JAMA  4 July 2007  Vol 298

49     As a substance both pleasurable and mildly addictive, chocolate is a natural cause of anxiety to health puritans. The fault lies with the British chocolate manufacturers (themselves of Puritan, or at least Quaker, descent) who market their cocoa solids mixed with sugar and milk fat. Cocoa itself is full of polyphenols which lower blood pressure and increase endothelial nitric oxide, as this trial of German dark chocolate demonstrates. I would occasionally get a nibble of this “bitter chocolate” in my childhood, and even then I much preferred it to the produce of Messrs Cadbury and Rowntree. In this trial, the comparator was white chocolate, with the polyphenols removed. This had no benefit. Other studies have shown that elderly Dutchmen who drink cocoa live longer. The case for regular chocolate consumption is building up. But has anyone discovered why chocolate tends to be more addictive to women than men? Or, for that matter, to dogs but not cats? Is there a hormone-dependent chocolate receptor http://jama.ama-assn.org/cgi/content/abstract/298/1/49

NEJM  5 July 2007  Vol 357 

9     The success rate of in-vitro fertilisation in women over the age of 35 is about 35% in this Dutch series, provided there is no tinkering with the embryo to remove a cell for preimplantation genetic screening. If this is done, the live birth rate drops to 24%. So it is best not done without some compelling reason. http://content.nejm.org/cgi/content/abstract/357/1/9

18     Did you realise that when you fly in a pressurised aircraft, you experience a rarefaction of atmosphere equivalent to nearly twice the height of Ben Nevis? That’s because cabin pressures are kept lower than ground atmospheric pressure to save on energy and structural stresses. The stress may be transferred to the occupants instead, who can suffer mild discomfort proportionate to their time at reduced pressure, according to this simulation study. http://content.nejm.org/cgi/content/abstract/357/1/18

28    In both meta-analyses and large randomised trials, ripeness is all. If you pluck the raw fruit, you will get indigestion, as the New England Journal continues to demonstrate with rosiglitazone and cardiovascular outcomes. Three weeks ago, a meta-analysis of the published trial data showed that there might be cause for worry, but just failed to reach the one-in-twenty significance upon which the medical world places absolute reliance. Now the investigators of the RECORD study have rushed out an unplanned interim analysis which shows approximately the same, i.e. possible harm, but within over-wide confidence intervals. No fewer than three editorials follow, all of them counselling caution, asking for openness, more data etc. The one definite fact is that rosiglitazone can precipitate heart failure. And whatever it may do to reduce HbA1c, it is very unlikely to reduce any meaningful end-point. http://content.nejm.org/cgi/content/abstract/357/1/28

39     Cutting-edge cancer pharmacology is not something most of us get too involved with, unless perhaps when a patient asks our advice about going into a trial, or one of the drugs becomes a major political issue, like trastuzumab (Herceptin).  Trastuzumab targets the HER2 receptor which is over-expressed in 20-30% of invasive breast cancers. But hang on a minute: HER stands for human epidermal growth factor receptor and elsewhere in the cancer literature this is abbreviated to EGFR, as in this week’s JAMA p.70. In that paper, HER2 is referred to as ErbB-2. If the oncology anoraks really want us to understand their territory, we need some better signposting. Here Clifford A Hudis attempts to take us on a guided tour of the mechanisms by which trastuzumab inhibits a subset of breast cancer, and concludes that we still don’t know how best to use it. http://content.nejm.org/cgi/content/extract/357/1/39 

http://jama.ama-assn.org/cgi/content/abstract/298/1/70

BMJ  7 July 2007  Vol 335 

28    Cervical cytology is a topic I find almost unendurably boring, and how some people can spend their lives looking at cervical smears passes all understanding. There is now a machine for doing the initial scanning of the slides, called the ThinPrep Imager, which depends on liquid based cytology slides. This first trial from Italy compares the characteristics of liquid based versus conventional cytology. It produces far fewer unsatisfactory slides but is otherwise much the same. The second trial (p.31) puts the ThinPrep imager through its paces and finds a useful difference in the number of readable slides and a slightly better pick-up rate for significant lesions. http://www.bmj.com/cgi/content/abstract/335/7609/28

http://www.bmj.com/cgi/content/abstract/335/7609/31

37     One of the biggest favours we can do our patients is to help them stop smoking. Compared with a lifetime of antihypertensive treatment or statins, smoking cessation interventions are stupendously cost-effective, and if I discover that a patient is still smoking I can hardly wait to hand them out. This Clinical Review confirms that the most cost-effective is nortriptyline, with better results than bupropion at a fraction of the cost. But in terms of results, the winner is the newcomer varenicline. Most of the trials also involved behavioural support, but hey, this is the real world. Give it your best shot and see me in two weeks. http://www.bmj.com/cgi/content/full/335/7609/37

Lancet  7 July 2007  Vol 370 

This week’s Lancet is devoted to HIV-1 and in particular to the effect of new anti-retroviral drugs in treatment-experienced patients. If you have such a patient, you might want to dip into the original papers on pp. 29, 39 and 49. But  if you have resigned yourself to never being able to remember the difference between lopinavir, ritonavir, efavirenz, duranavir and etravirine, to name but a few, you might just want to skim-read the commentary piece on p.3 – especially for its cheeky criticism of The Lancet’s publication strategy. It ends with the welcome prediction that “The day will come when suppression of the viral load to undetectable levels can be attained by all. We look forward to reading about it in The Lancet – three times over if need be.” http://www.thelancet.com/journals/lancet/article/PIIS0140673607610472/abstract

http://www.thelancet.com/journals/lancet/article/PIIS0140673607610484/abstract

http://www.thelancet.com/journals/lancet/article/PIIS0140673607610496/abstract

http://www.thelancet.com/journals/lancet/article/PIIS0140673607610228/fulltext

59     Immunosuppression leads to an increased risk of cancer, and is a common factor in patients with HIV infection and transplant recipients. A team from Sydney looked at the similarities, and found them to be quite striking – both groups have a raised incidence of  20 out of 28 cancer types, including the three AIDS-related cancers, the HPV-related cancers, cancers of the stomach and liver, plus Hodgkin’s lymphoma. http://www.thelancet.com/journals/lancet/article/PIIS0140673607610502/abstract

89      HIV infection continues to be associated with behaviours condemned by religious traditionalists, both Christian and Muslim – sex between men, multiple sexual partners, and intravenous drug use. The idea of pre-exposure prophylaxis is regarded in such circles as the encouragement of sinful behaviour; and like the Spanish Inquisition, they would rather the body were condemned to death than the soul go to Hell – though in most cases, both will do fine. From a rational perspective, stopping the virus entering cells is the ideal way of tackling the HIV problem (see p.81 for a review of HIV entry-blocking drugs) and so people likely to be exposed might do well to have antiretrovirals circulating inside them. There remain, however, difficult issues of cost, potential resistance and so forth which are touched on in this discussion piece. http://www.thelancet.com/journals/lancet/article/PIIS0140673607610538/fulltext

Ann Intern Med  3 July 2007  Vol 147 

1     The current fashion in Britain is to put every patient who is thought to need a statin on 40mg of simvastatin. Atorvastatin is a more powerful drug, weight for weight, with a wide dose range. This study compared a dose of 10mg with a dose of 80mg in patients aged 65 or over with stable ischaemic heart disease. There was an absolute difference in cardiovascular events of 2.3% between the groups, which the authors purvey as a strong argument for the high dose. But there was little attempt to quantify adverse events (except biochemically) or cost. A Polypiller would argue that you can get nearly all the benefit for an eighth of the dose. http://www.annals.org/cgi/content/abstract/147/1/1

10     Whereas statins remain in high favour for protecting the heart, beta-blockers are often relegated to the status of yesterday’s drugs. Not so, according to this pooled analysis of 4 trials using intravascular ultrasonography of the coronary arteries, demonstrating that patients on β-blockers show no increase in atheroma, whereas the rest show progression. All fine, dandy and very hi-tech, but β-blockers are a very heterogeneous group of drugs, and have effects on much more that atheroma. Which one should I use to prevent real events, and at what dose? http://www.annals.org/cgi/content/abstract/147/1/10

19     The gold standard for measuring renal function is the real glomerular filtration rate, measured in this study by a radiolabelling method (iothalamate). But this study of people with chronic renal failure discovered that a better predictor for progression to end-stage failure or death was a simple serum marker – cystatin C. So in both renal failure and heart failure, we have the odd situation that a simple blood test predicts outcomes better than the supposed “gold standard” for direct  measurement of function (I am referring to BNP and echographic ejection fraction, in case you hadn’t guessed). http://www.annals.org/cgi/content/abstract/147/1/19

41      It might be possible to help some people lose weight by the right kind of counselling, but I don’t seem to manage it. More intensive regimes can bring modest improvements for a period of time, according to this meta-analysis of counselling interventions. http://www.annals.org/cgi/content/abstract/147/1/41

51     Advance directives are one means by which individuals can try to exert some control over the process of their own dying – but do they work? This discussion piece from the Ecumenical Center for Religion and Health at the University of Texas points out all the potential inadequacies of advance directives in the actual messy business of modern dying. The argument is ostensibly based on Camus’ “existentialism” as illustrated in his novel, The Plague. The author concludes that it is our duty to “bear witness to the patients’ suffering”. Oh no it isn’t. It is to relieve the patient’s suffering. That was what Dr. Rieu in the novel risks his life doing for weeks in the plague-ridden, stifling hospital. He couldn’t do much: but if we can help achieve a death in accordance with a dying patient’s stated wishes, shouldn’t we be allowed to do so? http://www.annals.org/cgi/content/abstract/147/1/51

Fungus of the Week: Agaricus augustus

July in England is not usually a good time for fungus-hunting, though the season gets under way around now in Poland, with special steam-hauled mushroom-picking trains taking the populace to the woods. What heaven.

After weeks of early summer rain I decided to try my luck in the grounds of a nearby stately home, and was duly rewarded with a sighting of The Prince. Now I don’t know of anybody who actually uses these silly “common names” of fungi, as given in all the books: The Prince (A augustus) can’t ever be a common name because the fungus is hardly ever seen. He is a handsome fellow, distinguished by a cap with concentric orange-brown scales and a distinct smell of bitter almonds. Oddly enough, the smell of cyanide usually marks an edible fungus, as with the fairy-ring mushroom, Marasmius oreades. Princelings appear as fat stubby mushrooms with a surrounding veil and white gills, normally features of the deadly poisonous Amanita spp.  But they will usually be accompanied by slightly older Princes with the scaly cap well characterised, pink gills, and the distinctive smell. Really old Princes have dark brown gills. If you are uncertain, you don’t have to eat them, of course. If you do, they go best with a scrap or two of garlic and bacon or pancetta, like most Agaricus species. Fried briskly for a few minutes, they have a more delicate flavour than their close relatives on the supermarket shelves - slightly fennelly, with no remaining hint of cyanide.   

JAMA  11 Jul 2007  Vol 298

179    Because it is often difficult to conduct randomised trials in children, paediatrics can sometimes remain a bastion of untested dogma, as with the vexed question of recurrent urinary tract infections in children. The logic used to run: recurrent UTIs in childhood can cause renal scarring and lead to renal failure in early adulthood; many recurrent UTIs are associated with vesico-ureteric reflux, so all children with them should have micturating cysto-urethrography and if necessary reflux surgery; and those who are spared the knife need prophylactic antibiotics. Almost all of this is wrong, and thousands of children have been put through intense misery through misapplied clinical logic. Even the prophylactic antibiotics are useless: this study shows that they merely encourage microbial resistance. http://jama.ama-assn.org/cgi/content/abstract/298/2/179

187    Very occasionally, people taking chloroquine as an antimalarial experience hypoglycaemia, and pharmacological clues of this sort led a group of rheumatologists to analyse their clinic records for the past twenty or more years to find out if patients taking hydroxochloroquine for rheumatoid arthritis showed any difference in their incidence of diabetes. The difference is quite convincing: a drop of over 70% for those on HCQ for more than four years, and an overall 40% reduction among ever-takers. http://jama.ama-assn.org/cgi/content/abstract/298/2/187

194     Given that we’re not likely to be putting half the population on hydroxychloroquine in the near future, we badly need more and better drugs for type 2 diabetes. As we’ve seen with rosiglitazone, the problem is that HbA1c levels tell us little about vascular risk, so each new agent is on probation while we await the results of long-term studies with hard end-points. The latest drugs are those which either mimic incretin or slow down its breakdown by inhibiting dipeptidyl peptidase 4. The latter are oral drugs, but they have already shown a worrying trend towards increasing the rate of significant infection; the former (incretin analogues) need to be given by injection. At least they don’t cause weight gain, but I can’t see them becoming popular, as most diabetics of my acquaintance dread the day when they will have to inject themselves. Instinctively I’d infer that an inexorable impulse towards increasing initiation of incremental incretin-imitator injections is intrinsically improbable. http://jama.ama-assn.org/cgi/content/abstract/298/2/194

NEJM  12 Jul 2007  Vol 357 

115     Carriers of BRCA1 and BRCA2 mutations are of course much more likely to get breast cancer, but is it also true, as sometimes stated, that their cancers are more aggressive? There’s a crumb of comfort for such women in this Israeli study: this is not the case, and their survival rates do not differ from other women with breast cancer. For a guide to the management of inherited breast cancer risk, see p.154. http://content.nejm.org/cgi/content/abstract/357/2/115

135     The only argument I can think of against fortifying flour with folic acid is the theoretical risk that it may encourage some colonic polyps to become cancerous; we already know that it prevents neural tube defects and reduces the risk of stroke. Canada introduced folic acid fortification of cereal products in 1998, and this study observes a 46% reduction in neural tube defects, the greatest drop being in areas of previous high incidence. Figures for stroke and bowel cancer would be interesting. http://content.nejm.org/cgi/content/abstract/357/2/135

181    The introduction of pay for performance in UK general practice was regarded around the world as an exciting experiment – hence the appearance of this paper about our humble discipline in the New England Journal. To me, New Labour seems largely a continuation of Thatcherism by other means, but until Tony Blair went mad about two years ago, he was doing some good to the NHS. To suppress health spending, Thatcher introduced disincentives to diagnosing and treating chronic illness (called fundholding): Blair introduced positive incentives in 2004 (called the Quality and Outcomes Framework) and the money to pay for them. When this succeeded beyond expectation, his ministers ran a press campaign against greedy bastard GPs. Make the targets tougher! Make the bastards sweat! We wait to see if Gordon Brown will take a more rational approach. In the meantime, this paper shows that for coronary heart disease, diabetes and asthma, GPs were already improving their care of patients steadily before the introduction of QOF, and that since 2004 there has been little evidence of acceleration. It’s almost as if we had professional standards before the government started bribing us. http://content.nejm.org/cgi/content/extract/357/2/181

BMJ  14 Jul 2007  Vol  335 

Reading research papers is for most doctors an effort of duty rather than love, and although I have tried for nearly ten years to make it sound like fun, even for me the same usually applies. Since its remake, the BMJ has had so little worthwhile research material in some issues that I have been hard put to write about anything. On the other hand, every issue has been fun to read for the rest of its content. In her editorial Fiona Godlee tells us that this is part of a process of changing the focus to papers which will change practice. I hope so. We need much more research from working doctors who are grounded in daily clinical practice and have no desire to build academic careers, but do it purely from the urge to solve real life problems and improve patient care. http://www.bmj.com/cgi/content/full/335/7610/53

53      A sensible if rather generalised editorial on “The future of the medical profession” (no less) by Roger Jones ends with an awful clanger. “… there are signs that the new political administration may consider better ways of working with medical leaders and the NHS. The importance of doing so cannot be underestimated.” The importance of careful editing, on the other hand, cannot be overestimated. (Note for would-be professors wishing to write orotund editorials: the correct clichés are either “should not be underestimated” or “cannot be overstated”)http://www.bmj.com/cgi/content/full/335/7610/53

80     Antibiotic-related diarrhoea is certainly an important practical problem in British hospitals, especially when it is caused by Clostridium difficile. There is a plentiful literature about probiotic Lactobacillus preparations but much of it is difficult to apply to real life. Here the researchers gave a commonly available yoghourt drink, Actimel, or a sterile milkshake placebo to 135 elderly patients taking antibiotics in three London hospitals. This reduced the risk of all diarrhoea by two-thirds and none of the treated group got C difficile. Take along a tray of Actimel the next time you go into hospital. http://www.bmj.com/cgi/content/full/335/7610/53

83     Here is another nice example of well-focussed research: the topic is chronic venous ulceration. No opportunity here for fancy genomics, molecular pathways, and ingeniously crafted monoclonal antibodies. Human beings stand upright and subject the valves of their leg veins to a metre and more of fluid pressure. Blood products leak out through the effect of stasis and the skin breaks down and won’t heal. You can either squeeze the veins or strip them away, or both. This study shows that compression alone heals ulcers as well as compression plus surgery; but surgery helps to prevent further ulceration and so results in more ulcer-free time for patients. http://www.bmj.com/cgi/content/abstract/335/7610/83

87     A generally useful systematic review of treatments for painful diabetic neuropathy is marred by a subdivision of anticonvulsants into “traditional” and “newer generation” which is hard to decipher in the main text and in any case has no pharmacological meaning. It would have been better to tabulate the drugs individually. Anyway, it seems that the drugs I use most, like amitriptyline and gabapentin, are good safe bets for starters. http://www.bmj.com/cgi/content/abstract/335/7610/87

91    A nice clear guide to that baffling disease we call schizophrenia, which is associated with structural as well as chemical brain abnormalities. We are still left with many more questions than answers, but at least the authors feel justified in ending on an upbeat, pointing out that though most patients do get recurring episodes, most are able to lead nearly normal lives. http://www.bmj.com/cgi/content/extract/335/7610/91 

Lancet  14 Jul 2007  Vol 370 

135    The purpose of palliative chemotherapy is to provide the longest period of good quality life to a patient who is likely to die from the disease – in this case colorectal cancer.  Is this best done by hammering the cancer as hard as possible with combination chemotherapy from the start, or by using the chemo sequentially? Two trials – CAIRO here and MRC-FOCUS on p.143 – come out in favour of the sequential approach, but this is contested at some length in a commentary on p. 105.

http://www.thelancet.com/journals/lancet/article/PIIS0140673607610861/abstract

http://www.thelancet.com/journals/lancet/article/PIIS0140673607610873/abstract

http://www.thelancet.com/journals/lancet/article/PIIS0140673607610629/fulltext

153    In all age groups, but particularly in elderly men (see the Oxford study in this week’s Arch Intern Med p.1373), high levels of HDL-cholesterol are associated with lower rates of cardiovascular disease. But as I have pointed out before, all attempts to reduce cardiovascular disease with drugs which raise “good cholesterol” have failed. Here once again it’s torcetrapib, showing no more benefit in clearing carotid atheroma here than it did in clearing coronary atheroma in the recent study which appeared in the NEJM. http://www.thelancet.com/journals/lancet/article/PIIS0140673607610885/abstract

173    Prescribing for the elderly is the subject of an experiment in the UK at present, since the government decided to encourage community pharmacists to offer medication reviews to those on multiple drugs. According to this review of various interventions designed to improve prescribing, this is unlikely to help unless the pharmacists have access to the patient’s medical record. But as so often when The Lancet commissions a review of an important common but ill-defined clinical problem, the result is diffuse and inconclusive. http://www.thelancet.com/journals/lancet/article/PIIS0140673607610915/abstract 

Arch Intern Med  9 Jul 2007   

1345     The richest woman in Elizabethan England, Bess of Hardwick, conceived the idea that unless she kept building houses, she would die. Hence the two Hardwick Halls on a hilltop in Derbyshire, one left uncompleted while she ordered work to begin on the other. When freezing weather threatened a stoppage, she had hot beer poured down the walls, pour encourager les artisans. I sometimes wonder if Harlan Krumholz, a professor of medicine at Yale, harbours similar fears about what would happen if a paper of his did not appear in a leading journal every week. He and his team do fantastic work on the unglamorous aspects of US medicine, especially the care of cardiovascular disease in the elderly and in ethnic minorities. Here, typically, he looks at the treatment of myocardial infarction in “America’s Best Hospitals”. Most of it is good enough, but the majority of the best care goes on elsewhere. Now on to the next paper, team! The beer’s on Harlan. http://archinte.ama-assn.org/cgi/content/abstract/167/13/1345

1353    People with diabetes are at fivefold risk of myocardial infarction and at further risk of doing badly afterwards. What they need is primary percutaneous coronary intervention; compared with fibrinolysis, this reduces mortality by at least 30%, according to this pooled analysis of individual patient data from 19 randomised trials. http://archinte.ama-assn.org/cgi/content/abstract/167/13/1353

1373    A fascinating study of lipid profiles in older men shows that total cholesterol is not predictive of ischaemic heart disease in this group (mean age 77).  The main finding is that high HDL-cholesterol levels and apolipoprotein A1 levels are inversely related to ischaemic heart disease in these men, who were followed up by the Oxford Clinical Trials Support Unit. http://archinte.ama-assn.org/cgi/content/abstract/167/13/1373

1420    By and large (large especially) we know that waist circumference is a better predictor of outcomes than body mass index, but this study from Finland shows that this does not apply to stroke in women. http://archinte.ama-assn.org/cgi/content/abstract/167/13/1420

1428    Another not very important fact comes from the other side of the Baltic in Norway, where smoking is found to protect against hypothyroidism. On the other hand, smoking is associated with a higher incidence of hyperthyroidism. Just let’s bin the fags and forget about it. http://archinte.ama-assn.org/cgi/content/abstract/167/13/1428

Plant of the Week: Alcea rosea

As we English GPs drive down dreary town streets on warm afternoons, our hearts are suddenly lifted by the sight of tall waving mallow flowers in a wonderful variety of soft and dark colours: hollyhocks. The very best are often weeds, sprouting happily between paving stones or at the foot of some neglected wall.

They come from the drier parts of Asia, but despite the British climate they have become established as common cottage garden plants since the sixteenth century and have naturalised themselves all over the world. They do hate damp, however, and become covered in rust at the least provocation. This summer the provocation has been extreme, as so as a consequence is the rust on our own few struggling examples. In ideal conditions of extreme neglect, however, they are marvellously tough and virtually perennial. Thanks to clay soil, slugs and weather, ours are mostly annual.

JAMA  18 Jul 2007  Vol 298

289     This trial prejudged its outcome by calling itself the Women’s Healthy Eating and Living (WHEL) study; it was based on the supposition that a diet very high in vegetables, fruit, and fibre and low in fat might reduce cancer-related events and mortality in women with breast cancer. It did no such thing. History should teach us to be very wary of any fad diet for the treatment of cancer, even one we consider to be “healthy”. http://jama.ama-assn.org/cgi/content/abstract/298/3/289

299    We’re sending off more blood for fasting lipid profiles than ever before, but what are we supposed to do if they come back showing raised triglycerides? I tend to ignore them except as a warning of possible insulin resistance. And that’s probably correct, because fasting TG levels predict little, whereas nonfasting triglycerides are independently predictive of myocardial infarction, ischaemic heart disease and death in both men and women. This observation comes from a  Danish cohort study which ran from 1976/8 up to 2004; confirmatory data for women are available from the larger but shorter Women’s Health Study in the USA (median follow-up 11.4 years – p.309). So we really need to measure the fasting sugar and cholesterol and the non-fasting triglycerides in all our at-risk middle-aged patients.

http://jama.ama-assn.org/cgi/content/abstract/298/3/299 

http://jama.ama-assn.org/cgi/content/abstract/298/3/309

330     Electroconvulsive therapy is a crude treatment which has had a bad press, despite the efforts of The Journal of ECT (formerly Convulsive Therapy) to galvanise us in its favour. Images from One Flew Over the Cuckoo’s Nest and Janet Frame’s autobiography Angel at my Table haunt the imagination. Here’s a little article which tries to redress the balance by reporting on two recent trials, one in severe depression and the other in psychotic depression. The main thing is that it works – often very well – when all else has failed, and that we now know exactly how much to give and where to put the electrodes so as to balance the best response with the least memory impairment. http://jama.ama-assn.org/cgi/content/extract/298/3/330 

NEJM  19 Jul 2007  Vol 357

217    A big international trial gives a nice clear answer to an important clinical question: might patients with peripheral vascular disease do better taking warfarin as well as an antiplatelet agent? The answer, to the relief of all phlebotomists, is no. The patients on combined treatment had more bleeds for no extra benefit. The methodology of the study fell short of ideal – open label, and allowing a number of different drugs according to local preference, but I think we can accept its conclusion. http://content.nejm.org/cgi/content/abstract/357/3/217

228    “Certolizumab pegol is a pegylated humanized Fab’ fragment with a high binding affinity for tumour necrosis factor α that does not induce apoptosis of T cells or monocytes.” the NEJM informs its readers. Let me explain as best I can. Mab is a monoclonal antibody and pegol is polyethylene glycol, a neutral chemical which renders complex molecules soluble in various liquids including water. Fab’ is the fragment of an antibody which doesn’t kill T cells and monocytes (which is done by the Fc fragment). What we are looking at then is an agent which might induce remission in Crohn’s disease (and other inflammatory diseases in which TNF-α plays a harmful role) without causing some of the problems associated with a non-specific anti-TNF antibody like infliximab. Thank you for your attention. But I’m afraid that I’m leading up to telling you that the stuff is no miracle cure: it produces a modest improvement in remission and the treated group had more infections than the placebo group. Those who respond need to keep up the treatment to remain in remission (see p.239). http://content.nejm.org/cgi/content/abstract/357/3/228

http://content.nejm.org/cgi/content/abstract/357/3/239

266    You are vitamin D deficient, very probably, and this is making your muscles ache, slowing you brain, thinning your bones and making you more likely to get cancer and heart disease. The secret of the Mediterranean is not its food but its sunshine. Or both. Go on, take your clothes off, get outside, and eat lots of oily fish, cheese, wild fungi and eggs. Abandon your miserable existence in the dark North and start living before it is too late. Alternatively, get a sunbed and take large daily supplements of vitamin D. It’s the elixir of life, according to this very thorough and plausible review. http://content.nejm.org/cgi/content/extract/357/3/266

BMJ  21 Jul 2007 Vol 335 

132    This study of self-monitoring in type 2 diabetes calls into question a widely-used and expensive intervention and has drawn a stream of responses ever since it was first posted on the BMJ website some weeks ago. I must declare two kinds of bias: firstly in favour of the researchers, some of whom I know personally, and secondly against books of daily test results brought to me by patients who are not on insulin. About these I have never found anything intelligent to say, except to suggest they do fewer. Perhaps there is a small subset of badly controlled patients (who would have failed the entry criteria for this trial) for whom such exercises are motivational: but for most, it is just a waste of NHS money and digital pain. http://www.bmj.com/cgi/content/abstract/335/7611/132

136    A confession: I have never really used risk scores much. Does anybody? I used to try in the days of the Sheffield tables, whose greens and reds adorned my wall until quite recently, but damn it, if you smoke you need to stop, if you don’t drink wine you need to start, if your systolic BP is above 150 it needs to be lower and if your cholesterol is over 6 and you’re male, you need a statin. If you’re diabetic or you’ve got bad coronaries you need the whole works. But if you need some kind of quantification for an untreated patient, then QRISK probably beats the old Framingham score. http://www.bmj.com/cgi/content/abstract/335/7611/136

142     Many people seem to regard talking treatments as intrinsically (and indeed morally) superior to drug treatments for depression. It does seem true that cognitive behavioural therapy can produce lasting benefit for some aspects of depression, such as insomnia and agoraphobia; but this study of major depression in adolescents showed no advantage in combining a serotonin reuptake inhibitor with CBT over giving the drug alone. http://www.bmj.com/cgi/content/abstract/335/7611/142

155     Here’s a short article which you need to keep in a safe place: how to assess capacity to make a will. Every now and again you will be asked to decide this, and this piece tries tells you how, though half of it is taken up by legal waffle. Be sure to recover it before calling the patient in, because they may not be impressed to find you rummaging about and appearing more forgetful than they are. Do not compound your error by quoting awfully funny lawyerly jokes from the paper about leaving your money to President Putin. http://www.bmj.com/cgi/content/extract/335/7611/155

Lancet  21 Jul 2007  Vol 370 

204     A useful short reminder piece about new treatments for age-related macular degeneration. The story is much as was told in the New England Journal last October, under the apt heading “The Price of Sight”:  A drug developed for use in bowel cancer – bevacizumab – had already earned its manufacturer Genetech billions of dollars, but they wanted more billions from a drug for macular degeneration costing $1950 monthly, called ranibizumab. Fortunately, a retinal specialist in the USA realised that the two drugs are very similar, and started using an appropriate molar dilution of bevacizumab, costing one hundred times less. Thousands of ophthalmologists have followed. Naturally enough, Genetech are sulking, and won’t fund a comparative trial that might stop them getting rich at the expense of elderly people who are going blind. http://www.thelancet.com/journals/lancet/article/PIIS0140673607611040/fulltext

221     If you ever give a lecture involving the renin-angiotensin-aldosterone system, you can easily dumbfound your audience by asking them what the initial substrate is called. It is angiotensinogen, converted to angiotensin 1 by the action of renin. Until recently, we could block every stage of the RAAS except this first one, but now we have direct renin inhibitors like aliskiren. They have no effect on blood pressure in normotensive subjects but reduce it if inappropriately elevated. This study shows that aliskiren combines very well with a drug which works at the other end of the system, the angiotensin receptor blocker valsartan. But quite how it will fit in to the overall range of blood pressure lowering drugs is something that only time and further studies will tell (see commentary on p.195). http://www.thelancet.com/journals/lancet/article/PIIS0140673607611246/abstract

230    Chronic lymphocytic leukaemia is a common malignancy with a range of familiar chemotherapies: this trial establishes which is the best. It is fludarabine plus cyclophosphamide. Even ordinary doctors may be able to remember that. http://www.thelancet.com/journals/lancet/article/PIIS0140673607611258/abstract

263    I badly needed to update my knowledge of psoriasis, so I read this and the following paper from beginning to end. I think I now know a little more about the clinical features, but as for the pathogenesis, I’m not so sure. I like things to have a cause, not lots of genetic predispositions and pathways. http://www.thelancet.com/journals/lancet/article/PIIS0140673607611283/abstract

272    And then there are the current and future treatments of psoriasis. The current ones are comprehensively explained, with narrow-band ultraviolet light taking a star role; the emerging ones are mostly anti-TNFα drugs with unknown long-term effects. http://www.thelancet.com/journals/lancet/article/PIIS0140673607611295/abstract

Ann Intern Med  17 Jul 2007  Vol 147 

81     When penicillin was a new drug in short supply, its use in gonorrhea became the subject of heated debate; after that, decades passed before the first penicillin-resistant gonococci emerged and led to the abandonment of penicillin in favour of fluoroquinolone antibiotics. Now these in turn are losing their effectiveness, according to a survey of gonococcal resistance in the USA between 1988 and 2003. But penicillin sensitivity has returned widely to prevalent gonococci and there are many other antibiotics to which they remain susceptible. http://www.annals.org/cgi/content/abstract/147/2/81

89    One person in 400 between the ages of 14 and 39 in the USA has gonorrhea, but ten times that number have chlamydia. This is a major cause of female infertility and pelvic pain, and they like us, fret about the best screening strategy. The US Preventive Services Task Force takes its evidence-gathering seriously and there are two methodology papers here (pp.117,123) plus a summary of their systematic review (p.135) and the recommendations themselves (p.128), which are:

• Screen all sexually active women age 24 or younger
• Screen older pregnant women at increased risk
• Do not screen age 25 or older unless at increased risk
• Not enough evidence to screen men.

But follow different guidelines in the UK.

http://www.annals.org/cgi/content/abstract/147/2/117

http://www.annals.org/cgi/content/abstract/147/2/123

http://www.annals.org/cgi/content/abstract/147/2/135

http://www.annals.org/cgi/content/abstract/147/2/128

Saying of the Week:

Man’s one method, whether he reasons or creates, is to half-shut his eyes against the dazzle and confusion of reality.

R Louis Stevenson

JAMA  25 Jul 2007  Vol 298

405     Hypertrophic cardiomyopathy sometimes first presents as sudden death in apparently healthy young people, especially during sport. Over recent years, people (mean age 42) with an antemortem diagnosis of HCM have increasingly been fitted with implantable cardioverter-defibrillators, especially if they are considered at high risk because of a family history of sudden death, massive LV hypertrophy, ventricular tachycardia on monitoring, or unexplained syncope. But do these ICDs save lives, or are they just a shocking waste of money? This big registry study looks at outcomes in 506 patients with HCM and ICDs throughout the developed world. Within 4 years, 20% of patients had an appropriate ICD activation which may have saved their lives – more so in younger people. On the other hand, 27% of patients experienced an inappropriate activation and one died because the device failed to activate. So this technology is useful but far from perfect, as previous reports in older patients have shown. http://jama.ama-assn.org/cgi/content/abstract/298/4/405

413     Speaking of previous reports in older patients, we have read quite a lot about hip protectors over the years, but I hope we will hear less now that it is clear how useless they are. The study involved over a thousand nursing home residents who were supplied with underclothes containing a hip protector sewn into one side. In this way the other hip acted as the control, but the study was terminated at 20 months because there were more fractures on the “protected” side. Oops.http://jama.ama-assn.org/cgi/content/abstract/298/4/413

430    Now and again I take time out and actually read a paper properly, analysing the text and the figures with the help of such primitive statistical knowledge as may from time to time have accidentally lodged in my brain.  But there are whole classes of paper which all but a tiny handful of doctors have to take on trust – those involving multiple logistic regression, genetic analysis using complex arrays, and most meta-analyses. Peter Gøtzsche (director of the Nordic Cochrane Centre) is not the kind of chap who takes anything on trust, and for his zeal in spotting inappropriate methodology he deserves the title of Peter Gotcha. Here he gets those who use standardized mean differences wrongly when reporting continuous variable data. OK, Peter, it’s a fair cop. I shall know better in the future. http://jama.ama-assn.org/cgi/content/abstract/298/4/430

438    After getting a bit off track with erythema migrans and cardiac tamponade, the Rational Clinical Examination returns to the high road of primary care with “Does This Child Have Appendicitis?”. This is an example of a red flag or “limited rule-out” diagnostic category – one you must try never to miss. Now we don’t understand the natural history of appendicitis all that well, and it is typical of childhood infective illness in that the clinical features may only become apparent over time; so that if you even think of the possibility you must be sure to see the child a second time, or let the surgeons do the worrying. This is a fairly useful trawl through the studies, though only one out of 42 was from a context that resembled primary care (an A&E department), and it is plagued with vague terms like “clinical gestalt” (why not just say “suspicion”). I will continue to rely on the history, examination and the Mars Bar test: plus, if in doubt, seeing the kid a few hours later. http://jama.ama-assn.org/cgi/content/abstract/298/4/438

NEJM  26 Jul 2007  Vol 357

328    Thanks to this little piece in th

is week’s New England Journal, Oscar is currently the world’s most famous cat, for his unerring ability to sense the impending death of residents in the nursing home where he was reared as a stray kitten. His purrings and snugglings accompany them to the next world: in a medieval painting, Oscar would be seen slinking out of the death chamber, while the little soul is embraced in mid-air by an angel, and bunch of frustrated demons rages in the bottom left corner. Nor is he alone in his mystical abilities. Our late Burmese cat Wylie (1984-2005), who normally regarded us his servants with complete disdain, would infallibly diagnose illness and lie weightlessly with a soft rumbling noise on the sufferer’s chest until she or he recovered. http://content.nejm.org/cgi/content/full/357/4/328

331    Bronchiolitis will be back in a few months’ time, worrying GPs in and out of hours, filling the paediatric wards and causing recurring crackly coughs in infants for the next year or two. And we still don’t have any effective treatment for it – see the editorial on p.402. This big well-conducted study knocks out a leading contender: oral dexamethasone. In 20 US emergency departments and 600 children, it made no difference to the course of the acute illness.http://content.nejm.org/cgi/content/abstract/357/4/331

http://content.nejm.org/cgi/content/extract/357/4/402

340    If only all cancers were as responsive to treatment as testicular cancer. The great majority are cured at first attempt: most of the rest are mopped up by further chemotherapy, usually with platinum-based drugs: and for the remainder, this study shows that high-dose chemotherapy with stem-cell rescue is usually successful. But nasty: it killed 3 out of 184 patients, while another 3 developed acute leukaemia. http://content.nejm.org/cgi/content/abstract/357/4/340

360    A final little tack in the coffin of rofecoxib, once our most popular COX-2 inhibitor and a potential preventer of bowel cancer. The abandoned Oxford-based VICTOR trial in patients with colorectal cancer showed that even in the first 7.4 months, there was an excess of cardiovascular events, of a magnitude similar to other studies (RR2.7, compared with approx 3.5 in others). http://content.nejm.org/cgi/content/abstract/357/4/360

370   Richard Dawkins has popularised the idea of “memes”, units of cultural behaviour which follow Darwinian rules of natural selection, and this paper extends the idea to the spread of obesity in a large social network over 32 years. Now where do you think this network might be? Yes, it’s Framingham, the supreme seat of all long-term epidemiology: here displayed in blobby diagrams of startling indecipherability. Some of this is due to genes – if you carry a single allele for the FTO gene, you are likely to get fat – and some of it is due to memes – people habituated to modern American eating. You could call this the diseasome, like the editorial on p.404: but please stifle the urge. http://content.nejm.org/cgi/content/abstract/357/4/370

http://content.nejm.org/cgi/content/full/357/4/404

BMJ  28 Jul 2007  Vol 335 

184    At home we’re watching old episodes of Cardiac Arrest, a series written 13 years ago by an ex-junior-doctor which depicts hospital medicine through a fog of anger and sleep deprivation. The only dignity seen in the series is in the behaviour of ethnic-minority relatives of patients killed by the system. A caricature? Yes, but an uncomfortably realistic one: we now teach medical students a lot about communication skills but we should also be teaching them the ABCD of dignity conserving care. Hang on, did I say medical students? Sorry, I meant to say – as a priority – hospital administrative staff, nurses, and bed managers. And why stop there: how about everyone in the Department of Health, including our elected Secretary of State?http://www.bmj.com/cgi/content/full/335/7612/184

198    The sorting out of children who wheeze has defied logic for almost the whole time I have been a GP: millions have been urged to keep puffing in steroids which do them no good, and may do harm, while every year a couple of dozen children die from acute asthma. GPs take their advice from “experts” who study studies and see a completely unrepresentative selection of wheezy children: their guidelines sometimes stand the evidence on its head, as with the British Thoracic Society and allergen avoidance. One thing we do know is that a lot of allergens in early life protect against atopy, the main cause of true chronic asthma, and that allergen avoidance later makes no difference. Most other kids suffer from episodic viral wheeze, and need only intermittent bronchodilators.  Although written by experts, this clinical review contains much sense.http://www.bmj.com/cgi/content/extract/335/7612/198

Lancet  28 Jul 2007  Vol 370 

319    Cannabis is very widely used, particularly by people who later show signs of psychosis; as to whether use of cannabis actually causes a 40% increase in the development of psychosis, I don’t suppose we shall ever be completely sure. This much-discussed systematic review is laudably cautious in its conclusions. Maybe on the whole cannabis is better avoided, and perhaps the best social policy would be regulated availability, so that people who wish can obtain the weaker varieties with due warning. http://www.thelancet.com/journals/lancet/article/PIIS0140673607611623/abstract

336   Some years ago, Alec Logan asked me to write a column for the back pages of the BJGP, which I called Flora Medica, ending with something arcane and amusing from the lesser medical literature. I soon realised that if all else failed I could always turn to journals of occupational allergy, since anything can trigger asthma in the workplace, including boiling broccoli, as I found in one paper. Here a rigorous prospective cohort study (the European Community Respiratory Health Survey, ECRHS-II) finds that after jobs that involve exposure to smoke and chemical spills, nursing carries the highest risk for the development of asthma. But why? Do nurses boil a lot of broccoli? http://www.thelancet.com/journals/lancet/article/PIIS0140673607611647/abstract

342    This seminar points out that chronic myeloid leukaemia was the first cancer to yield to genetically tailored therapy – imatinib. It is a rare disease, occurring in a scattering of mostly elderly people, the great majority of whom can be cured using this drug. If one of them happens to be a patient of yours, this is the place to read about it. http://www.thelancet.com/journals/lancet/article/PIIS0140673607611659/abstract

351    Although in-vitro fertilisation has now been carried out for 30 years, we are still learning about its long-term outcomes, especially as the largest cohort has yet to reach adulthood. In the short term, multiple birth provides the biggest range of hazards. The leading congenital abnormality associated with assisted reproduction is urogenital malformation in boys, but there are wide confidence intervals for the overall risk of malformation, and the risk is unlikely to be more than 30% above unassisted gestation. As far as social discord within families goes, there is no increase at all, despite the emotional strain and financial cost which IVF commonly brings. http://www.thelancet.com/journals/lancet/article/PIIS0140673607604565/abstract

Arch Intern Med  23 Jul 2007  Vol 167 

1460    Various groups of higher beings keep watch over the lives of us humble mortals, including the American Council on Science and Public Health, which here pronounces on reducing sodium intake to prevent cardiovascular disease. “A 1.3g/day lower lifetime sodium intake translates into an approximately 5mm Hg smaller rise in blood pressure as individuals advance from 25 to 55 years of age, a reduction estimated to save 150 000 lives annually.” Whether or not you question the extrapolations behind this statement, there is no doubt that this reduction could be achieved easily by lowering the salt content of processed food. http://archinte.ama-assn.org/cgi/content/abstract/167/14/1460

1471    Which patients are most likely to get a deep vein thrombosis? Those in hospital, of course. And which patients outside hospital are most likely to get a DVT? Those who have just left hospital, according to this study conducted in Worcester, Mass. In fact more VTEs were diagnosed after the patients had left hospital than those diagnosed while they were still there. The other big risk factors in the community are cancer and previous DVT; oestrogen-taking is a very minor risk by comparison. http://archinte.ama-assn.org/cgi/content/abstract/167/14/1471

1503   Poor reading fluency independently predicts all-cause mortality and cardiovascular death among elderly people in American cities, after adjusting for baseline health and socioeconomic status. For some reason, the authors equate reading fluency with “health literacy”, whatever that may be. http://archinte.ama-assn.org/cgi/content/abstract/167/14/1503

1533    How often do you check the serum thyrotropin (TSH) levels of your patients when they come back year after year feeling tired all the time, and putting on weight though they “hardly eat anything”? In extreme desperation, I’ve been known to do it more than once in the same year. But this important study of TSH levels measured in a large network of US primary care physicians shows that they vary very little over 5 years. More than a half of patients with an isolated abnormal result are normal on repeat testing, and only 2% became abnormal within 5 years of a normal test. Do fewer. http://archinte.ama-assn.org/cgi/content/abstract/167/14/1503

1545    Some guidelines on the diagnosis of diabetes still recommend a glucose tolerance test, or at least the measurement of glucose two hours after a 75g load. In fact this is liable to much more random variation when measured twice than the fasting level or the HbA1c. Don’t bother. http://archinte.ama-assn.org/cgi/content/abstract/167/14/1545

Plant of the Week: Buddleia x “Lochinch”

All over England, buddleias have been in flower for weeks already, often sprawling over railway embankments and waste ground, or lodged in the mortar of high walls and chimneys to the greater peril of the populace. They are not distinguished plants, by and large: they sprawl thuggishly and their flower spikes go brown and refuse to fall off. But we think fondly of them for the sake of the butterflies they attract, for their scent of childhood holidays and for the colour they bring to the garden in the latter half of summer.

I think that Lochinch is the best of them, with its grey leaves and its straightforward mid purple flowers. It associates very happily with another generous plebeian shrub, Lavatera rosea “Barnsley”, and together they fill the garden with colour until October. Both can be propagated by sticking branches in the ground during winter, and there will be many such branches, since both plants need to be cut back hard in November. “Lochinch” will then begin to sprout new pale grey leaves before Christmas: a substantial addition to its garden worth, reminding you of Spring long before it is due.