Author: Art Diamond

With Metformin Patent Expired, No Firm Has Incentive to Fund $50 Million Randomized Clinical Trial to Show It Aids Longevity

The article quoted below was published eight years ago. Dr. Barzilai and his team are still, even now, trying to raise the (probably higher) funds to conduct the metformin clinical trial. Firms have no incentive to conduct the clinical trial. Since the patent for metformin (originally issued for its efficacy against diabetes) expired in the year 2000, even if the clinical trial succeeded, no firm would be able to recover in revenue the $50 cost of conducting the clinical trial. Clinical trials are so hugely expensive largely due to the large and long Phase 3 component, intended to prove efficacy. That is why I salute Milton Friedman’s suggestion that a step in the right direction would be for the FDA to only mandate the smaller and quicker Phase 1 and Phase 2 components, mainly intended to prove safety. If the total cost of the clinical trial was much lower, it might be easier to find non-profit or academic funding. (It’s hard to raise $50 million on a GoFundMe page!)

The system is set up so that cheap (off-patent) drugs like metformin do not get tested, and so do not get FDA approval for off-label uses. So the system is set up to reduce the use of low cost, but possibly effective, medicines.

(p. D5) “Aging is by far the best predictor of whether people will develop a chronic disease like atherosclerotic heart disease, stroke, cancer, dementia or osteoarthritis,” Dr. James L. Kirkland, director of the Kogod Center on Aging at the Mayo Clinic, said in an interview. “Aging way outstrips all other risk factors.”

He and fellow researchers, who call themselves “geroscientists,” are hardly hucksters hawking magic elixirs to extend life. Rather, they are university scientists joined together by the American Federation for Aging Research to promote a new approach to healthier aging, which may — or may not — be accompanied by a longer life. They plan to test one or more substances that have already been studied in animals, and which show initial promise in people, in hopes of finding one that will keep more of us healthier longer.

As Dr. Kirkland wrote in . . ., “Aging: The Longevity Dividend”: “By targeting fundamental aging processes, it may be possible to delay, prevent, alleviate or treat the major age-related chronic disorders as a group instead of one at a time.”

. . .

The team, which includes Dr. Nir Barzilai, director of the Institute for Aging Research at Albert Einstein College of Medicine in The Bronx, and Steven N. Austad, who heads the biology department at the University of Alabama at Birmingham, plans to study one promising compound, a generic drug called metformin already widely used in people with Type 2 diabetes. They will test the drug in a placebo-controlled trial involving 3,000 elderly people to see if it will delay the development or progression of a variety of age-related ailments, including heart disease, cancer and dementia. Their job now is to raise the $50 million or so needed to conduct the study for the five years they expect it will take to determine whether the concept has merit.

. . .

Several studies have . . . found that individuals with exceptional longevity experience a compression of morbidity and spend a smaller percentage of their life being ill, Dr. Barzilai and his colleague Dr. Sofiya Milman wrote in the “Aging” book.

For the full commentary see:

Jane E. Brody. “Pursuing the Dream of Healthy Aging.” The New York Times (Tuesday, February 2, 2016 [sic]): D5.

(Note: ellipses added.)

(Note: the online version of the commentary has the date February 1, 2016 [sic], and has the title “Finding a Drug for Healthy Aging.”)

Dr. Kirkland’s co-edited book mentioned above is:

Olshansky, S. Jay, George M. Martin, and James L. Kirkland, eds. Aging: The Longevity Dividend, A Subject Collection from Cold Spring Harbor Perspectives in Medicine. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press, 2015.

One study that documents that those who live 107 or more years do not have more years of illness and morbidity (the “compression of morbidity hypothesis”) is:

Sebastiani, Paola, and Thomas T. Perls. “The Genetics of Extreme Longevity: Lessons from the New England Centenarian Study.” Frontiers in Genetics 3 (Nov. 30, 2012).

“Funny, Obsessed Weirdos . . . Taking Children’s Entertainment . . . Seriously”

(p. C4) . . . to everyone other than Muppet obsessives, Henson the artist is still a bit shadowy. Good news: Now we have “Jim Henson Idea Man” (on Disney+), a tribute to the artist and a treasure trove of archival footage and interviews about his work and life.  . . .

The film, directed by Ron Howard, starts with Henson and two of his Muppet friends, Fozzie Bear and Kermit the Frog — Henson’s alter ego — being interviewed on TV by none other than Orson Welles.

. . .

. . . what struck me especially was that Howard has made a movie that every young artist should watch (and older ones, too), whether they’re making puppets, paintings, music, movies or anything that requires creative labor.

That’s because the film shows that Henson’s work was rooted in an unquenchable drive for exploration. One interviewee notes that he was lured into working on “Sesame Street” by the promise that he could make the kind of short experimental films he loved — and suddenly I realized that my taste for unhinged abstraction in film had been partly shaped when I was 4 and plopped in front of PBS.

. . .

The immense delight in “Jim Henson Idea Man” comes with simply watching funny, obsessed weirdos like Henson and his friends doing something nobody else was doing, something few people do anymore: taking children’s entertainment (and later adult entertainment) seriously as craft. I’ve heard naysayers argue that it’s silly to ask children’s movies to be any good, since they’re just for kids. But Henson knew better: Every opportunity to make something was a chance to explore with the audience. There’s a reason, then, that his work lasts.

For the full review see:

Alissa Wilkinson. “CRITIC’S NOTEBOOK; Took Kid Stuff Seriously.” The New York Times (Wednesday, June 5, 2024): C4.

(Note: ellipses added.)

(Note: the online version of the review has the dated May 31, 2024, and has the title “CRITIC’S NOTEBOOK; ‘Jim Henson Idea Man’: In a Joyful Weirdo, Lessons for Young Artists.”)

The Effect of Global Warming on Tropical Islands “Is Not an Exact Science”: Many Islands Are Stable or Even Growing

Environmentalists warned for decades that the biggest threat from global warming is to the survival of small low-lying islands. But as the late great physicist Freeman Dyson observed, the earth is more resilient than we know. In the three-full-page article quoted below, The New York Times (yes, The New York Times) reports that the small low-lying islands are mostly doing just fine.

(p. A6) On a wisp of land in the Indian Ocean, two hops by plane and one bumpy speedboat ride from the nearest continent, the sublime blue waves lapping at the bone-white sand are just about all that breaks the stillness of a hot, windless afternoon.

The very existence of low-slung tropical islands seems improbable, a glitch. A nearly seamless meeting of land and sea, peeking up like an illusion above the violent oceanic expanse, they are among the most marginal environments humans have ever called home.

And indeed, when the world began paying attention to global warming decades ago, these islands, which form atop coral reefs in clusters called atolls, were quickly identified as some of the first places climate change might ravage in their entirety. As the ice caps melted and the seas crept higher, these accidents of geologic history were bound to be corrected and the tiny islands returned to watery oblivion, probably in this century.

Then, not very long ago, researchers began sifting through aerial images and found something startling. They looked at a couple dozen islands first, then several hundred, and by now close to 1,000. They found that over the past few decades, the islands’ edges had wobbled this way and that, eroding here, building there. By and large, though, their area hadn’t shrunk. In some cases, it was the opposite: They grew. The seas rose, and the islands expanded with them.

. . .

(p. A7) It was Darwin who first theorized that atolls were burial sites for dead volcanoes, that these modest, almost shy, formations had astonishing pasts. Only later did scientists discover a key piece of their more recent history: Swings in sea level, they realized, had drowned and exposed the islands several times through the ages. Which didn’t bode particularly well for them today, now that global warming was causing the oceans’ rise to speed up.

To understand what had happened to the atolls since this acceleration began, two researchers, Arthur Webb and Paul Kench, decided to look down at them from above. The scientists collected aerial photos of 27 Pacific islands from the middle of the 20th century. Then, they compared them to recent satellite images. “I’m not sure we really knew what we would find,” Dr. Kench recalled.

Their findings caused an uproar.

The seas had risen an inch or so each decade, yet the waves had kept piling sediment on the islands’ shores, enough to mean that most of them hadn’t changed much in size. Their position on the reef might have shifted. Their shape might be different. Whatever was going on, it clearly wasn’t as simple as oceans rise, islands wash away.

Dr. Webb and Dr. Kench’s study, which came out in 2010, inspired other scientists to hunt for more old photos and conduct further analysis. The patterns they’ve uncovered in recent years are remarkably consistent across the 1,000 or so islands they’ve studied: Some shrank, others grew. Many, however, were stable. These studies have also added to the intrigue by revealing another pattern: Islands in ocean regions where sea level rise is fastest generally haven’t eroded more than those elsewhere.

And yet, to really grasp the forces at work, and to anticipate what they might do to the islands next, scientists also need to study atolls up close. Which is why Dr. Kench came back this spring to the Maldives.

On a blob of jungly land just a few miles north of the Equator, Dr. Kench walked past a section of beach that the currents had eaten away. Several palm trees lay toppled, half-buried in the sand.

“People obsess on that end of the island,” he said. Then he pointed up ahead. “This side has got bigger.”

SCIENCE AS ‘DETECTIVE WORK’

The day before, another island in the same atoll was abuzz with activity. One group of scientists and graduate students measured currents using makeshift buoys. Another group fiddled with a tower-mounted sensor that mapped the waves running up the beach. A third team dove down to the seafloor, where they installed instruments within the intricate coral canyons that, from above, gave the reef its streaky, ethereal look.

One doctoral researcher, Aitana Gea Neuhaus, scooped up a spadeful of sand and beheld the miniature universe it contained: puzzle-piece fragments of coral and calcareous algae in a mad variety of shapes and textures; crushed shells of bivalves, crustaceans and single-celled foraminifera; the sugar-white sand particles that parrotfish churn out of their digestive tracts.

. . .

One morning, Dr. Kench and a few other researchers hacked away a clearing in the jungle and bored a hole in the ground. Down went a six-foot steel pipe.

They were trying to glimpse the island’s deep past, to reconstruct its major chapters, layer by ancient layer. And they had some idea of how far below ground to look, thanks to seismic measurements that Tim Scott, an ocean scientist at Plymouth, had taken. Still, he warned the group: “It’s not an exact science.”

Dr. Scott sledgehammered the pipe down. “This is the moment of truth,” Dr. Kench said.

They levered out the pipe and hoisted it above a tarp. Out came a messy line of sediment and gravel and coral bits. Everyone leaned in close. No group of people in human history had ever seemed more interested in some chunks of damp sand.

Dr. Scott tried to puzzle out why the fine and rough material were jumbled together, not crisply layered as they’d hoped. Gerd Masselink, a coastal scientist at Plymouth, grinned. “Well, you know, it’s not an exact science,” he said.

. . .

On its own, coral bleaching isn’t necessarily bad for islands. When corals go white and frail, they can become infested (p. A8) by even more of the cyanobacteria that parrotfish love to munch on. The parrotfish flourish; they produce more sand.

. . .

It’s . . . less-populated islands where scientists say people can still learn to coexist with expanding and contracting shores, to adapt to nature’s give-and-take.

The issue is whether people can wait. Whether their needs for modern services, for better lives, will lead them to demand sea walls and breakwaters and land reclamation, the very things that could diminish the islands’ natural resilience. Or whether they will simply leave.

For the full story see:

Raymond Zhong, Jason Gulley and Jonathan Corum. “The Vanishing Islands That Failed to Vanish.” The New York Times (Saturday, June 29, 2024): A6-A8.

(Note: ellipses added; capitalized heading in original.)

(Note: the online version of the story has the date June 26, 2024, and has the same title as the print version.)

“Extended School Closures Did Not Significantly Stop the Spread of Covid, While the Academic Harms for Children Have Been Large and Long-Lasting”

(p. A13) Four years ago this month, schools nationwide began to shut down, igniting one of the most polarizing and partisan debates of the pandemic.

Some schools, often in Republican-led states and rural areas, reopened by fall 2020. Others, typically in large cities and states led by Democrats, would not fully reopen for another year.

A variety of data — about children’s academic outcomes and about the spread of Covid-19 — has accumulated in the time since. Today, there is broad acknowledgment among many public health and education experts that extended school closures did not significantly stop the spread of Covid, while the academic harms for children have been large and long-lasting.

For the full story see:

Sarah Mervosh, Claire Cain Miller and Francesca Paris. “Pandemic School Closures Came at a Steep Cost to Students, Data Shows.” The New York Times (Friday, March 29, 2024): A13.

(Note: the online version of the story was updated March 19, 2024, and has the title “What the Data Says About Pandemic School Closures, Four Years Later.”)

Arthur Diamond Praises The Bear in “The Bear’s Out-Stuck Neck”

My commentary on The Bear was posted to the American Institute for Economic Research (AIER) web site on Tues., July 9, 2024.

A direct link to the commentary is: https://www.aier.org/article/the-bears-out-stuck-neck/

On Facebook, I added the following comment:

“The Bear has the courage to show a passionate persevering crew of misfit chefs prioritizing merit (the food) over so-called D.E.I. (the color and gender of those who prepare the food). Courage is not the only virtue of The Bear–count also wit, plot, admirable (though flawed) characters, and intelligence. My review applies to seasons 1 and 2, and not as fully to the still-enjoyable season 3 that was posted to Hulu on June 27. At the end of season 3 we are left hanging on whether season 4 will uphold or betray the spirit of the The Bear in seasons 1 and 2.”

Jerry Seinfeld Knows “the Extreme Left and P.C. Crap” Hampers Comedy

(p. C1) Since the attacks of Oct. 7 [2023] in Israel, and through their bloody and volatile aftermath in Gaza, Mr. Seinfeld, 70, has emerged as a strikingly public voice against antisemitism and in support of Jews in Israel and the United States, edging warily toward a more forward-facing advocacy role than he ever seemed to seek across his decades of fame.

He has shared reflections about life on a kibbutz in his teens, and in December traveled to Tel Aviv to meet with hostages’ families, soberly recounting afterward the missile attack that greeted him during the trip.

He has participated, to a point, in the kind of celebrity activism with which few associate him — letter-signing campaigns, earnest messages on social media — answering simply recently when asked about the motivation for his visit to Israel: “I’m Jewish.”

And as some American cities and college campuses simmer with conflict over the Middle East crisis and Israel’s military response, Mr. Seinfeld has faced a measure of public scorn that he has rarely courted as a breakfast-obsessed comedian, intensified by the more vocal advocacy of his wife, Jessica, a cookbook author.

. . .

(p. C4) Since “Seinfeld,” he has spoken most expansively about the art of comedy itself, framing it as a morally neutral pursuit whose highest aim is to make people laugh. (Mr. Seinfeld recently made headlines for suggesting in an interview with The New Yorker that “the extreme left and P.C. crap” had hampered comedy.)

For the full story see:

Matt Flegenheimer and Marc Tracy. “Jerry Seinfeld Is Clearly No Longer About Nothing.” The New York Times (Monday, May 6, 2024): C1 & C4.

(Note: ellipsis, and bracketed year, added.)

(Note: the online version of the story has the date May 4, 2024, and has the title “Jerry Seinfeld Can No Longer Be About Nothing.”)

The “Silver Linings” of Illegally Trafficked Corals

(p. D4) Corals are not plants: They are tiny invertebrates that live in vast colonies, forming the foundation of the world’s tropical reefs. Marine life traffickers hammer and chisel them off reefs in places like Indonesia, Fiji, Tonga, Australia or the Caribbean, then pack them into small baggies of seawater so they can be boxed up by the hundreds and shipped around the world. While most coral is shipped into the United States legally, individuals and wholesalers, growing in number, are being intercepted with coral species or quantities that are restricted or banned from trade, often hidden inside shipments containing legal species.

. . .

Corals are better left in the wild, experts say, but there are silver linings after illegally trafficked specimens are confiscated and properly cared for by experts. In fact, there’s a good chance you’ve seen a confiscated coral if you’ve visited some aquariums.

Walk past the Indo-Pacific Barrier Reef exhibit at the Georgia Aquarium, for instance, and you can view a Turbinaria coral that was confiscated in 2005, shortly after Ms. Stone joined the aquarium.

It took years for the Turbinaria to recover, but now the colony has grown to more than 2.5 feet in size under her care and taken on a shape like a giant eye.

For the full story see:

Jason Bittel. “Mobilizing a Network to Save Marine Corals.” The New York Times (Tuesday, June 25, 2024): D4.

(Note: ellipsis added.)

(Note: the online version of the story has the date June 24, 2024, and has the title “Unlikely Wild Animals Are Being Smuggled Into U.S. Ports: Corals.”)

Physicians Are Reluctant to Assign Their Patients to a Clinical Trial of a New Therapy That Might Replace the Therapy They Know and Practice

(p. D1) After learning he had early stage prostate cancer, Paul Kolnik knew he wanted that cancer destroyed immediately and with as little disruption as possible to his busy life as the New York City Ballet’s photographer.

So Mr. Kolnik, 65, chose a type of radiation treatment that is raising some eyebrows in the prostate cancer field. It is more intense than standard radiation and takes much less time — five sessions over two weeks instead of 40 sessions over about two months or 28 sessions over five to six weeks.

. . .

The National Cancer Institute has just agreed to fund a clinical trial that researchers hope will settle which treatment is better. It will randomly assign 538 men to have either a short course of five intense radiation sessions over two weeks or 28 treatments over five and a half weeks, comparing outcomes for quality of life as well as disease-free survival.

But it will be at least eight years before the answers are in. In the meantime, men and their doctors are left with uncertainty.

“Ideally, we want to show five treatments (p. D4) is better,” said Dr. Rodney J. Ellis, a radiation oncologist at Case Comprehensive Cancer Center in Cleveland and the principal investigator for the trial.

One reason for the dearth of data is that prostate cancer usually grows slowly, if at all, so it can take many years to see if a treatment saved lives. It is expensive and difficult to follow patients for such a long time, and the treatments given to the men often change over a decade, making doctors wonder if the results are relevant.

Also, researchers who have tried to conduct studies comparing treatments often failed because specialists were already convinced that the method they used was best and were reluctant to assign men to other treatments. Dr. Ian Thompson of the University of Texas Health Science Center in San Antonio, said he was involved with several clinical trials that withered for that reason.

. . .

The researchers on the new study think recruitment will not be a major problem because they are comparing different courses of radiation, rather than entirely different approaches — for example, surgical removal of the prostate versus implantation of radioactive seeds in the prostate. A study to investigate those two approaches closed because investigators were able to enroll only 20 patients, Dr. Thompson said.

. . .

A few years ago, Dr. Yu and his colleagues looked at Medicare data and reported that men who had more intense radiation therapy were more likely to have urinary problems after two years than those who had the longer-course therapy.

Dr. Yu noted that his study was not a randomized trial, the gold standard, but he said the results were not reassuring. Now, though, he is not so sure the intense therapy is worse.

“In my own experience, these men have done really well,” he said. “That tells us that techniques improved, or the medical claims we evaluated were not indicative of major toxicity, or the way we and others at high-volume centers deliver radiotherapy is different.”

The lack of solid data bothers Dr. Daniel W. Lin, chief of urologic oncology at the University of Washington. When men ask him about the shorter radiation course, he tells them, “It probably can work but it doesn’t have long-term results and it hasn’t been tested against standard radiation.”

At centers like Sloan Kettering, doctors are relying on their own experience.

Dr. Michael J. Zelefsky, a radiation oncologist who treated Mr. Kolnik there, said that several years ago, 90 percent of his patients had the standard course of treatment. Now 90 percent choose the shorter course. On the basis of Sloan Kettering’s experience with several hundred men who had the intense radiation therapy over the past three years, the treatment, he said, “is emerging as a very exciting form of therapy.”

For the full story see:

Gina Kolata. “Unproven Therapy Gains Ground.” The New York Times (Tuesday, March 21, 2017 [sic]): D1 & D4.

(Note: ellipses added.)

(Note: the online version of the story has the date March 20, 2017 [sic], and has the title “Popular Prostate Cancer Therapy Is Short, Intense and Unproven.”)

Monarch Butterflies Thrive on Poisonous Milkweed

(p. D5) The caterpillar of the monarch butterfly eats only milkweed, a poisonous plant that should kill it. The caterpillars thrive on the plant, even storing its toxins in their bodies as a defense against hungry birds.

For decades, scientists have marveled at this adaptation. On Thursday [Oct. 3, 2019 [sic]), a team of researchers announced they had pinpointed the key evolutionary steps that led to it.

Only three genetic mutations were necessary to turn the butterflies from vulnerable to resistant, the researchers reported in the journal Nature. They were able to introduce these mutations into fruit flies, and suddenly they were able to eat milkweed, too.

Biologists hailed it as a tour-de-force that harnessed gene-editing technology to unscramble a series of mutations evolving in some species and then test them in yet another.

“The gold standard is to directly test mutations in the organism,” said Joseph W. Thornton, an evolutionary biologist at the University of Chicago. The new study “finally elevates our standards.”

For the full story see:

Carl Zimmer. “MATTER; How Monarch Butterflies Evolved to Eat Poison.” The New York Times (Tuesday, October 8, 2019 [sic]): D5.

(Note: bracketed date added.)

(Note: the online version of the story was updated Oct. 3, 2019 [sic], and has the title “MATTER; These Butterflies Evolved to Eat Poison. How Could That Have Happened?”)

The article in Nature mentioned above is:

Karageorgi, Marianthi, Simon C. Groen, Fidan Sumbul, Julianne N. Pelaez, Kirsten I. Verster, Jessica M. Aguilar, Amy P. Hastings, Susan L. Bernstein, Teruyuki Matsunaga, Michael Astourian, Geno Guerra, Felix Rico, Susanne Dobler, Anurag A. Agrawal, and Noah K. Whiteman. “Genome Editing Retraces the Evolution of Toxin Resistance in the Monarch Butterfly.” Nature 574, no. 7778 (Oct. 2019): 409–12.

The “corresponding author” (often considered the primary author) of the article is Noah K. Whiteman, who has published a book that extensively discusses cases such as the monarch butterfly, where a creature has evolved the ability to consume or make use of chemicals that are poisonous to other creatures:

Whiteman, Noah. Most Delicious Poison: The Story of Nature’s Toxins―from Spices to Vices. New York: Little, Brown Spark, 2023.

Wind Turbines and Solar Panels Are Destroyed by Severe Wind and Hail

(p. A15) The footage from southwest Iowa is shocking: In the trail of a tornado, a wind turbine is bent in half like a cheap straw, its hub engulfed in flames and thick black smoke, its blades on the ground.

“You’re seeing multiple of these big wind turbine towers that have been destroyed,” Zane Satre, a meteorologist for KCCI 8 News in Des Moines, told viewers. “These are big tall ones — I think they’re what, like 250 feet tall? Well that tornado took them out.”

. . .

The damage in Iowa to three turbines was part of a spell of bad weather that struck the state on Tuesday [May 21, 2024], . . .

. . .

When it comes to extreme weather and renewable energy, the larger problem is the vulnerability of solar panels to hailstorms, Mr. McLachlan said.

To reduce costs, panels have become larger over time, and the glass has become thinner, making it more likely to crack when hail strikes. That’s happening as more solar panels are being installed in the hail-prone Midwest — and as the frequency and severity of hail increase.

The standard way to protect solar panels from hailstones is to change their angle, Mr. McLachlan said, tipping them so that their surface is less exposed to direct hits. But that creates a new problem: those panels start to act like sails, catching the winds that often accompany hail, increasing the risk of blowing away.

Hail made up 54 percent of incurred costs from insurance claims for the solar sector over the past five years, according to a report from GCube last year, despite accounting for just 1.4 percent of claims. Growing losses from hail have made it harder to get insurance for solar projects, Mr. McLachlan said.

For the full story see:

Christopher Flavelle. “Giants Built for a Gale Crumple to the Ground.” The New York Times (Thursday, May 23, 2024): A15.

(Note: ellipses, and bracketed date, added.)

(Note: the online version of the story has the date May 22, 2024, and has the title “Tornado Pummels Wind Turbines in Iowa.”)

Movie Entrepreneurs Often Self-Finance Their Projects

(p. C4) The essential tragedy of movies is that they are wildly expensive to make and release. That’s one reason that filmmakers, especially those who want to control the means of production, have funneled their own money into their projects as long as movies have been around. Charlie Chaplin invested in his own work, as did John Wayne and Spike Lee. In 1979, when Coppola’s partly self-financed war film, “Apocalypse Now,” opened, he told The Times, “If I ever get the bucks that, say, George Lucas got from ‘Star Wars,’ I’d put every penny into changing the rules.” Lucas, who had invested his own money to help make “Star Wars,” used profits from that film to continue the series.

. . .

Weeks later, . . . all I could think about was something [Coppola] said in 1982. “It’s so silly in life not to pursue the highest possible thing you can imagine, even if you run the risk of losing it all,” he said. “You can’t be an artist and be safe.”

For the full story see:

Manohla Dargis. “Willing To Risk It All For Art.” The New York Times (Friday, June 8, 2024): C1 & C4.

(Note: ellipses, and bracketed name, added.)

(Note: the online version of the story has the date June 6, 2024, and has the title “Francis Ford Coppola: ‘You Can’t Be an Artist and Be Safe’.” In the last quoted paragraph, I quote the numbers from the print version. The online version, as of the time I checked, had numbers from June 10, 2024.)