Richard Lehman’s journal review—22 December 2014

richard_lehmanNEJM 18 December 2014 Vol 371
2353 Try to make winter bearable by thinking of the joys of late spring, such as seeing laburnum trees in full blossom. But you need to have plenty of garden space for the brief show they provide, and you also need to warn children against their poisonous seeds. This poison binds to the nicotinic acetylcholine receptors, which, as their name implies, are also the receptors that nicotine binds to. That is why laburnum extract has been sold as an aid to stopping smoking ever since the 1920s, under the name cytisine. Apparently, it is still available in some eastern European countries, but elsewhere we prescribe its vastly more expensive derivative, varenicline. I applaud the NEJM for publishing this open label New Zealand trial in which cytisine was compared with standard nicotine replacement therapy for smoking cessation. It was better. With vaping and cytisine becoming widely available, I really cannot see why combustible tobacco products should remain on the market.

OL What is progesterone for? Far more things than we dreamt of at medical school, it seems. According to the excellent Wikipedia article, there are progesterone receptors all over the body, female or male. It is a potent antagonist of the mineralocorticoid receptor, so don’t be too surprised if somebody does a trial of it in heart failure. And it is synthesised within the central nervous system where it acts as a neuromodulator, regulating neurotransmission and myelination, and protecting neurons from damage. So it is not surprising that people have tried using it in animal studies and small human trials after traumatic brain injury. But it is the too familiar story: success in animals, success in small open label human studies, then failure in large randomised controlled trials. In PROTECT-III, 882 patients with acute head trauma were randomised in 49 US trauma centres to receive intravenous progesterone or placebo within four hours of injury. The trial was stopped for futility and there was actually a small amount of harm from increased venous thromboembolism.

The SYNAPSE trial ran concurrently, and recruited 1195 patients across 21 countries. No benefit was found and no significant harms. If some keen medical student is reading this, home for Christmas and getting a bit bored, could they please have a go at updating the Wikipedia entry with the results of these trials?

OL It is quite possible that somebody is planning a trial of progesterone for acute ischaemic stroke, but don’t hold your breath. In the meantime, Dutch researchers have investigated the effect of removing clot from the blocked cerebral arteries following stroke, usually after initial treatment with alteplase. Collectors of silly acronyms will be pleased to note that this trial was called Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands—MR CLEAN. Intraarterial thrombolysis, mechanical treatment, or both, was compared with usual care—which could include intravenous alteplase—in patients with a proximal intracranial arterial occlusion of the anterior circulation that was confirmed on vessel imaging. The primary outcome was the score on the modified Rankin scale at 90 days. The modified Rankin scale is a 7 point scale ranging from 0 (no symptoms) to 6 (death). A score of 2 or less indicates functional independence. This score was obtained over the telephone by an assessor blinded to treatment allocation. There was an absolute difference of 13.5 percentage points (95% CI, 5.9 to 21.2) in the rate of functional independence (modified Rankin score, 0 to 2) in favour of the intervention (32.6% vs. 19.1%). There were no significant differences in mortality or the occurrence of symptomatic intracerebral haemorrhage. Now this is significant news. If you ask any doctor what they would like if they have a stroke, it is either to die or to come out relatively unscathed. This intervention does not reduce your chance of dying but it increases your chance of regaining independent function. So I’d go for it—although the stroke services and delivery times in your part of the world probably aren’t as good as those in the Netherlands.

JAMA 17 December 2014 Vol 312
2531 A pitifully short trial, with a small sample size, poor completion rate, and entirely surrogate markers. Is this what we need to guide a lifelong intervention for hundreds of millions of people? Alas, it is not. This was an overambitious crossover trial in which 163 overweight adults (systolic blood pressure, 120-159 mm Hg) were given four complete diets that contained all of their meals, snacks, and calorie-containing beverages, each for five weeks. The results were gathered for all who completed at least two diet cycles, and they showed that diets with low glycaemic index of dietary carbohydrate, compared with high glycaemic index of dietary carbohydrate, did not result in improvements in insulin sensitivity, lipid levels, or systolic blood pressure. No matter: I am strongly inclined to believe that a low glycaemic index diet might be beneficial to vast numbers of people, but this is not the way to test it.

JAMA Intern Med December 2014
OL I spent my middle aged years thinking about how old I was getting and how soon I would die. Now that I am really getting old—65 next birthday—I feel about 17 most of the time. Giving up clinical practice could have something to do with it, because doctoring drains you, and puts you in constant touch with the misery and unfairness of life and the squalid side of ageing. But I’m delighted that all the things that used to get me happy and excited still do. They don’t tell you about this much, but it is important. Here is a research letter about self-perceived age and mortality. In a cohort of people with a mean age of 66 years, the crude mortality figure over 8+ years for those who felt younger than their age was 14%, for those who felt the same as their age 18.5%, and for those who felt older than they really were it was 24.6%. Tomorrow I will probably catch a cold and feel 90. C’est la mort.

Lancet 20 December 2014 Vol 384
2213 The best time to give a vaccine is obviously before any likelihood of exposure to the infective agent, but that does not mean that it will be of no benefit if given later. The main purpose of vaccination against human papillomavirus is to prevent cancer of the cervix, and the best time to give it is before people become sexually active. But in the VIVIANE trial, healthy women older than 25 years were randomised to receive HPV 16/18 vaccine or control, and so far they have been followed up for a mean of 40 months. This interim analysis shows that the vaccine is highly effective at preventing cervical atypia owing to these HPV strains and also cross-protective against HPV types 31 and 45.

OL Several recent trials have shown that liberal blood transfusions in some situations can be associated with higher short term mortality than a restrictive policy, usually with a haemoglobin threshold of 8G/dl. The FOCUS trial recruited 2016 patients in 47 North American hospitals who had a haemoglobin of 10 or less after surgery for hip fracture, and who had an increased risk of cardiovascular disease. After a median follow-up of 3.1 years, 42% of these patients were dead. There was no difference in survival between those who were transfused to maintain a haemoglobin of 8 or 10. Less is the same as more.

OL It’s nice to see an increasing number of free research articles appearing on the websites of both the NEJM and the Lancet. This one describes the Deciphering Developmental Disorders (DDD) study, which has developed a UK wide patient recruitment network involving over 180 clinicians across all 24 regional genetics services, and which has performed genome-wide microarray and whole exome sequencing on children with undiagnosed developmental disorders and their parents. This is generating an enormous amount of data, much of which is of unknown significance. “Around 80 000 genomic variants were identified from exome sequencing and microarray analysis in each individual, of which on average 400 were rare and predicted to be protein altering. By focusing only on de novo and segregating variants in known developmental disorder genes, we achieved a diagnostic yield of 27% among 1133 previously investigated yet undiagnosed children with developmental disorders, whilst minimising incidental findings. In families with developmentally normal parents, whole exome sequencing of the child and both parents resulted in a 10-fold reduction in the number of potential causal variants that needed clinical evaluation compared to sequencing only the child. Most diagnostic variants identified in known genes were novel and not present in current databases of known disease variation.”
So large scale sharing of raw data is gradually transforming our understanding of rare developmental abnormalities in children. But just think of the difference similar routine data sharing could make to the management of common diseases in adults. I am not talking about genomics any longer, rather a coordinated system to collate every piece of individual patient data from clinical trials. The DDD was made possible by funding from the Wellcome Trust and the UK Department of Health. A system to collate and analyze all data from clinical trials would require global funding and coordination at a higher order of magnitude. But without it, we flounder and waste a huge percentage of the global research effort.

OL Speaking of huge funders, the Bill & Melinda Gates Foundation has supported a massive survey of global, regional, and national age–sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013. This would be just the thing to mull over on Boxing Day afternoon when it gets dark and you decide to slump into a sofa and have your first unwise glass of leftover sherry. Three more and you would be well into solving all the challenges to global health. But the Lancet or Elsevier has decided to put the article behind a paywall. If I was Mr or Mrs Gates, I would be on the phone to give them a Christmas earful.

The BMJ 21 December 2014 Vol 349
The Christmas edition of The BMJ is the one its readers look forward to most, and this year the journal has given them lots to go on, with a few serious(ish) contributions thrown in. I thought the funniest concept in the issue was vitamin D to prevent the adverse effect of earthquakes, although it isn’t the funniest article.

For me, that was the New Zealand study of disappearing magazines in waiting rooms. But there are enough other good ones to occupy plenty of time before, after, or—in the case of a hardened armchair socialist like me—during the Queen’s speech. Jeff Aronson on eponyms is unmissable and there is something to take away from every piece, notably that cardiologists are far more addicted to silly acronyms than any other specialty.

Mistranslations and mistranscriptions round off the funny bits, some of which may induce “grandma” seizures after dinner or generate a “coffin pulse” in hernia sufferers. Better than most cracker jokes, anyway.

Plant of the Week: Helleborus x ericsmithii “Winter Moonbeam”

Hellebores used to be rather fancifully called “Christmas roses,” especially H niger, which has dark leaves and white flowers, and always dies in our garden. This species is one of the parents of the original H x ericsmithii, which was raised by—you guessed it—Eric Smith. The other parent was a hybrid called H x sternii, created by Frederick Stern from a marriage between the Mediterranean species H lividus and H argutifolius. I fear I may be losing some readers here, but the point is that hellebore breeding—a lengthy and often pointless exercise—has now produced one of the most desirable garden plants of the century so far.

There is no evergreen perennial plant to match it for foliage. Some hellebore leaves are nice to begin with, but get brown or black and tatty as they age. But the ericsmithii hybrids have wonderful dark half-matt green leaves, large with fringed edges, held in formations of five, and beautifully mottled and veined with patterns of grey. And thanks to poisons that kill everything from fungi to slugs, insects and people, they last the whole year. Just now our two are beginning to produce beautiful white flowers, but they have already given us a season of delight just from their leaves.

  • George

    The HPV vaccine study is great. We might be waiting a long time to see if giving it to children really prevents cancer. Obviously, there are extremely good reasons for thinking it will, but still.
    That someone had the sense to see if it would work in adults is highly laudable, because here is the “proof of concept” that it will be effective for vaccinated children.
    Many persistent viruses trick the immune system into ignoring them. and Introducing an effective vaccine into an infected individual may well be beneficial in such cases.