NEJM 28 May 2015 Vol 372
2087 Now that the NEJM has flagged up its position on conflicts of interest, it’s definitely a case of caveat lector—looking hard at what it decides to publish. First in this week’s issue is a GSK-funded trial of its new herpes zoster vaccine (HZ/su) aimed at preventing shingles in older people. There is already one vaccine licensed for this indication in the USA, but its efficacy falls off the older you are. So there was a plausible gap in the market for older people, which GSK now hopes to fill, since its vaccine is nearly 100% effective at all ages, whereas its rival was only 38% effective over the age of 70. A reasonable trial then, though it would have been better had it used the rival vaccine as an active comparator. The claims of the abstract conclusion are modest and accurate. Not much to pharmascold about then, though I’d like to know how much the journal makes out of selling reprints of papers like this to GSK.

2108 Money can definitely buy people, and cash is generally much more welcome than promises. FIFA could perhaps provide some nice examples, but failing that, here is a study of bribing smokers to give up. They set their trial up as a set of four rational gambler scenarios like those you can read about in Kahneman’s Thinking, Fast and Slow. I’ll leave you to look up the details. The message was that brown paper envelopes, containing 800 bucks and still moist from the sweat of a hand, get results. “Reward-based programs were much more commonly accepted than deposit-based programs, leading to higher rates of sustained abstinence from smoking. Group-oriented incentive programs were no more effective than individual-oriented programs.”

2127 Slouchy old killer is how I’ve described Mycobacterium tuberculosis in the past, and slouchy old killer he looks like remaining for a while yet. This clinical review of latent TB infection describes the diagnostic limitations we still labour under, because the new interferon-γ release assays (IGRAs), although more sensitive than the old tuberculin skin test, are also more likely to fluctuate with time. And treatment is still mostly isoniazid-based and lasts months. Yet the old enemy may at last be at bay: “Modelling shows that if 8% of persons with latent tuberculosis could be permanently protected each year, the global incidence in 2050 would be 14 times as low as the incidence in 2013, with no other intervention needed.”

OL “Precision Medicine—Personalized, Problematic, and Promising” is an exploration of the various things this term is employed to mean. Many of them are good. But the immense information load threatens to overwhelm every person—be they healthy, ill, medical, or technical—with data that leads to nothing but more data-seeking and more anxiety. “Medical school curricula will need to focus even more on information management. Physicians will require informatics support and algorithms that work in the background to assist with information management and decision making. Health systems will need to design pathways that facilitate ready access to specialists when appropriate.” Strange—they’ve just argued that specialists will be no better able to understand it than anyone with the right decision support. Let’s just hope they can feed patient preferences into those algorithms. Precision Medicine—Pricey, Profitable, and Perplexing. The latest way to make the luckiest humans in history anxious during their short stay on Earth.

JAMA 26 May 2015 Vol 313
2019 I wrote that last paragraph before turning to JAMA and reading their two viewpoint pieces on Scientific Discovery and the Future of Medicine. Don’t read them before bedtime. You will have a nightmare in which you visit a psychiatrist who invites you down to his cellar filled with strange equipment and coils of light, straps you to a bench and inserts lasers and fibre optics for light delivery into the nervous system. He proceeds to inject you with genes called microbial opsins, which encode light-activated proteins that regulate transmembrane ion conductance. So you say you are feeling depressed, my friend? We shall soon find out. Ygor, turn on the scanner. No, not that wavelength you fool! Aha, this is better. “Circuit-level understanding of psychiatric symptoms is allowing generation of more sophisticated pathophysiological hypotheses, which is important for replacing the current symptom and subjective report-based psychiatric nosology with one based on more sophisticated understanding of etiology.” O help! Somebody help me!

2021 You wake up sweating and can’t get back to sleep. Maybe that second glass of Bourbon was a mistake. You ponder the great and comfortless mysteries of existence. Deoxyribonucleic acid is just a molecule. Molecules are subject to random (stochastic) change. They can even, in some circumstances, behave like quantum objects, which do not take a fixed state until observed. If we were able to know everything, would we actually know anything? Time would ensure that what we knew was no longer true. Xiaoliang Sunney Xie, PhD, seems unperplexed by these doubts in her/his piece called Single Molecules Meet Genomics: Pinpointing Precision Medicine. Here is his or her concluding summary: “DNA exists as single molecules in an individual cell. Consequently, gene expression and genomic variations occur stochastically, necessitating single-cell and single-molecule measurements. Single-cell genomics is where single molecules meet genomics. The ability to count the copy numbers of a gene and detect a point mutation in a single cell is now not only possible, but is critically important as well. Such single-molecule methods have allowed for probing, understanding, and bettering life at the single-molecule level and provided a tangible example of precision medicine.”

Does my bottom look big in these genes?
Oh, that depends on observation:
For genes are made of DNA
Which alters with time and replication.

But do not worry ’bout your bum,
It’s fixed in time and cannot harm you.
It’s all the other little genes
That gnomes can probe at to alarm you.

2033 Soy isoflavones. I have no idea what they are and I have no intention of finding out. Somebody decided to see if they might improve asthma control. “Among adults and children aged 12 years or older with poorly controlled asthma while taking a controller medication, use of a soy isoflavone supplement, compared with placebo, did not result in improved lung function or clinical outcomes. These findings suggest that this supplement should not be used for patients with poorly controlled asthma.” Now hang on, don’t take it out on the poor old isoflavones. It’s not as if they did any harm. For all I know, they may taste nice.

2044 Now let us travel to Estonia for a tour of the other side of genomics: not single molecules but whole populations. It begins with a trawl through the genomes of 7877 Estonians for copy number variations (CNVs) associated with clinically apparent intellectual disability. The idea was to determine the significance of these CNVs in carriers within the general population. I don’t want to go into detail, but the results were replicated on a high-functioning group of 993 Estonians and 3 geographically distinct populations in the United Kingdom, the United States, and Italy. It seems that we are once again faced with information of uncertain value which is difficult to share with individuals: “Known pathogenic CNVs in unselected, but assumed to be healthy, adult populations may be associated with unrecognized clinical sequelae. Additionally, individually rare but collectively common intermediate-size CNVs may be negatively associated with educational attainment.”

JAMA Intern Med May 2015
Good things keep popping up on the website of this terrific journal at a rate I can’t keep up with. This list is by no means complete:

OL Performance of Wells Score for Deep Vein Thrombosis in the Inpatient Setting. A study showing how little discriminatory ability it has in hospital patients. If you need any persuading, there is an editorial entitled The Wells Deep Vein Thrombosis Score for Inpatients: Not the Right Tool for the Job. I don’t think D-dimer is much better. If you have the patient lying there in front of you, why not learn how to use a hand-held ultrasound?

OL The Effect of Primary Care Provider Turnover on Patient Experience of Care and Ambulatory Quality of Care. “Primary care provider turnover was associated with worse patient experiences of care but did not have a major effect on ambulatory care quality.” I’m reminded of reading one of Donabedian’s key papers where he said “Perhaps the ultimate test of quality of care is the experience of patients.” So measuring quality without the experience of patients is not measuring quality at all.

OL Choose wisely and stop harming people with non-cardiac chest pain. “In adult patients with chest pain admitted with two negative findings for serial biomarkers, nonconcerning vital signs, and nonischemic electrocardiographic findings, short-term clinically relevant adverse cardiac events were rare and commonly iatrogenic, suggesting that routine inpatient admission may not be a beneficial strategy for this group.”

OL Choose wisely and stop invading people with stable chest pain. The study is called “Informed Decision Making for Percutaneous Coronary Intervention for Stable Coronary Disease.” And who are the patients informed by? Surely not a person who gets paid per procedure—that would be absurd. Even the most innocent bystander could see there might be a conflict of interest. Karen Sepucha and colleagues listened in to 59 conversations that went on between patients and cardiologists. Two of them included all seven elements of informed decision making; eight met a more limited definition of procedure, alternatives, and risks. Then there were the other 49. And there is a further article about this called “The Recommendation for Stenting in Stable Coronary Artery Disease—Ignoring the Evidence, Excluding the Patient: A Teachable Moment.” And a superb editorial by Grace Lin and Rita Redberg. If the Choosing Wisely campaign falters, it won’t be for lack of ammunition. Get out there and fight, folks.

Lancet 30 May 2015 Vol 380
2153 Anacetrapib. Dalcetrapib. Torcetrapib. I find myself rapibly getting pibbed off with these new cholesterol lowering agents. But I must be patient, because this trial shows that Merck’s new cholesteryl ester transfer protein inhibitor does lower LDL-C in patients with heterozygous familial hypercholesterolaemia who are already on an optimal dose of statins. Only I don’t expect they will market it under its generic name of anacetrapib: perhaps they will find something that trips off the tongue more lightly. “Whether this change [in LDL-C] leads to a reduction of cardiovascular events will be answered in an outcome study.” Good: and some long-term safety data would be nice too, given what happened with the other two rapibs.

2183 Ah, it’s bionic wizardry time at The Lancet again. This paper describes how three patients with global brachial plexus injury including lower root avulsions underwent bionic reconstruction in Austria. It is awesome stuff indeed, and comes complete with three videos. Fortunately these do not include footage of the hand amputations which preceded fitting of the “mechatronic prosthesis”. Note for Jeff Aronson: maybe “mechatronic” needs reporting to the Oxford English Dictionary.

2197 If you have a patient with multiple myeloma waiting for her/his three years to be up, or somebody with the “smouldering” form, it’s worth trying to get hold of this interesting seminar/update. We all used to think that the disease arose from a single rogue stem cell, but now it has been discovered that myelomas, like other cancers, are composed of clonally diverse subsets of tumour cells harbouring an immense genetic diversity. There’s a wonderful array of promising new treatments, which would suggest that every patient with MM should be offered the chance to participate in a randomized controlled trial.

BMJ 30 May 2015 Vol 350
When I started out as a trainee in general practice in 1977, the standard contraceptive pill was Microgynon 30, a mixture of ethinylestradiol 30 mcg and levonorgestrel 150mcg. It had been around for some years and in those days new oral contraceptives were still appearing annually. Now in those days I was young and felt that there must be grown-ups in charge of drug licensing. It was obvious that these authorities would demand that when new products were to be taken by millions of healthy young women, they must have been through trials to prove they were better and/or safer than existing products. And where better to hear about them than at a lunchtime meeting given by a local family planning expert? No matter about the pedigree of the sandwiches: we all ate whatever was offered, and seldom talked to the drug reps who provided it. We were above being fooled by those guys. And so we used to listen to lots of stuff about new progestagens being more “physiological,” causing less breakthrough bleeding, better sex drive, less fibrinogen activation or whatever, and duly went away believing that “third generation” oral contraceptives must be better than sad old Microgynon. Now there are two basic things required from an oral contraceptive: no babies and no harms. Microgynon stops you having babies: fact. Microgynon causes venous thromboembolism in a few women: fact. But over 40 years since it became the standard pill, no other combined oral contraceptive has caused less VTE, and almost all the third generation pills cause more. Which is confirmed by this analysis of data from the two huge UK primary care databases, CPRD and QResearch.

Last week we had a trial showing that oral corticosteroids did not have any effect on the pain of sciatica. Now here’s a trial where the steroids were actually injected into the epidural space. But still they did not work better than gabapentin. And yes, sham injections were given in the drug-only group.

Plants of the Week: Tall bearded irises

They take up a lot of room with their silly swords of leaf. They only flower once, over a couple of weeks. Slugs love them. They quickly exhaust the soil.

But what would the garden be without them? Exuberance is beauty, said Blake. Add ripe scents of fruit salad or chocolate. These weeks of iris heaven are what we wait for all year.