Journal Watch - February 2010

JAMA  24 Feb 2010  Vol 303

This is an exceptionally uninteresting issue of JAMA for an old generalist like me. It was probably important for someone to test the hypothesis that blood lactate might be a better marker than central venous oxygen for success in treating septic shock: well, they've done it and it isn't (p.739). It's faintly interesting to look over the Atlantic and see how the work hours of US physicians have fallen over recent years (p.747); but small beer compared with the disastrous effects of the European Union Working Time Directive on hospital staffing and the total breakdown of continuity in UK primary care. It's yawn-stifling time as we learn that platelet function tests are all pretty useless at predicting the clinical outcome of coronary artery stenting (p.754). And in case you hadn't guessed, old people who go into hospital (especially intensive care) show worse cognitive outcomes than those who don't (p.763). That's it folks. It almost has you trying out the dreaded JAMA Poem. But I wouldn't advise it.
http://jama.ama-assn.org/cgi/content/abstract/303/8/739
http://jama.ama-assn.org/cgi/content/abstract/303/8/754
http://jama.ama-assn.org/cgi/content/abstract/303/8/747
http://jama.ama-assn.org/cgi/content/abstract/303/8/763

NEJM  25 Feb 2010  Vol 362

677    I have often used these columns to mock the stuttering progress of genomics, but here's a paper on stuttering that's a true tour de force in the art of the gene gnome. Like pretty well the whole of genomics, it has no immediate clinical relevance, but boy is it a feat of patience and hard work. First find a group of consanguineous Pakistani families with a fairly high frequency of stuttering. Then chase this down to an unlikely region on chromosome 12q23.3 which turns out to be a missense mutation of the N-acetylglucosamine-1-phosphate transferase gene (GNPTAB). Then find out how common this mutation might be in stutterers and non-stutterers in Pakistan and the USA. Having established that there is indeed a strong link, I think you've earned the right to top billing in the NEJM, though it's still far from clear how a gene governing the metabolism of lysosomes can cause people to stumble over their words.
http://content.nejm.org/cgi/content/abstract/362/8/677

686   Selective oestrogen receptor modifiers are known as SERMs, even in the UK, though it would be more patriotic to call them SORMs (cf. GERD/GORD and other ungordly Americanisms). It doesn't much matter, since hardly anyone prescribes them - them currently being raloxifene. Now she is joined by lasofoxifene. The primary end-points in this trial were "vertebral fractures" - defined radiologically, not clinically - nonvertebral fractures, and oestrogen-receptor (ER/OR, let's call the whole thing off) positive breast cancer; the secondary end-points were coronary events, stroke, and venous thromboembolism. Lasofoxifene had numerically small favourable effects on everything except VTE, which showed an expected doubling. But it's still very hard to find a place for this drug, and the accompanying editorial will not please its manufacturers by concluding baldly that it "offers no major clinically important benefits over raloxifene for the skeleton, breast, heart or reproductive tract."
http://content.nejm.org/cgi/content/abstract/362/8/686

726   Graves' ophthalmopathy is a strange phenomenon, caused in some way by anti-thyrotropin-receptor antibodies acting on the muscles and fat of the orbit. If you're swotting for MRCP, you'll want to mention thyroid dermopathy as well, associated in 20% of cases with thyroid acropachy, or finger clubbing. These Grave(s) eye and skin phenomena are seven times commoner in tobacco smokers and the effect is dose-related. There's not much else in this review to make the eyes bulge: the pastel illustrations are restrained and comprehensible; there's no genomics whatever; and there are some interesting therapeutic speculations towards the end.
http://content.nejm.org/cgi/content/extract/362/8/726

Lancet  27 Feb 2010  Vol 375

727    Not long ago, a friend of mine had a myocardial infarction on a transatlantic flight. I haven't had a chance to talk to him about this ordeal, so I don't know what a professor of surgery does under these circumstances, but I imagine he took an aspirin and prayed a good deal. He should also have squeezed his arm repeatedly for periods of five minutes or so at a pressure above systolic. Believe it or not, this simple manoeuvre can reduce the area of myocardial damage, as proved in this Danish trial where patients with presumptive MI were randomised to have the squeezing done (or not done) by a sphygmomanometer in the ambulance conveying them to hospital. This is known as ischaemic preconditioning, though in such circumstances it should perhaps be known as simultaneous ischaemic conditioning. There were no hard end-points in this trial but a convincing reduction in damage on myocardial perfusion imaging at 30 days. More trials are needed, but meantime there seems no possible reason not to give it a try.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62001-8/abstract

735    Every day, members of the British public present me with data sheets from their pill boxes to prove that I have poisoned them in some way. Often this is backed up by evidence from the Daily Mail. "You can keep it to read later" is a generous offer I often accept, but seldom fulfil to the letter. I don't know it there's been a Mail take on the link between statins and diabetes, because it's not really news: there has been a trickle of evidence from the randomised trials (especially JUPITER) over several years and this is gathered into a single stream in this collaborative meta-analysis. It's true that statins cause the odd extra case of type 2 diabetes, but it's a feeble little brook, and outmatched 9:1 by a river of protective cardiovascular effects. And of course if a person is at risk of developing diabetes, that's one more factor to weigh in the balance in favour of giving them a statin.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)61965-6/abstract

743    We're nearly there: a closed-loop insulin delivery system for type 1 diabetes has been dreamt of for three decades but now seems in reach. An Anglo-American collaboration has been testing various versions on children and adolescents with the aim of tight prandial control and reduced nocturnal hypoglycaemia. In the devices tested here, manual operation usually predominated. Expect a great deal of tweaking, a commercial war, and much debate about cost and safety in the journals of the next decade.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)61998-X/abstract

752    A rather rambling 10-page review of dilated cardiomyopathy had me yearning for less. The Panel of Mechanisms covers just about everything except interference by aliens, and there's a panel of gene loci too, but no panel of relative frequencies and prognoses for each aetiology. There is no mention of spontaneous recovery, which can't be rare if I've seen it twice.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62023-7/abstract

763    Say you had stable coronary artery disease: would you want an angiogram? And if the cardiologist saw a stenosis, would you want a stent put in? A year or two ago, these questions would have seemed like no-brainers, but then along came COURAGE and BARI-2D showing that medical treatment is as good as percutaneous intervention. Do you truly and deeply believe this, though? See how you feel when you read this review by two Swiss and an American cardiologist. It presents enough evidence to allow a tailored approach, and says that it "proposes a treatment algorithm that is applicable to daily clinical practice." Personally, I avoid the word "algorithm", but people who use it generally refer to a flow chart. Well, there ain't none here.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60168-7/abstract

BMJ  27 Feb 2010  Vol 340

459    A useful systematic review compares the results of carotid endarterectomy vs. carotid stenting in 11 randomised trials. On the face of it, endarterectomy wins, because the risk of periprocedural stroke is less; in the longer term there is little difference. Techniques and experience increase all the time - it may happen that the guy who puts in stents near you does that better than the guy who scrapes arteries. So more studies are justified and the matter is not quite settled yet.
http://www.bmj.com/cgi/content/full/340/feb12_1/c467

463    People who have had renal transplants are at greater risk of cancer, and a useful study of everyone in this category from Australia and New Zealand looks at which cancers arise most during immunosuppression, compared to those that happen when the transplant fails and immunosuppressant drugs are stopped or reduced and dialysis commenced. The incidence ratios are given on the printed pico page, but as usual, the study design and results are much more easily followed in the full paper. It's a case of more meaning more.
http://www.bmj.com/cgi/content/full/340/feb11_2/c570

464   All medicine should be directed at understanding and modifying the experience of illness. We have become awesomely good at some aspects of understanding the mechanisms of illness, but by and large remain awesomely bad at understanding the experience. Our tools - including those known as PROMS - are crude, and often our ways of using them are worse than crude (think of all those PQ9s you send off to your depressed patients). I have an awful feeling that this can only get worse with a steady increase in the routine use of patient reported outcome measures in healthcare settings. In principle this is a welcome development, but if it is not properly regulated I foresee meaningless point-collecting on a vast scale, using every short cut this paper warns against. No doubt it went on in Staffordshire, and it certainly goes on in British general practice.
http://www.bmj.com/cgi/content/abstract/340/jan18_1/c186

468    Two authors from Newcastle (upon Tyne) are to be congratulated on an exceptionally clear and useful article about syncope in adults, aimed at the generalist. A lot will be learnt from the history alone - and remember that twitching does not count as fitting - and most of the rest from the resting ECG and a proper measurement of blood pressure after lying for ten minutes and then standing for three. You may be forced to do Holter monitoring but don't expect much of a yield.
http://www.bmj.com/cgi/content/extract/340/feb19_1/c880

Arch Intern Med  22 Feb 2010  Vol 170

321    If you sit around with a chronic illness, you stand a high chance of becoming anxious. Maybe the answer is to get out of your chair and exercise. I say maybe, because although this systematic review is very thorough and contains immense tabulations of all the trials and their outcomes, there's always a bit of wiggle-room when it comes to measuring anxiety and the duration of any benefit.
http://archinte.ama-assn.org/cgi/content/abstract/170/4/321

340    I remember a time in the NHS when practically nothing was costed, and managers were rare beasts. Stuff happened: there was a budget envelope, people blamed each other when it was exceeded, and if money ran out, patients waited longer. It was hardly a golden age, but it grew a lot worse when Margaret Thatcher adopted a quasi-market approach based on the US experience of competition "to bring down costs." What is this US model in 2010? The paper here looks at costs and outcomes in hospital care for two medical conditions. The cost of one admission for pneumonia is $1,897 in one hospital and $15,829 in another. Outcomes are the same. They don't know how to fix it. Look elsewhere if you want to run a health system.
http://archinte.ama-assn.org/cgi/content/abstract/170/4/340

381    "Getting to 'No' - strategies primary care physicians use to deny patient requests". This, of course, is a key skill for general practice, one I was never taught and probably remain very bad at. With four months to go, it's little use learning now, and to be honest this paper analysing consultation in the USA is not much of a help. I suspect that with all their earnest supervision and consultation analysis, today's young British GPs are much better at it. On the other hand, what I lack in training I probably make up for in guile.
http://archinte.ama-assn.org/cgi/content/abstract/170/4/381

Medical Word of the Week: Hymen

I am trespassing on Jeff Aronson's territory here, but I was trying to find something interesting to quote from an exceptionally dull collection of pieces by Southey and Coleridge, when I came across this:

"The origin of the worship of Hymen is thus related by Lactantius. The story would furnish matter for an excellent pantomime. Hymen was a beautiful youth of Athens, who for the love of a young virgin disguised himself, and assisted at the (Eleusinian) rites: and at this time, he, together with his beloved, and divers young ladies of the city, was surprized and carried off by pirates; who supposing him to be what he appeared, lodged him with his mistress. In the dead of the night, when the Robbers were all asleep, he rose and cut their throats. Thence making hasty way back to Athens, he bargained with the Parents that he would restore to them their Daughter, and all her companions, if they would consent to her marriage with him. They did so, and this marriage proving remarkably happy, it became the custom to invoke the name of Hymen at all nuptials."

Omniana (1812) 109: ORIGIN OF THE WORSHIP OF HYMEN.  S.T. Coleridge

And so "hymeneal rites" became an affected term for marriage, and the "hymeneal membrane" replaced good old English "maidenhead", and a boy's name became a girl's private part.


JAMA  17 Feb 2010  Vol 303

623    A child in today's USA has a 50% chance of having a chronic health condition, according to this study of three cohorts covering 6-year periods between 1988 and 2006. Asthma, behavioural and learning problems, and a variety of other physical conditions have all increased during that period, but the biggest factor is obesity. A remarkable 38% in the most recent cohort manage to be above the 95th percentile for weight (explain please, ed.). But apart from weighing, this study didn't actually do anything but ask the mothers a few questions. Not surprisingly, children floated about among the diagnostic categories from year to year. Look elsewhere for hard data about American kids.
http://jama.ama-assn.org/cgi/content/abstract/303/7/623

631    The Women's Genome Health Study is a prospective cohort of 19,313 women followed up for a median of 12.3 years, during which they experienced 777 cardiovascular events. In these women, 101 single nucleotide polymorphisms were added with one or two other genomic factors to create a genetic risk score. Surely this would usher in a new era of refined cardiovascular risk prediction? Well, actually it showed no significant association with the incidence of total cardiovascular disease: a simple family history alone was more predictive. On the other hand, there is so much anonymized data about the participants that you could probably find out the full disease status of any individual if you could identify their genome from some other source. This is discussed in a fascinating commentary on p.659. Genomic studies seem almost disconcertingly useless at the population level, but if you know 35,000 gene variants in a single individual, you can measure their left ventricular mass more accurately than if you had an echocardiogram.
http://jama.ama-assn.org/cgi/content/abstract/303/7/631

639    You can do it on King Tut too, to a degree. Not many medical papers begin their author affiliations with the Supreme Council of Antiquities of Egypt, but it was they who gave the investigators access to MRI scans and DNA samples from eleven royal mummies of the New Kingdom (1550-1000 BCE). What fun it all must have been, loading up pharaohs into the magnet truck. As a result, we know a lot more about the probable relations between such individuals as Amenhotep III and KV35YL. We know that Tutankhamun had chronic falciparum malaria and died from a broken leg. Bong! Molecular medical Egyptology is born. But beware: I have read the Book of the Dead, and through a curtain of mist I descry investigators perishing mysteriously from the Curse of the Mummy's DNA, to the sound of spooky music.
http://jama.ama-assn.org/cgi/content/abstract/303/7/638

NEJM  18 Feb 2010  Vol 362

579     Readers of Raymond Tallis, or of Iain McGilchrist's astonishing new book about the brain(s), The Master and his Emissary, will know better than to try and define consciousness. But at least we thought we could define unconsciousness. Now comes this study - disturbing in every sense of the word - which proves that people in a deep coma can respond if you ask them to think about tennis. Functional MRI showed purposive responses to tennis-based verbal interrogation in a few people in a permanent vegetative state and/or with severe brain injury. If you haven't time to follow the whole paper here, there's a good simplified account in the New Scientist. There is also an editorial by a Boston neurologist on p.648 which ends "... physicians and society are not ready for 'I have brain activation, therefore I am.' That would seriously put Descartes before the horse." Hah! I doff my hat.
http://content.nejm.org/cgi/content/abstract/362/7/579

590    Call me old-fashioned, but I like to see evidence from randomised controlled trials with hard end-points before I believe in computer predictions that a certain intervention will reduce new cases of CHD in America by up to 120,000 annually, stroke by up to 66,000, and death by up to 92,000. The editorial on p. 650 suggests a saving in health costs of $10-24 billion. Aha, we save health costs by keeping older people alive longer, do we? Apart from that basic point, there is also the problem that the evidence for salt reduction is - as far as I can tell - nowhere near as strong as the computer model in this economic simulation suggests. The evidence we have is about a surrogate marker - blood pressure - which can be reduced slightly by the sort of salt reductions proposed here and already in force in the UK for prepared foods. On the balance of probabilities, I'm happy to support salt reduction, as I am carbon emission reduction; but that doesn't mean swallowing every extrapolation that zealots come up with. A paper like this doesn't really belong in the world's leading medical journal.
http://content.nejm.org/cgi/content/abstract/362/7/590

Lancet  20 Feb 2010  Vol 375

649    The Lancet's usual selection of papers is fairly predictable - a couple of drug-company funded studies of their latest product, a bit of tweaking to some kind of cancer treatment, and then if we are lucky, some good old-fashioned head-counting epidemiology of the textbook sort. Here, four researchers from Newcastle have done a wonderfully thorough analysis of 20-year survival of children born with congenital abnormalities, based on the UK Northern Congenital Abnormality Survey. The charts here will become the definitive reference point for parents and professionals looking after these children.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)61922-X/abstract

673    Non-melanoma skin cancer is not an intellectually challenging topic, but it is an important one: as the population ages, basal cell carcinoma incidence will overtake the total of all other cancers. Perhaps GPs winding down towards retirement should be encouraged to run BCC removal clinics,  freeing up dermatologists and plastic surgeons to do more exciting things. BCCs are a product of British summers, when from childhood onwards we rush out and overexpose ourselves on the few days that the sun appears. Squamous cell carcinoma and actinic keratoses are more an ex-colonial and Antipodean phenomenon, caused by constant sun exposure in white-skinned people who weren't designed for this purpose.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)61196-X/abstract

686    A nicely written article on the placebo effect, well worth getting hold of and spending some time with, since "accumulated evidence suggests that the placebo effect is a genuine psychobiological effect attributable to the overall therapeutic context." This is the placebo effect of the clinical encounter, not the dummy pill of the randomised controlled trial. You relieve anxiety, create positive expectations, show empathy, etc: this expenditure comes from the economy of your soul, and creates endorphin-mediated good and addictive feelings in your patients. That is why, after about 20 years, half your consultations are with the same 150 or so patients, for whom you can generally do nothing, and who leave you exhausted. Perhaps you should try them all on naloxone, which abolishes much of the "wonderful doctor " effect in clinical investigations of placebos. That would be unkind: but so, they all tell me, is retirement.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)61706-2/abstract

BMJ  20 Feb 2010  Vol 340

405    In the old days, I would have said "this is a copy of the BMJ worth keeping handy in your consulting room", and so it may be, just for the editorial on urinary tract infections in women by Dee Mangin; but for the substance of the studies, it's best for you to print off the full articles from the links I give. I am soon to visit Party HQ for a quick Introduction to Correct Pico Thought, but as yet I am a shamelessly unreconstructed bourgeois deviationist paper-lover. This Southampton UTIS study deserves your full attention, because it explores all the main strategies that you employ every day in dealing with the lady who rings up with cystitis. OK, get that printer whirring: this is a paper you must discuss with your colleagues, registrar, medical students, patients even. Press PDF, five copies: who needs trees anyway. "I've had awful cystitis since last night doctor." "OK, I'll leave you a prescription for three days of the cefalexin you had last time." Discuss the evidence for this and other strategies for managing uncomplicated UTI in healthy women in the community (15 points).
http://www.bmj.com/cgi/content/full/340/feb05_1/c199

406    The mandatory UTIS spin-off cost-effectiveness study. It costs £10 for each day of symptoms saved. Piddling.
http://www.bmj.com/cgi/content/full/340/feb05_1/c346

407    The mandatory UTIS spin-off qualitative interview study. Urgently and frequently women with cystitis want antibiotics, and often exhibit dysuria when told to delay. Should I stop taking the pee - or do women expect a sample to be tested? Learn all about it from this analysis of women's views about the management and cause of UTI.
http://www.bmj.com/cgi/content/full/340/feb05_1/c279

408   Finally, the loose ends UTIS study, of which more are needed. This shows that women who have a resistant UTI, or are not given antibiotics, get worse symptoms that last more than 50% longer. People of the antibiotic-sparing persuasion should take note. These studies cover most of the questions that needed answers, and I would take them as supporting my normal (quick and easy) strategy, as given above, which doesn't even use a dipstick most of the time. But it would be good to have more detailed information on the effect of duration of symptoms on outcomes and a few other things. Women of Southampton, we have not done with you yet.
http://www.bmj.com/cgi/content/full/340/feb05_1/b5633

410    This paper promising ten steps towards improving prognosis research is rather angry in tone, but not angry enough for my taste. "Stemming the tide of low quality, low impact, prognosis research is an urgent priority for the medical and research community."  - nice opening. I met one of the authors (Doug Altman) about 15 years ago, when he was just beginning to explore this field of "mile wide, inch deep" research, as shown in Figure 1. I was interested because I'd just learnt about the prognostic value of BNP in heart failure. Eventually I wrote a chapter on prognostic markers and scores in HF, of which there are more than 100. But two stand head and shoulders above the rest: BNP and co-peptin. The rest are junk, by-products of freezers full of blood samples from interventional studies, raided by careerists in search of a quick paper. The promised ten steps in this paper are hidden as a jumble of suggestions in the "ten challenges" chart. Let there be just one step, and the rest will follow: every new prognostic marker or score should be compared with the best marker or score in existing clinical practice.

Ann Intern Med  16 Feb 2010  Vol 152

201    When King James I of England wrote his Counterblaste to Tobacco (1604), the "vile habit of tobacco taking" he blasted against was of course the smoking of pipes rather than cigarettes. Jacobean anger notwithstanding, the pipe has acquired a sentimentally benign image in our own day, a fashion statement to be worn with a soup-stained V-neck jumper and a tweed jacket with leather patches. Why, if I go on any longer in this vein I shall have to buy one. But this stern paper from the USA points out the Jacobean tragedy that awaits even the most bumbling pipe-smoker: increased cotinine levels and decreased lung function.
http://www.annals.org/content/152/4/201.abstract

211    The Women's Health Initiative trial was an RCT of hormone replacement therapy which brought about a volte-face in clinical practice but which is described as "far from impeccable" in a letter in this week's BMJ (p.382). Peccability is openly confessed in this Lenten analysis of the effect of continuous combined HRT on coronary heart disease. They more or less admit to residual confounding and small subgroup sizes. The bottom line message is that continuous HRT may confer added risk of CHD in the first years, then decreased risk after 6 years. Which is not quite what we were all initially led to believe.
http://www.annals.org/content/152/4/211.abstract

218    A couple of times over the last 30 years, I have initiated permanent anticoagulation for severe recurrent superficial thrombophlebitis with the reluctant concurrence of the local haematologist. We're taught that such events are benign and self-limiting and do not herald serious thromboembolism, but this French study casts doubts on that. In fact 25% of subjects with superficial phlebitis of 5cm or more had or went on to develop deep vein thrombosis in this series of 844 consecutive cases in a specialist referral centre. We need some primary care studies, quite urgently.
http://www.annals.org/content/152/4/218.abstract

Some Proverbs of Sumer

I love the proverbs of Sumer, which are the oldest recorded sayings of mankind, set down in collections on clay tablets around 2,500 BCE, but clearly much older than that. Human beings have not changed at all.

Whatever it is that hurts you, don't talk to anyone about it.
He who possesses many things is constantly on guard.
He who keeps fleeing, flees from his own past.
If the lion heats the soup, who would say "It is no good"?


JAMA  10 Feb 2010  Vol 303

519    Hemicorporectomy, lobotomy, whole body cryopreservation... well, laparoscopic gastric banding for severely obese adolescents doesn't quite come into that category, but as remedies go, it smacks of desperation. No doubt in a hundred years' time it will seem crude, almost barbaric. Yet it works, which is more than can be said for the alternatives. In this Australian trial, the subjects were between 14 and 18 years old and already suffered from physical, psychological and/or social consequences of having a BMI over 35 adjusted for age. Those randomised to a rigorous lifestyle intervention lost a mean of 13% excess body weight, while those who had surgery lost a mean of 79%. However, nearly a third required operative revision down the line.
http://jama.ama-assn.org/cgi/content/abstract/303/6/519

535    It's not entirely impossible that one day a breakthrough in our understanding of oncogenesis will suddenly produce a cure for cancers of all types. Meanwhile progress depends on the painstaking delineation of the minute particulars of each subtype of cancer and its survival patterns. I don't expect you to do more than quickly flip through this paper on age- and sex-specific genomic profiles in non-small cell cancer, but it's a good and self-effacing example of the kind of work this entails, complete with mazes of colour representing various oncogenes. Somewhere among them may lie the target for a truly magic bullet.
http://jama.ama-assn.org/cgi/content/abstract/303/6/535

NEJM  11 Feb 2010  Vol 362

485    I have never knowingly met a Pima Indian, but there is a group of them near the Gila River, presumably home to the Gila Monster which expectorates a drool of incretin mimetics and is pharma's favourite beast of the moment. The human Pimas have submitted to epidemiological study since 1966, so that we can now discover what factors in the children (n=4857, mean age 11) predict disease and death in adults up to the age of 55. Cholesterol and blood pressure in childhood have no predictive value. On the other hand, obesity and insulin resistance are highly predictive, with a doubling of mortality in the highest quartile of weight. This spells real trouble if, as seems likely, these trends apply to the generality of American children, who are now more than twice as fat and insulin resistant as these Pima children.
http://content.nejm.org/cgi/content/full/362/6/485

513    Some reassuring figures for women with breast cancer treated with breast-conserving surgery, with clear surgical margins and negative axillary nodes. If they have five weeks of radiotherapy the risk of local recurrence within ten years is 6.7%: if they have an accelerated course of three weeks it is 6.2%.
http://content.nejm.org/cgi/content/abstract/362/6/513

529    Often when people are honoured with a request to write a review for the New England Journal, they panic and cover pages with tables and coloured blobs and paragraphs loaded with accounts of genomic dead ends, plus zillions of references. The Enigma of Spontaneous Preterm Birth is written in English from beginning to end. For example, the section on The Timing of Human Birth begins, "The way in which the timing of birth is controlled in humans, either at term or preterm, is not known." Or in the section on genetic factors, "To date, the associations between polymorphisms in candidate genes and the risk of preterm birth have been modest at best." The Baroque extravagances which accompany general ignorance are here avoided. Maybe an even better review would have read: "We don't know why it happens, and we don't know how to stop it."
http://content.nejm.org/cgi/content/extract/362/6/529

Lancet  13 Feb 2010  Vol 375

555    A single dose of levonorgestrel works well as a morning-after pill, but less so the longer you delay beyond the morning after. Ulipristal acetate may be the answer for girls who are too shy or too disorganised to get emergency contraception within 72 hours of the event. This trial shows that ulipristal is about as good as levonorgestrel in the first three days and probably effective for five, though the numbers were small.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60101-8/abstract

563   The name COMICE makes me salivate like a dog in Pavlov's laboratory, and comice pears themselves salivate sweet juices to meet yours as you cut them open in December. Ah, but which comice pear? Besides the DoyennÃÆ'© du Comice of commerce there are the Fondante du Comice, SucrÃÆ'©e du Comice, Cassante du Comice, Super Comice and DoyennÃÆ'© du Comice PanachÃÆ'©e, according to WikipÃÆ'©dia. Grow them all in ÃÆ'©spaliers on the huge south facing wall that your garden boasts. I digress. I should really be telling you about the COMICE trial, which shows that pre-operative MRI before breast cancer surgery is largely a waste of time.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62070-5/abstract

583    Comice-related bulimia has not yet made it into the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) but binge-eating disorder may soon join anorexia nervosa, bulimia nervosa (non-comice) and eating disorder not otherwise specified. Not that it matters. So far as I can tell from this update on eating disorders, nobody knows what causes them and nobody knows how to treat them.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)61748-7/abstract

BMJ  13 Feb 2010  Vol 340

350    I suspect that for most readers, the words "thematic synthesis of qualitiative studies" have about the same appeal as Welsh ministers' question time on the Parliament channel (Freeview 81 on your presets, everybody). I must do something about this as I try to become an effective medical adviser to a patient experiences research group. Here is a really interesting study completely undersold. The views of patients and carers should be of vital concern to all clinicians, especially when dealing with difficult decisions in end-stage disease. Unfortunately the term "chronic kidney disease" now embraces 10% of the population, most of whom are perfectly well. This study is about the really poorly and frightened ones, two thirds of whom get little say in whether they carry on with haemodialysis, or go on to transplantation, home dialysis, or palliative care. Shared decision-making seems to happening least where it needs to happen most.
http://www.bmj.com/cgi/content/full/340/jan19_2/c112

352    Venlafaxine is a short-acting antidepressant with SRI actions at low doses and additional NRI actions at higher ones, I seem to remember. Because it is expensive and was alleged to carry a risk of arrhythmia, its use has come to be restricted to psychiatrists, at least in my part of the world. This is good, because psychiatrists need a cache of drugs that only they can prescribe when GPs have tried everything else. This nested case-control study shows that in fact venlafaxine is no more dangerous than fluoxetine, dosulepin or citalopram.
http://www.bmj.com/cgi/content/full/340/feb05_1/c249

355    Here is a population based cohort study showing that women with treated breast cancer who take paroxetine alongside tamoxifen have a higher mortality than those who take other SSRIs with tamoxifen. The obvious pharmacological explanation is that tamoxifen needs to be metabolised by CYP2D6 into endoxifen and that paroxetine inhibits this cytochrome iso-enzyme, rendering tamoxifen inert. But the same editorial that explains this says that fluoxetine does the same, yet it  produces no attenuation of tamoxifen's protective effect in this same study. They call for more studies on other populations. Meanwhile, it might be worth checking your practice register for any women who may be taking tamoxifen with paroxetine.
http://www.bmj.com/cgi/content/full/340/feb08_1/c693

Arch Intern Med  8 Feb 2010  Vol 170

230   The effect of giving global coronary risk information to adults is systematically reviewed in this paper based on 14 randomised trials and four other studies of "fair to good" quality. Hard-end points aren't on offer, but in general better compliance with treatment can be expected it you tell people their cardiovascular risk on at least two occasions. I doubt whether it matters which score you use. I even wonder if you need a score. I use BME (body mass estimate, or "does s/he look fat?"), age, smoking, BP, and a total cholesterol over 6. Maybe I should call this the Lehman Eyeball Test (LET): the first comes from eyeballing the patient entering the room and the rest comes from eyeballing the notes, with the odd question or test when required.
http://archinte.ama-assn.org/cgi/content/abstract/170/3/230

251   A German study takes a look at non-specific chest pain in primary care. It's non-specific, it's felt in the chest, and it is often found in primary care. After six months, it may or may not have gone away. Patients are often unsatisfied with the explanations that doctors attempt, but German GPs score high marks by ordering totally irrational investigations in only one tenth of cases. There is generally no medical treatment. But on Valentine's Day I might suggest the one offered by RÃÆ'¼ckert and Schubert in Du bist die Ruh, an incomparable song to the beloved:
Treib andern Schmerz
Aus dieser Brust!
Voll sei dies Herz
Von deiner Lust.
http://archinte.ama-assn.org/cgi/content/abstract/170/3/251

251   I'm afraid that GPs aren't much good at treating low back pain either, and here Schubert has little advice to offer. His song Atlas fails to mention simple analgesics and exercise, like many Australian general practitioners. I don't blame them. "Look cobber, I didn't come here and pay you 20 flamin' dollars to be told to do what I've already done" is too likely a response.
http://archinte.ama-assn.org/cgi/content/abstract/170/3/271

Dish of the Week: Basil and the Dove

The connection between Basil and the Dove goes back to the treatise On the Holy Spirit written by Basil the Great of Caesarea in the fifth century. Milton alludes to Basil's image of the Holy Spirit as the Mother Dove of Creation in the great passage which begins Paradise Lost, where he invokes the Spirit who

with mighty wings outspread
Dove-like satst brooding on the vast Abyss
And mad'st it pregnant

Elizabeth David rather enigmatically introduces a recipe for pigeon cooked with basil (among other things) with the quotation:

"Much anger arose from a Piedmontese officer giving the name of Santo Spirito to a dish of stewed pigeons."

The officer clearly knew his Basil the Great, and the dish given in Italian Food is one of the best dishes you could prepare from a dove or pigeon which has enjoyed a long and active life (impregnating the Universe) and so needs stewing a while.

Our take on the Basil and Dove theme uses quails instead of pigeons. Take the quails and insert a knob of butter and a leaf of basil under the skin of the breasts. Season the cavities with salt and pepper and insert a clove of garlic into each, followed by more butter, two more leaves of basil, and as many pine nuts as the cavity will hold. Cover with strips of smoked streaky bacon and roast in an open dish in a high oven. 25 minutes at 220 will suffice for those of a slightly bloody disposition; 30 minutes for cooked through and juicy; 35 minutes for drier tastes.


JAMA 3 Feb 2010  Vol 303

423     Everybody dies; quite a lot of people get myocardial infarction; few people get renal failure. This study of 920,985 people in Alberta ran for 35 months, so only 3% of them died. Proteinuria was more predictive of these outcomes than estimated glomerular filtration rate, and a combination of the two was especially predictive. But it's pointless to give the risk estimates because they were unadjusted for anything else. The tables are not much help, and you could spend a long time poring over this paper trying to work out how this might impact on clinical practice. Instead you should spend these hours writing to all your patients with an eGFR of less than 60 asking them to bring along a urine sample. In this way you can cause them stacks of anxiety for no known benefit, waste a lot of nurse time, and collect several thousand pounds of QOF income.
http://jama.ama-assn.org/cgi/content/abstract/303/5/423

438    "Evidence-based Medicine Requires Appropriate Clinical Context" declares the thoughtful editorial on this meta-analysis of deep vein thrombosis following a single negative whole-leg ultrasound. By lumping all the studies and patients from the community with those who have cancer or have had major surgery, the reviewers come up with a figure of 0.57% for VTE in the three months following negative ultrasound. But as the editorial points out, this is not the way we should work in real life. Systematic reviewers are always lumpers, but clinicians should always be splitters.
http://jama.ama-assn.org/cgi/content/abstract/303/5/438

448    If I ever get round to compiling the Good Death Cookbook from the recipes appended to these reviews, I shall have to confront the evidence linking dietary sodium with cardiovascular disease outcomes. All of it is observational; and according to this article, the studies are in equipoise. That's right: there are some studies showing cardiovascular harm from lowered salt intake; most are neutral; some show benefit. But there has never been a prospective randomised trial.
http://jama.ama-assn.org/cgi/content/extract/303/5/448

NEJM  4 Feb 2010  Vol 362

387    We have now definitely entered the age of effective oral treatment for relapsing multiple sclerosis. Effective means clinically effective , resulting in a clear reduction in disability over two years in this placebo-controlled RCT of fingolimod, a sphingosine-1-phosphate-receptor modulator that prevents the egress of lymphocytes from lymph nodes. Since we often need our lymphocytes need to achieve egress from their little nodes, you might expect a lot of infection-related adverse events; but in fact the biggest problems seem to have been bradycardia and macular oedema - both uncommon. Naturally, the safety jury will be out for some time yet.
http://content.nejm.org/cgi/content/abstract/362/5/387

402    The next trial of fingolimod was only a year long but this time it was compared with intramuscular interferon in a double-dummy double blinded RCT. And in this study two subjects receiving the higher dose of fingolimod died of infective complications - generalised herpes zoster in one case and herpes simplex encephalitis in the other. There were also six cases of macular oedema in the orally treated groups, all of which resolved, but it looks as if regular eye examinations are going to add to the cost of this drug.
http://content.nejm.org/cgi/content/abstract/362/5/402

416    Another promising oral drug for relapsing MS is cladribine. This is a fairly basic chemical (metabolised to 2-chlorodeoxyadenosine triphosphate) which interferes with DNA synthesis and repair. Surprisingly it is quite specific in its effects and knocks out CD4+ and CD8+ lymphocytes preferentially. Over the best part of two years, it was clinically beneficial in reducing the number and time course of relapses, compared with placebo. Inevitably it caused lymphocytopenia and there were 20 instances of herpes activation, none of them fatal, and one instance of TB activation, which was fatal. Expect many more studies over the next few years, including head-on efficacy and safety comparisons between Cladry Bean and Fingummybob.
http://content.nejm.org/cgi/content/abstract/362/5/416

440    In general, I can be fairly smug about my carbon footprint, and I read this article on jet lag with purely academic interest. Of course, if anyone wants to pay for this to change, they should contact me immediately. My lecturing fees, over and above first-class air travel and accommodation, are quite reasonable. I shall buy my own melatonin and try to follow the excellent advice summarised in Table 2 of this paper.
http://content.nejm.org/cgi/content/extract/362/5/440

Lancet  6 Feb 2010  Vol 375

481    Just over a year ago, I wrote about VADT, the third interventional trial in type 2 diabetes to show that lowering glycated haemoglobin (HbA1c) below 7 had no meaningful benefit. I suggested that all diabetologists should forthwith give a lecture eating their previous words on this subject. Fiona Godlee spotted my rantings and invited me to write a BMJ editorial on the subject, which I duly did with marvellous assistance from Harlan Krumholz. We ended with the suggestion that the QOF incentive to lower HbA1c to 6.5 might cause harm and should be abandoned forthwith. It wasn't, of course. Its proponents riposted feebly citing observational evidence of a linear relationship between all adverse events and HbA1c at every level, which we did not dispute. It's what happens to real patients when you treat them that counts. Well, here are the observational data from UK primary care, where I work. Turn to figure 1, and you will see that in diabetic individuals treated with combined oral therapy, all cause mortality varies little between HbA1c 7 to 9, being lowest at 7.5. Go as low as 6.4 and it jumps to higher than at 9.4. In patients treated with insulin, the 7.5 target is even more important; if you go any lower, mortality gets higher, even at 7.2, which is worse than being at 9. These data are from 28,000 patients observed after an intensification of treatment. So eat your words, diabetologists, and bin your target, QOF.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)61969-3/abstract

500    Pulmonary embolism in pregnancy is a good illustration of the triad described by Rudolf Virchow - hypercoagulability, venous stasis, and vascular damage. At this point I usually go into a panegyric about Virchow, a wonderful scientist and visionary social progressive; but to redress the balance I must also point out that he was a stubborn German professor who blocked the careers of anyone supporting the germ theory of disease. This however has nothing to do with PE in pregnancy, which may be accompanied by negative leg vein scans as clots can arise from the pelvic veins. It's also tedious to treat, and if this is something you are involved with, here is all you need to know, with 135 references.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60996-X/abstract

BMJ  6 Feb 2010  Vol 340

302    The dear young BMJ is always an interesting fireside read these days unless you want some research to get your teeth into. I decided to look online at this paper on social variations in access to hospital care in three common cancers because as usual I couldn't even understand the question it purports to address from the one-page condensation. So far as I can tell, the authors aren't claiming that people in the lower social categories have less access (in the normal sense) to hospital services for cancer, but that they present later to such services, and that this hasn't changed from 1999 to 2006. I am only telling you this because there is so little else to tell you this week.
http://www.bmj.com/cgi/content/full/340/jan14_1/b5479

303   It's a convenient belief, supported by some systematic reviews of randomised trials, that all blood pressure lowering regimens are equally beneficial in proportion to the  degree to which they succeed in reducing BP. This population based case-control study seeks to dispute that, and in particular to blacken the name of calcium-channel blockers compared to ACE inhibitors and ARBs. Again, you won't learn much from the one-page version. In the full on-line article, you can see the confidence intervals in all their unconvincing glory. There may be some differences, but we need better evidence than this.
http://www.bmj.com/cgi/content/full/340/jan25_2/c103

314   One of the reasons I proposed the Easily Missed series was to find out what I personally had been missing these last thirty-five years. Long QT syndrome is a definite case in point. If you have a young patient who has fainted during exertion or on being woken by a loud noise, get an ECG at once and make sure it is looked at carefully: the next episode may be sudden death.
http://www.bmj.com/cgi/content/extract/340/jan08_1/b4815

Ann Intern Med  2 Feb 2010  Vol 152

144    Just as you wouldn't give up and blame the patient if their blood pressure remained at 186/112 despite a short course of treatment, so you mustn't give up treating nicotine addiction until people no longer run the awful cardiovascular and pulmonary risks of smoking. Give them nicotine replacement therapy for as long as it takes, and bin any guidelines which instruct you to do otherwise on grounds of cost. This study unsurprisingly found that  a nicotine patches are more effective prescribed for 24 weeks than for 8. Many smokers won't need this length of treatment, others will need more.
http://www.annals.org/content/152/3/144.abstract

167    Non-invasive coronary angiography sounds like a great idea, but there are problems. Magnetic resonance imaging would be ideal if it worked, because it doesn't involve ionizing radiation. But this head on comparison with computed X-ray tomography shows that it is not nearly as accurate, according to the published studies. This may change as techniques develop, of course. The problem with CT is that it uses big doses of radiation and needs iodine-base contrast material; and so does the gold standard of coronary angiography, which the patient will then have to undergo if the CT shows a lesion requiring intervention. The real-life radiation dosage studies are worrying, though every article predicts that doses will fall in the future.
http://www.annals.org/content/152/3/167.abstract

Dish of the Week: Crab

Although the life of early humans may have been precarious, our ancestors must  also have enjoyed many hours of pure bliss as they wandered the shores gathering molluscs and crustaceans and spearing the odd fish.

The most highly prized crustaceans are fat lobsters and crayfish, but there is nothing to beat a good crab. And it seems unlikely that the human population will ever outstrip the supply of crabs, so they are cheap in relation to their merits, except in posh restaurants.

It is a mistake to eat crab in a restaurant in England. It is unlikely to be fresh, and you never get given enough. You need to buy your crab freshly boiled and directly from a fisherman you can trust. It can be as big as you dare, because big crabs do not get fibrous flesh, like big lobsters. You must set aside enough time to smash it and retrieve its contents, and to make a mayonnaise. This should be made with the best eggs you can find, hen's or duck's, with a mild olive oil and quite a bias towards lemon. However its crowning glory should be a few drops of truffle vinegar. The Italian firm called Elfos make one with Tuber melanosporum, which is excellent; but if you can find one made with white truffles, do let me know.

This is not an extravagant dish. A bottle of truffle vinegar will last you for months and a crab costing about £6 from a peripatetic fish seller will feed two people royally. However, if the heavenly nature of crab mayonnaise leads you to open a bottle of your best white Burgundy, the cost might soar. But it will be worth it.

 

 

 

 

 

 

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Page last edited: 09 March 2010