Category: medicine

The National Academies of Science, which issues reports on opioid use, took $31 million from the Sackler family, pharmaceutical gazillionaires who largely created the opioid crisis

April 24, 2023 • 11:30 am

The book below (click on the cover to go to it) is one of the best piecces of nonfiction I’ve read in a year. It details the story of the Sackler family, in which three Jewish brothers, the sons of immigrants, worked together to push opioids for pain relief, and not in an ethical way. They eventually devised Oxycontin and Oxycodone, marketing them (via the company Purdue Pharma) to doctors as a kind of safe cure-all for pain, in the meantime completely ignoring reports of widespread addiction and deaths. (They also covered their tracks but not going public about what they really did and by becoming philanthropists, always insisting that the name “Sackler” be prominently associated with their buildings and galleries.)

The lawsuits eventually began, detailed by Wikipedia;

By 2017, a series of articles linking the Sacklers to Oxycodone as well as a public campaign by photographer Nan Goldin to link the Sacklers to the opioid crisis, led to stigmatization of the Sackler name with many museums and universities refusing financial gifts from the Sacklers.

While the family was eventually sued, the Sacklers used their company to declare bankruptcy, link their personal finances to the fortunes of Purdue Frederick, and ultimately managed to escape any financial consequences at all. The family continued to maintain that they knew nothing about the abusive and deceptive marketing practices of the company and maintained the lie that their opioids were not addictive and that the few people who abused their drugs were already addicts to begin with.

Eventually, the Justice Department settled with Purdue Pharma for an $8 billion criminal and civil settlement and another $225 million from the Sacklers themselves.  Nobody in the family has faced criminal charges, and they’re still living like kings.

The book is a page turner, and well worth reading, but it doesn’t paint a flattering portrait of the Sacklers, who come across as an affable but nefarious family determined to get as rich as possible no matter how much damage they did to humans in pain.

Imagine my surprise, then, to see this long article in yesterday’s New York Times. It details how the National Academies of Science (NAS), a private organization (but partly funded by the government) took millions from the Sacklers at the same time it was producing reports on opioid policy in America. The NAS exists as a body of elite elected scientists and doctors whose job is to produce definitive reports to help steer U.S. government policy.  Even if the NAS said it wasn’t swayed by the donations to come up with favorable takes on opioids, this is one of the most arrant conflicts of interest I’ve seen in science. The NAS didn’t even divulge in its reports that there was a “potential conflict of interest.”  This has really made me depressed about the NAS, which is supposed to be free of commercial taint.

Click to read the article. And remember, even if the Sacklers didn’t influence policies recommended by the NAS, scientists are still required to disclose potential conflicts of interest no matter what. And why, I wonder, did the Sacklers give so much money to the NAS?

Some excerpts:

For the past decade, the White House and Congress have relied on the National Academies of Sciences, Engineering and Medicine, a renowned advisory group, to help shape the federal response to the opioid crisis, whether by convening expert panels or delivering policy recommendations and reports.

Yet officials with the National Academies have kept quiet about one thing: their decision to accept roughly $19 million in donations from members of the Sackler family, the owners of Purdue Pharma, the maker of the drug OxyContin that is notorious for fueling the opioid epidemic.

The opioid crisis has led to hundreds of thousands of overdose deaths, spawned lawsuits and forced other institutions to publicly distance themselves from Sackler money or to acknowledge potential conflicts of interest from ties to Purdue Pharma. The National Academies has largely avoided such scrutiny as it continues to advise the government on painkillers.

“I didn’t know they were taking private money,” Michael Von Korff, a prominent pain care researcher, said. “It sounds like insanity to take money from principals of drug companies and then do reports related to opioids. I am really shocked.”

Unlike the World Health Organization, which was accused of being manipulated by Purdue and later retracted two opioid policy reports, the National Academies has not conducted a public review to determine if the Sackler donations influenced its policymaking, despite issuing two major reports that influenced national opioid policy.

One of those reports, released in 2011 and now largely discredited, claimed that 100 million Americans suffered from chronic pain — an estimate that proved to be highly inflated. Still, it gave drugmakers another talking point for aggressive sales campaigns, primed doctors to prescribe opioids at an accelerating rate and influenced the Food and Drug Administration to approve at least one highly potent opioid.

Another problem arose in 2016, months after the National Academies received a $10 million Sackler family donation. The F.D.A. had tapped the institution to form a committee to issue new recommendations on opioids. But one senator took exception to some of the members selected by the Academies, complaining they had “substantial ties” to opioid makers, including Purdue. Before work began, four people were removed from the panel.

It’s a total disaster, and the NAS hasn’t even investigated whether there may have been a real conflict of interest, even though the organization took at least $31 million from the opioid-pushers and issued two reports about opioids, one of which has already been discredited.

A wee bit more from Lisa Bero, “chief scientist at the University of Colorado Center for Bioethics and Humanities”:

Accepting millions of dollars from the Sackler family while advising the federal government on pain policy “would be considered a conflict of interest under almost any conflict-of-interest policy I’ve ever seen,” Dr. Bero said.

Indeed. So what does the NAS say when caught with its pants down? They simply equivocate. This is NOT the NAS I know of:

Megan Lowry, a spokeswoman for the National Academies, said in a statement that the Sackler donations “were never used to support any advisory activities on the use of opioids or on efforts to counter the opioid crisis.” Ms. Lowry added that the organization had been prevented from returning the Sackler money because of legal restrictions and “donor unwillingness to accept returned funds.” The Academies declined to make senior officials available for interviews.

And there’s more:

Soon after the National Academies report was issued, Dr. Andrew Kolodny, president of Physicians for Responsible Opioid Prescribing, emailed the institution and asked whether it would disclose that Ms. Christopher’s organization [Myra Christopher was an NAS panelist whose own group took Purdue money] had received funds from Purdue.

This is another conflict of interest, for panelists have to disclose their own conflicts.

“No, sorry, can’t do that,” Clyde Behney, an official with the Academies, replied in an email in August 2011 reviewed by The New York Times. “Keep in mind that the report is done and released, so the future is more important than the past.”

Seriously?? What kind of bullshit answer is that?

In its reports, some involving panelists who took money from Purdue, the NAS never disclosed any potential conflicts of interest.

In the end, the NAS now has millions of Pharma/Sackler money that it can’t use. As the paper suggests, perhaps the NAS should emulate Brown and Tufts, who used their Sackler money to help alleviate drug addiction:

Given the devastation of the opioid crisis, Michael West, senior vice president of the New York Council of Nonprofits, said that it would be worth the effort for the Academies to follow their lead.

“This would be a way,” he said, “of trying to make it right.”

Never in my life would I have expected the august NAS to be so sleazy. It’s not just that they took the money and didn’t disclose it, but also that they’re now pretending they didn’t do anything wrong.

NYT op-ed touts the power of dreams to help you make decisions

March 27, 2023 • 9:20 am

The link to this NYT came from reader Mike, who said, “I guess I won’t be the only subscriber sending you this article. [He was.] Serious Deepak Chopra vibes. I think it’s arguably worse than the Tish Harrison Warren opinion pieces because those are obviously religious. This one is stealthily religious, and comes with a “I’m a practical salt-of-the-earth science person” disclaimer. Disingenuous at best.”

Well, the piece does tout the useful power of woo, or rather of dreams, but I have to feel sorry for the author. Farris was diagnosed with breast cancer that had spread to the lymph nodes, and had radiation and a single mastectomy. Now she says she’s “NED” (“no evident disease”), but the waiting and waiting in cases like this must be awful, and could last a lifetime. Plus her radiation treatments apparently brought on heart disease, so she’s had a rough time. I want to avoid criticizing her, but do want to take issue with her view that her dreams were useful aids to making medical decisions.

Farris describes how she was was guided by her dreams when facing treatment options that, according to the doctors, were about equally efficacious. Because she’s still alive, she gives credit to her dreams as factors that helped her survive. That is the “woo” bit, and I don’t think the NYT should give people the idea that their medical decisions should be guided by their dreams—especially because dreams are often either bizarre or ambiguous.

Click to read:

Throughout her cancer treatment (including its first detection, revealed in a dream about two helicopters crashing on a highway), Farris responded to what she saw was the message of her dreams.  Here’s the way she decided to get chemotherapy when it was a judgement call:

Because my cancer is hard to see, often invisible on scans, the doctor told me it was likely to be even more advanced than my other doctors thought, but we wouldn’t be sure until after my surgery. “There are nearly equally good arguments for and against doing chemo,” he said. “What do you want?”

That night I had a dream of soaring above a garden full of light. I woke laughing with delight, but then my laughter turned ironic — who has ecstasy dreams about chemo? Still, I took what felt to me to be the dream’s advice. I started chemotherapy.

Note that there’s no clear message in this dream—a clue to what was might really have been going on (see below).

When faced with the option of having a single or double mastectomy, she opted for the single based on this dream:

This appointment was about my “choice” between a single and a double mastectomy, and between reconstruction and no reconstruction. Double mastectomy, she said, would mean a much lower chance of developing a new breast cancer.

But not zero. “My sibling had a double mastectomy and then had a recurrence,” I told her, “and since the doctors don’t regularly scan double mastectomies, the recurrence was nearly missed.”

She made a quietly compassionate face. I’ve learned to pay attention to doctors’ silences. However, I’d already made my choice, based on the first dream I’d had in months.

In my apartment, flames were creeping up the blinds and down the back of the couch. I had two jugs in my hands, though only one was full of water, which I threw on the fire. I went to refill both jugs, but when I returned, the fire was already out. And so, with some relief and a laugh at the strange ways dreams communicate, I decided on a single mastectomy. One jug was enough. I didn’t tell my doctor about the dream, but I did tell her about my decision.

When doctors found a suspicious sign later on, she was faced with the decision of whether to opt for more radiation. She did, based on a dream:

That weekend, while I struggled, I had my last and strangest breast cancer dream. I saw nothing, as if I was in a dark room. A man’s voice, inflectionless, American-sounding, said, “You must continue with radiation.” It was as if my subconscious was drained of all the symbols, the stories, the irrational desires and impossibilities. The only straightforward dream of my life.

I did the extra radiation.

At the end of the piece, Farris weighs science (which offered no clear-cut choice in her treatments) versus her dreams, and more or less sees them as coequal:

It doesn’t matter whether you “believe” in science — the earth is still round. But we are creatures who need something to believe in — stories and symbols to make meaning from a chaotic universe. Are dreams the flotsam of our waking lives, washed up on the shores of consciousness? Or are dreams, like pain, meaningful messages from our bodies?

Imagine my open, uncertain, freckled hands. There’s no conclusive evidence supporting either hypothesis. But when I felt betrayed by my own body, dreams gave me a feeling of meaningful connection to, and faith in, myself. I’m as grateful for that connection as I am for highly advanced medicines, and for the doctors who spend every day reckoning with the mystery that is cancer.

Well, I’m not sure I’d choose dreams or something numinous to believe in. Neither did Christopher Hitchens when he got throat cancer. As he wrote in his book Mortality,

“To the dumb question “Why me?” the cosmos barely bothers to return the reply: why not?”

His answer was that cancers happen, and he happened to be an unlucky victim. Yes, he had hope, but I don’t see that as “something to believe in” or a “symbol to make meaning from a chaotic universe.”  The idea that you need to confect something numinous or metaphysical to guide you is one that Farris made, but I can’t help but think that the NYT is somehow printing this article to tout the effectiveness of the spiritual—something it does quite a bit.

Now I wouldn’t tell Farris that I think her explanation was bunk. But I want to advance an alternative explanation for Farris’s using dreams as guidance for her treatment—one that doesn’t depend on thinking that dreams are somehow prescient or useful. You might have thought of this explanation as you read her piece. And it’s this: while she was sleeping, and perhaps dreaming as well, her mind kept turning over her alternatives and working away on making a decision, even if she wasn’t conscious of it.

We’ve all had the experience when we’ve forgotten something like a name, and, after trying to remember it, you just give up.  Then, suddenly, hours later, the name pops into your mind. What that says to me is that though you were not consciously trying to remember it in the interim, the neurons in your brain kept working away on the problem. 

That working may or may not be reflected in the contents of your dreams, since we don’t know how dreams work, but what is making the decision is the program in your brain. You wake up and that program has spit out a decision: get the radiation. Or have a single mastectomy.  Your choice may have had nothing to do with the dream, or it may have been reflected in the dream. For all we know, the dream content may be correlated with your unconscious musing, or it may not (some of her dreams weren’t obviously connected to her medical decisions). The dream, then, might be the correlate of a decision made without conscious reflection, not the “thing” that arose to help you make the decision.

Thus, I think Farris’s alternative takes on dreams, below, is insufficient.

Are dreams the flotsam of our waking lives, washed up on the shores of consciousness? Or are dreams, like pain, meaningful messages from our bodies?

Rather, the answer may be “neither.” The content of dreams often reflects what’s going on in our lives, but rather than see them as “meaningful messages from our bodies,” I’d say that Farris’s decisions were based on unconscious reflections in her brain. This, I think, is a more sensible interpretation of what she experienced than her thinking, as she seems to do, that dreams were interacting with the doctors’ indecisions to help her settle on a course of treatment. And of course, despite the title of her headline, there’s no guarantee that the dreams gave her the best advice—advice better than the doctors could give.  In other words, it’s not the dreams telling her anything, but her brain producing the dreams as a byproduct of its unconscious work.

An article in Science takes implicit bias (and its measurement) for granted despite the problems, and suggests interventions that haven’t been shown to work

March 25, 2023 • 11:30 am

Nearly all psychologists have lost their enthusiasm for the idea of implicit bias because of its manifold problems; and the most common test for implicit bias, the IAT (implicit association test) has largely been abandoned by its users. In light of this you’d think the idea and its IAT metric would have dropped out of sight in academics. But that’s not the way it works these days. If an idea like implicit bias fits into the academic Zeitgeist, and we can actually (pretend to) measure how biased people are when they don’t even know it, then it’s full steam ahead with the idea. Ferret out everybody’s bias, because we all have it! And ignore those niggling doubts about the IAT!

This, along with the often problematic notion of “systemic racism”, which persists in all of academia, are two examples of how the authoritarian Left will cling to a concept when it’s been found empirically useless, simply because the idea comports with their ideology.  And this article in Science—one of the world’s two most prestigious science journals—buys straight into the idea of implicit bias and IAT, hardly mentioning that they’re deeply controversial and have not been found to improve race relations. The article also assumes that inequities are due to racism (another dubious conclusion), and that the racism within science is a structural racism, not maniftested by biased individuals but baked into the system. Finally, the article raises the possibility of Big Brother-like monitoring of people to catch the implicit bias that we all know they harbor. (We discussed this suggestion the other day.)

There is no science journal I know of that has not gone in this direction if it’s weighed in at all on that ideology. Science is one and Nature is another.  It’s embarrassing how the two most prestigious journals concerned with understanding nature play so fast and loose with the facts.

Click to read:

The article’s largely about bias in medicine. I’ll give a few quotes showing how embedded the idea of implicit bias is in the article, how little the author and the IAT-users recognize the weaknesses, and describe new methods of measuring implicit bias in light of the IAT’s failure (which they don’t admit). The article is long, but is so similar to others of its ilk that I’ll be brief.

Note the immediate buy-in of the concept of implicit bias below. The article begins with the story of Chastine, a patient with autoimmune disease whose steroids made her gain weight, and then, she claims, doctors would assume that her extra weight was her primary medical condition. (This could, of course, be dispelled by the patient simply telling the doctor this at the outset).:

Stories like Chastine’s are unfortunately common, say researchers who examine how implicit biases—unconscious assumptions based on skin color, gender, sexual preference, or appearance—in health care providers affect patient care. Chastine, who is Black and queer, is now channeling her troubled experience with the medical establishment to aid studies of implicit bias and identify ways to counter it. She is part of a 5-year collaboration between various departments at both the University of Washington (UW) and the University of California, San Diego (UCSD), in which a team is developing a tool to give physicians feedback in real time during patient visits—or shortly after—on what they can do to mitigate their unconscious prejudices.

Here comes the IAW as used by Janice Sabin, a researcher at the University of Washington:

Sabin used the well-known Implicit Association Test (IAT), which determines how strongly an individual associates a trait—such as race or sexual orientation—with a subjective value, such as “good” or “bad.” The quicker you match each concept to a subjective value, the greater the association and the higher your score, which broadly indicates a stronger implicit association between the trait and value.

Sabin found the doctors she tested—a few of them nonwhite—held the unconscious bias that white patients took their medication as prescribed more so than Black patients. It was one of the first studies showing health care providers had unintentional racial prejudices. “It was kind of scary because this was a concept completely foreign to [many] people at the time,” Sabin says.

As I said, the article does mention issues with the IAT, but doesn’t state that its problems (lack of replication, evidence against the unconscious nature of the bias, and the failure of the tests results to lead to effective antiracist programs) are so severe that serious psychologists have abandoned the test:

The IAT remains a standard tool for measuring implicit bias, although some have criticized it because it has to be taken several times to reveal a reliable result, as people’s scores could change every time they take it. Even when people come out neutral on race, most studies will reveal some kind of unconscious prejudice, such as an unrecognized preference of certain sexual orientations or religions.

. . . Scientists have long studied several kinds of interventions that attempt to “erase” implicit bias, but few of them have shown lasting effects. “There is a robust science around implicit bias,” Hardeman says. But, “There is no gold standard for how to intervene right now. It’s imprinted in our brains in ways that make it really hard.”

Simple interventions can dampen biases, as measured by successive IATs, but the changes are usually modest and don’t persist.

. . .Simply asking health care providers to take the IAT without providing context or tools can be counterproductive. A study in 2015 indicated that when medical students are told about their unconscious bias without direction on overcoming it, they tend to get anxious, confused, and nervous interacting with patients who belong to social groups different from their own. That’s why even a quick training on skills to mitigate implicit bias can go a long way, according to Hardeman.

But as the article says (and other articles agree) why measure bias in a way that’s counterproductive if there is no “gold standard about how to intervene” to mitigate bias? Is this all just performative action with no effect on what it hopes to change? And so researchers move on to the Big Brother tests:

That made him [Brian Wood, an infectious disease specialist] eager to take part in UnBIASED’s first experiments, which rely on cameras installed in exam rooms. The cameras in Wood’s Seattle clinic captured interactions between him and his patients, including close-ups of his and their facial features and body language. “I found quite quickly that the patient and I both forgot the cameras were there and just fell into our usual routine and conversation,” he says.

The UnBIASED team then used a type of artificial intelligence (AI) known as machine learning to analyze patterns in the recordings and identify nonverbal cues that could indicate implicit bias. In one of the clips Wood was later shown, he was talking with a patient while leaning forward with his arms crossed on the desk, body language he worries may have made him seem closed and unapproachable. “I reflected on my own as to how that body language might be felt and perceived by the patient,” he says. Wood, who hopes to improve his demeanor, says he welcomed such feedback and is eager for more.

“Reflecting on possible negative moments during a visit was not easy, but felt important and valuable,” Wood says.

The team is now working on translating the experiment’s results into feedback like “digital nudges”—such as an icon that pops onto the computer screen, a wearable device, or other mechanism telling physicians to interrupt patients less or look them in the eye more often. But the UnBIASED team still has challenges interpreting the data in the recordings. For instance, nonverbal signals are nuanced, Hartzler says. “It’s not always as simple as ‘more interruptions means bad.’”

Translation: this method doesn’t seem to work. But nevertheless, the article persists, describing other methods of measuring hidden bias, including clinical simulations of biases and “microaggressions”, constructing training exercises for physicians and nurses, and calling out people on the spot. The problem is that while the article describes a panoply of methods, with at least one “increasing their recognition of bias” in a way that lasted a year (but their own biases or other people’s?), none of the methods seem to have an effect on mitigating bias, conscious or unconscious.  Despite the failure of developing an efficacious program so far, they will persist—forever:

Getting buy-in from whole health care systems could accelerate the process. Recently, California, Michigan, Maryland, Minnesota, and Washington state passed legislation mandating implicit bias training for the medical professionals they license. And since June 2022, Massachusetts physicians are required to take implicit bias training to get a new license or get recertified to practice.

Although researchers see this as a good step, they worry mandated training will become a one-off box-checking exercise. Sustained implicit bias training for physicians should instead be the norm, some emphasize. Hospitals also need to monitor and collect data on health care outcomes for different groups in order to monitor equity, Sabin says. “You have to know where the disparities lie and then begin to work backwards from that.”

It won’t be easy, Hardeman says, noting that, at least in the United States, centuries of white supremacy and other forms of bigotry have resulted in deep-rooted stereotypes and other implicit biases. “Every single person should be thinking about doing this work,” she says. “But if they’re doing it within a system that hasn’t addressed its own biases and racism, then it’s not going to be fully effective.”

Clearly, we’re going to have mandated training for the rest of our lives (much of it involving a form of compelled speech), and all of us who aren’t people of color will be told that we harbor implicit biases and participate in white supremacy, which is now structurally built into medicine.

And yes, of course some people are biased! I can’t help but assume that these people really do mean well instead of just trying to enact an ideology that they know won’t help the situation. But perhaps they should be using methods that work, and if they can’t show they work, they shouldn’t be part of mandated training. It’s not going to make people more “inclusive” to tell them all that they’re ridden with biases they don’t even know about the invisible Klan robes we all wear.

When this kind of palaver invades all of the prestige science journals—in article after article that all say exactly the same thing—you know that we’re in for a long haul.

If you want to measure your own implicit bias for race using Harvard’s IAT, try it here.

h/t: Steve

A “miracle antibiotic” in the offing? New compound works against all multiple-drug-resistant bacterial strains, and also stymies the evolution of bacterial resistance

February 22, 2023 • 10:30 am

A new article from The Lancet reports the synthesis of an antibiotic that not only kills all drug-resistant bacteria that have been tested (in vitro or in vivo in mice), but also seems impervious to being rendered ineffective by the evolution of bacteria. If this works out in humans, it would be a terrific advance in medicine: an antibiotic that can be used on people whose infections aren’t treatable because the bacteria are drug-resistant (this is common in TB, for instance), but also an antibiotic that seems to be impervious to the evolution of bacterial resistance. It’s also easy to synthesize using organic chemistry, and can be easily tweaked in its structure just in case some bacteria eventually do develop resistance.

Click on the screenshot below to read the original article, or download the pdf here.  The researchers hail mostly from UC Santa Barbara, but also come from UC Davis, Singapore, and Australia.

I found the link from reader Jeannie, who sent me a short piece on kottke.org calling attention to the results. That linked to the original paper (above), but added this:

The discovery was serendipitous. The U.S. Army had a pressing need to charge cell phones while in the field — essential for soldier survival. Because bacteria are miniature power plants, compounds were designed by Bazan’s group to harness bacterial energy as a “‘microbial”’ battery. Later the idea arose to re-purpose these compounds as potential antibiotics.

“When asked to determine if the chemical compounds could serve as antibiotics, we thought they would be highly toxic to human cells similar to bleach,” said Mahan, the project lead investigator. “Most were toxic — but one was not — and it could kill every bacterial pathogen we tested.”

Such are the totally unexpected side effects of research, and although this was applied research, it’s also a justification for pure research. Remember: the whole apparatus for sequencing DNA, and then the CRISPR technique, gene editing, and so on, began with the simple observation that some bacteria live in hot springs near the boiling point, and some curious scientists who asked “I wonder how they do it.”

Back to the paper. My take will be short as it’s complicated and, to be sure, parts of it are beyond me. The compound they found was COE2-2hexyl, and below is the structure. It can be synthesized without much difficulty using standard methods of organic chemistry, so you don’t have to get it from massive quantities of fungi or other organisms. Captions are from the paper.

Asyou see, it consists of two aromatic central chains with four long carbon tails, each of which has a nitrogen atom in it:

b and c, COE structural modules are depicted by coloured boxes. The intercalation into phospholipid bilayers is driven by the hydrophobic centre and the terminal ionic functionalities, consisting of the conjugated aromatic core (gold module) and hydrocarbon pendants (blue module), which resemble the fatty acid centre of the bilayer. Additionally, the cationic end groups (red module) and terminal acyl chains (pink module) interact via coulombic and hydrophobic interactions with the membrane surface functionalities; specific example: COE2-2hexyl.

It works, as implied in the caption above, by attacking the cell membranes of bacteria, disrupting essential functions of the membrane. These include the ability of the bacterium to absorb and emit cell contents, to help the bacterium metabolize, and also, critically, to divide. Here’s how COE2-2hexyl looks when it gets into the bacterial membrane and disrupts it. Other similar compounds, called COEs, have the same shape and do the same thing:

COEs share a modular structure that spontaneously integrates into the bacterial membrane

This compound was tested on 17 bacterial isolates taken from people with drug-resistant infections:

You’ll recognize some of these as bacteria that cause gonorrhea, tuberculosis, pneumonia, dysentery (Shigella flexneri) Acinetobacter baumannii, which causes bad infections associated with hospitals, and so on. All of these were isolates taken from humans who had shown antibiotic resistance.  The drugs were tested in vitro, using mouse cell cultures that were infected with bacterial isolates from humans, and also in vivo, in mice that had been infected (there were of course controls that had been mock-treated). (I have to add that I feel sorry for the mice in the control group.)

As the authors note (my emphasis):

Expanded antibacterial activity analyses revealed that COE2-2hexyl exhibited broad antibacterial activity against all 17 clinical bacterial isolates tested (Table 1). Notably, methicillin-resistant S. aureus (MRSA, MT3302) and CRE K. pneumoniae (MT3325) were derived from sepsis patients with refractory bacteremia, whereby the CRE organism was resistant to 20/22 antibiotics determined by clinical VITEK testing (bioMerieux, Inc.) and 19/24 antibiotics determined by broth microdilution.

Note that it worked when nearly all antibiotics had failed. The authors also made two derivatives of this compound, adding one cabon atom to two of the four chains; these two compounds also showed antibacterial activity against 9 drug-resistant bacterial isolates tested.

Of course you’re wondering “well, this is great, but is it safe?”  It was, even in higher doses, and in the doses that killed bacteria. But of course it was safe in mice but may not be in humans. Clinical testing will be in order, and that might take a long time before we see if this and its derivatives are truly “wonder drugs”.

Finally, testing the compound for relatively long periods against bacteria showed that the bacteria did NOT develop immunity to the drug (that’s via natural selection, of course), which is really good news, since few antibiotics have not been overcome by mutations that render bacteria immune to them. (I believe that the Streptococcus bacterium that causes “strep throat” has never evolved resistance to penicillin, nor has the polio virus evolved immunity to polio vaccines, but such cases are rare.) Now, as Orgel’s Second Rule states, “evolution is cleverer than you are,” and eventually, if COE2-2hexyl is used for long enough, bacteria might find a way around it. But right now, things look promising.

Finally why are bacteria unable to evolve resistance to COE2-2hexyl? The clue is in this sentence in the paper:

COE2-2hexyl had specific effects on multiple membrane-associated functions that may act together to disrupt bacterial cell viability and the evolution of drug-resistance through a mechanism of action distinct from most membrane disrupting antimicrobials or detergents which destabilize.

The compound, it seems, disrupts many different functions of the bacterial membrane, and while one disruption might be fixed by one or more mutations in the bacteria, something that screws up your system big time, and in multiple ways, may be impossible to repair, as bacterial mutations that overcome one disruption may make it harder to fix the other disruptions. The more ways a drug can screw up a bug, the less likely it is that the bug can evolve resistance. But remember—bacteria are clever.

I’ll end with the authors’ final paragraph about what’s good about this compound and what needs to be done (mostly efficacy and safety testint in humans). But if this thing works out, it will be a medical advance of almost unparalleled value (bolding is mine):

The ease of molecular design and modular nature of COEs offer many advantages over conventional antimicrobials due to their intermediate molecular size, sufficient aqueous solubility to achieve efficacy, and the absence of complex chemical structures/chiral centers, making synthesis simple, scalable and affordable. The COE refinement workflow potentially accelerates lead-compound optimization by more rapid screening of novel compounds for the iterative directed-design process. It also reduces the time and cost of subsequent biophysical characterization, medicinal chemistry and bioassays, ultimately facilitating the discovery of novel compounds with improved pharmacological properties. Additionally, COEs provide an approach to gain new insights into microbial physiology, including membrane structure/function and mechanism of drug action/resistance, while also generating a suite of tools that enable the modulation of bacterial and mammalian membranes for scientific or manufacturing uses. Notably, further COE safety and efficacy studies will need to be conducted on a larger scale to ensure adequate understanding of the clinical benefits and risks to assure clinical efficacy and toxicity before COEs can be added to the therapeutic armamentarium. Despite these limitations, the modular design of COEs enables the construction of a spectrum of compounds with the potential as a new versatile therapy for the emergence and rapid global spread of pathogens that are resistant to all, or nearly all, existing antimicrobial medicines.

h/t: Jeannie

Should you get that bivalent booster shot?

October 4, 2022 • 12:00 pm

My primary-care physician, Dr. Alex Lickerman, discusses the question everyone’s asking: should you get that bivalent booster? (For most people it would be their third booster and the fifth Covid shot). You can access Alex’s post by clicking on the screenshot below. (Be sure to look at the graphs and read it all.)

Alex always looks at the science before he decides what’s to recommend, and by that I mean the primary literature. When I first asked him about whether to get a booster, he said he didn’t know because the data hadn’t been published, and all the existing studies were on antibody levels in mice. Now he looks at more data. I’ll give his conclusion below but do have a look at his post.

My own decision was to get the booster simply because I’m traveling tomorrow, but, as always, consult your own doctor or decide from the data themselves. People tend to get covid on airplanes these days (a friend who just returned from Boston said only 5% of the passengers on her Southwest flight wore masks), and Alex said that it couldn’t hurt me to get one before traveling—but it might not help me much, either.

CONCLUSION: Should you get the bivalent booster? In the absence of human trial data, we might think about this question as follows: We can be reasonably certain that the bivalent booster will produce a level of neutralizing antibodies that diminishes the risk of infection from COVID. We don’t know how long that protection will last, but a fair guess would be from 3 to 6 months. If there is some reason you feel the need to reduce your risk over the next 3 to 6 months, say, for travel, getting the bivalent booster would seem reasonable. On the other hand, if in addition to being vaccinated, you’ve had COVID recently (meaning you’ve been infected with an Omicron variant), likely the same level of protection accrues, obviating the need for the bivalent booster. If your main concern is dying from COVID and you’ve already received the primary series and one or two boosters, your risk is so low that getting another shot would seem superfluous. If you are at high risk for dying from COVID, while there is no data to suggest the bivalent booster might further reduce your risk beyond levels afforded by the primary series and one or two boosters, there is also likely little risk of getting it. In the absence of data to guide us, this would then be a personal decision.

Often Alex answers questions in the comments, so if you have any, put them below. I’ll tell him that he might look at the comments.

The biomedical importance of sex (and its binary nature)

September 15, 2022 • 12:00 pm

One might almost think, with widespread denial of a sex binary of men and women—a denial that in most animal groups is both fatuous and ideologically motivated—that there are no average biological differences between men and women. “Blank slaters” tend to outright deny the existence of behavioral or cognitive differences between men and women, often doing so on the erroneous grounds that “some women are in the range of men’s scores and vice versa”. In such cases the concept of averages seems to have slipped their minds.

But as the dogs bark, the caravan moves on. Increasingly recognizing the biological and medical differences between men and women—note the implicit recognition of dividing up the species into two sexes— funding institutes and journals dealing with illness and medicine (as well as  are increasingly recognizing the importance of studying men and women separately (or partitioning the data by sex) in biomedical work. That includes using model organisms such as mice, which may show related sex differences. This is the topic of the new feature in the journal Nature shown below. Click on the screenshot to read (it’s free).

 


First, some indicators that dividing up test subjects by sex can give useful and potentially lifesaving results:

Many of science’s gatekeepers — granting agencies and academic journals — feel the same way. Over the past decade or so, a growing list of funders and publishers, including the US National Institutes of Health (NIH) and the European Union, have been asking researchers to include two sexes in their work with cells and animal models.

Two major catalysts motivated these policies. One was a growing recognition that sex-based differences, often related to hormone profiles or genes on sex chromosomes, can influence responses to drugs and other treatments. The other was the realization that including two sexes can increase the rigour of scientific inquiry, enhance reproducibility and open up questions for scientific pursuit.

When studies do include two sexes, the results can be important for health. For example, sex is known to affect people’s responses to common drugs, including some antibiotics. . .

And here are some important biomedical differences already detected:

. . .Despite the bumpy ride, the federal guidelines that were put into place in the early 1990s have led to some important medical discoveries, perhaps a signal that key revelations could emerge from basic research in a few years.

For instance, there are sex-based differences in the heart’s electrical response to several classes of drug, including antidepressants and antibiotics. As a result, sex-based dose adjustments are now recommended for some drugs.

Steroid hormones such as oestrogens and androgens are thought to be primary actors in many of these differences between men and women. For example, women metabolize propranolol, a blood-pressure drug from a class known as beta blockers, more slowly than men do. Researchers think that sex-related steroid hormones acting on the liver can exert these effects. Other factors could include body size and composition, such as the fat:muscle ratio, which tends to be higher in women.

The cut-offs for risk might also differ between men and women. A 2021 analysis of cardiovascular risk related to systolic blood pressure shows what happens if data for two sexes are pooled rather than analysed appropriately. The authors found that when data were pooled, the range for increased risk was a systolic pressure of 120–129 millimetres of mercury (mmHg). But the sex-specific analyses showed that for women, the risk actually begins to climb when systolic blood pressure tops 110 mmHg. If other studies solidify these findings, the result would be a sea change in risk calculation for cardiovascular disease.

That study, as it happens, “was very much inspired and motivated by an NIH request for applications” about sex differences in health outcomes, says Susan Cheng, a cardiologist at Cedars-Sinai Medical Center in Los Angeles, California, and senior author on the report. Without that call for studies specifically designed to look for sex differences, she says, “we had a lot of ideas, but not a thematic focus”. Their findings that men and women differ in risk cut-offs “was actually a real ‘eureka moment’”, Cheng says. “I was like, ‘how did we not see this before?’.” She attributes the results to the NIH’s challenge. “They made it all happen.”

And good for the NIH!

Now surely you can’t attribute all these differences to “socialization,” as the disparity in hormones is based on genes that are differently activated in men and women. Of course, differences in biology due to any factor, like the Patriarchy, still need to be studied for their biomedical effects. But it’s foolish to attribute everything like the above, including the response of the heart to drugs, to environmental influences.

And, of course, if there are no differences between the sexes with respect to a biological trait or response, we need to know that too! This is true for any groups that a priori may differ biologically, but men and women are the most obvious and least ambiguous grouping.

The article highlights some problems with past research, including an apparent lack of knowledge by investigators about how to use statistics to judge the effects of sex, including the simple dictum of using half men and half women in a generalized test on “the population”.  Below is one chart from the paper partitioning 147 biomedical studies starting in 2019. As you see, more than third of them (55) didn’t even consider sex as a factor to study (and that’s dead easy), more than a third (60) didn’t look for interactions between sex and treatment (essential if you want to know if a treatment works differently in men than in women), and only 32, or about 22%, looked for interactions between treatment and sex (16 of these reported a significant interaction, and 10 a nonsignificant interaction).

Finally, even when sex differences were found, as in the red group that didn’t look for interactions, most studies that found a difference didn’t test that difference statistically. The blue group is the one that used statistical tests, but even in that moiety, 6 tests didn’t report the results and one non-significant result was erroneoously reported as a difference.  I thought biomedical researchers would be more savvy than this.

Now there’s a few gestures in the paper toward the “sex isn’t binary” trope by bringing in gender. For example:

The publishing community is pushing for similar clarity. In 2016, it published the Sex and Gender Equity in Research (SAGER) guidelines, which set out how to report sex-based differences in published research. Individual publishers, including Springer Nature (which publishes Nature), have their own policies encouraging researchers to report results by sex, defined as a cluster of biological traits, and sometimes also gender, which is socially defined.

Since “gender” is a social construct, and progressives say there are a gazillion of them, I don’t see how you can report results by gender unless you lump everyone besides men and women as “other”. (I won’t quibble with “sex defined as a cluster of biological traits”, which is technically incorrect but good enough for the purposes of biomedical research.)

And this is thrown in as well, seemingly out of nowhere:

Defining sex as a crude binary, predicated on the chromosomes present, or on specific anatomy, could be too limiting. Some species, such as the nematode worm Caenorhabditis elegans, have one sex that makes only sperm cells and one that makes both sperm and egg cells. And in a vast assortment of species, sex is determined environmentally rather than chromosomally. And still other species can change sex during their lifetime. Placing cells, tissues or even whole organisms into a pair of categories takes on layers of difficulty in these contexts.

Note the pejorative adjective “crude,” meant, I think, to disparage the binary.  Once again they send in the clownfish, nematodes, and turtles, but these don’t refute the idea of separate sexes. Nematodes can be either males or hermaphrodites, the latter being both male (making sperm) and female (making eggs), some clownfish can change from male to female if the alpha female dies—but there are still two sexes, and temperature-specific sex determination, as occurs in many turtles, still gives you males and females. In that case the two sexes are developmentally channeled via an external stimulus rather than via chromosomes and genes, but there are still men turtles and women turtles. (Why some species do this is still not well understood).

 

The fact remains that these species do not show more than two sexes, that they are in the minority of vertebrates and in an even smaller minority of birds and mammals, and, in the end, humans aren’t clownfish, turtles, or nematodes.

Besides emphasizing the valuable lesson that men and women are biologically different in ways that can be important for medical treatment, this article also shows us that where it really counts, where the rubber meets the road—that is, when lives are at stake—the palaver about the binary of sex being a fiction vanishes.

None of this, of course, is intended to ignore those who have disorders of sex determination or transsexuals who have had hormone therapy or surgery, for those patients may need separate study rather than lumping them into one sex or another. That will be hard to do given the paucity of such people, but everyone deserves the best treatment that science can offer.

Are advocates of “affirmative therapy” pulling back?

September 13, 2022 • 12:45 pm

The other day I got an email from a reader suggesting that perhaps extreme “affirmative-care” activists for transsexuals are backing off of some of their more extreme claims—most notably that some adolescents who demand to transition from one sex to the other might be influenced, perhaps to their detriment, by social pressure.  I have little doubt that this occurs, and that it has influence some young people, for it’s been amply documented. Abigail Shrier’s book Irreversible Damage gives some examples, but that’s not the only source. Some trans people as well as authors have recounted this kind of pressure.

What I don’t know is how many transitions or requested transitions would have occurred without social pressure (which is often intense and always “affirmative”), nor are there much data about transsexuals who bowed to social pressure and then had regrets. (As far as I know, the vast majority of adult transsexuals do not have regrets.

The online impetus to transition is, of course, only part of the “affirmation” of this species of therapy, which involves a rah-rah-go-ahead concatenation of treatment from parents, doctors, and psychiatrists.  These people don’t mean to do harm by giving puberty blockers to children or adolescents; they think they are not only doing good, but are also adhering to what many in the therapeutic community see as the “best practice” for children or adolescents with gender dysphoria. Those standards are promulgated by an organization mentioned below.

Many of these with gender dysphoria”suffer from mental problems, are confused, or might really be gay, which behooves everyone to ratchet back on the instant affirmation. I’ve reported before that European countries are beginning to pull back on affirmative therapy, employing puberty blockers only in clinical trials, and practicing a more objective and watchful therapy whose purpose is to analyze and support rather than to affirm.  The U.S., however, seems to be digging in its heels, holding onto practices that in some cases could be harmful.

Let me emphasize that I don’t object to “affirmation”, but only after rigorous psychological (and medical) investigation shows that transitioning sexes would be the helpful thing to do. What you can’t do is put kids on a treadmill that involves medical intervention merely on the word of the patient and his/her desires alone. The patient much surely be old enough and mature enough to give rational consent.

And while I think there should be age limits for taking hormones (probably 16 or 18, but surely after puberty), I don’t approve of puberty blockers, whose long-term safety (despite the claims below) is not known. On the other hand I also don’t approve of states banning “gender affirming care” unless they specify exactly what they’re banning vis-à-vis psychological therapy and medical practice. Like abortion, such a complex medical issue should not be put in the hands of the state.

But I digress. Here’s the email I got from the reader, who referred me to the NBC article shown below:

Did you know that in the Standards of Care Version 8 released in July this year, the World Professional Association for Transgender Health, or WPATH, they give credence to the possibility of the social contagion hypothesis. Plus, NBC actually covered it. Notice how CHILDREN and trans activists suddenly poo-poo WPATH (previously considered to be the eminent authority on trans health issues). Also, the significance of 4,000+% increase in FTM [female to male] transition is because the majority of transitions prior to around 2015 were MTF. I think it’s important to pay close attention to the Tavistock situation and I’m glad you are.

The Tavistock Gender and Identity Development Service (GIDS) in London practiced hardcore affirmative therapy, often on adolescents, for several decades, treating thousands of young people and helping them transition. But it was closed after a scathing report on poor practice written by an external reviewer, Dr. Hilary Cass. Tavistock is now closed and its activities, made less “affirmative”, are being farmed out to clinics in London and Manchester (see this NYT article for details).

But when you actually read the NBC piece, from June, there’s not much reason to be heartened. Yes, there’s some pulling back from outright rejection of the “social contagion” hypothesis, but otherwise it’s a mess of contradictory claims and anecdotal testimony from patients. Click to read:

But the pulling back doesn’t consist of much,, and even that is drawing criticisms from activists (emphases below are all mine):

The World Professional Association for Transgender Health, or WPATH, a nonprofit professional association devoted to transgender health, will release its Standards of Care Version 8 in July. The last time the standards were updated was in 2012.

The nearly 400-page guidelines, which the association’s president, Walter Bouman, described in an emailed statement as “the most comprehensive set” of guidance ever produced for health care providers who support transgender people, include many significant changes, according to a copy of the guidelines that WPATH shared with NBC News.

The change that is drawing the most criticism is a new chapter dedicated to adolescent care, which was previously part of the chapter on care for children. The chapter presents conflicting statements on support for adolescents: It gives credence to the claim that more young people might be coming out as trans due to “social influence.” It also notes that there’s limited longitudinal research on the effects of gender-affirming care for adolescents, but a growing body of recent studies show it’s beneficial enough that withholding care would be unethical. 

Well, the second sentence seems to be a grudging admission, while the last one I don’t know how to interpret.  What does the growing body of studies say? And surely there can be hardly any data on “gender affirming care” versus “other kinds of care that are more objective and less affirming”! I suspect the data show that gender affirming care is better than no care, which it probably is in terms of self-assessment of patients, but the real question is of the relative efficacy of different kinds of care, some of which may result in out homosexuality rather than gender transition, and for that comparison I would bet shekels to donuts that there are no data.

WPATH is even more grudging about social contagion (my emphasis), devaluing the idea using the words “anecdotal evidence” and “small percentage”.

WPATH’s new chapter on adolescence also states that there has been a “sharp increase in the number of adolescents requesting gender care,” and that anecdotal evidence from a small percentage of people who have changed their minds about being transgender shows that some young people might believe they are trans due to “social influence.” 

But the biggest hedge is to point out that “social contagion” is just one result of social influence:

Regarding criticism of the information in the adolescent chapter about social influence, WPATH said in a statement that, “When discussing social influence, it is important to discuss that it is only one aspect of social development for adolescents, which should also include a discussion of the positive aspects of social connectedness and a feeling of belonging.”

. . . Ducar added that painting transness as a “social contagion” propagates “this myth of ‘grooming’ that the right wing has really been spreading,” even though there’s no data to support it.

(Dallas Ducar is “a psychiatric nurse practitioner and co-founder and CEO of Transhealth Northampton, a trans-led organization that provides health care to trans and gender diverse patients in western Massachusetts.”) But social contagion is not the same thing as “grooming”, and taking the former seriously doesn’t mean you accept the latter. And I don’t know of gender dysphoric youth going online and having their peers tell them that transitioning is a bad idea. It’s nearly always “affirming”, for the advice is often given by those who have transitioned and are seeking post facto affirmation.

According to WPATH, a bunch of peers on the internet telling you to go ahead and have puberty blockers (and telling you where to get them), surgery, and hormone treatment gives you a sense of belonging, which is good. In the abstract, a sense of belonging is good, but probably not when you’re looking for people to tell you to change sex, and how to do it.

There’s more:

Advocates say that language is evidence that WPATH has been influenced by the culture war debate created by some Republicans over the last few years, and it ignores the lived realities of transgender youths themselves.

“We know trans childhood is not a trend,” said Dallas Ducar, a psychiatric nurse practitioner and co-founder and CEO of Transhealth Northampton, a trans-led organization that provides health care to trans and gender diverse patients in western Massachusetts. “We know that gender diversity is part of the human experience. It’s been documented since the Neolithic period and the Bronze Age.”

OF COURSE it’s a trend, whatever its cause. Below are referral rates to Tavistock in just ten years. If you can’t see a trend, you’re blind. As for the Neolithic and Bronze age, well, ten to one we have early historical examples of people of one biological sex saying that they feel like they’re of another, but from these early periods? I’d like to see the  specific claims.

Not only that, but WPATH seems to be making the standards for transitioning more relaxed:

WPATH will make a number of changes to its recommendations for adolescent care in the new chapter. The group will lower the minimum recommended age that providers can prescribe hormone therapy to 14, from 16, if an adolescent has parental consent and meets a list of other criteria, including undergoing a comprehensive evaluation regarding their gender identity.

The association will also lower the minimum recommended age for some surgeries such as chest masculinization and breast augmentation to 15 and 16, respectively, down from 18 in the previous guidelines.

What about PUBERTY? Is that a criterion? And what about puberty blockers? Hormone therapy at fourteen? Is a child capable of making decisions about her whole life at that age? (Parents, many whom have heard that they should be “affirming”, aren’t of much use here.) If WPATH have tightened the criteria for allowing transitioning, that is good, but lowering ages seems to me a precipitous thing to do.

In the end, the article seems to strive for balance by giving both a positive and negative views of “affirmative care”:

Here’s the negative, which isn’t really an attack on affirmative care, but a call for more evidence before it’s practiced:

Allowing adolescents to access treatments worries some advocates who say there isn’t enough research to ensure that the care is safe in the long term.

“The body of evidence to support (hormone replacement therapy) or surgery for anybody, really, but especially for people who are young, it’s extremely flimsy,” said Corinna Cohn, who had gender-affirming surgery when she was 19 and felt afterward that she was “never going to finish becoming myself.”

Cohn, now 47, testified in favor of an Ohio bill in May that would’ve barred gender-affirming medical care for minors and would have also prohibited medical professionals from referring a minor to a different doctor for such care. She said she supported the bill because it would have given people who received transition care as minors the ability to sue their doctors if they regretted the procedure as adults and believed they weren’t mentally sound enough to consent to treatment.

And the response by Ducar:

Ducar said the assertion that there isn’t enough research to support gender-affirming care for adolescents isn’t true.

She said puberty blockers and hormones have been prescribed to cisgender children and cisgender adults for decades, and the scientific research in those populations has shown that the treatments are safe.

“We need to be investing more research money into understanding long-term effects of hormones or blockers or surgery in specific trans populations” — something she said Transhealth Northampton is working on — but “the lack of a robust amount of studies in specific trans populations does not imply that it’s not a valid form of treatment.”

As far as I know, puberty blockers haven’t been used long enough to show that they’re “safe”, and while hormone treatment may be “safe”, it also has side effects like sterility. The side effects of “bottom surgery”, too, are often dire.

As for the last paragraph, let’s see it again:

“We need to be investing more research money into understanding long-term effects of hormones or blockers or surgery in specific trans populations” — something she said Transhealth Northampton is working on — but “the lack of a robust amount of studies in specific trans populations does not imply that it’s not a valid form of treatment.”

If we don’t understand the long-term effects of surgery, hormones, and puberty blockers, then how can they represent a “valid form of treatment”? To me, “valid” means “safe and has been shown to work”.  But maybe WPATH has a different understand of the term.

In the end, the article just shows me that WPATH only reluctantly admits that maybe a few kids have transitioned because of social pressure, but hey, social pressure can be a good thing! And they’re still making quasi-scientific statements that aren’t supported by data.

Until recently I thought that if wokeness was going to recede in America, the first place we’d see it would be in the transsexual controversy, with a greater insistence on proper experimentation and care. After all, wokeness in medicine has the potential to do far more actual harm than wokeness in, say, academia, so the price of getting it wrong is higher.  This is what the Europeans are realizing. But in the U.S., not so much. My bellwether of wokeness has lost its bell.

Uncle Joe doesn’t help: