participants (in terms of OS) compared against 10/10. (not all of these persons appear to be censored, which is good, but many are).

3. Gains in OS exceed PFS gains. This raises the question of whether experimental drug is followed by chemo while chemo is followed by hospice or some other palliative option. Thus some of the gains of the experimental drug may be due to this additional care. Yet post protocol treatments not reported to explore this further. Neither in the paper nor the supplemental appendix. This is unfortunate.

4. Daraxonrasib will be harder to give older frailer people due to side effects.

Overall: A significant step forward for patients with metastatic pancreatic cancer but much more needs to be accomplished for this disease. I hope this is only the first of other advances to come in the future.

Also continued best wishes to Ben Sasse whom I have long admired.

Some physicians and researchers, myself included, felt that in order to recommend Paxlovid to younger adults, those who had been vaccinated, those who had already had covid, or both, we needed positive randomized trials to support its’ use. Others, including most famously the Biden COVID Czar Ashish Jha felt that one could extrapolate to these lower risk populations. Dr Jha spent massive tax-payer money on his faith in Paxlovid.

He frequently appeared in the media claiming that Paxlovid was underused, and pushed it widely, even outside of the EPIC HR population.

Many famous individuals who had already been vaccinated and boosted proudly took the drug. (Also from Gemini).

All took Paxlovid.

Meanwhile, my colleagues and I cautioned that the use of Paxlovid in populations outside of EPIC-HR without further randomized data was a gamble. A guess.

We performed a systematic review of all the randomized data, which undermined claims of efficacy.

We warned that observational studies were unreliable, and plagued by immortal time bias and residual confounding. The Biden administrations spending outpaced the evidence.

I pointed out how COVID’s declining hospitalization rate meant that EPIC HR was irrelevant data in a video on the topic, based on a UCSF presentation I gave.

Well, now the results are in:

From 2 trials— the primary endpoint is stone cold negative

And more importantly, the event rate is so low, it would be futile to continue the study.

The authors claim improvement in some secondary endpoints like time till you recovered from symptoms but those are (a) tiny absolute differences and (b) biased and unreliable estimates. In an unblinded, open label trial people who take the pill may report feeling better due to placebo effect and a not real effect. To truly test their hypothesis, the authors should have used a placebo that contained a tiny bit of zinc or other substance to mimic the metalic taste that plagues the product. An active placebo is necessary for these endpoints. Since this was not used, the trial cannot inform symptoms. *the virologic study is uninformative as well, it could be coinicidental & not substantiating.

One final irony is that Jha favorably compared Paxlovid to Tamiflu, a drug nicknamed “Scamiflu” because it’s tiny reduction in symptoms was offset by initial toxicity, and because it didn’t improve outcomes that mattered (like hospitalization)

The irony of course that Paxlovid turned out to be precisely the same thing.

History doesn’t repeat itself, it rhymes.

One last thought for subscribers…

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In 2026, in a world sold on whole body imaging, CT DNA assays, and deep sequencing, do healthy people still exist? Or are they an endangered species?

I was reminded of this question when I heard a debate recently about whether we ought to treat smoldering myeloma (SM).

SM sounds bad— the sort of thing you wouldn’t want to have— I mean, it is smoldering—but what does it actually mean to a person?

Well, the person feels fine. He has aches and occasionally feels tired, but no more than the average joe.

His BMI is normal, he looks good, his bones are intact, his blood counts are reassuring, his kidneys are working fine, and his blood calcium is perfect.

Instead, he has some proteins that are elevated in his blood stream, and when we drove a hollow bore needle into his pelvis (PS: you’re welcome!), we found a higher fraction of some cells than other people would have.

He has a higher chance than the average person to someday have one type of cancer, but that chance is not 100%— the best models likely overestimate the risk (see the Will Rogers phenomenon)— and some people don’t get the cancer even with many decades of follow up— to the point something else strikes them down.

In other words: he might be healthy or seriously ill.

Jesus said, “Those who are healthy have no need for a physician, but those who are sick do.”

In this case, there are massive financial incentives to consider this gentleman sick. Should he take a monthly 10 to 20,000 a month medicine? Should doctors prescribe it?

Our patient who feels just fine, might ask: Will I live longer?

Oohh, tough question. The best answer is it is unclear. OS estimates are early and volatile. The control arm likely got care that doesn’t represent what you would have get as well.

Will I feel better for longer?

Ahhh, good question. Sadly the trial wasn’t designed to answer the how you feel question, but principally measured a lot of other blood tests. Fully explained here:

My friend John Mandrola says, “My view of health prevention is that time spent being a patient is less time living a normal life.” Yet, others may add it up differently.

But it isn’t just cancer

Each week I hear about a “healthy” person who found out their testosterone or vitamin D or some other level was “low.”

What does low mean?

• Outside the laboratory provided 95% CI… i.e 95% of healthy people (perhaps not the same age/ demographics) have labs in this range?

• Randomized trials show you would benefit from supplementation?

• Something else?

How did this all begin?

When I see a patient, I like to understand how it all got started. Sometimes it goes like this:

• I had been losing weight and coughing for many months

• I had been having worse pain in my hip.

• I have been feeling these episodes of being winded

But increasingly it sounds like this

• My doctor scheduled my annual mammogram

• I had some routine blood work, and they asked me to come back for more

• My smart watch told me to come in

Medicine has a professional duty to ensure that the services we offer, on balance, do more good than harm. We also have to resist the temptation not to turn every healthy person into a paying customer. Over my 20 year career, I have seen the profession fall short, and we might not be far away from a world where we see the last healthy person. All of us instead having some pre-condition or abnormal biomarker.

Do we end up living longer and better lives from all this medicalization? That’s a question our studies are not powered to answer, and our profession seems to lack the power to ask.

Bezos makes many important points.

Some fields of business are heavily dependent on government handouts or regulation that stifles competition and ensures profits generated from the public purse— even irrespective of public value. These groups lobby heavily to ensure that system continues, creating a false narrative. In contrast, other businesses truly compete in the free market, and have generated massive societal good. These business are often only hampered by illogical government restrictions.

Bezos makes an important point on whether we should have any tax at all on the bottom 50% of earners in America. It generates a pittance (3% of the budget) with great pain to those individuals. Better to remove it entirely.

Bezos is correct that there is massive— nearly incomprehensible— waste in government spending. Perhaps in some departments the majority of the budget is wasted. And yet, there is no incentive for (and strong pressures against) this reform. Many seem incapable of seeing that not using money optimally is a form of waste.

Bezos is right about the Washington Post. A newspaper that loses money is one that is not relevant. It is not doing the best job for its readers. The converse is not true: a newspapers that makes money is not perfect— it can do better, but losing money is a non-starter.

Thanks for subscribing and ensuring this substack stays relevant.

On the short end of the spectrum, all agree— less than 7 or 6 hours of uninterrupted night time sleep, for years on end, is bad for body mass, cortisol and mortality. I think it is uncontroversial to say that fragmented, short, irregular sleep is not healthy.

On the long end of the spectrum, there is disagreement. Two books advise 7 to 8 hours as the ideal amount, and one even cautions that there are risks to oversleeping. A third book however is more open minded, arguing that some people may benefit from 9 or 10 hours. I discuss the specific books in the video, if you are curious. Spoiler alert: ultimately, I tend to share the open-minded view.

Here, I want to tackle the evidence that is used to argue that more sleep is deleterious. It is an observational study that provides an important lesson for scientific readers. Here is the main result.

The figure shows data from the UK biobank— a longitudinal study of hundreds of thousands of individuals with different sub-cohorts that complete unique surveys and/or imaging or other modalities.

The paper shows a simple observational design that plots a range of outcomes against hours slept per night.

As you can see, there is a J-shaped curve— which is epidemiologic speak for a curve where there is an optimal point. Here that occurs between 7 to 8 hours. Additional sleep is associated with worse outcomes, including cognition and depression.

When you read a study like this, you have to have a crystal clear idea of how they collected the data. Is the x axis— hours slept— coming from a video of participants sleeping? a sleep tracker? a diary? a survey? And, how precisely is the information gathered and coded?

Turns out, it is a sleep survey with this specific question:

It is 24 hour sleep totals, including all naps.

Your first thought should be: that is different than uninterrupted sleep overnight. In fact a person who sleeps 9.5 hours every night is lumped together with a person who sleeps 6 hours and takes a 3.5 hour nap. Or a person who sleeps 5 hours and takes 2 naps.

Suddenly we have at least one alternative explanation.

People who sleep 7 to 8 hours might be disproportionately those who do it at night, while higher hours might include relatively more people who are nappers. Nappers are different than non-nappers because they may be more likely to have chronic medical conditions, more likely not to work, more likely to be otherwise in poorer health, etc.

There is a clue in the lower figure— that among persons most likely to be in the workforce— longer sleep is particularly “bad” but probably only because it is a greater selection filter for these confounders.

I am not aware of convincing evidence that a healthy person is dis-advantaged by sleeping 9 or 10 hours, if their body desires it, and in the video I discuss evidence from Athletes to show more sleep is likely beneficial for athletic performance.

Stay tuned for more updates from this series and a new video on nutrition science dropping soon. But here take home the lesson that all science requires a detailed examination of the methods.

I read 4 longevity books (shown below), and over 100 of the underlying research articles to put together this series, and the first episode introduces my philosophy on the topic, as well as includes Episode 1, Sleep Science, which I will cover in a separate post.

My rules are simple: I am interested in advice given to healthy people to enhance their quality and quantity of life. Of course, I love CAR-T therapy— and happen to know a bit about it— but that is out of scope because CAR-T is being used and developed to treat people who are ill. Instead, I want to know what a healthy person should do to live longer or better.

Next, I read books that spanned a range of voices— from functional medicine doctors to professors. Yet, no matter the ‘expertise’ of the writer, I neutrally appraise the underlying evidence. I am also fascinated by the sheer volume of recommendations that the books have in common— despite the dramatic differences in the authors backgrounds and approaches, and I feature those prominently.

Third, I am interested in, and will judge adherence. Advice that cannot be acted upon and adhered to is wasted breath. If adherence didn’t matter then every diet every devised with caloric restriction would be a winner. You could tell people to follow the “don’t eat anything diet” and complain that anyone who is unsuccessful simply did not adhere to it. Of course, this is ludicrous. Part of what we seek with diet advice is something we can live with and incorporate into our lives.

I believe that just because adherence is high doesn’t mean something extends your life, but rather that we can further investigate it. Instead if adherence is abysmal— then an intervention probably won’t work, and is not worth our time.

Consider a high and low adherence intervention. Many observational studies show pet ownership is linked to living longer. I love dogs, but am unpersuaded this association is causal, i.e. owning the dog extends your life, rather than confounded, people who are living longer and better seek the companionship of a dog— but one thing we must admit is that adherence is high. If you get a new dog, 90% still own the animal a year later. (Interestingly no book recommended pet ownership).

Contrast this with a piece of advice that does make one book: introduce yourself to a new person each day. I spent time trying to find a study of how well people could adhere to this practice, but couldn’t. My commonsense is the same as yours— it is likely unsustainable. As such, I don’t put much stock in it.

Finally, I draw a distinction between avoiding untimely death— i.e. living to 80 instead of dying at 55 from a heart attack— versus true life extension— living to a 120. I am happy to concede that there are many things that can help us prevent untimely death, but which of the authors’ advice pushes us into the latter category. I will discuss over the series.

Listen to the audio podcast here, and video link above. And I will be back with more installments in this series. I also have book reviews, and more observations and thoughts to share with you.

The film depicts two weeks in the life of Hirayama, a toilet cleaner in Tokyo, who indeed lives Perfect Days. Koji Yakusho’s near silent performance is deserving of all the accolades it has received and more. In the final, two minute close-up of his face, (Spoilers to follow) we witness all the emotions of life: joy, sadness, disappointment, regret, betrayal, pain— and the way life gives it to us, unpredictably— washing over his face. The scene itself a staggering aesthetic achievement.

How can you live perfect days when you scrub a toilet? Wenders spends two hours showing the audience. By appreciating everything. By noticing the sunlight filtering through the leaves, casting dancing shadows. By taking pleasure in your job, no matter what it is. And, by accepting what life gives you: one day, your colleague calls in sick and you work like a dog, the next, your niece visits you unexpectedly.

And all the details: the cassette tapes, the stereo, the simple desk lamp on the floor, the buckwheat pillow, his coins laid next to his watch and keys— Wenders shows how joys of simplicity and a world where everything was analog.

When I was a high school student, my summers were like Hiroyama. I worked in a grocery store, bagging and pushing carts. I must have read a 100 novels a summer, devouring the same writers Hiroyama reads. I listened to music on my car’s Sony CD player, which I personally crammed into the dashboard. Later, this would lead to an easy theft. After work, I would drive to my friend Colin’s house. I didn't have a cell phone. At the time, I felt poor, but what was that worth? More than all of Hiroyama’s cassettes.

I read that the initial title of the film was Komorebi, which is a Japanese word that means to appreciate the light filtering through the trees. In our modern world, this has been completely lost.

The only time Hiroyama drinks in the film is after he witnesses his favorite waitress in an embrace. But he misunderstood the situation. Her ex husband was dying of cancer. As the husband reflects on his mortality he asks a simple question: do shadows get darker when they overlap?

That's how life is: when we die, it feels like we barely scratched the surface. We don't even know the answers to the most simple questions. Yet Hiroyama shows us life isn't over yet for any of us. Hiroyama tries to answer the dying mans question, on the bank of the river, under the street lamps. Their game of shadow tag, takes them back to childhood, the moments of pure unadulterated joy.

All the best moments in life are simple. Sitting in the grass on a sunny day. A dinner with old friends. Listening to a cassette tape.

Recently, a friend I hadn't seen in many years stopped by for dinner. He lamented where we were as a country, and said he wasn't sure that he would bring kids into this modern world. I told him what I tell everyone: that those thoughts are a mental illness, and should be purged. He was brainwashed by the brainwashed people who write for the news. He cared too much about politics that was more ambiguous than he would like to admit.

I gave him some advice. I told him he already didn't use social media, all that was left was for him to stop reading the news. He was so close to having perfect days. He just couldn't see it. But neither can so many of us. It's right there.

Here are my tips for how to read news stories in the era of biased and weak reporting.

Step 1. Fact check the source material. If you read an article that says Jay Bhattacharya supported the use of Ivermectin, locate the raw video or audio. You will find the article is factually wrong. Jay supported conducting randomized trials of ivermectin. I have had countless essays misinterpreted and misconstrued by illiterate journalists.

For e.g. this essay, read exactly what I said.

Step 2: Look up the quoted experts. If there is a quote by former CDC director Mandy Cohen, you can quickly find that she is the kind of scientist who actually thought cloth masking would make a difference (=/- praying to lord fauci?). AKA neither smart nor reliable

Another example. Michael Osterholm. How much of an ‘expert’ can you be if you were wearing a mask 3 YEARS after the pandemic started?

Step 3: Don’t listen to panicked statements from people who are worried about losing their jobs or funding. Of course researchers who are funded by taxpayers to study DEI will say that cancelling their funding will kill millions or billions of people and lead to a comet striking earth. But they are not objective. Someone fearful of their own job/ or someone recently laid off has no objective view on their value. Just ignore them, and seek out third parties who are not directly affected.

Step 4: Put things in context. If you read CDC has laid off 10% of the work force, ask how big the workforce was 3 years ago or 5 years ago. Often the media is depriving you of broader context that shows it is not that big a deal.

Step 5: Anyone who uses the word “misinformation” is an idiot. Scientific arguments exist on a spectrum from high to low confidence. And even some weak arguments contain a kernel of truth. For instance, COVID vaccines did harm one group on average— for mRNA young men btw the ages of 18-24, high confidence, and 12-40, slightly lower confidence. Misinformation is a word used by weak thinkers who don’t understand the nuance of claims. It is poorly defined and has been overused to the point of meaningless. Often they mean to say: I just disagree.

Step 6: Read prior stories from that reporter. Some reporters are hopelessly bad. We analyzed NYTimes corrections, and found one reporter is a correction factory. If a single spine surgeon for e.g. was an outlier like this with so many botched surgeries, you would suspend their license, and yet, reporters face no accountability.

These are 6 tips to combat the current media, which is doing a horrific and dishonest job of covering this administration. If you want to support someone who is objective, please subscribe.

1. Helen’s argument that COVID-19 shots can’t be tested because the timespan the virus is transmitted is within a short season is false. The virus spreads year round. This is a basic fact, and in contrast with the actual seasonal respiratory viruses.

Contrast that with Flu and RSV

2. It is standard practice for vaccines to undergo clinical testing, showing improvement in clinical endpoints, prior to approval. This standard practice was even adhered to in 2020 with the initial vaccine studies. Although we can debate the methodological rigor of the trials, they were done. It was later abandoned in the setting of subsequent boosters— leading to the resignation of Gruber and Krause at FDA— but there is no logical basis to abandon it now, as the risk of bad COVID outcomes has fallen.

3. The American people have shown they are unwilling to get an unproven annual booster. Rates of booster uptake remain abysmal. This graph would be EVEN WORSE if you include babies over 6 months olds. The surest way to get a lower percentage in 2025 is to further waive the basic requirements of trials.

   

4. Other nations do not give COVID shots annually to all babies over 6 months old. This is not the practice across Europe. It is hard to fully capture just how absurd such a policy is. Taking the lowest risk individuals in a society and exposing them to an absolutely unproven, injected novel medical product. Under Joe Biden, America was a demented outlier.

5. As vaccines undergo strain modification, they are entirely new products. Their efficacy and safety may be untethered from prior products. Without trials, it is only a matter of time before the FDA approves a vaccine that causes some bad outcome like vaccine-induced narcolepsy If this happens, you can kiss faith in vaccines goodbye. You will see vaccine hesitancy like you have never seen before. The FDA must have a strong commitment to safety and efficacy to preserve vaccine’s remaining reputation.

Folks who think COVID-19 vaccines should continue to roll out without randomized trials are anti-vaccine, anti-science, and pro-corporate.

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Yet, in the article, I was disappointed to read this quote by Paul Offit, whom I generally respect.

“It’s like in Jurassic Park, when the Tyrannosaurus rex keeps checking where in the fence is a weakness,” said Paul Offit, a pediatric infectious disease specialist at the Children’s Hospital of Philadelphia. “He could do a lot of harm. I think he will do a lot of harm unless somebody stops him.”

Removing an unproven vaccine from the schedule, and one that is widely not accepted in Europe is not akin to letting a t-rex escape, but rather an important course correction. Medicine must admit when we make mistakes. If anything, removing unnecessary shots from the childhood schedule will bring focus to the necessary ones, such as measles.

Next, look at this. The CDC is finally contemplating what it should have done ALL ALONG. The COVID shot should only ever have been recommended to populations with a net benefit.

It is astonishing that this is remotely controversial. As you well, know, I, and some of my colleagues, have been saying this all along.

The Trump administration wants universities to do some things. Ban masks so protesters can be identified. Note: there is no evidence that community masking improves any health outcome based on high quality data. End DEI. Use merit to govern admissions and many other things. Right now, universities are squirming. Harvard claims it will #resist. But they are borrowing cash and will soon be crippled if they do not capitulate. I think Alan Garber is smart enough to know this.

Let us be clear. This is not censorship. Harvard can give up federal funds and stop admitting whites and asians and men, and only admit under represented minorities. It can violate title IX, and commit fully to DEI. But as long as it chooses to accept public funding, it must follow the rules of the federal government, which are numerous. Trump is adding to these rules in an effort to make universities less woke.

The American people voted for this. They are sick of faculty being cancelled for saying “pregnant women” not “pregnant persons”. They think “people with uteri” is Orwellian. It's women. Why do unis hire someone to review slides to police for these words? (They do!)

They don't want Harvard to admit students who need to take remedial math (Google it), but rather the best. Universities meanwhile want to fire faculty who supported school reopening. If a faculty member opposed cloth masking 2 year olds, universities worked to punish that view, stripping them of teaching duties. In other words, universities are completely lost: veritas is replaced with left wing partisanship.

They also won't fix themselves. They don't admit error. They keep lying about lockdown and masks and school closure and gender medicine, etc. They have hired so many deranged left wing faculty to the point that the avg university professor makes AOC look conservative. Enter Trump: with the mandate of the people, he seeks to punish universities.

He is just getting started. First he threatens Harvard 9 billion in funding. He stops 2 billion. They fund raise 1 million, so they are only minus 1999 million. Next he threatens their tax exempt status. Next his DOE asks for a list of all foreign donors. Harvard does not want this. They will soon find unimaginable dirt. If Trump's IRS kills the tax exemption Harvard is game over. And Trump can do so much more. He can run Harvard into the ground. Harvard has no leverage on him. Trump can wipe Harvard from the face of the earth.

Some say Democrats would never do this. That is because they don't have to. When Biden wanted Universities to fire workers who didn't get a covid shot, he didn't threaten their funding. That's true. He just called and asked. Biden’s admin used soft power to make Universities their puppet. He fired nurses who got COVID on the job. Only a fucking moron would do that. Universities happily complied. That's because universities just do whatever Democrats ask for. That's how deep the bias is.

I think if a university takes federal funding, the average faculty should be close to the average American. Some faculty should be conservative, and some liberal, and the average should be centrist. At a minimum, universities should not punish faculty with views that align with conservatives. That's not the case.

And until it is, Trump should use all his powers to crush universities. He has no alternative. And Harvard has no public support. The average American thinks they have their head up their ass. The average American is right. Universities are a Democrat think tank. So why should tax payers fund them?

Ultimately, I am confident that Harvard will comply. They will comply because I think Alan Garber agrees that dei has gone crazy on Harvard campus. I think he agrees that viewpoint diversity is in crisis. I suspect he agrees that the treatment of Roland fryer and Martin kulldorf was inappropriate. I bet he is sick of incessant protests. And he knows, Harvard cannot afford to lose the money.

But Garber is smart enough to know that he can't look like he agrees too easily. If the faculty at Harvard smell that he is capitulating too quickly, he will be fired instantly. You saw that happen at Columbia.

He has to give the appearance of fighting back. And that is what Harvard did today. But make no mistake: Harvard will yield. All universities will.

The last few weeks have highlighted that universities are a giant welfare program funded by the taxpayer. Instead of trying, even a little bit, to represent the views of Americans, they went completely insane, and preferentially, almost exclusively, represent the views of a deranged minority on the far left. It's far beyond the humanities. It permeates biomedicine. It's the reason why you would reprimanded for saying 2-year-olds shouldn't wear a cloth mask. Because the people with power in the University have become left-wing ideologues who turned off their brain, or, even if they are not, they know they have to Shepherd so many such people.

The Trump administration has correctly deduced that they have all the power. These universities are completely addicted to this cash. Without the cash, taken from plumbers and bus drivers, they will go belly up in a matter of months.

They can sue all they want in court. But if the Trump administration merely delays the payments, files appeals, and otherwise relies on the machinations of government delay— that will be enough to cripple universities.

Anyone who works at University who was forced to write DEI statements or forced to take DEI training (akin to indoctrination) knows that Universities have gone too far. The American people don't care about the suffering of academics who didn't care about school closure or the other major expert lies. Thus Trump has the perfect moment to apply maximal pressure. And notably, universities have no way to pressure Trump back. It's entirely asymmetric.

For these reasons, and because I believe Garber is smart, I think he is trying to thread the needle of complying with Trump, while keeping his job at Woke University. An initial strong statement was needed to save himself. And now, the slow, and eventual capitulation begins. To be perfectly honest: many of these reforms are needed to make sure the set point of Universities mirrors the set point of America.

There are lots of things I prefer to avoid. I don't eat cake. I don't eat fries or any fried food. I don't drink sugary drinks. And yet, like many, I am not perfect and once every few months I do. If I am travelling and jet lagged and skipped meals and feel headache-y and have to give a lecture, I will have a coke. If I am in Belgium and order mussels, I will eat pomme frites. If it is a special occasion, I will have a piece of cake.

In these situations, I don't want a diet coke. I want a Mexican coke with real sugar not high fructose corn syrup. I don't want a cake baked with half the sugar and half the butter, but one that sticks to the recipe fit for Paul Hollywood. I don't want fries cooked in safflower oil, but ones made in tallow.

If you are going to indulge, then indulge. And yet, I see so many protest this philosophy. Don't eat fries, but if you do, it's better they are cooked in shitty oil and are floppy and lifeless. Really? Don't drink coke, but if you do, take the one with aspartame. And the shitty cake that comes in a box and doesn't rot is the same as the handmade cake from simple ingredients with butter frosting. Proponents of this view cite disgracefully poor observational studies and act so confident. Seed oils are better than tallow they claim!

Really? If you randomize people to tallow vs seed oils do they eat the same amount of fries? Do they get hungrier sooner? What else do they eat over the course of the day? If tallow makes the price go up, do they eat fries less per month? Also what about pleasure, texture, mouth feel? What happens to mood?

They have no fucking clue. And yet they keep talking.

The move away from simple ingredients to processed ones was largely a profit maximizing move by the food industry. Improving shelf stability makes more money. Meanwhile, the quality of food has deteriorated from a chefs/ diner perspective. That's why Bourdain continued to use tallow. That's why Bakers use butter and eggs and not margarine and whatever sad polymer you need to replace eggs.

Along comes RFK and others who are skeptical that advances in food technology are unalloyed good. They want to ban or reduce dyes and stabilizers and novel oils that can only be produced under industrial level conditions. And many oppose this saying: we don't have strong evidence that these are harmful.

Who gives a fuck? The entire modern American diet is the end product of unprecedented chemistry for which there is no evidence people are healthier. And, the food tastes shitty. And, any chef worth their salt, rejects these conveniences from their kitchen. So why is the burden of proof to show that tallow is healthier and not the other way around? And what about all the forgotten and understudied aspects of eating?

In the absence of data on all these questions, I think it is better to stick the recipes, as they were intended to be made, and as they have been made for centuries. I find it odd to defend seed oils and dyes and food that doesn't rot.

It's funny to me that the same people who happily consented to closing schools for poor kids for years, absolutely indifferent to their suffering, saying nothing, while simultaneously sending their kids to private school, have finally found an issue worth #resist ing: their government subsidized jobs.

Yet unspoken throughout all this is a series of assumptions:

1. All scientific work being done is scientifically credible

2. If 10 scientists can find 1 cure, 100 scientists will find 10 cures (science is like a lottery and each ticket has equal odds)

3. Diversity research helps poor, black and hispanic kids

4. The best use of taxpayer money are these grants. They are more valuable than other uses like improving nutrition in kids schools, etc.

5. It is totally ok to preferentially fund grants loaded with DEI buzzwords. It is totally wrong to preferentially cancel grants with DEI buzzwords

6. It is totalitarian for a new government to pressure universities to do what it wants.

I think the challenge is nearly all these assumptions are wrong. Let's take them in turn.

All scientific work being done is scientifically credible.

The majority of science is neither true nor useful. Much of this work— particularly on hot issues like DEI- is prima facie biased. They won't publish results that don't fit the narrative (see recent gender identity study NYTimes). The methods are flawed. And much of even apolitical basic science is entirely irreproducible. The product of a system with massive incentives to make tall claims and nearly no incentives to verify them. The research being cut is some of the lowest quality science. Worse, universities don't even attempt to verify their own labs. Labs rarely reproduce their own findings. It's a sea of bullshit and most are happy to look the other way.

If 10 scientists can find 1 cure, 100 scientists will find 10 cures (science is like a lottery and each ticket has equal odds)

We know nearly nothing about he relationship between scientists and discoveries. Many of the real discoveries are forced moves in design space, as the philosopher Dan Dennett would say. Meaning that within a short period of time, multiple groups will reach the same conclusion. E.g. crispr-cas9, sequencing the human genome, sequencing 1000 pts with AML and looking for recurring mutations. Very likely science is a lottery where in the beginning of funding, each ticket has greater odds of winning, and then with excess funding, tickets have diminished odds. We don't even know. Moreover, we train far too many phD students. They are used as indentured servants. Dulce et. decorum est. pro patia mori.

Diversity research helps poor, black and hispanic kids

To my knowledge there is no credible evidence that funding upper class and upper middle class academics to study diversity has helped poor black kids writ large. It has however given a lot of academics something to be smugly morally righteous about. It's like giving Generals more money to study the rations of soldiers and then watching the Generals get private drivers and chefs and the soldiers eat the same canned sardines.

The best use of taxpayer money are these grants. They are more valuable than other uses like improving nutrition in kids schools, etc.

Again, it is almost certainly not the case. Imagine a pipe has blown in my basement and it is filling with water. I could hire a plumber to fix it or an academic to study the problem. Obviously, remote, via zoom.

It is totally ok to preferentially fund grants loaded with DEI buzzwords. It is totally wrong to preferentially cancel grants with DEI buzzwords

This one I love. The Biden administration went so overboard with DEI. For a while everyone was told to find a way to tie their work to diversity. And, like sheep, most complied. And no one protested. Then we had an election and the shoe is on the other foot. Canceling a grant given and never funding one in the first place are treated very differently psychologically but practically they are similar.

It is totalitarian for a new government to pressure universities to do what it wants.

It is not. It's the consequence of elections. And if they did not take these actions: what would happen? Universities would slide further into mandatory DEI statements and training and pledges. Protesting would become the new most popular major. Faculty who voice different opinions would not just be pulled from teaching duties and stripped of teaching positions (as we saw during the pandemic), they would be forced to wear a sign “misinformation spreader, per MSNBC”. The only check and balance on universities is the public. And they are owed that right because as we see: Universities are a welfare program, so addicted to federal funds. The center point of the public and woke University is so far apart that a reset is needed. Even if it is painful to some, and, even if, it sometime misses.

Just like the pandemic, the media is totally wrong about what is going on today. They are in the “make sure you wipe down your packages” and “let's turn to Apoorva for school facts” stage of their coverage.

First, the media keeps talking about mass lay-offs but does not put this into the context of HHS growth over time. A reader sent me the figure I was asking for. HHS staffing by year.

I would not have truncated the y axis, but the point is clear. The recent cuts merely reduce the bloated agency to earlier staffing levels.

Second, this is White House guidance for what NIH grants to cut

It all seems reasonable to me. Issues that the voters directly voted upon. I would cut most of these as well. Vaccine hesitancy is an important issue, but most current researchers are not studying it honestly. They do not consider the impact of the unethical Biden vaccine mandates on public trust.

Finally, this was cut off from my last post

This issue remains entirely undiscussed in the media.

The media coverage has used words like blood bath, or the FDA is dead, or the US is over. Yet, here are some questions I have not seen answered.

1. The reduction in work force returns the size of these agencies to what levels? 2019 levels? 2015 levels or 1976 levels? The media coverage suggests the latter, but given the massive growth of these agencies we may be talking about the former.

2. In the private sector corporations downsize of all sorts of reasons, including incorrect ones. What is the burden in the public sector? Can it never downsize? Does it have to first commission a ten year committee to find out who should be laid off, and, in doing so, hire a few more people in the interim? How often do politicians run on cutting government size and actually cut government size?

3. Where is the US on the curve of spending on biomedicine and biomedical advances? Are we on the steep slope, i.e. each dollar spent means many more cures, or are we on the flat tail, meaning that we have long surpassed efficient spending. (provide data not quotes)

4. When people are laid off, how many staff remain in those departments? How many entire departments are instead gone, and what did they work on?

5. When experts are quoted, what percent were appointed by Democratic presidents?

6. And …

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At FDA, Peter eventually became director of the Center for Biologics— overseeing vaccines and gene therapies. In this role, he made some of tbe biggest regulatory errors in the 21st century.

Without randomized data regarding clinical outcomes, he repeatedly approved COVID boosters for kids as young as 6 months

Without randomized data he approved these boosters for individuals who recently had COVID

When Biden wanted to mandate the COVID 19 vaccine via OSHA and to military members and to pressure companies to do the same, he faced a challenge. The vaccine was authorized only under Emergency use authorization and not full biologic licensing agreement. Legal experts disagreed if a vaccine could be mandated without BLA.

Peter Marks then pressured Gruber and Krause at FDA to grant full BLA. When they did not play ball, Marks pressured them to resign (This was also documented in Krause’ testimony to Congress.

Then, with the BLA in hand, Biden was allowed to advance the single greatest anti-vax action in the 21st century. Mandating a vaccine that did not halt transmission and has no third party benefit.

This has resulted in massive vaccine hesitancy.

Then to top it all off, Peter was a long time proponent of lowering the bar for gene therapy. Against the advice of 3 FDA scientists on 2 occasions he granted both accelerated and regular approval to Sarepta’s Duchenne’s MD gene therapy. A therapy that has no evidence it helps boys. Sadly, now, at least 1 is dead

Peter Marks, single handedly has indirectly killed more boys with DMD than he has saved with this regulatory action. The drug does not actually improve motor outcomes in randomized trials.

Meanwhile the media is lying about Peter Marks. They state that Marks was pressured to be anti-vax by RFK Jr. Yet, no single specific action is cited. What precisely did RFK Jr ask Marks to do? Some articles even call Marks a hero, and he is praised by past FDA officials who now consult for drug companies or serve on their board.

In short, Peter Marks was one of the most dangerous, pro-pharma regulators of the 21st century. He is leaving and crafting an narrative that portrays him as a saint. That’s natural. But what is shocking is that the media is so uncritical, and not honest about his actions. The same media that lied about lab leak, masks, and all things covid is lying about Peter Marks.

Overall, he is what happens when a mediocre academic becomes a pro-Pharma FDA regulator, and makes a series of the most calamitous mistakes in 21st century drug regulation. Because of him, the American people are poorer and worse off. Companies meanwhile profited from his actions. My only question is whether he starts working at Pfizer, Moderna, Sarepta or a consultant for all three.