Journal Watch - June 2010

JAMA 23-30 Jun 2010 Vol 303

2479 Although aseptic surgery is over a hundred years old, this paper shows that that there is still room for a bit of improvement through close adherence to infection-prevention process-of-care measures. Interestingly the ones that count in this American study are not the ones that get listed in public reports. I don't know whether this has anything to do with the lingering remains of macho maleness in American surgery. In my day in England, I was taught by a surgeon who was a huntsman and a surgeon who was a pig farmer: each would occasionally turn up in the costume of his trade, leaving a trail of mud, or worse, at the threshold of the operating suite. Perhaps in America, some surgeons are cowboys.
http://jama.ama-assn.org/cgi/content/abstract/303/24/2479

2486 Homocysteine got us all excited ten years ago. Just as the complications of diabetes show a straightforward association with levels of glycated haemoglobin in observational studies, so vascular events show a nice straight-line relation to levels of homocysteine. The problems start when you try to run these relationships backwards. In the case homocysteine, all you need to lower it is plenty of folic acid and B12, but here in the SEARCH trial it had no effect on events in British survivors of myocardial infarction. The only consolation is that it did not increase the incidence of common cancers, which some feared it might.
http://jama.ama-assn.org/cgi/content/abstract/303/24/2486

2504 Sometimes, however, the obvious turns out to be true. The fatter you let yourself get in middle age and later, the greater your risk of diabetes. I didn't realise that this needed demonstrating, but evidently this miscellaneous American cohort study is one of the first to establish this fact.
http://jama.ama-assn.org/cgi/content/abstract/303/24/2504

NEJM 24 Jun 2010 Vol 362

2351 Not long after I first went to school, I was back at home again because of an outbreak of polio. I was too young to notice anything but the slightest whiff of the terrible fear that this produced. Two or three children didn't come back. Iron lungs were spoken of in whispers. There was a palpable sense of joy when the first vaccines arrived a year later, and happy queues formed at the centres that provided injections of the Salk type of inactivated virus. Later on, all you needed was a sugar lump for the Sabin strain of live attenuated polio. Now polio is on the verge of global eradication; but unfortunately the Sabin strains are going wild in places, and in remaining polio pockets the Salk type is once more the vaccine of choice. It's more expensive, so this trial in Oman looked at the effect of giving one-fifth doses by an intradermal method rather than a standard dose intramuscularly. Unfortunately, this is a bit less effective. And a study from Nigeria (p.2360) shows that the threat of oral vaccine strains mutating back to wild pathogenic strains is real. The road gets bumpier as we near the end of polio, as the very good perspective piece (p.2346) points out.
http://content.nejm.org/cgi/content/full/362/25/2346
http://content.nejm.org/cgi/content/full/362/25/2351
http://content.nejm.org/cgi/content/full/362/25/2360

2370 I don't imagine that many of my readers dabble in the early treatment of oesophageal varices due to hepatic cirrhosis, but I guess that most of you will encounter a patient or two with bleeding from such varices, and I don't want you to stare at their hospital discharge summary with bafflement at the mention of TIPS. Time was when such acronyms would never appear in the title of a New England paper, but alas, we seem to have reached a Tipping Point. TIPS stands for transjugular intrahepatic porto-systemic shunt. In this European multi-centre study, early use of this procedure produced much lower mortality than trial of medical therapy. But please, if you are a doctor working in a centre which provides this procedure, do write it out in full for the benefit of GPs and medical secretaries. When encountering unheard-of acronyms, we can easily be tipped into regrettable ones of our own devising.
http://content.nejm.org/cgi/content/abstract/362/25/2370

2380 Last week, not for the first time, I invited you to meet some tinibs. These, you remember, are tyrosine kinase inhibitors which target tumours that have particular expressions of epidermal growth factor receptor (EGFR). Such tumours include non-small-cell lung cancer with mutated EGFR, and for these a novel treatment is gefitinib. Now we get into the usual territory of modern cancer treatment: not stuff that you and I can hope to remember, but lots about genomic markers and some Kaplan-Meyer charts that show that gefitinib slows progression in properly selected patients but has only modest survival benefit compared to standard chemotherapy. Also it can cause pulmonary fibrosis and one patient died from that.
http://content.nejm.org/cgi/content/full/362/25/2380

2389 The clinical reviews in NEJM usually set a standard for all the other journals, and this one on endometriosis is certainly good, but no more satisfying than any other. What we are looking for, and can't find, is a good straightforward treatment for the condition. Instead there is a list of fourteen treatments (Table 1), none of them satisfactory and all of them with possible adverse effects. Nor does it seem that there is much else on the horizon.
http://content.nejm.org/cgi/content/extract/362/25/2389

Lancet 26 Jun 2010 Vol 375

2215 This issue of The Lancet is devoted to diabetes and is a good display case for everything that is wrong with The Lancet and with research in diabetes. The best paper is this first one which analyses 102 prospective studies to determine the relation between fasting blood sugar and risk of vascular disease. In people with no known vascular disease, this shows a definite threshold effect, with the threshold starting at 5.4mmol after which risk climbs steeply between 6 and the current defining threshold of diabetes, which is 7. It also varies between men and women and by age. And if my own fasting sugar is anything to go by, this is a measurement which can bob up and down. To use these data for individual patients, we need a very sophisticated computational method which factors in other vascular risk factors and all the known benefits and risk of available treatments according to age and sex. As far as I'm aware, we're nowhere near having any such thing. We don't even have rational criteria for defining "type 2 diabetes" or "dysglycaemia".
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60484-9/abstract

2223 We do however have dapagliflozin. But before you go to the considerable effort of pronouncing and memorising this latest drug for type 2 diabetes, wait for some evidence that it does more good than harm. This may take some years to arrive. In the mean time, all we know is that it reduces glycated haemoglobin in patients who are deemed to have inadequate glycaemic control with metformin, over a period of 24 weeks, during which it promotes renal excretion of glucose and may increase symptoms of genital infections (not fully defined). This was a phase 3 trial, so on past form we can expect this drug to be given a licence before we know anything about its real long term effects.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60407-2/abstract

2234 We don't know an awful lot about the long-term effects of exenatide either, though lots of us are using it because it helps patients avoid insulin and hypoglycaemia and weight gain. In this manufacturer-sponsored trial (DURATION-3), once-weekly exenatide is compared with once-daily insulin glargine. There is plenty here to please the advertisers and the drug reps, and a two-and-a-half year extension will produce more data; but what we need and probably won't get is a head-on comparison with its rival incretin mimetic, liraglutide. Nor will we really know what we have really done to our patients till another few years have gone by.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60406-0/abstract

2244 Remember Exubera? This was a form of inhaled insulin marketed between August 2006 and October 2007: despite an exuberant advertising campaign it flopped and then came under a cloud for its irritant effects on the lung, which might even be carcinogenic. (Exubera, by the way, means "out of the breasts"; the original exuberant woman was a Roman matron with overflowing breast milk, rather than one who inhaled insulin or laughed too much.) But manufacturers remain enamoured by the idea of packaging insulin in a way that doesn't require frequent injections, and The Lancet remains enamoured of anything manufacturers come up with: hence this paper describing a trial of insulin inhaled inside magical microspheres. "The Technosphere system allows for pulmonary delivery of peptide hormones, resulting in safe and rapid absorption of large molecules. Once inhaled, the insulin dissolves immediately on contact with the lung surface, and is rapidly absorbed into the systemic circulation." With scientific prose like this, who needs advertising?
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60632-0/abstract

BMJ 26 Jun 2010 Vol 340

Although my joints are not wearing out just yet, I regard each step towards evidence-based orthopaedics with a mixture of joy and apprehension. Perhaps, by the time I need orthopaedic surgery, they will know what they are doing. Perhaps, on the other hand, they won't. This systematic review of hemiarthroplasty versus total hip replacement for displaced intracapsular fractures analyses a mixture of inadequate randomised trials and retrospective cohort studies. It demonstrates a small difference in outcomes (favouring THR) which it somewhat overstates, and then goes on to call for bigger, better trials. I can only hope I don't meet the inclusion criteria any time soon.
http://www.bmj.com/cgi/content/full/340/jun11_1/c2332
The big issue in the treatment of neovascular age-related macular degeneration is whether to use bevacizumab or ranibizumab to block vascular endothelial growth factor-A (VEGF). Most ophthalmologists use the first because it's a hundred times cheaper than the second, but it isn't licensed for this use and there is no direct evidence of equivalence. However, this trial proves that bevacizumab is safe and effective, and in the real world I think it seals the fate of ranibizumab. The editorial carries on plaintively arguing that this is unfair, but what is really unfair is that the manufacturers of monoclonal antibodies can charge anything they like.
http://www.bmj.com/cgi/content/full/340/jun09_4/c2459
I'm a great admirer of the various studies done over the years by the Edinburgh team of Scott Murray and Marilyn Kendall, looking at various aspects of the experience of people dying from lung cancer and heart failure. The great advantage is that they look beyond the patient - in one study, they looked at the whole team and here they re-examine the experience of carers and how much this replicates the experience of the patients themselves. In spiritual and psychological terms, the similarities are generally close.
http://www.bmj.com/cgi/content/full/340/jun09_4/c2581

Plant of the Week: Catalpa fargesii var duclouxii

Of all the plants we saw while wandering around the famous East Sussex garden at Nymans last week, this flowering tree was the most striking. It was about 10m high and entirely covered in scented small foxglove flowers, pink stained with yellow.

Late June is a time when most trees have stopped flowering, so this one ought to be planted wherever there is enough room for a succession of massed lofty blossom. Why then is it so rare? I blame Bean. This oracle on Trees and Shrubs Hardy in the British Isles since 1914 declares, "Although beautiful in flower, C. fargesii in both its forms makes a rather gaunt, narrow crowned tree. The f. duclouxii in particular is of poor habit as seen in cultivation and seemingly short-lived." Not so at Nymans. If you are planting an arboretum, do give it a try. We, alas, are not planting an arboretum and will have to admire it where we can.

Quotation of the Week: Jefferson on Conformity

I have never submitted the whole system of my opinions to the creed of any party of men whatever, in religion, in philosophy, in politics or in anything else, where I was capable of thinking for myself. Such an addiction is the last degradation of a free and moral agent. If I could not go to Heaven but with a party, I would not go there at all.

Thomas Jefferson, sent to me by Michael O'Donnell

JAMA 16 Jun 2010 Vol 303

2377 I'm always interested to read something about the protective effects of B vitamins, even if, as in this case, it is clinically irrelevant. This paper seems to indicate that you can halve your risk of lung cancer by having a high serum level of vitamin B6, but I would rather you reduced it by nine-tenths by avoiding smoking. Moreover, I find it hard to follow the biochemical logic of this study, generated by crunching data from 385 747 participants in the EPIC study. Several B vitamins raise serum levels of methionine, which is here associated with a lower risk of lung cancer. On the other hand, the only B vitamin that they find to be independently associated with such protection is 6 (pyridoxine). I suppose you could argue that we need more prospective studies of various vitamins for the prevention of otherwise unpreventable cancers; but then the results of these have so far been disappointing.
http://jama.ama-assn.org/cgi/content/abstract/303/23/2377

2386 During my working lifetime as a clinician, which officially came to an end this weekend, there have been major increases in the life expectancy of people with cystic fibrosis. Unfortunately there has also been an enormous rise in the prevalence of meticillin-resistant strains of Staphylococcus aureus, which don't pose much of a threat to people with intact protective mechanisms but are bad news if your airways are full of sticky mucus. This cohort study of nearly 20 000 patients treated in approved CF centres in the USA shows higher mortality in those with MRSA. Duly adjusted, the added risk is about 27%.
http://jama.ama-assn.org/cgi/content/abstract/303/23/2386

2393 Often in the course of these reviews I've praised the small countries of northern Europe for their contributions to epidemiology, and here they go again. Denmark has collected data on all but 2 million little Danes born from 1977 to 2008, out of which 3362 needed surgery for pyloric stenosis. Many of them were related to each other. In fact if you are the monozygotic twin of a baby with pyloric stenosis, your risk of needing a pylorotomy is increased about 200-fold. Even if you're just a half cousin, your chances of enriching the soil of Denmark with a projectile offering of curdled milk go up by about 60%.
http://jama.ama-assn.org/cgi/content/abstract/303/23/2393

NEJM 17 Jun 2010 Vol 362

2251 I have previously introduced you to many members of the mab family (monoclonal antibodies, with kinship structures that rival the Australian aboriginal tribes); also a few olimusses; but so far not many tinibs. But there's a lot of them about.: in fact there is even an erlotinib. But here we're comparing nilotinib with imatinib in the treatment of chronic myeloid leukaemia. These tinibs all target the enzyme tyrosine kinase which many cancers need to flourish, and when imatinib first appeared it was hailed as a magic bullet for everything from atherosclerosis to smallpox. These are always dangerous claims for a drug, and imatinib now comes under sustained assault from its pushy cousins. This study shows that nilotinib is more specific and more effective in CML.
http://content.nejm.org/cgi/content/abstract/362/24/2251

2260 Dasatinib is the other drug set to displace imatinib in CML. It has previously been used for relapses after imatinib treatment, but here it is used in a head-on comparison for chronic disease. Again, it's better. So now it's a contest between nilotinib and dasatinib, and I suspect there isn't erlotinit.
http://content.nejm.org/cgi/content/abstract/362/24/2260

2295 Nicotine addiction remains one of the greatest health problems in the world. Not because of the nicotine, which is probably as harmless as heroin (though more addictive), but because of the smoke that commonly accompanies it. Heated tobacco smoke in the lungs is an amazingly potent vehicle for getting this drug straight to the brain, where it excites pretty well every mechanism that potentiates addiction. So if you want to find out all about these mechanisms, this review is the place to look. The article also explains why nicotine replacement therapy alone has such a low success rate.
http://content.nejm.org/cgi/content/extract/362/24/2295

Lancet 19 Jun 2010 Vol 375

2152 "We still don't know what autism is, or to be precise what the 'autisms' are", declares the front cover of The Lancet. They are the offspring of "refrigerator mothers", claimed that old fraud Bruno Bettelheim, thus deepening the agony of mothers with strangely inconsolable and uncommunicative small children, usually male. The treatment, therefore, might consist of teaching parents how to communicate intensively - a hypothesis tested as well as it's ever going to be in this MRC trial (PACT). The result is uncertain. I suspect that most parents of autistic children do this anyway, and in the case of the boy I've lived with this fifteen years, maternal love and encouragement have seen him turn from a 9 year-old child thought unreachable by his teachers into a successful young man in employment following a commended Master's degree in the history of political philosophy.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60587-9/abstract

2161 Golly - here's something you don't often see in The Lancet: a trial puffing a new drug for angina which costs about £20 per year. Nor is it subsidised and ghost-written by the drug's manufacturers, who have probably long ago lost interest in it. Because the drug is our old friend allopurinol, at 600mg daily, used to improve exercise tolerance in ischaemic heart disease as opposed to preventing gout. It's a very small short-term trial, but there seems to be no reason not to give the drug a go - and quite a few reasons to believe that it may be a good thing for the strained myocardium (see editorial on p.2126).
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60391-1/abstract

BMJ 19 Jun 2010 Vol 340

1338 I don't normally point out opinion pieces, but this one for and against the abolition of QOF is one I suggested to the editor a while back, as I'm sure many others did. Anyway, it comes as a nice present for my official retirement, coinciding with news that the bottom HbA1c target for type 2 diabetes is going to be raised, as Harlan Krumholz and I suggested in an editorial more than a year ago. As for the merits of QOF itself, I was too kind to them in that editorial: the points system did not encourage the proper care of diabetes, as has been shown in subsequent analyses, and I doubt whether it is capable of improving the care of anything. Several of the later additions are not just useless but nonsensical, as Des Spence points out in relation to "chronic kidney disease" on p.1366.
1345 My first nickname in primary school was Goggles, in honour of my NHS designer eyewear circa 1959. The first thing I noticed when I started wearing glasses was that I tripped over things, and that's an experience repeated with every change in lens prescriptions since, right up to the time I went for varifocal lenses in my mid-fifties. With single lens distance lenses the effect wears off after a day or two, but since multifocals play continuous tricks with heights and distances, you never really get used to them. Thus, if you are elderly, as in this trial (mean age 80), you fall more with multifocals and less with singles. Simple as that. In my old age I shall go back to being Goggles.
http://www.bmj.com/cgi/content/full/340/may25_1/c2265

1349 I'm trying really hard to find some good research to report from this week's BMJ, and to be nice about it. Here is a study about the effect of smoke-free legislation in England and hospital admissions for myocardial infarction. Now all studies of MI admissions in the developed world show seasonal wiggles and an overall trend downwards. So does this one. If you were asked to guess where the introduction of a public smoking ban came among the wiggly graphs in this paper, you could have chosen almost anywhere. I shall refrain from comment.
http://www.bmj.com/cgi/content/full/340/jun08_1/c2161

1350 Faecal incontinence is not a subject much discussed in polite company, and alas most people don't even want to discuss it with their doctors. Nor do most doctors know what to do about it. This helpful review tries to put that right. It goes through the basics that can be done in primary care (including rectal irrigation - 47% success at 2 years) and then discusses the evidence base for all sorts of attempted technical fixes such as sacral nerve stimulation and graciloplasty.
http://www.bmj.com/cgi/content/extract/340/jun15_2/c2964

Archives and Annals of Internal Medicine

For a third week I can't find anything worth reporting on from these normally worthwhile journals. I shall keep trying: it may just be peri-retirement fatigue.

Stray Thoughts of a Retiring Man

When I first started in medicine, I never thought I'd see it as anything more than a convenient way to support an nice life style. I even bunked off to have fun doing a degree in English between preclinical and clinical studies, and headed off for general practice as soon as I could.

But now as I give up the onerous tasks of general practice, so many of them externally imposed, I feel a continuing urge to be involved with medicine in other ways. I want to put the patient experience at the centre of all medical teaching and service development. I want to raise the profile of kindness, as Angela Jones advocates so beautifully in this week's BMJ (p.1363). I want health professionals to have richer lives and pursue wider goals than the technocracy-driven systems of today permit. I want there to be much more genuine interchange between the rich world and the needy world.

Perhaps these come over as just the sentimental fantasies of an old man in a sudden hurry. But I've been thinking about them for years; and I hope these reviews have helped a bit to infect you with them, because that will be the greatest incentive to continue.

JAMA 9 Jun 2010 Vol 303

2253 Reading the American journals from the perspective of a British small town GP can be a bit disorienting at times. This study deals with the US phenomenon of the long-term acute care hospital, which seems to be a hospital designed specifically for people with complex comorbidity which will require a long period of hospital care. Not surprisingly, the cost of these hospitals is huge and growing, and patients admitted to them after a period in critical care have a poor life expectancy - 52% die within a year. I think we'll muddle on with our present system of NHS acute hospitals, thanks.
http://jama.ama-assn.org/cgi/content/abstract/303/22/2253

2273 Even more alarming to the literal-minded Limey is the idea of an ambulatory surgical centre. I think if I saw a surgical centre walking down my road I would turn and flee. Which might be just as well, since according to this survey such units in the USA, their standards of infection control leave much to be desired.
http://jama.ama-assn.org/cgi/content/abstract/303/22/2273

2280 "Does This Patient Have a Haemorrhagic Stroke?" asks the latest in The Rational Clinical Examination Series. "How should I know, I haven't seen the scan" might be the usual answer, and it also turns out to be the correct one. Features like coma, headache, neck stiffness and high blood pressure all make haemorrhage a bit more likely, but the only way to know with sufficient certainty is by putting the patient through a CT scanner, preferably within the window for thrombolysis if the stroke turns out to be ischaemic. This is confirmed by 19 prospectively studies, meticulously analysed here; but although I'm a great admirer of this series, I think this was a bit of a no-brainer.
http://jama.ama-assn.org/cgi/content/abstract/303/22/2280

NEJM 10 Jun 2010 Vol 362

2155 This study is based on the Kaiser Permanente insured population of California and it tells a pretty amazing tale - ST elevation myocardial infarction has fallen by 62% in the last decade. Interestingly the incidence of non-ST elevation MI went up between 2002 and 2004 as troponin assays became widely adopted as the diagnostic gold standard, but even taking this into account, the incidence of any MI has gone down by a third. During this time, Californians became a bit fatter, did slightly more exercise, were banned from smoking in public places, and were prescribed more statins, beta-blockers and ACE inhibitors. We are not told if they drank more of their sometimes passable wines.
http://content.nejm.org/cgi/content/abstract/362/23/2155

2166 While a row brews in the BMJ over how much the drug manufacturers influenced policy on antiviral drugs for H1N1 influenza, here from Singapore is some evidence that at least they work. This hot little island city of nearly 5 million people is well-ordered and authoritarian: the young have to become soldiers for a time during which they are kept in barracks during the week and let home for the weekends. When the threat of H1N1 loomed, various strategies were deployed to try and contain spread amongst these young military, all involving oseltamivir and isolation. The more you used the drug among cases and contacts, the less the flu spread.
http://content.nejm.org/cgi/content/full/362/23/2166

2175 Moving north east to another even more crowded but slightly less hot once-British city, Hong Kong gives us some insights into the differences between seasonal and H1N1 influenza. According to this study of households, using PCR assays, the two are more alike in their symptoms and their infectivity than we have been led to believe by the studies already published.
http://content.nejm.org/cgi/content/full/362/23/2175

2185 Determining the exact risk of drugs taken during pregnancy is a difficult science, carried out with great patience in this EUROCAT study of valproate acid monotherapy and major congenital malformations. It's a cohort study with a couple of case-control studies thrown in, and it confirms that of all anti-epileptic drugs, this is the one to avoid in pregnancy.
http://content.nejm.org/cgi/content/abstract/362/23/2185

2194 Everyone over the age of 55 is convinced that they have early Alzheimer's disease. The signs are plain to see: the forgotten car keys, the lost names of familiar people, the incredible slowness of uptake when confronted with any computer-related task. My only comfort is that I was like that at 40. This review makes the point that while Alzheimer's is always prefaced by mild memory problems, not all mild memory problems presage Alzheimer's. So this article just becomes a fairly useful summary of the therapeutic options, which essentially amount to donepezil, with a couple of less effective also-rans. Can you remember their names?
http://content.nejm.org/cgi/content/extract/362/23/2194

Lancet 12 Jun 2010 Vol 375

2073 From the point of view of someone like me who is fixated on the cardiovascular system, the body consists of a central pump supplying blood to various tufts - lung-tufts to oxygenate it, gut-tufts to feed it and kidney tufts to get rid of waste products, and so on. I can see that for some the kidney is an interesting organ, but for me it's essentially a dangling footnote to the business of assessing cardiovascular risk, and delicious when prepared correctly. Now assessing risk (or prognosis) is itself of little importance unless you can use it to guide interventions to reduce risk. All of which makes it very frustrating to wade through a paper like this which pools data from 14 studies (over 100 000 individuals) to derive risk tables for all-cause and cardiovascular mortality graded by eGFR and albuminuria, independently of blood pressure, cholesterol and smoking. There seems to be a definite association which, surprisingly, is slightly U-shaped when you combine the two factors. So was QOF right to make us identify and check out everyone with an eGFR under 60? That's another question entirely, which depends on how much these factors contribute to total CV risk, and what we can do about it.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60674-5/abstract

2092 I don't generally comment on studies of HIV, since I encounter so little in my practice, but I was stopped in my tracks by the final sentence of the Summary of this paper: "Provision of antiretroviral therapy to HIV-1 infected patients could be an effective strategy to achieve population-level reductions in HIV-1 transmission." Why yes: and by the way it stops HIV-1 infected individuals from dying as well; but how did we come upon such data from a prospective cohort analysis? It's because this cohort with HIV-1 from several African countries was not given antiretroviral drugs for HIV but aciclovir to prevent or treat concomitant herpesvirus infection. Only a tenth of these people got HIV antivirals, when their CD 4 cell count fell below 200, and among these transmission of HIV to their regular heterosexual partners was nearly zero. Among the rest, who were untreated for HIV, the rate of transmission was related to the plasma HIV-1 concentration, with 70% occurring at concentrations over 50 000 copies per ml. As we face the unpleasant consequences of tighter rationing in our pampered country, spare a thought for the African countries where even basic life-saving treatment has to be rationed according to affordability and population arithmetic.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60705-2/abstract

BMJ 12 Jun 2010 Vol 340

1255 As Tony Delamothe makes clear in his Editor's Choice, the best bits of this week's BMJ lie in the commentary sections and not the original papers. The multiple sclerosis risk sharing scheme is discussed by a neurologist in this editorial and by several other people on pp.1282-88. This scheme was a compromise struck by the government and the manufacturers of three types of interferon beta and copolymer-1 for multiple sclerosis, after NICE declared them to be of unproven cost-effectiveness. If the stuff worked, the taxpayer would continue to fund it; if it didn't, the money would clawed back. A likely story: the money has flowed out, to the tune of £500 million, while the outcomes assessment suggests that these drugs accelerate deterioration in MS - but this assessment uses such bad methodology that nobody really knows one way or the other. The drug companies have ploughed back some of their profits into supporting MS specialist services, and this is hailed as a welcome spin-off by some neurologists, as indeed it is. But good value for £0.5 billion? asks Tony D, and replies "I don't think so."
http://www.bmj.com/cgi/content/extract/340/jun03_1/c2882

1256 The second editorial is by Fiona Godlee , questioning the influence of commercial lobbying on the decision by the World Health Organization to declare an H1N1 influenza pandemic and recommend the stockpiling of antiviral drugs. Some key advisers in this process received money from the manufacturers of oseltamivir, zanamivir, and H1N1 vaccines. Which is wrong, and remains wrong even though the policy itself may have been the only logical one in response to what then seemed likely to be a serious global health threat. That it was a damp squib is not the point. The point is that (particularly in the USA) it is very hard to get health policy advice which is not contaminated by commercial interest, and this is especially serious when decisions need to be taken rapidly in response to a perceived global crisis.
http://www.bmj.com/cgi/content/extract/340/jun03_4/c2947
1292 So what of H1N1, now downgraded to something rather more benign than seasonal flu for all but a few unfortunates, many of them children? The consensus is that it's still worth vaccinating the age group from 6 months to 12 years and therefore still worth pursuing the most immunogenic vaccine. This study compares two vaccines, one an adjuvanted split virion vaccine derived from egg culture, the other a whole virion non-adjuvanted vaccine derived from a different strain grown in cell culture. The adjuvanted vaccine gave kids lots of fevers and sore arms and better antibody levels. No pain, no gain, conclude the authors; though they have thrown four variables into this study rather than the usually recommended one. I'm not going to be rolling up my sleeve any time soon.
http://www.bmj.com/cgi/content/full/340/may27_1/c2649

1293 The swine flu panic seems such a long time ago, yet it is only a year since that unheroic mess of conflicting advice and unsafe triage consumed our summer days. "Doctor, I was on a plane sitting near a man who kept sneezing and coughing so can I have some Tamiflu." "Of course you can my dear just ring up this telephone number, no, attend the local garden centre and you will be given a number and hopefully you'll get some. Are you pregnant? Oh no, you're 60.Bye". Next please. Here's a paper which measures your chances of getting H1N1 by sitting in a airliner for 13 hours. It's a nice bit of old-fashioned closed-system epidemiology from New Zealand which reminds me of Wilfred Pickles and his wife plotting the spread of measles through 1930s Wensleydale. I think that must be why the BMJ - which published the Pickles charts so many years ago - decided to accept this paper, based on the assumption of a single index case and two infected passengers.
http://www.bmj.com/cgi/content/full/340/may21_1/c2424

Plant of the Week: Paeonia "Garden Treasure"

I gave you the history of this plant a year ago, when we had just bought one. Now let me give you a first-hand account of its merits. If ever a plant deserved its name, this one does.

You may remember that it is a complex hybrid which includes ancestral qualities from older Chinese hybrids of tree peonies such as suffruticosa and the yellowish delavayi, and also some genetic material from herbaceous peonies, all melded by a process of incredible patience and perseverance over 1,600 years. The reason that early plants were sold ten years ago for $1,000 is that the flowers are not only magically beautiful but also are borne on strong long stems, making this a sure winner in the commercial cut-flower market.

We bought ours in a 3L pot a year ago for £70 and put it straight into the rather poor soil of our sunny front bank with a bit of good compost and waited to see what it would do this year. It came up in a mass of attractive firm green cut leaf, and then formed 8 flower buds which have taken about a fortnight to open. They crack to reveal a glowing gold colour, slightly flushed with red. As the papery petals open they form a wide four-ply rosette of pure and somewhat golden yellow, with the usual peony central boss of prominent ovaries and stamens, flushed with the softest red. The flower matures over several days, becoming about 12 cm across and turning into the purest soft lemon-yellow, while the red central flush becomes slightly more extensive though remaining little more than a hint. I honestly don't know of a more beautiful flower, or indeed of a more perfect garden plant.

Most peonies with tree-genes in them start by smelling of roses, but later on of dish cloths; this one has stood on the table for five days without shedding a petal and still smells sweetly, albeit not strongly. Buy this plant now, if you can find it: it may halve in price over the next few years, as it becomes commoner, but meantime for a week or two each June it will outshine everything else in your garden, and it will last for decades, if not centuries.

JAMA 2 Jun 2010 Vol 303

2141 Acute heart failure is regarded by most members of the public as synonymous with death, and indeed a proportion of patients admitted to hospital with HF do die within 30 days, but this stands at barely more than one in ten, and has hardly changed between 1993 and 2006, dropping from 12.8% to 10.7%. During that time, nearly 7 million Americans covered by Medicare have been to hospital with acute HF, and very little else has changed either: they get discharged a bit sooner, and readmitted slightly more often. A huge, meticulous, well-described outcomes study of this kind inevitably has one looking for Harlan Krumholz; yes, there he is.
http://jama.ama-assn.org/cgi/content/abstract/303/21/2141

2148 The heart failure figures are rather disappointing, whichever way you spin them; but one definite way to reduce HF is to save myocardium by timely reperfusion therapy for acute myocardial infarction. We know this from many interventional trials, of course, but given the immense organisational effort that has gone into providing access to immediate percutaneous intervention for MI, it is nice to have observational evidence from a large population too. Voici QuÃƒÆ’Ã†'Ãƒ" 'ÃƒÆ’" 'ÃƒÆ’Ã†'" 'ÃƒÆ’Ã†'Ãƒ" '" 'ÃƒÆ’Ã†'Ãƒ" 'ÃƒÆ’" '" '©bec. In 2006-7, nearly 80% of quÃƒÆ’Ã†'Ãƒ" 'ÃƒÆ’" 'ÃƒÆ’Ã†'" 'ÃƒÆ’Ã†'Ãƒ" '" 'ÃƒÆ’Ã†'Ãƒ" 'ÃƒÆ’" '" '©bÃƒÆ’Ã†'Ãƒ" 'ÃƒÆ’" 'ÃƒÆ’Ã†'" 'ÃƒÆ’Ã†'Ãƒ" '" 'ÃƒÆ’Ã†'Ãƒ" 'ÃƒÆ’" '" '©cois with ST elevation MI received PCI, but in 68% of cases this occurred after more than 90 minutes. If you look at a map of Canada, you will see why: the province is more than twice the size of France and stretches up and beyond the Arctic Circle. Of those who received thrombolysis, 54% got it later than the ideal 30 minutes. The mortality figures following the two modes of treatment are remarkably similar, but outcomes such as recurrent MI and the need for bypass grafting favour PCI. By contrast, the treatment within the ideal window halves your chance of death within 30 days.
http://jama.ama-assn.org/cgi/content/abstract/303/21/2148

2156 Now the most that a mere GP knows of these wonderful interventions is the odd patient who returns from PCI with a large groin haematoma, or even, in one recent case of mine, with a cold leg and claudication at 50m. Puncturing the femoral artery sufficiently to get a stent up to the coronary arteries is not a risk-free procedure, and it's surprising that merely pressing hard on it afterwards while asking the patient where they went on holiday has been deemed sufficient for so long. This American registry study shows that vascular closure devices should probably be used in all patients, especially those at highest risk of bleeding.
http://jama.ama-assn.org/cgi/content/abstract/303/21/2156

2165 The Emergency Medicine Shock Research Network lives up to its name in this study which shows that the biggest predictor of mortality following cardiopulmonary resuscitation is not hypoxia but hyperoxia. In other words, this Shock Research probably indicates that we are killing patients by giving them too much oxygen during CPR. If this is the kind of thing you get up to on a regular basis, then read this multicentre study in full and pore over possible adjustment biases and so forth. On first principles, we know that oxygen is a dangerously reactive chemical and not always the best thing to feed into areas of acute cell damage.
http://jama.ama-assn.org/cgi/content/abstract/303/21/2165

2172 Over the years, I've come across a number of reviews of female urinary incontinence, but somehow I'd missed the fact that oral hormone replacement therapy is actually a risk factor for it. In fact the incidence shows a peak during the peri-menopause, abates afterwards, and then starts rising again until it affects at least one in 3 women over 65. An early menopause is actually protective. This review goes through the treatment options with a suggested flow-chart (if that is the right expression) for managing both stress and urge incontinence.
http://jama.ama-assn.org/cgi/content/abstract/303/21/2172

NEJM 3 Jun 2010 Vol 362

2053 Incremental advance in the treatment of cancer has achieved extraordinary results in some areas, such as many childhood cancers and the lymphomas: but how complex the process can sometimes be, and how tiny the increments. This large US trial looks at three different ways of giving docetaxel-containing chemotherapy for early breast cancer. A particular sequential regime wins, by a margin of 4%. But the accompanying editorial points out that things have moved on since, with new and different regimes directed according to HER status, for example. The editorial also argues that single-agent trials should be the norm unless you can prove that the combined cytotoxicity of a regime is more than compensated for by a survival benefit. Complex stuff: I am glad I work elsewhere.
http://content.nejm.org/cgi/content/abstract/362/22/2053

2066 The thought of puncturing the female perineum with a large curved needle bearing tension-free tape is appalling enough to give anyone pelvic floor contractions. But these outpatient midurethral sling procedures are remarkably effective at curing stress incontinence, and caught on long before there was clear evidence in their favour, let alone a comparison between competing procedures. Here is a head-to-head trial of the two main methods: retropubic versus transobturator. If your ability to visualise female perineal anatomy is as bad as mine, I can offer you no help: you have to have a NEJM subscription and access the very last bit of the supplementary web material for pictorial assistance. But no matter: the two methods do not differ in effectiveness or adverse effects (surprisingly uncommon).
http://content.nejm.org/cgi/content/abstract/362/22/2066

2077 Deep-brain stimulation for Parkinson's disease is usually a last-ditch procedure for advanced disability - and rightly so. Whenever I see these studies I go straight to the adverse effect section: a total of 335 serious events occurring in 160 patients out of a total of 299 randomised to receive stimulation in the globus pallida interna or the subthalamic nucleus. Both provided equal improvement in motor function, at equal and heavy cost in complications and money.
http://content.nejm.org/cgi/content/abstract/362/22/2077

2092 CISH is the sort of sound I make whenever I see a paper about genomics in a major medical journal. But this one may be worth noting: not for any immediate benefit if may bring to sick people but for the possible light it may in time shed on the mechanisms of susceptibility to major infection. CISH stands for cytokine-inducible SRC homology 2 (SH2) domain protein, as I'm sure most readers realise. Moreover - and again I'm sorry to go into such basics - CISH is a suppressor of cytokine signalling and so controls interleukin-2 signalling and hence the interleukin-2 immune response which is critical for host defence against infectious pathogens. And here we get to the nub of the matter: "Variants of CISH are associated with susceptibility to diseases caused by diverse infectious pathogens, suggesting that negative regulators of cytokine signalling have a role in immunity against various infectious diseases. The overall risk of one of these infectious diseases was increased by at least 18% among persons carrying the variant CISH alleles." That's an extraordinarily large percentage for any one gene.
http://content.nejm.org/cgi/content/abstract/362/22/2092

2102 Is there such a thing as dietary therapy in hypertension? DASH it, of course there is: as this review shows, the two DASH trials, with 459 and 412 participants, account for almost all of the dietary advice we are supposed to give to millions of patients with mildly elevated blood pressure, or even with normal blood pressure ("prehypertension"). When a vast belief system rests on such a narrow foundation, I get worried. We need many more interventional trials of much larger scale, however difficult they may be to conduct: moral certainty about what fat "unhealthy" people should do is no substitute for evidence.
http://content.nejm.org/cgi/content/extract/362/22/2102

Lancet 5 Jun 2010 Vol 375

1969 Once again The Lancet goes nobly global and the generalist reader in a rich country is left pondering over great tables of appalling statistics. Communicable diseases are still the overwhelming killers of children under the age of 5. Nearly all of these are preventable or treatable. For example, 4 children died of diarrhoea in the UK in 2008, compared with 0 in many European countries and 237 482 in India. The Millennium Goal was to reduce child deaths worldwide by two thirds, and it still might be achievable - see the study on p.1988. There may not be a lot that most of us can do here on the sidelines, but I would suggest that as a start everyone should join in the achievement of a Millennium aim that really is achievable - Health Information for All by 2015, or HIFA 2015. Google it up and subscribe to it. We don't even ask for your money.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60549-1/abstract
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60703-9/abstract
http://www.hifa2015.org/

BMJ 5 Jun 2010 Vol 340

1231 The star of this week's BMJ is Julia Hippisley-Cox, professor of primary care in Nottingham, who has used the EMIS database of British general practices to derive an improved cardiovascular risk score (QRISK) and has also (see below) worked out from it what the true risks and benefits of statins are in UK primary care. We are lucky to have such studies to refine our practice, since they apply directly to the population we treat. As she has been working on the two versions of QRISK, Gary Collins and Doug Altman have been dogging her footsteps, and here they publish an independent and external validation of QRISK2. Use it with confidence in British general practice - you won't get a better Good Housekeeping Seal of Approval than this.
http://www.bmj.com/cgi/content/full/340/may13_2/c2442

1232 I don't often read on-line first publications before they appear in print - sufficient unto the week is the evil thereof - but Julia H-C's paper on the unintended effects of statins was getting onto the front pages of newspapers when it first appeared about a fortnight ago, and there were bound to be questions from patients. Besides, I take a statin. These are very wonderful drugs indeed, unless you happen to get muscle pains with them, in which case you may be vitamin D deficient ( I can assert this untested hypothesis with confidence, knowing that most of you are vitamin D deficient). Anyway, why don't we put them in the water supply? They might be slightly bad for the liver, they seem to increase the risk of acute renal failure and people who take them get more cataracts. They seem to protect against oesophageal cancer. For some reason they don't show any effect on dementia, whereas alcohol does: but then alcohol gives you more vascular protection all round.
http://www.bmj.com/cgi/content/full/340/may19_4/c2197

1233 In 1999 I was seriously interested in heart failure and around that time I even went up to Dundee to meet one of my heroes, Allan Struthers, who had done much of the basic work on BNP and the renin-angiotensin pathway. The end product of this pathway is aldosterone, and the Dundee-led RALES trial published in 1999 showed that by blocking it with spironolactone in patients with chronic heart failure, you could improve outcomes even if they were on other RAS-inhibiting treatments. So off I went and gave some to a few of my HF patients, noting that the RALES trial encountered few problems with hyperkalaemia. I duly checked the electrolytes of one patient a couple of weeks later and sent him straight to hospital with a potassium of 6.8. This alarming event proved to be common enough in Canada, too, according to a paper which appeared in the New England Journal in 2004. But here Allan Struthers et al rebut their critics with data from Tayside, proving that your canny Scots GP can use sprironolactone with perfect safety, laddie, aye perfect safety. As the great poet of the Tay might have put it:
Physicians of England and Canada kill their patients with hyperkalaemia;
But by the banks of the silvery Tay our doctors behave much more seemlier.
W. McGonagall op posth.
http://www.bmj.com/cgi/content/full/340/may18_2/c1768

Plant of the Week: Decumaria sinensis

This is an evergreen, self-clinging climber with abundant scented flowers. How many of those can you think of? Moreover, it is hardy (to minus 12, to my certain knowledge) and grows to whatever height you like - there is one in Pembroke College, Oxford which must be 10m high.

The flowers on ours appear scentlessly in little tufts around mid-April, but only open fully and fill the air with honey and lemon around early June. Then they are gone and you are left with an interesting wall presence for the rest of the year - as good as most ivies and far less invasive. When it reaches your roof you will find it very reluctant to cross the gutter and start lifting off your tiles. Just hop up there every now and again and snip it back. Unlike ivy, it will not display contemptuous resistance.

As I've said before, I can't understand why this excellent plant isn't seen on every other house wall in England. Find one and start growing it now. It takes about five years to get into its stride.

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Page last edited: 05 July 2010