“Outside of a dog, a book is man’s best friend. Inside of a dog it’s too dark to read.” ― Groucho Marx

About a year ago, two reviews of Annie Proulx’s novel, Barkskins, appeared in the New York Times. Neither was particularly favorable.

I bought an audiobook recording of the novel and have listened to it, all 26 hours of it, while driving up and down I-75 from Ann Arbor to the Upper Peninsula. I finished the last disc a few days ago driving west on M-28.

Two of Proulx’s previous works, The Shipping News and Brokeback Mountain, have won a Pultizer Prize and a National Book Award. Barkskins probably won’t scale those heights. Nonetheless, the book appealed to me at several levels.

First, Proulx is now over 80, and any octogenarian who has the dedication and energy to write and publish a 717 page novel spanning 300 years is OK in my estimation. Second, the tale is a prolonged, slowly intensifying, protest against the wholesale exploitation of natural resources for corporate profits. It’s a protest that might be more effective at a fraction of the length, but it certainly conveys the intensity of her feeling. At this stage of life, having intense feelings about issues seems to me extraordinarily admirable. And from time to time, she delivers positively lyrical descriptions.

Finally, though, I was drawn to her failure to get the story ended. I’m sure we have all sat through to one or another piece of classical music in which the audience raises its’ collective arms, ready to applaud and get the damn thing over with, only to have the orchestra continue on, repeatedly swelling toward but not achieving a grand finale. In the last chapters of Barkskins, Proulx just can’t stop the music.

Most stories often have natural endings. The detective solves the crime. The traveler returns home. The horse wins the race. But Barkskins won’t end for Annie.

I find that appealing. She doesn’t want to hang it up, to say, “There, that’s all I have to say about that.” Good for her!

I don’t think many Weekly Packet visitors will head to the local bookstore to buy this very long novel. You just won’t have time to read it. So, here’s an offer you can’t refuse. Anyone who is facing a long drive, for instance, New York to Los Angeles by way of New Orleans, can let me know. I’ll send the audiobook to the first reader I hear from. You’ll enjoy it.

Aargh! By AARP







I have several medical journals open on my desk with interesting topics that I thought I might mention in “The Weekly Packet.” By and large, the open journals are now properly aged, like pieces of meat at a fine steakhouse.

Nonetheless, they will have to wait. The most comment-worthy item to come along this week was in the AARP weekly flimsy.  Painful truth: my wife and I joined AARP to get the substantial discount offered by our local optometrist’s shop on new glasses. Even more painful truth: I was pulled in by the headlines about “why do drugs cost so much?”

I did not have high hope for a rigorous exegesis in the AARP journal, but the presentation was actually quite balanced. The writers covered the long timelines from drug discovery through clinical trials and the FDA approval process, and even covered phase 4 studies. They also touched on the vast amount that “big pharma” spends on marketing. In all fairness, they at least mentioned that Medicare cannot, by law, negotiate drug prices and touched on the strange role that “pharmacy benefit managers” play in the US system.

What’s my point? An AARP member who actually spent some time carefully reading the article would have a basic vocabulary, would become familiar with some of the players in the market, and would have been introduced to two key facts: pharmaceutical costs are only about 10% of overall health care costs, and big pharma spends as much on marketing as on basic research. Not bad. Although the authors did not point out to their readers that without this industry, their diabetes, high blood pressure, high cholesterol, and cancers could not be treated.

More importantly, what the AARP reader would NOT know, struck me last week when I attended the Clinical Leader Forum in Philadelphia. The pharmaceutical industry, particularly the clinical research organizations that have proliferated in the past couple of decades, exemplifies the new economy.

Let me try to explain. In one lifetime, mine, pharmacology has gone from a collection of empiric facts about medicinally useful herbs like digitalis or compounds, like sulfa, to an integrative science and technology focused on identifying “drug targets” in pathophysiologic processes.

From this point of view, the new drugs that pharma generates are the physical tokens, the representation of knowledge and of enormous amounts of data. The patients are not really paying for the drugs, they’re paying for the data. I think eventually, we will work out something more functional for drug pricing. But take a step back, and look again.

Kids who under-achieve academically will not find jobs in this industry. What I saw during last week’s meeting was a relentlessly driven technological and sociological wedge splitting the workforce into those who could deal with complexity and those who could not.

And I’m sure that other industries are similar.

There is no going back. No matter how much we would like to idealize the post-WWII economy, it’s gone.

Here’s the really scary thing; there’s good evidence most AARP members don’t understand what this kind of industry means for our society.


Time Travel is REAL!

This time last week, I was in Havana.

This is not a report from last week. It is a report from the late 1950s or early 1960s. If you don’t want to take my word for it, read Carlos Manuel Alvarez in the New York Times. 

Packet-style breaking news from Cuba: we Americans have been involved in armed conflicts twice there, in the Spanish-American War in 1898 and in the 1961 Bay of Pigs invasion. The count so far looks like one and one. After 1898, Cuba shook off Spanish rule to become a unique and vibrant society, and most Cubans seem to view that intervention positively. Plus, San Juan Hill gave Theodore Roosevelt an enormous boost.

By the mid-1930s, Fulgencio Batista, strongman, dictator, and certainly a friend of the mob, consolidated his hold on Cuba. He eventually brought rampant gambling and widespread corruption to Cuba. Although the US government supported Batista, revolution was in the air by the mid-1950s. A young lawyer, Fidel Castro, and his brother Raoul, along with Che Guevara, led the successful overthrow of the Batista government in 1959.

In April of 1961, a Nicaragua-based, CIA-sponsored, 1400-man anti-Castro “brigade” invaded Cuba at the Bay of Pigs. The invasion was a disaster. Over 1100 of the brigade were captured. “14 were put on trial for crimes allegedly committed before the revolution, while the others were returned to the U.S. in exchange for medicine and food valued at U.S. $25 million. Castro’s victory was a powerful symbol across Latin America, but it also increased internal opposition primarily among the middle-class Cubans who had been detained in the run-up to the invasion. Although most were freed within a few days, many fled to the U.S., establishing themselves in Florida.” https://en.wikipedia.org/wiki/Fidel_Castro

Having seen the terrain around the Bay of Pigs, including the dense Cienaga de Zapata, it’s not hard to understand why the invasion stalled. Most Cubans seem to view the Bay of Pigs for what it was, a fiasco.

After the events of 1961, time stopped. In fact, with the fall of the Soviet Union, from 1990 to about 2000, time went backward. This was Cuba’s “Special Period,” when support from the Soviets ended and the entire country fell into dire straits, short of everything.

Today, what we saw was how Castro’s unrestrained idealism, with the best of intentions, nearly destroyed a country. Cubans have universal education, universal healthcare, and no homelessness. But in this society, the infrastructure has crumbled; housing stock has steadily deteriorated, and the highly educated are vastly under-employed and underpaid.

The current government has reduced restrictions on free enterprise. Independent restaurants, “paladars,” flourish in Havana (see the photos). Some restoration and refurbishing is happening. But the work to be done is daunting!

High points of the trip: the Hemingway museum at Finca Vigia  and the National Museum of Fine Arts in Havana.

If you click on any of the photos in this post, you should get a slide-show view that will have nice size and detail. I have almost 900 photos sitting in Lightroom; more to come.

The Day After April Fool’s

True confession. If one refuses, and I do, to write about current political events, then finding subjects can be challenging. As I wondered how to appropriately memorialize the day after April Fool’s, I thought about my recent reading. “Gosh, I thought, I haven’t read much lately.” Then, I looked around the room I call “my office.” (My wife calls it something rather different; let’s not go there.) I really have read quite a lot, but mostly related to “The President and the Poet,” a project that is worth checking out  if you are not familiar with it. (Also, have a look at Reunion ’64 and please consider some modest support, $10 or $20, for the project on Kickstarter.)

Then, I thought about my Kindle. Yes, I’ve read a good bit on it, too. Most recently, I completed Aldo Schiavone’s Pontius Pilate. Deciphering a Memory. The book received a nice review in the New York Times, but there are two problems. First, the translator was very fond of obscure academic English terms. He lost me, not once, but several times, in a dense fog of theological scholarship. Second, the entire historical record can be summarized in two sentences. Solid historical evidence indicates that a Roman, Pontius Pilate, governed the territory around Jerusalem around the time that we have arbitrarily picked as the beginning of the “common era.” A brief interaction between Pilate and an itinerant Jewish teacher named Jesus resulted in the latter’s death. Building a full book from those sentences requires injecting a lot of material that, at the best, could be called ‘scholarly interpretation.’  Not highly recommended.

So then, I really looked around the office. I’m struck that the books I keep coming back to are the ones I should write about. The two that never get far off my desk these days are Daniel Kahneman’s Thinking, Fast and Slow and Leonard Mlodinow’s The Drunkard’s Walk. How Randomness Rules our Lives.

Back in the early 1980s, I thought that game theory might offer a useful approach to understanding clinical decision-making. I published a little-known paper about this, but the real bonus was that the background reading lead me to Kahneman. I have been a fan ever since.

I found Mlodinow after I started working at Scios and realized that I was so inept at statistical thinking that I did not even know how to ask statisticians good questions. This ineptitude became embarrassing when it was revealed on an almost-daily basis, and it accounted for my purchasing a number of books. Mlodinow’s is one of the better ones; his strength is that his language makes critical concepts accessible for lay readers.

So, as I look around the office, I’m going to come up with a new rule. I hope you know some of my old ones, for example “Sicker patients do worse.” Or, “Non-fatal diseases generally get better.”

Here is the new rule, based on the concept of “presentness,” (last post) and the two books I have just discussed…

“Any intuitively obvious conclusion based on present data is very likely incorrect.”



In high school, I learned that writing offered an opportunity to display one’s vocabulary, and thus, presumably, one’s erudition. Complex sentence construction was laudable, save for the dreaded “comma splice.”

Then I arrived at Amherst, where Theodore Baird dominated my freshman year. Baird lived in a Frank Lloyd Wright “Usonian” house, and was a friend of Robert Frost. In his course for freshmen, English 1-2, Baird taught writing. He rewarded simple straightforward sentences. He derided complex constructions.

A few years ago, Dan Chiasson reviewed Baird’s book, English at Amherst, and said, “It would be an exaggeration to say that getting Frost right was the great mission of English 1-2. For one thing, the course read no Frost. In fact, after its early, provisional years, it read nothing: no literature, no text of any kind. But I think it is true to say that the air of Robert Frost pervaded English 1-2.”

I agree.

With this background, I was drawn into a recent New Yorker book review titled “The Illiberal Imagination” by Adam Gopnik, a long-time staff writer for the magazine. He pulled me in with two sentences. “Of all the prejudices of pundits, presentism is the strongest. It is the assumption that what is happening now is going to keep on happening, without anything happening to stop it.”

The review covered three books: Pankaj Mishra’s Age of Anger, Joel Mokyr’s A Culture of Growth, and Yuval Noah Harari’s Homo Deus. I understood very little of Gopnick’s commentary, which was obviously erudite and involved quite a lot of Rousseau and Voltaire. On the other hand, I really liked the concept of “presentism.” More accurately, I liked Gopnick’s identification of the concept as faulty.

“That’s what I’ve been trying to say!” I thought. That’s what I had in mind when I wrote that I wanted to capture the perspective of the reader who is delighted to have a month-old newspaper arrive on the mail packet.

Thinking about presentism seems important to me. The past is debatable. For instance, the slogan “make America great again” seems patently false. What was great about the Depression, polio, segregation, the Cuban missile crisis, or the Viet Nam war?

The future is, by definition, unknowable. This leaves us with the present. Here and now is what we have to work with, and where we have to become engaged. We must not fall into “the assumption that what is happening now is going to keep on happening.”  Presentism is disheartening, paralyzing.

But this is when the month-old newspaper arrives, like the cavalry coming over the hill. We read it. My goodness, that was terrible! But whatever it was, it ended. By now, something else has happened. The present, whatever it is, will change. How invigorating!

Shaping the outcome of today, shifting a bit toward something better, becomes the relevant question for us. This is the antithesis of presentism. How do we bend toward better without breaking something? Ah ha! Read the month-old paper, carefully. Did yesterday’s crisis require solution, or did it self-resolve? How did the leadership muddle through? Just as important, what were the unintended consequences of what they implemented?

Chiasson had another thought about Theodore Baird. He wrote, “If you can convince a large number of 18-year-olds that making up sentences is an act of deep moral imagination, you do it, no matter how much work that entails.” By extension, recognizing good sentences when reading can also be important. So thank you, Mr. Gopnick, for those good sentences.

“Déjà vu all over again”

In keeping with longstanding Packet policy, I’m offering readers some well-seasoned news for the sake of context. This is not intended as humor, although some may initially view it as such. My point is serious. Without the context of the past, we have no basis for evaluation for current events.

The facts for this post, and all of the otherwise unattributed quotations, come from Robert Strauss’s book, Worst. President. Ever., a history of James Buchanan’s term as President of the United States.

The first year of James Buchanan’s term, one hundred sixty years ago, was not a good year for the United States.

First, two days after the inauguration, came the Dred Scott decision from Chief Justice Roger Taney and the Supreme Court. “In March 1857, in one of the most controversial events preceding the American Civil War (1861-65), the U.S. Supreme Court issued its decision in the case of Dred Scott v. Sanford. The case had been brought before the court by Dred Scott, a slave who had lived with his owner in a free state before returning to the slave state of Missouri. Scott argued that his time spent in these locations entitled him to emancipation. In his decision, Chief Justice Roger B. Taney, a staunch supporter of slavery, disagreed: The court found that no black, free or slave, could claim U.S. citizenship, and therefore blacks were unable to petition the court for their freedom.” Buchanan, before his inauguration, had vigorously lobbied the Court justices for a broad and binding decision; they went along with him.

Buchanan chose a mediocre cabinet. “There was not a rival or a grand thinker” among them. Lewis Cass, his choice for secretary of state, “was growing senile and Buchanan would essentially be his own secretary of state.”

The Panic of 1857, one of the periodic major financial downturns that plagued the country, was largely a response to Buchanan’s reduction of tariffs. “The Panic of 1857 was … caused by the declining international economy and over-expansion of the domestic economy. Because of the interconnectedness of the world economy by the 1850s, the financial crisis that began in late 1857 was the first worldwide economic crisis.” Buchanan’s  (ineffective) solution was to reduce the physical size of U.S. coins. These smaller coins required less gold and silver to mint. Thousands lost their jobs, and several major companies went bankrupt.

“Buchanan’s personal attitude [was that] …rugged individualism would triumph over adversity; the buoyancy of youth and the energy of the people would enable them to recover.”

As the year wore on, a dispute in the Utah territory between Mormons and federal justices became heated. Without any effort to determine the validity of the Mormon’s claims, Buchanan sent federal troops to “defend American law.” Brigham Young “formed an army of his own and ordered them to burn everything – every building, every tree, every piece of hay – that the federal force might capture on the way toward the presumed invasion.”

“Thousands of Mormons …lost their homes and livelihoods, scorching all, as Young had ordered, and fleeing in the face of the army.” The Mormons, for their part, were responsible for the deaths of more than 120 innocent settlers on their way to California, the Mountain Meadows massacre.

Russian Grizzly and her cubs, 8/19/2013. KZM photo.

In summary, 160 years ago, in his first year of his first and only term, Buchanan had a mediocre cabinet, a Supreme Court crisis, and a major financial crisis precipitated in part by the fact that America had become part of a global economy; in addition, he directed the power of the federal government against a specific religious sect.

So, we’ve got that goin’ for us, which is nice.

What you see is what there is…


One of my medical school classmates recently posted a Washington Post article on Doximity, a “social media” site for physicians. The article caught my attention. I think it’s worthy of some comment. The author of the Post article is a brilliant young physician, Dhruv Khullar; his subject was a recent paper in JAMA by Denson, Jensen, Saag, et al. titled “Association Between End-of-Rotation Resident Transition in Care and Mortality Among Hospitalized Patients.” 

The primary finding from this large, retrospective, multicenter observational study was, “end-of-rotation house staff transition in care was associated with significantly higher in-hospital mortality.” The headline for the Post article was “When a new team takes over your care at the hospital, it can be a precarious time.” The change in titles itself is a pretty dangerous transition.

After 14 paragraphs describing the intellectual and emotional uncertainties inherent in teaching-hospital house staff transitions, Khullar finally wrote, “Patients who remain hospitalized during transitions may simply be sicker.” An editorial raising this issue, and the data in the JAMA publication from a restricted analysis that showed markedly lower mortality after attempting to adjust for the degree of illness, at last got some attention in the text.

Here’s my point. There is a critical feature that links all three pieces: the research paper, the editorial, and the Post article; they all acknowledge that the basic premise of the work is flawed, but all three then go on to propose solutions to the  undefined “transition problem” anyway.

Why do I suggest that the analysis is flawed? I’m not a statistician, but after decades of reviewing medical papers, I know enough to realize that this retrospective study was not a statistical problem of tossing fair dice. Patients who are or are not candidates for discharge from hospital on any given day differ in many ways. The study population was not randomized, and as the researchers commented, “the differences observed in patient populations might represent a direct consequence of clinical decisions made because of an upcoming transition rather than confounding. That is, if clinicians try to discharge as many patients as possible prior to transitioning off service, but have more difficulty discharging complex and long-stay patients, the average severity or complexity of patients exposed to transitions in care could be increased.”  [Italics mine]

An ad hoc attempt to adjust for these issues with an alternative approach to analysis demonstrated that the findings were highly dependent on unmeasured factors. As the researchers noted, “The increased 30-day and 90-day mortality risks observed in the main analysis suggest that the delayed discharge of these complicated patients following transition could be detrimental…   The alternative analysis, however, did not demonstrate these findings, [italics mine] which could be related to the noted differences between analyses.”

So, I would like to pose a really interesting question. Why did the authors (and the reviewers and editors) of all three pieces perceive a problem and then propose solutions to it in spite of the facts that the “adjusted” data suggested that the effect of house staff transition was not nearly as great as initially suspected, and that both the authors and the editorialists realized that, “Patients who remain hospitalized during a change in personnel on the inpatient service are likely different than (sic) those who are discharged”?

For the answer, I suggest we ask Nobel Prize winner, Daniel Kahneman. In his book, Thinking, Fast and Slow, Kahneman pointed out, “even compelling causal statistics will not change long-held beliefs…” In the transition-of-care publications authors, reviewers, and editors cling to the long-held belief that doctors can somehow overpower the poor prognosis of old age, frailty, and severe disease by improving the mechanics of healthcare delivery.

In our society, this belief encourages us to think about developing better hand-off forms for interns and residents instead of thinking about how we might really care for patients.

All’s not lost! These observational data do suggest a testable hypothesis. With an upcoming transition in care, rather than pushing early discharge for patients who are basically going to do well, a more productive approach might be to focus effort on recognizing the sicker patients and making appropriate arrangements for them, for example, earlier initiation of specialty consultations, social services for discharge planning, or consideration of hospice or palliative care transfers. In other words, one could randomize two large groups to either usual care (perhaps with the undeniably attractive hand-off forms) or pre-transition intervention starting a week or so before transitions and focused on appropriate discharge planning for sicker patients.

But then again, shouldn’t that be happening now?

P.S. The bird pictured is a blue-footed booby that Katherine photographed in the Galápagos Islands. I included it to make the point that blue-footed boobies do, indeed, have blue feet. This is directly related to the clinical concept that sicker patients do, indeed, do worse.

London in the 1850s


“It was estimated that in 1839, for every person who died of old age or violence in London, eight died of disease caused by poor sanitation practices.”

London began as a Roman town in about 50 AD. By the mid-1800s, the city had become “a Victorian metropolis trying to make do with an Elizabethan public infrastructure.” Thus opens Steven Johnson’s spell-binding non-fiction book, The Ghost Map.

The Ghost Map chronicles the London cholera outbreak of 1854, and central to the story, John Snow and Henry Whitehead’s demonstration that cholera was a water-born epidemic and that the likely source of contamination of the Broad Street pump was a nearby cesspool.

The train of thought establishing the relevance of this 150 year-old story to drug prices today may seem a little erratic at first, but bear with me. As readers of The Weekly Packet know, the evidence supporting pharmaceutical pricing as an important driver of the overall increase in the cost of healthcare in the US is shaky.  On the other hand, the February, 2017 issue of Nature Reviews Drug Discovery has an opinion piece on immune-oncology that shows the huge growth of pharmaceutical research in that discipline. When they come to market, these drugs will not be inexpensive generics, and their prices will reflect the relatively limited numbers of patients for who they are appropriate.

Now, take a look at the facts on the World Health Organization website:

  •  2.4 billion people still do not have basic sanitation facilities such as toilets or latrines.
  • Of these, 946 million still defecate in the open, for example in street gutters, behind bushes or into open bodies of water.
  • The proportion of people practising open defecation globally has fallen almost by half, from 24%to 13%.
  • At least 10% of the world’s population is thought to consume food irrigated by wastewater.
  • Poor sanitation is linked to transmission of diseases such as cholera, diarrhoea, dysentery, hepatitis A, typhoid and polio.
  • Inadequate sanitation is estimated to cause 280 000 diarrhoeal deaths annually and is a major factor in several neglected tropical diseases, including intestinal worms, schistosomiasis, and trachoma. Poor sanitation also contributes to malnutrition.

In addition, WHO says, “The situation of the urban poor poses a growing challenge as they live increasingly in mega cities where sewerage is precarious or non-existent and space for toilets and removal of waste is at a premium. Inequalities in access are compounded when sewage removed from wealthier households is discharged into storm drains, waterways or landfills, polluting poor residential areas.” Sounds like London 150 years ago, doesn’t it?

Here’s how these stories are related. In terms of overall human health, and in environmental quality, the return for dollars spent on sanitation infrastructure is far greater that the return on immuno-oncology. What we are seeing here is that not only has our own US society become divided along economic lines, but our global society has as well.

OK, that’s not exactly “new news.” (I promised that Packet would focus on well-seasoned news.) But here’s a thought. The pharmaceutical industry has a serious problem with its public image. What if, just what if, the industry as a whole agreed to major reductions in direct-to-consumer advertising, focused ads on R&D, and took the lead in supporting improved public health and sanitation infrastructure? What if?

Long-term, it could be a great investment.

(PS: I photographed this mosaic in 2012 at an archaeological site in Greece. It’s not far from the famous ancient latrine often pictured on websites, but much more attractive.)