Richard Lehman’s journal review—13 January 2014

Richard LehmanJAMA Internal Medicine  Jan 2014  Vol 174
I was amazed at the richness of the contents of JAMA Intern Med this week, but then I sadly realized that the journal has changed from being a fortnightly treat to being a monthly one. I had been warned this would happen; it’s a natural consequence of online publication and a direct challenge to my old-fashioned practice of reviewing the papers as they appear in the print journal rather than on the website. So I will have to come up with a transition strategy. For now, I will just give you a couple of juicy morsels from this print issue.

15   I can remember chatting with a cardiology professor about fifteen years ago, when the concepts of “insulin resistance” and the “metabolic syndrome” were becoming fashionable. “It’s just a way of calling people fat, isn’t it?” he said. And that, by and large, is what this Danish population study finds. “We examined 71 527 individuals from the Copenhagen General Population Study and categorized them according to body mass index (BMI) as normal weight, overweight, or obese and according to absence or presence of metabolic syndrome.” “Conclusions and Relevance:  These findings suggest that overweight and obesity are risk factors for MI and IHD regardless of the presence or absence of metabolic syndrome and that metabolic syndrome is no more valuable than BMI in identifying individuals at risk.”

25   Ever since the Women’s Health Initiative trial showed increased risk in women randomised to postmenopausal hormone replacement, doctors have been beating themselves up for prescribing oestrogens so widely for menopausal symptoms. But actually we were often prescribing different drugs from those used in WHI to women quite different from the WHI subjects. In the trial, the oestrogen used was the old fashioned one derived from pregnant mares’ urine—Premarin or conjugated equine estrogens (CEEs). Moving to American spellings, the alternative is synthetic estradiol. And here is another North American study showing that the two have different risks: “In an observational study of oral hormone therapy users, CEEs use was associated with a higher risk of incident venous thrombosis and possibly myocardial infarction than estradiol use.”

NEJM  9 Jan 2014  Vol 370
107   One topic you won’t have come across in these reviews, though it crops up quite frequently in the journals, is tight glycaemic control in intensive care units. Somehow the belief sprang up some years ago that very sick people (without diabetes) are more likely to survive if you monitor their blood glucose and give them insulin when it goes up. In fact all that happens is that they become hypoglycaemic, which is never a good thing. As neither I nor most of my readers are intensivists, I have failed to report this discredited fashion. The trial reported here shows that what applies to critically ill adults also applies to critically ill children on English paediatric ICUs. It’s just one more illustration of doctors doing harm when they apply untested notions of physiological logic to the treatment of seriously ill patients.

119   O joy, more pharmacogenomics. But for once, I am slightly interested. Some people with bipolar disorder respond to lithium while others do not. And bipolar tendencies are highly heritable. Now could it be that a therapeutic response to lithium is governed by one or two single-nucleotide polymorphisms? The answer is yes, at least in a Taiwanese cohort of Chinese Han descent: “Two SNPs in high linkage disequilibrium, rs17026688 and rs17026651, that are located in the introns of GADL1 showed the strongest associations in the genomewide association study (P=5.50×10−37 and P=2.52×10−37, respectively) and in the replication sample of 100 patients (P=9.19×10−15 for each SNP). These two SNPs had a sensitivity of 93% for predicting a response to lithium and differentiated between patients with a good response and those with a poor response in the follow-up cohort.” I find myself curiously impressed. 10−37 is an amazing order of minitude. If you shrank the mass of the sun by that much, it would weigh about the same as a hair. Well, all right then, perhaps I made that bit up.

139   Continuous positive airway pressure is a great treatment for sleep apnoea, says this satisfied customer. But evidently some customers are not so satisfied, and in the trial reported here they “underwent a surgical procedure to implant the upper-airway stimulation system (Inspire Medical Systems). The stimulation electrode was placed on the hypoglossal nerve to recruit tongue-protrusion function; the sensing lead was placed between the internal and external intercostal muscles to detect ventilatory effort; the neurostimulator was implanted in the right ipsilateral mid-infraclavicular region.” Woo! That meant more than two hours of fairly complex surgery. And this for people with a median Epworth Sleepiness Score of 11 points (10 being normal)! Sure, their oxygenation increased and their apnoea episodes decreased impressively, but not surprisingly the subjects didn’t notice all that much. I would say that this is a procedure only for very rich, very apnoeic people with intractable mask phobia.

JAMA  8 Jan 2014  Vol 311
135   This week, JAMA has disappeared in a puff of smoke. Well, that’s not quite true, for better or for worse: it has just decided to devote itself to meditating on 50 years of tobacco control. The research papers are mostly of little interest, but there are two Viewpoints worth reading. The first one is about the Promise and Peril of e-Cigarettes. The author concludes that “The more appealing e-cigarette innovations become, the more likely they will be a disruptive technology. Although the science is insufficient to reach firm conclusions on some issues, e-cigarettes, with prudent tobacco control regulations, do have the potential to make the combusting of tobacco obsolete.” I agree. However unsettling it may be to see youngsters puffing on nicotine inhalers, the prize of saving millions of people from unpleasant premature death due to inhaling tobacco smoke is worth the small potential risk. After all, as a respondent to the BMJ‘s article on this writes, “They (e-cigarettes) are not a “gateway” to smoking. Why switch from a habit costing £5 a week to one costing £50 a week which is banned in every non-residential building?”

137   Two of the research papers in this week’s JAMA plot the steep decline in smoking over the last few decades, while another two are about pharmacological aids to stopping smoking. So how hard do most people find it to give up? Nicotine is arguably one of the most addictive substances known, yet most people give it up without help. We know very little about them. The authors of this Viewpoint comment that  “…knowledge of mass smoking cessation across 50 years reflects the ‘inverse impact law of smoking cessation.’ Far more is known about the ‘tail’ of people who quit smoking via pharmacological and professionally mediated interventions than about the mass ‘dog’ of ex-smokers who continue to quit unassisted.”

Lancet   11 Jan 2014  Vol 383
119   A beautiful essay on “How we endure” by the great Arthur Kleinman is informed by his own experience as a medical student of helping a little girl with severe burns go through the agony of her daily dressings, through to the daily sorrow of looking after his wife as she declined with Alzheimer’s disease. But it is neither self-centred nor sentimental: a wonderful and deeply humane piece of writing.

127   A German trial of treatments for anorexia nervosa managed to recruit 242 patients from ten specialist units and to retain 70% of them for the 12 months of the trial. On the basis of their results, they conclude that “Optimised treatment as usual, combining psychotherapy and structured care from a family doctor, should be regarded as solid baseline treatment for adult outpatients with anorexia nervosa.” Fair enough. I am a family doctor and I don’t understand anorexia nervosa. But nor does anyone else. As the specialist writing the editorial says, “We know little about the biological factors that allow individuals with anorexia nervosa to defend such low bodyweights and to maintain high activity levels in the absence of nutritional fuel. For too long, people have presumed that anorexia nervosa is simply a behavioural choice and that all individuals with the disorder wilfully maintain a low bodyweight to chase a societal appearance ideal. Anyone who has worked with anorexia patients will attest that even if the disorder started with a desire to attain a physical ideal (and it often does not), the low weight soon eludes wilful control. Identification of aberrant pathways that contribute to these regulatory anomalies and uncovering gut—brain connections that interrupt the usual processes of hunger and satiety will hopefully lead to novel ways to interrupt this perplexing biological obstinacy.” I’m not quite happy with that final phrase, but there are certainly important physical and mental processes at work that we scarcely begin to understand.

146   Vitamin D remains an enigma: does it or does it not have all sorts of beneficial effects on the function of the numerous tissues that contain vitamin D receptors? Bone is of course the best known of them, and huge numbers of white adults of both sexes take vitamin D after the age of 50 to “preserve bone health.” But the evidence that it does them any good is extremely slender. The Health Research Council of New Zealand funded three excellent researchers to carry out a systematic review of the effect of vitamin D supplements on bone mineral density. There was a small effect on this weak surrogate (femoral neck bone density) in a few of the randomised trials. Overall, they conclude that “Continuing widespread use of vitamin D for osteoporosis prevention in community-dwelling adults without specific risk factors for vitamin D deficiency seems to be inappropriate.”

156   This issue of The Lancet includes the first three papers in of a series of five called “Research: increasing value, reducing waste”. I do wish everyone would stop using these jingly gerunds. Many of the people I most admire have been involved in the writing of these papers and they are a wonderful resource—and open to all, though The Lancet does its best to hide the fact. The first one’s principal author is Iain Chalmers and its title is “How to increase value and reduce waste when research priorities are set.” It is excellent, but I would like to see more of Iain’s moral passion shine through than the format of a multi-author Lancet paper allows.

166  The lead author of the next paper is John Ioannidis and it is a terrific summary of correctable weaknesses in the design, conduct, and analysis of biomedical and public health research studies. Again, we are all in debt to John’s tireless work in this area; and again this is an excellent summary of both the problems and the solutions. Non-academic readers will skip plenty but still find lots to inform their understanding of where medicine needs to go if it is ever to address the real needs of users.

176   “After identification of an important research question and selection of an appropriate study design, waste can arise from the regulation, governance, and management of biomedical research. Obtaining regulatory and governance approval has become increasingly burdensome and disproportionate to the conceivable risks to research participants.” This will have resonance for all who have ever tried to do any piece of research. It is one of the reasons that most interested non-academic clinicians simply give up trying. As a result, practically all medical research is done by career academics and by companies trying to sell products. What could possibly be better?

BMJ  11 Jan 2014  Vol 347/8
The first research paper in this week’s BMJ comes from a young friend who was working with colleagues in the Yale Center for Outcomes Research and Evaluation. He looks at patterns of readmission among Medicare patients in American hospitals, and I can understand if readers who never go near American hospitals are tempted to skip it and move on. That would be a mistake: this paper is a great read, full of lively questioning, and it uncovers an important and general truth about hospital readmissions, which is that the same patients are often readmitted with a different primary diagnosis within a month of discharge. Being in hospital has done them no good. Those interested in exploring this phenomenon should start with Richard Asher’s classic 1947 essay, The Dangers of Going to Bed, and move on to Harlan Krumholz’s groundbreaking NEJM 2013 piece on Post-Hospital Syndrome, which was inspired by the present study. This subject urgently needs more enquiry.

Moving upshore from Yale to Harvard, the message is the same when researchers look at patients readmitted to the main Boston Hospitals: “The five most common primary diagnoses of potentially avoidable readmissions were usually possible complications of an underlying comorbidity. Post-discharge care should focus attention not just on the primary index admission diagnosis but also on the comorbidities patients have.” This is not rocket science. It is revolving door science. What we need is humane-care-of-complex-patients science.

How could metal-on-metal hip prostheses achieve enormous popularity before anyone became aware that they were far less durable than the devices they replaced? I gave you the answer last week, and here it is again, in the conclusion of this systematic review of hip replacement prostheses and their evidence base: “This study shows that a considerable proportion of prostheses available to orthopaedic surgeons have no readily available evidence of clinical effectiveness to support their use. Concern exists about the current system of device regulation, and the need for a revised process for introducing new orthopaedic devices is highlighted.”

Plant of the Week: Skimmia x confusa “Kew Green”

As I look out of the window writing these reviews, this is the plant that cheers me up all winter long. Just now it is catching low shafts of cold pallid sunshine, reflected variously by its glossy green leaves. For weeks it has been covered with trusses of flower bud which seem about to open. This is a false hope just now – it will not flower until April – but it is a happy reminder that spring will come, and that each week brings it closer.

I have praised this shrub several times before. It has every possible virtue. It grows imperturbably anywhere you put it, even in the driest shade. It can be pruned back to any size or shape you like; and any cutting you put into the soil, at any time of the year, will give you a new plant. And such a plant! It has evergreen leaves of beautiful shape and mid-green colour, which never become yellow, however limy your soil. Its flower buds appear before Christmas and eventually open 4 months later, spreading a wonderful scent through the whole garden. You then have to compete with early bees to come near the abundant flowers which cover the whole plant. I can’t wait.
Westron wynde, when wilt thou blow?