Research Translation Podcast

I entered med school in 1994, three years after 60 Minutes’ infamous “French Paradox” segment. In it, Morley Safer traveled to France to investigate why French people live longer and better, despite eating far more cholesterol-rich and fatty foods than Americans. Conclusion? Red wine. Which the French have at lunch, dinner, and as a gargle after brushing their teeth.

Like most of America, which saw an instant jump in red wine sales after the segment, my instructors were believers. Perhaps it was the show’s close-up of differently colored poop from lab rats (sacre bleu!), or the microscope slides of clogged arteries (mon dieu!), or the mouth-watering cheese shop visit (oh là là). Whatever the hook, my teachers made me a believer. As a result, since my grandfather had died in his 50s from a third heart attack, I began drinking a glass a day of red wine.

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But this meant figuring out what type of wine I like, and it quickly became clear that bottle labels weren’t helpful. Also, wine books and wine language made me want to kick the s**t out of someone. So I started blind tasting. I explained to salespeople and wait staff that I was trying to learn about wine. I would tell them a price cutoff and ask them to choose, then cover or hide the label. And I would try to guess the wine.

Sommeliers and wine people loved the challenge. They would giddily pick their most instructive lesson, or their best deal, and after I tasted we would discuss it. I learned a lot, and was wrong a lot. Eventually, friends joined ‘The Game’ and we played regularly. Thirty years later, the game continues. I haven’t chosen a wine for decades. My favorite nights involve a wine bar, a mystery wine, and a crossword puzzle.

One such recent evening I was approached by someone who asked if I do it to “stay sharp.”

“The wine, or the crossword?” I asked.

She looked over my shoulder, “Four down is ebb.”

Seemed like a good guess that my rude interloper was referring to crosswords, not wine. More importantly, this nervy nebbish had committed a serious faux pas by calling out an answer on my crossword. The coup de grâce: she was wrong—it was ‘eel’.

J’accuse!!!

The evidence red wine can stave off dementia is, notably, observational (read: weak, unreliable, merde). But for crosswording there is, incredibly, an excellent randomized trial.

Starting in 2017, at centers in New York and North Carolina researchers randomly assigned 107 people with mild cognitive impairment to perform either weekly cognitive training games on a computer or weekly crosswords. MCI is a kind of pre-dementia in which there are changes in memory and other cognitive processes, but people are still functionally independent and safe. (When people stop being able to independently complete or handle the tasks of daily living, it’s dementia).

The training games for the study subjects were designed to improve memory, visual matching, and processing speed, and became increasingly challenging. The crosswords were equivalent to a Thursday NY Times crossword (they get tougher through the week), and didn’t change. Then, after a year and a half, the researchers measured any changes in cognitive function.

Their expectations for the trial were based on a seminal 2002 study of healthy elderly adults, in which cognitive exercises, not crosswords, improved performance and daily function durably (immediately, and 10 years later). Therefore the researchers guessed that the group assigned to do games would fare best. Since cognitive decline is generally thought to be irreversible, but can be slowed, they hoped this might mean slower declines for the training games group than the crossword group.

But that’s not what they found. Au contraire! Weekly crosswording didn’t just slow decline better than games, incredibly, it actually improved cognitive function.

Excusez moi?! Improving cognitive function in such trials is virtually unheard of. Which is why the crossword study is a potential game-changer (literally). Perhaps, it seems, cognitive decline isn’t hopelessly progressive.

After the recent, and brazenly misrepresented, failures of the new Alzheimer’s drugs it’s worth revisiting the crossword data to find some Zen. There is hope, after all.

There are also, however, caveats. For one, the trial enrolled people with MCI. Whether crosswords will help me ‘stay sharp’ is still conjecture. Plus, the study is small and participants were a well-educated, mostly white crowd, averaging four years of college. The study will need to be replicated, preferably in a much more diverse group.

In the meantime, however, the best available data strongly suggests crosswords are good for cognitive function. I can also attest they’re kind of addictive.

And despite the fact that red wine is no longer de rigueur, or à la mode (or even really supported by any good evidence) it’s still fun to blind taste, yet another way of exercising the brain.

Or maybe pickling it. If so, c’est la vie.

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Readers note: Due to time constraints and editing issues this week is podcast/audio ONLY. Sorry to my dedicated readers, I’ll make it available for those who want to try and read the transcribed audio (looks weird to me, guess I should clean up my verbal work…) and I’ll get back to writing soon. Happy to have any thoughts on which you like better or use more, too.

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Aiming to place a daunting 18-foot model of Stonehenge on the stage, Nigel Tufnel drew the structure on a napkin. Ian, manager of the mockumentary band Spinal Tap, took the napkin to a prop designer, who then built what she saw. Unfortunately the drawing used double quotation marks for size, indicating inches rather than feet. Too frightened to tell the band of the flub, Ian surprised them mid-concert by unveiling the tiny Stonehenge (and tiny people to dance around it).

Last week the New England Journal of Medicine published the research equivalent of tiny Stonehenge. The flu drug being studied was embarrassingly ineffective, unable to keep the flu from spreading within households. This result was clear enough that anyone who read the study (or the abstract) knew it. Based on the broad failure of drugs in the same class, like Tamiflu, this shouldn’t have been surprising. But also unsurprising was how the study authors applied multiple layers of lipstick to their shiny new pig.

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For instance, they magnanimously concluded the drug “led to a lower incidence of transmission of influenza virus to close contacts than placebo.” Which is weird, because the drug did not prevent illnesses in close contacts.

Here’s what happened. To determine whether the antiviral drug baloxavir could reduce household transmission, the researchers randomly assigned 1,457 people ill with influenza to baloxavir or a placebo. Then, for 5 days the researchers recorded the nasal swab results and symptoms experienced by 2,681 people living in the same households.

By reporting the swab results as a primary outcome, the study authors were able to claim that 4% less in the baloxavir households tested positive than in the placebo households (9% vs 13%). The study was large enough that this measly (and clinically unimportant) difference was statistically significant.

But much, much more importantly the rate of flu illness was 5.8% vs 7.6% in the two groups—statistically the same. In other words baloxavir didn’t prevent close contacts from falling ill, but it did slightly reduce the chance of finding traces of the virus in a person’s nose.

Which one, would you guess, matters to the study participants?

It is borderline hilarious to have the researchers claiming the drug worked, when we all know what the participants would say. It’s a lot like having little people dance around a little Stonehenge, while a band manager pretends it’s exactly the effect they were hoping for.

There’s a darker and more disturbing note, however. The trial was sponsored, executed, and authored primarily by employees of the manufacturer (Hoffman-Laroche). We expect drug company employees to distort and spin results. But in this case they deliberately planned an 18-inch Stonehenge. The study was designed to show a difference in nasal swab results—illness, the thing that matters to people, was an afterthought. In other words researchers knew the drug couldn’t prevent illness, so they targeted a meaningless surrogate instead.

But they would only do such a thing if they also knew the New England Journal of Medicine would both publish their study, and allow them to claim victory. And indeed, the Journal went further, preparing and posting a video to hype and advertise the result, a promotional service offered only to select papers hand-picked by the editors.

In 2005 Richard Smith, a longtime editor-in-chief of the prestigious British Medical Journal, wrote that medical journals act as “an extension of the marketing arm of pharmaceutical companies.” The baloxavir study is a brazen and odious example. For not only did the editors fail to point out the emptiness of preventing a nasal swab result; not only did they allow the authors to claim unqualified success; not only did they publish an editorial suggesting the drug might be great for a pandemic (stockpile, anyone?); they also took special steps to highlight and amplify the deceptive findings.

When Spinal Tap unveiled their wee Stonehenge, accompanied by threatening music and an ominous narration, the crowd guffawed. Only Ian, the band manager, could even pretend it worked. Similarly, when a drug company claims breakthrough success for a drug that any educated reader can tell helps no one, the Journal should be the crowd—not Ian. Instead, their peer review is ineffectual and their editing incompetent, as it was decades ago for Tamiflu, and continues to be for Alzheimer’s drugs, cardiac risk, paxlovid, stents, and more.

This is why the conclusions from most New England Journal of Medicine studies should be taken about as seriously as an itty-bitty Stonehenge.

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In 1908, three years after Albert Einstein proposed the Theory of Relativity, Hermann Minkowski offered a theory of his own. Minkowski, one of Einstein’s teachers, said the best way to explain the undeniable math of Relativity was to understand space and time as a single, four-dimensional entity—a continuum of space and time. More than a century later Minkowski Spacetime endures.

From Minkowski we therefore learned everything, literally everything, exists on a continuum. It should be unsurprising, then, that health and disease are no different.

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When, for instance, does everyday sadness tip into the disease called Major Depression? Tricky. Psychiatrists use criteria that are, in essence, a way of gauging severity—in other words, determining where someone is on the continuum.

I was an incorrigible a*****e during my mania episode a decade ago. As neuropsychologist Stephen Hinshaw wrote of his father’s mania, “When full-blown mania hits, irritability and anger are part of the picture just as much as euphoria and expansiveness.” I lashed out at my wife, lied to friends and family, and thought only of myself. But assholery wasn’t new to me—I was capable of it long before that. Still am.

And yet, just as the boiling frog is deceived by a gradual change in temperature, manics and their families typically miss the transition. Why? Because mania exists on a continuum with normal fluctuations in mood and personality. A friend once recounted how, toward the end of her own manic episode, she fell madly in love and eloped with a wonderful man. Her family, who had been frustrated with her odd behaviors, finally realized something was terribly wrong—because she is, and has always been, a lesbian.

The absence of a clear tipping point for disease is common, and not just in mental health. Most men over 50 will die with prostate cancer. Not of it, but with it. In other words it can be found on autopsy despite never affecting its host. Which is why screening for prostate cancer is controversial, and (like most other cancer screening) has failed to save lives in large trials. Finding cancer may be important, but only if it’s dangerous. Even cancer exists on a continuum.

Dementia is trickier still. At age 55 my memory isn’t getting better. I constantly forget why I entered a room and I’m terrible with names. But that’s not new. It’s just worse. (I think). Because cognitive impairment, like everything else, exists on a continuum.

Contrary to the claims of many, dementia can’t be diagnosed by MRI, or a blood test, or a PET scan. The new blood tests in the news do not test for Alzheimer’s (despite media and even expert claims). Instead, they test for the brain plaques that can be found in most who die with Alzheimer’s. But like prostate cancer those plaques are also present in most older people who don’t have any signs of Alzheimer’s.

Healthcare profiteers have learned how to monetize this grey-scale of health and disease, mostly by pretending the normal end of the continuum represents disease. The new dementia blood tests, like the pricey (but dangerous and ineffectual) new drugs for dementia, target the amyloid plaques that are so often found in perfectly normal brains.

The strategy of disease-ifying the normal works similarly with, for instance, cholesterol. Targeting cholesterol—instead of heart disease—has generated trillions in profits. Similarly, most partial blockages in the coronary arteries are a normal part of aging that the human body works with, or around. Targeting them with stents, a harmful practice in most instances, yields billions annually. And targeting prostate cancer, instead of deaths due to prostate cancer, has yielded an economy of biopsies, imaging, and treatment, overwhelmingly for cancers that pose no danger.

And so it goes with dementia, which is common (about 15% get it eventually). But concern about it is ubiquitous. Other than in extreme cases, properly diagnosing dementia is a slow, complicated, stuttering process. There is no single test and the continuum is different for different people. Making the diagnosis means ruling out mimics like strokes and other illnesses, carefully testing for hallmarks like short-term memory loss, and watching for progression over time. But it only works when doctors respect the continuum, and the individual on it.

So to my mom, asking about blood tests: They don’t work. And to a friend worried about her dad: For now he hasn’t hit the extremes, so keep hope alive.

But above all, keep in mind: Normal is not a disease. It is a shade of grey.

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Franklin Delano Roosevelt had wicked hypertension. When the arteries in his brain finally blew apart, causing a massive stroke and death, his blood pressure had been hovering for months around 300 over 200. As I’ve written previously, Howard Bruenn, the president’s cardiologist, believed strongly in ‘Essential Hypertension’. This is a theory suggesting high blood pressure was necessary—essential—to power blood flow through FDR’s calcified, thickened arteries.

But it’s wrong. Hypertension is not essential, it’s bad and should be treated.

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The Plumbing Theory of coronary disease holds that inserting stents to open blocked and partially blocked arteries will prevent heart attacks and extend life. But other than in the throes of a heart attack, we now know that’s wrong. Such stents are harmful, not helpful.

Virtually every major depression drug prescribed and sold in the past three decades is engineered to correct a ‘chemical imbalance’, serotonin deficiency. That’s because the Serotonin Theory identifies this as the cause of Major Depression. But there is no serotonin deficiency with depression—we now know the theory is wrong.

The Lipid Hypothesis proposes that cholesterol causes coronary disease, and lowering it will prevent coronary events and prolong life. Last week’s post discusses a new study, however, that plainly disproves that theory—again.

Last week I wrote about the Semmelweis Reflex, a tendency to cling to pre-existing beliefs even when data challenges them. While it may be a common and very human reflex, it is deeply anti-scientific. The charge of the academic and the scientist, as Thomas Jefferson once said, is “to follow truth wherever it may lead.”

Physicians, moreover, swear an oath to put patients ahead of their egos, money, and everything else. And yet here we are, in the midst of a Semmelweis Setback, a period during which overwhelming data have debunked a theory of practice, while the practice continues, hurting everyone. We chase cholesterol as a primary means of preventing heart disease; we place millions of pricey stents that can only do harm; we treat depression almost exclusively with serotonin drugs.

To reverse these moral and practical wrongs, we must understand why they’re happening. In that spirit I offer the following well known theory, with a twist:

Follow the money, deprogram the ideology.

Cholesterol lowering, stents, and serotonin drugs are financial blockbusters. Knowing this, however, is not enough. It is true what Upton Sinclair said, “It is difficult to get a man to understand something, when his salary depends on his not understanding it.” But there is more than money at stake. While some physicians gain financially from placing stents, even in socialized systems where physicians don’t gain, stents are rampantly overused. And few make extra money for prescribing statins or Prozac.

Instead, what physicians gain is gumption. Ideologic gumption is an inflated belief in the impact of one’s actions and therefore the theories underlying those actions. To tell a cardiologist cholesterol is meaningless in preventing most heart disease, or stents don’t work, is to challenge their identity. They are true believers, not thieves or con men.

So who slayed Essential Hypertension? FDR and his hapless cardiologist. They didn’t do it on purpose but they shocked the world into seeing something hitherto invisible. FDR’s death deprogrammed the ideology, and forced a reckoning.

Similarly, Joseph Lister and Louis Pasteur elaborated the Germ Theory piercing the ideologic bubble that allowed physicians to deny they themselves were vectors for the infections killing women in childbirth. This too was a reckoning, a slap in the face for doctors who had denied Semmelweis’ data with a vitriol and defensiveness that only comes from a challenge to one’s own identity.

It will likely take a slap for doctors to see cholesterol, serotonin, and stents for what they are. Doctors are good people, overworked, nose to the grindstone, seeing patients and moving mountains. They do not have the time, nor often the training, to read every new study or puzzle through every new theory. They rely on professional guidelines and experts, information sources deeply influenced by money and usually oblivious to their ideologic capture—but that is a subject for another post, when we tackle how to Follow The Money.

Meantime, grassroots work can shift the views of doctors, because there is one group they listen to more than any other: patients. So tell everyone you know, including your doctor, what you’ve learned about cholesterol, and serotonin, and stents. It will take time and gumption of your own, but do them the favor of treating them like scientists.

In other words, pierce their bubble. Do it lovingly, with respect and admiration. But do it.

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Get full access to Research Translation at researchtranslation.substack.com/subscribe

Get full access to Research Translation at researchtranslation.substack.com/subscribe

Get full access to Research Translation at researchtranslation.substack.com/subscribe

Get full access to Research Translation at researchtranslation.substack.com/subscribe

Get full access to Research Translation at researchtranslation.substack.com/subscribe