NEJM 21 May 2015 Vol 372
2064 The NEJM has the highest reputation of any medical journal, so it’s impossible not to feel dismay when it lets its standards slip towards the near-nonsensical. When the first part of Lisa Rosenbaum’s three-part series on conflicts of interest appeared, I wondered if it might be some kind of elaborate joke: but sadly it seems not. I hate to see it when a clearly talented young writer is encouraged to write below standard, and at great length for no obvious reason. This final article, “Beyond Moral Outrage,” is an attempt to describe people who worry about conflicts of interest as beyond rationality. In a typical section she writes: “As Haidt concludes, moral reasoning is not ‘reasoning in search of truth,’ but rather ‘reasoning in support of our emotional reactions.'” Interesting that Haidt was actually citing an example not of moral reasoning but of emotional reasoning from the start (unless you count putting the American flag down the toilet as a moral issue), and in which no-one was harmed. Is Lisa actually suggesting that the pharmaceutical industry just flushes away used American flags and has never harmed anyone or concealed harm? But there I go—I am responding to wholly unserious arguments seriously, which I suppose must be the purpose of this exercise. I think the NEJM has shot itself in the foot. And also exposed some awful editorial decisions. Please, if you are going to publish someone attempting to persuade us against bias, don’t let through a sentence like “Being a pharmascold conferred the do-gooder sheen many of us coveted.” The only unbiased words in it are “being,” “a,” “the,” and “of.”
1987 I succumbed to moral outrage fatigue long ago, and my do-gooder sheen has disappeared beneath the tarnish of age and the lichens of despond. Lisa wins, and I shall henceforth assert with Alexander Pope that “Whatever IS, is RIGHT” and with Voltaire’s Dr Pangloss that all is for the best in the best of all possible worlds. Our admirable establishments of learning have discovered that “The most prevalent phenotype of asthma is characterized by eosinophil-dominated inflammation that is driven by a type 2 helper T cell (Th2). Therapeutic targeting of GATA3, an important transcription factor of the Th2 pathway, may be beneficial.” An admirable partnership between Sterna Biologicals and the German Federal Ministry of Education and Research funded a tiny phase 1 RCT of Sterna’s new agent SB010 on 40 people with allergic asthma with sputum eosinophilia and who also had biphasic early and late asthmatic responses after laboratory-based allergen provocation. So from the active treatment group of 21 people who fitted into this subtype of asthma, we now know that “After 28 days, SB010 attenuated the mean late asthmatic response by 34%, as compared with the baseline response, according to the AUC for FEV1, whereas placebo was associated with a 1% increase in the AUC for FEV1 (P=0.02).” Um, yes. Why exactly did we need to know this? Why does this little preliminary study appear in the NEJM? The editorial attempts to explain: it’s the first glimmer of hope in three decades that drugs which block type 2 cytokine responses may work for real patients. Let’s wait until they do, perhaps.
1996 Using fewer antibiotics in hospitals is probably a goal worth striving for, since it is here that the biggest problems of resistance and Clostridium difficile infection are seen. Not that these were end-points in the STOP-IT trial, which instead sought to find out if patients with peritoneal infection could respond as well to a 4 day fixed course of antibiotics as to longer courses judged by clinical response. This was a tough ask, since people don’t get intra-abdominal sepsis without some good reason and when they do they tend to get infected with a host of faecal pathogens. This account of the trial is not ideal: for example, you have to go to the supplementary appendix to find that the same antibiotics, by and large, were given to both groups. They achieved much the same results given as a short course as if they were given for twice as long.
2039 At least the clinical reviews in the NEJM remain excellent, and are generally more clinically focussed and less showy than they used to be. Pelvic inflammatory disease is regularly missed in primary care, and I found this review rather reassuring, because it provides many reasons why this is inevitable. It is often asymptomatic and we still don’t have a full understanding of its bacteriology. Investigation hasn’t improved much over decades: even laparoscopy has high inter-observer variability. We don’t even know if adding metronidazole to antibiotic regimens makes much difference, though we should find out later this year.
JAMA 19 May 2015 Vol 313
1915 Lumbar nerve root entrapment causes a horrible form of pain often accompanied by muscle spasm and immobility. It is usually caused by herniation of a lumbar intervertebral disc, and generally there is nothing to be done about sciatica in the first few weeks, while things need time to settle down. I always felt very sorry for people during these weeks, as I handed them sick notes and a variety of usually ineffective analgesics. In the USA, it is apparently quite common to use oral steroids as well. In this Californian trial, participants were randomly assigned in a 2:1 ratio to receive a tapering 15 day course of oral prednisone (5 days each of 60 mg, 40 mg, and 20 mg; total cumulative dose = 600 mg; n = 181) or matching placebo (n = 88). This achieved a small overall increase in functional improvement but no relief of pain and no difference in longterm outcomes.
1939 At school we learnt that science is clear and deterministic and that effects follow causes. Only ten years before I started learning biology, it had been discovered that the prime cause that governs living creatures was DNA, which had a double helical structure and was arranged conveniently into genes, one per immutable effect. Like the Latin and Greek I was learning at the same time, Nature had a grammar, and if only you learnt that and the vocabulary well enough, you could understand everything. It was clear at that point (1964) that during the rest of my lifetime, people were going to map genes and cure everything. But a couple of years on, I learnt about quantum uncertainty and started to think about how complexity actually works, and so began a journey of intellectual doubt which is doomed to go on until my intellect packs up. Nowadays this is usually labelled “Alzheimer’s disease”(AD). Now Alzheimer’s is (or isn’t, if you are contrary) characterised by certain patterns of amyloid deposition in the brain which can only be detected in living people by positron emission tomography . And it is known that some APOE genes which encode for amyloid deposition also increase susceptibility for AD. Hence a meta-analysis like the following:
“The prevalence of amyloid pathology increased from age 50 to 90 years from 10% (95% CI, 8%-13%) to 44% (95% CI, 37%-51%) among participants with normal cognition; from 12% (95% CI, 8%-18%) to 43% (95% CI, 32%-55%) among patients with SCI; and from 27% (95% CI, 23%-32%) to 71% (95% CI, 66%-76%) among patients with MCI. APOE-ε4 carriers had 2 to 3 times higher prevalence estimates than noncarriers. The age at which 15% of the participants with normal cognition were amyloid positive was approximately 40 years for APOE ε4ε4 carriers, 50 years for ε2ε4 carriers, 55 years for ε3ε4 carriers, 65 years for ε3ε3 carriers, and 95 years for ε2ε3 carriers. Amyloid positivity was more common in highly educated participants but not associated with sex or biomarker modality.”
1939 Now that you are clear on these basic points, you can read the next study, which concludes:
” Among participants with dementia, the prevalence of amyloid positivity was associated with clinical diagnosis, age, and APOE genotype. These findings indicate the potential clinical utility of amyloid imaging for differential diagnosis in early-onset dementia and to support the clinical diagnosis of participants with AD dementia and noncarrier APOE ε4 status who are older than 70 years.”
I have no idea what justification lies behind the second sentence, but let that go. I shall henceforth avoid all machines that might cause my brain to emit positrons. I prefer to decline in peace, pretending to read Latin and Greek, which are easier to understand.
JAMA Intern Med May 2015
OL When I retired from my practice five years ago, I decided I’d try and work on patient experiences and knowledge dissemination. Mix the two, and you are bound to start wondering about how patients actually perceive the information we give them. How do real people combine it with other knowledge sources, and actually achieve some form of decision making, “shared” or otherwise? How do these dialogues actually work in each context and for each individual? How can we make them work better? Is our lofty rhetoric about the importance of the consultation just a form of self-aggrandizement? Do we have any idea of what patients think?
I must say that I feel I am fumbling, but I’m in good company. A systematic review of tools to promote shared decision making in serious illness concludes: “This field of research is in an early stage; future research is needed to develop novel decision aids for other serious diagnoses and key decisions.” But equally important is to know what already works well in routine practice, with or without decision aids. We need to understand the skills we need to acquire as well as the tools we need to develop. In the end, we must try to make ourselves into the effective shared decision aids we crave. This, after all, is the essence of our job.
Lancet 23 May 2015 Vol 385
2047 “157 studies comprising 43 256 participants, mostly with type 2 diabetes and chronic kidney disease, were included in the network meta-analysis. No drug regimen [for hypertension] was more effective than placebo for reducing all-cause mortality.” Yes, you read that right. No blood pressure-lowering strategy prolonged survival in adults with diabetes and kidney disease. But was not this the QOF that earned ten thousand pounds? Per practice, per year? This is what extrapolation beyond the evidence combined with pay for performance achieve. Massive overtreatment, diversion of effort and resources, no patient benefit. We need to Choose Wisely and bin the whole QOF system in favour of sharing uncertainty and solid evidence with patients.
2107 Another useful reality check comes in the form of a review of heart failure in diabetes. Men labelled as diabetic are twice as likely to develop HF as men without: for women, the risk is five fold. And once they have it, they are twice as likely to die from it. These are approximate figures, and coming from Framingham, are based on clinical criteria, not ejection fraction. So what do we know about the effects of glucose-lowering therapy? Above all, that all thiazolidines, and also saxagliptin, increase the risk of heart failure. Insulin promotes sodium retention and may also be harmful. The others are probably neutral. This has become such an issue that in this Lancet, Takeda publishes a study to show that its saxagliptin competitor drug, alogliptin, did not increase the risk of heart failure. Would it be too much to ask for a glucose lowering drug that actually reduces the risk of this horrible condition?
BMJ 23 May 2015 Vol 350
I don’t much like public speaking, but one of the talks I give is called “The Deadly Hospital.” I can give for you if you will pay my fare. Offers from New Zealand are particularly welcome. I’ll now have to augment it with a few bits from this study of the role of intervening hospital admissions on trajectories of disability in the last year of life. When my parents were dying concurrently, one from heart failure and the other from ovarian cancer, my main aim was to try and keep them out of hospital. A study from New Haven, Connecticut, illustrates why. “In the last year of life, acute hospital admissions play an important role in the disabling process.” The authors call for consideration of a palliative care approach. I can give you a talk about that too, centred on heart failure. Two for the price of one.
The randomized trials of statins, as we all know by now, are said to support the idea of universal dosing above a certain threshold of risk, with age as a critical component. As a devoted follower of the late David Sackett, I’m much more inclined to believe a meta-analysis of individual participant data from RCTs than a population based cohort study when the two give conflicting results. This French cohort study finds that in people over 65 with no history of vascular events, use of statins or fibrates was associated with a 30% decrease in the incidence of stroke, but no decrease in coronary heart disease. In fact the stroke reduction was only just within the 95% confidence interval, and then only if you lumped statins with fibrates. On this one I’ll stick with Rory Collins, though I think his trawl through the trials to detect adverse effects will prove meaningless, since the most important adverse effects may be unrecorded decreases in activity by elderly people due to muscle weakness. It will take a different, prospective approach to test that hypothesis.
Plant of the Week: Daphne cneorum
This is the sort of plant that few nurseries now bother to sell, because it is small and temperamental and takes a long time to grow. It was once common enough to acquire English names like “rose daphne” or “garland flower.” It is one of the most highly scented of this whole odoriferous genus, and it sprawls a few inches above the soil. So it is best to grow it on a raised bed where you can fully appreciated both the full loveliness of its abundant pink flowers and the heady delights of their perfume.
For some reason I had conceived that the “cneorum” was a genitive plural from some word meaning “dwarf” in garden Latin. In fact the plant itself was known as kneoron in Greek, and that’s the reason the genders of the two names don’t agree. Thought you’d like to know.
Let the incomparable Reginald Farrer tell you the rest:
“Daphnes are born democrats, and D cneorum shows neither fear nor favour. You may court it in vain, as you may court a cat, with cossettings and comforts uncounted – but with no result to show but the sickliness of a dying plant; yet in some neighbour’s garden, where it was ignorantly shovelled into hard common earth to act as an edging like Arabis, it will have run far and wide, with masses of neat well-furnished shoots each ending in those ample heads of waxy, brilliant, rosy trumpets that fill the air of June with fragrance. Or, having had the plant in glory for many seasons and filling wide beds, you may see it one day departing from you firmly, and never be able to establish it again.”
The English Rock Garden 1918