Richard Lehman’s journal review—15 January 2018

Richard Lehman reviews the latest research in the top medical journals

richard_lehmanNEJM  11 Jan 2018  Vol 378

Fresh or frozen embryos?

Take the most delicate and potentially complex object in the Universe. It turns out that you can freeze it in liquid nitrogen at a temperature of minus 196 degrees centigrade or implant it in the womb straight away at 37 degrees centigrade with equal success. Two trials in this week’s NEJM demonstrate this in women with polycystic ovaries or women with normal ovaries. Perhaps the most remarkable thing about this is that we don’t find it remarkable. In the IVF community it seems that there is already a presumption that frozen embryo implantation will result in more live births, whereas these trials demonstrate equivalence.

Yet the very fact of life, let alone conscious life, remains as wonderful as ever. To remind yourself of this, read Life on the Edge by Jim Al-Khalili and Johnjoe McFadden (2014). Everybody has heard of Schrödinger’s imaginary cat, which remains in an superposition of life and death until somebody observes the photon which will seal its fate. Schrödinger came up with this thought experiment in 1935, in order to question the Copenhagen interpretation of quantum physics. Following the outbreak of war he moved to Dublin, where he started to think more deeply about the unique status of life as a physical phenomenon. What is Life (1944) is an exploration of the basic principles whereby physical order could acquire the ability to beget further order, in defiance of the otherwise universal laws of thermodynamics. Watson and Crick took inspiration from his ideas in their quest for the code of life, and so do the proponents of quantum biology in our own day. Well worth tunnelling into.

Multiple sclerosis: the latest

I marked up this review to read in a lean week for research in the journals. I’ve read similar reviews for the last 45 years, and always found that the most recent one looks dispiritingly like the previous one. I had hoped to learn of some promising new therapeutic developments (there have been so many false dawns over the decades), but this article doesn’t go into that area. Instead it is the usual catalogue of tantalizing epidemiological evidence, complex micropathology, and puzzling mechanistic half-clues.

JAMA 9 Jan 2018  Vol 319

Alzheimer drug despondency

Senescence is a natural process, and to be honest, we aren’t much good at slowing it. And we’re pretty bad at medicating any diseases of the central nervous system, especially those that come with ageing. I suspect that most of us would rather not lose our marbles at all; but if I had to, I would hope that they would all spill out of the bag at once so I would die quickly without being a burden on those I love. A breakthrough drug for Alzheimer’s would not merely show weak statistical evidence of a overall slowing effect on cognitive decline—like the cholinesterase inhibitors—but would get the senile me leaping from my chair, cooking complex dishes and chanting chunks of Milton (correctly, for a change). Appalled onlookers would beg me to stop. In trials of over 100 drugs (not on me personally, I hasten to add) there has been not the slightest glimmer of this happening. Idalopirdine is a drug that set out with low expectations and failed to come up even to those. As a selective 5-hydroxytryptamine-6 receptor antagonist, it was supposed to have a bit of add-on effect for people with Alzheimer’s who were already taking a cholinesterase inhibitor. But in three manufacturer-funded trials, it had no effect in the course of 24 weeks.

As the editorial puts it, “Another Therapeutic Failure in a Complex Disease Process.”

Ann Intern Med 9 Jan 2018  Vol 168

PFO closure for stroke revisited

In 20-25% of people, the foramen ovale never quite closes. Millions walk around with a hole in their heart which can allow blood—or gunk—to pass straight from their right atrium into their left atrium, from where it can shoot off into the brain. It is very difficult to know how many strokes are caused this way. Given the high prevalence of PFO, clot passage from the right atrium into the left must be a relatively rare event. For a time it became popular to look for PFOs in people with unexplained (“cryptogenic”) stroke and to close the hole using newly invented percutaneous devices. Then came a series of trials which failed to show any benefit from these procedures compared with medical treatment alone. But in the last half year, the pendulum has swung back a bit with two new studies showing that there may be an overall reduction in subsequent strokes or transient ischaemic attacks from PFO closure, despite an increased incidence of atrial fibrillation after the procedure. You can read all about it in two very up-to-date systematic reviews. It’s a sign of progress that in one of them, the conclusion reads: “In patients with PFO and cryptogenic stroke, transcatheter device closure decreases risk for recurrent stroke compared with medical therapy alone. Because recurrent stroke rates are low even with medical therapy alone and PFO closure might affect atrial fibrillation risk, shared decision making is crucial for this treatment.” Someone needs to create a usable tool quickly, and these reviews provide an ideal foundation.

Too old to exercise?

Sir Muir Gray, author of Sod Seventy, will not like this trial Muir is the knight who says No! to old age. He wants us all to get up as often as possible while watching television and lift bags of sugar. But when the US researchers took 1635 free-living adults aged 70-89 and compared an exercise programme with health education over two years, there was no difference in progression to frailty, as defined by standardized criteria. To be sure, this was not an ideally designed trial and the intervention did help people stand up more easily. But if you decide to stay on the sofa sipping your cocoa while channel-hopping or watching an old episode of Morse, the difference will be small and the comfort will be great.

The Lancet 13 Jan 2018  Vol 391

Hyping hyperparathyroidism?

I didn’t read this update on hyperparathyroidism when it first appeared on The Lancet website last September, despite having a first degree relative with the condition. These days it is terribly easy to diagnose and can be treated by surgery under local anaesthetic. Its prevalence jumped sixfold when testing became simple in the 1980s and 90s, and now nearly 1% of the population in developed countries has the diagnosis. So is this a case of Easily Missed or Overdiagnosed? Reading the review I couldn’t be sure. Kidney stones, anxiety, muscle aches, maybe cognitive decline and osteopenia: golly, it’s always a mistake to read about stuff. I’d better see my GP and get my calcium checked. Uncuffed please. Oh, and could you ask for a parathyroid hormone (PTH) as well?

The BMJ 13 Jan 2018  Vol 360

Who is going to get aggressive prostate cancer?

In medical science, there is usually a fumbling stage before usable knowledge is arrived at. This can go on for decades, or even centuries. While it goes on, pity the fumblees. Millions of men have contemplated death and had life-altering surgery because of a blood test introduced in 1980s, but relatively few of them would have died of prostate cancer. The PRACTICAL consortium was formed to develop and validate a genetic tool to predict age of onset of aggressive prostate cancer (PCa) and to guide decisions of who to screen and at what age. In keeping with current practice, single nucleotide polymorphisms (SNPs) were sought which showed a correlation with PCa. A scoring system was then developed, and when men in the validation set with high scores (>98th centile) were compared with those with average scores (30th-70th centile), the hazard ratio for aggressive cancer was 2.9. So that’s about three times as good as before: but how much aggressive prostate cancer does it actually predict, and will this be enough to tip the balance towards screening? What will be the cost?  I fear we will be fumbling for some time to come.

Proverbs of Sumer

Until the Sumerians invented writing over 5,000 years ago, we could only guess what was going on in ancient people’s minds. Then, through marks incised in baked clay, we could look inside. Women and men had exactly the same thoughts as today:

It is on account of being the boss that you bully me.

Flies enter an open mouth.

The house built by the upright man is destroyed by the treacherous man.

Give me my tools and I will launch my boat.

The good thing is the beer. The bad thing is the journey.

A heart never created hatred; speech created hatred.

To be sick is acceptable; to be pregnant is painful; but to be pregnant and sick is just too much.