Richard Lehman reviews the latest research in the top medical journals

NEJM  5 Apr 2018

Childhood obesity and later-life hyperglycaemia

Warning: this article is entirely about Danish men. It is like Hamlet without Gertrude or Ophelia. Let’s say you grew up like a Danish prince, well fattened on bacon and pastries, so that you were overweight by the age of 7. But then you became thinner by the age of 13 as a result of eating the air, promise-cramm’d. You survive the poisoned sword, reign wisely, and reach a ripe age, free of the label of type 2 diabetes: “Men who had had remission of overweight before the age of 13 years had a risk of having type 2 diabetes diagnosed at 30 to 60 years of age that was similar to that among men who had never been overweight“ says this study involving 62,565 Danish men. They were part of a male cohort whose weights and heights had been measured at 7 and 13 years of age and in early adulthood; their diabetes status was determined from a current national registry. On the other hand, let’s imagine that Hamlet had grown obese from eating funeral baked meats and the tempting sweetmeats of the Elsinore kitchens throughout adolescence. In this case, his risk of a diagnosis of T2DM by the age of 60 would have risen fourfold.

Now: was Shakespeare’s Hamlet thin or fat?

I’m afraid his mum gives us the answer:“He’s fat, and scant of breath” (5.2.287).

Epigenetics update

Was Hamlet’s obesity the result of his genes or his eating choices? I hope you see that there is some entanglement between the two, and that the “choices” available to a Danish prince might have been different from those of a Danish peasant. Also, that chance may play a role besides genes and environment. Let’s move to epigenetics: a subject wonderfully explored in a single-author article by Andrew Feinberg. “The epigenome consists of nuclear information, heritable during cell division, that controls development, tissue differentiation, and cellular responsiveness. Epigenetic information is controlled by genome sequence, environmental exposure, and stochasticity, or random chance. As such, epigenetics stands at the interface of the genome, development, and environmental exposure.” I can’t possibly try to convey the subtlety and complexity of this piece, which even contains a new mathematical definition of biological entropy quite separate from the familiar (and equally confusing) thermodynamic definition of entropy. You can skip all that if you wish. The title of the piece is “The Key Role of Epigenetics in Human Disease Prevention and Mitigation” which incorporates the compulsory American posture of scientific positivism. The Elizabethans were deeper and wiser. Hamlet (c.1600) can be read as a post-Christian discourse on the essential unpreventability or mitigation of the human condition. Of course it can also be read as a thousand other things: like all the greatest art, it has no circumference. Edmund Spencer’s Mutabilitie Cantoes, written at the same time as Hamlet, are an essentially pre-Christian Platonic meditation about the same thing, which tries to end on an optimistic note. Towards the end of the poem, Mutability (you can read epigenetics) points out her ubiquitous power, but gives the last word to the goddess Nature. A long silence ensues, but then Nature speaks:

At length, she looking vp with chearefull view,

The silence brake, and gaue her doome in speeches few.

 

I well consider all that ye haue sayd,

And find that all things steadfastnes doe hate

And changed be: yet being rightly wayed

They are not changed from their first estate;

But by their change their being doe dilate:

And turning to themselues at length againe,

Doe worke their owne perfection so by fate:

Then ouer them Change doth not rule and raigne;

But they raigne ouer change, and doe their states maintaine.

 

All very well if you’re Nature, but sometimes a bit of a bummer if you’re a human being.

 

JAMA  3 Apr 2018

Atorvastatin loading before acute PCI

“To be, or not to be, I there’s the point.” Hamlet says in the First Quarto of the play, which was probably a loose recollection put down by some panicky idiot in the audience. But for many clinical trials, this really is the point. A trial conducted in 53 cardiac centres in Brazil compared survival in patients who were or were not given two loading doses of atorvastatin at the time of planned percutaneous coronary intervention, 80mg before and after. For death, there was no difference in outcomes: for the rest of the composite primary outcomes, there was a weak signal in favour of the early statin, but nothing that would suggest statistical or clinical significance. Bizarrely, the editorial on this trial has the title “Lipid Lowering in Acute Coronary Syndrome”. If there was one thing this trial did not test, it was lipid lowering. The aim was to test whether statins lower acute cardiac mortality long before they have any time to lower lipids. I, there’s the point. That is the question. I doubt whether this will be the last word on the matter.

Negative wealth shock

And now—in this very sparse week in the journals—we come to the slings and arrows of outrageous fortune and their effect on life expectancy in Americans. The title of the study refers to “Negative Wealth Shock“, something the Elizabethans were very familiar with. The most popular song ever written in England ends:

From the highest spire of contentment
My fortune is thrown;
And fear and grief and pain for my deserts, for my deserts
Are my hopes, since hope is gone.

Hark! you shadows that in darkness dwell,
Learn to contemn light
Happy, happy they that in hell
Feel not the world’s despite.

(John Dowland 1600, Flow my tears)

In the case of this 1994-2014 survey, negative wealth shock was defined as a loss of 75% or more of total net worth over a 2-year period, or asset poverty, defined as 0 or negative total net worth at study entry. There were 30.6 vs 64.9 deaths per 1000 person-years for those with continuously positive wealth vs negative wealth shock. There is a striking lack of data about causes of death in this paper. I couldn’t find the overall figures for suicide, let alone bare-bodkin-related injuries.

Hamlet’s Garden

What little we know about Shakespeare as a man is mostly inferred from his plays. Hamlet shows us that he was an experienced theatrical director—which we had kind of guessed already—and that he was a gardener who hated weeds. The adjective “rank” appears several times in the play, beginning with Hamlet’s first soliloquy:

O God, God,

How weary, stale, flat and unprofitable

Seem to me all the uses of this world!

Fie on’t, ah fie, ’tis an unweeded garden

That grows to seed; things rank and gross in nature

Possess it merely

Hardly a word in this passage has survived unaltered by Shakespeare’s use of it: everybody speaks and thinks a different English since Hamlet. But four hundred years of familiarity have done nothing to dull its terrible force.

Hamlet’s confrontation with his mother remains unbearable. The word rank is repeated, twice:

Lay not that flattering unction to your soul

That not your trespass but my madness speaks,

It will but skin and film the ulcerous place

While rank corruption mining all within

Infects unseen…

And do not spread the compost on the weeds

To make them ranker…

Of Ophelia and her flowers we need not speak or paint: too many Victorians have been at this already.

The garden which Shakespeare’s son Hamnet played in was destroyed in the middle of the eighteenth century. An adjacent public walled garden may include part of it, and is still a pleasant place to escape the Stratford tourists, who mostly don’t seem to know about it. But there are ominous signs of new interest in this site: I suspect that before long there will be plantings of rosemary and rue and other boring knot-gardeny plants, and a gate to take money from people.