JAMA  26 Aug 2009  Vol 302

849    What’s the connection between the pharmacogenomics of clopidogrel and religious dissent amongst devout Protestants in rural seventeenth century Switzerland? The answer is the Amish people of North America, a gift to genomics because they have only married amongst each other since they came to America around 1700 to pursue a godly life and produce 6.8 children per family. Although they shun the trappings of modern civilisation they do allow their blood to be taken in the interests of medical science, and this has allowed confirmation of the link between polymorphisms of the CYP2  gene and clopidogrel platelet activity. This was then confirmed as clinically important by a study of patients receiving percutaneous coronary intervention at Sinai Hospital in Baltimore, with a twofold event rate in patients who can’t metabolise the pro-drug clopidogrel into its active moiety. The investigators must have gnashed their teeth when the NEJM published a similar study earlier this year. We are supposed to interest ourselves in the question of whether genotyping should be done on patients receiving clopidogrel, but most of us would just like to know if prasugrel is going to replace it, and how soon.  http://jama.ama-assn.org/cgi/content/abstract/302/8/849

866   If I grab a can saying “Baked Beans” I expect some nice slimy tomato-covered things to pour on buttered toast or eat with sausages. Similarly, if I read a paper called “Hormonal therapy use for prostate cancer and mortality in men with coronary artery disease-induced congestive heart failure or myocardial infarction”, I expect to learn something about the risks of hormone treatments used mainly for advanced prostate cancer. I don’t expect to be told about a subset of patients who have received prophylactic neoadjuvant treatments following brachytherapy for localised prostate cancer and their survival stratified by coronary disease history. The study shows that these treatments, including goserilin and flutamide, provide no survival benefit generally to men receiving radioactive prostate implants (rare in the UK) and specifically kill off men according to their degree of coronary disease – which is interesting, but not what it says on the can. JAMA needs to get its labels sorted: Baked Beans, please, not lima beans in mushroom sauce.  http://jama.ama-assn.org/cgi/content/abstract/302/8/866

883    We are living longer, which may be a mixed blessing, but surprisingly the rate of hip fractures is falling in Canada, which is an unmixed blessing, especially for old Canadians. Men as well as women. There has been a steady decline from 1985 onwards, more rapid in recent years. The investigators don’t know why. Keep your BMI around 28, go for walks and take vitamin D, say I. http://jama.ama-assn.org/cgi/content/abstract/302/8/883

NEJM  27 Aug 2009  Vol 361

849   Last week I promised you another mega-study with Harlan Krumholz among the authors, and here it is: a survey of exposure to low-dose ionizing radiation from medical procedures in the Great American Public aged 64 or under. There is a lot of it about. The brilliant Perspective piece on p.841 shows how easily one investigation can follow another in a seemingly logical progression which adds nothing to clinical judgement but exposes the patient to a lot of radiation, especially from CT scanning and nuclear imaging. We base our assessment of the risk from this on an assumption of continuously distributed and cumulative effects, carefully examined by various scientific heroes of mine like Joseph Rotblat, Alice Stewart and Ernest Sternglass in the 1950s and 60s. But it is an inexact science, in part based on extrapolation from accidents and atrocities such as nuclear plant leakages, Hiroshima and Nagasaki. We don’t know how many people will get cancer from medical radiation but the numbers are bound to go up until we are more careful.
http://content.nejm.org/cgi/content/abstract/361/9/849
http://content.nejm.org/cgi/content/extract/361/9/841

859   I can remember being dazzled by the appearance of cardiac troponin assays about ten years ago: it was obvious from the start that they would transform the diagnosis and management of myocardial infarction, and it took very little time – about two years in the UK – for them to be universally adopted. But the problem from the start has been that they can only provide a diagnosis after the main opportunity for treatment. Current assays measure the main surge of troponin released by dead or damaged cardiac myocytes, 6-12 hours after the event: this study and the one after show that sensitive troponin 1 assays can measure troponin release as early as three hours after the event. Still a bit late for the ideal interventions, but bound to improve clinical management.

http://content.nejm.org/cgi/content/abstract/361/9/858
http://content.nejm.org/cgi/content/abstract/361/9/868

Lancet  29 Aug 2009  Vol 374

This issue of Britain’s senior medical journal is devoted to chronic obstructive pulmonary disease and showcases everything that is wrong with our understanding of COPD and everything that is wrong with The Lancet. For me the best sentence comes at the end of an editorial written by four New Zealanders: “We propose that, as with asthma, it is time to abandon COPD as a disease concept, and to define, identify, and treat the different disorders that make up this complex syndrome.”

685   But hang on, why redefine a syndrome complex when there is so much money to be made from selling new drugs for it? In real life, we know that COPD is largely irreversible lung damage caused by smoke inhalation, and we treat it by getting rid of the smoke and by various weakly active symptom-relieving drugs, with antibiotics for infective exacerbations. The pompous cover of the journal asks whether phosphodiesterase 4 inhibitors might be the Holy Grail for COPD treatment and actually reduce mortality. There is nothing whatever in the journal to suggest this is true, and the two studies of roflumilast published here (both paid for by its manufacturer, Nycomed) simply show that it might have some effect on the rate of exacerbations, depending on how you define them.  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)61255-1/abstract

695    The fact is that we are desperate to try anything that might help people with moderate-to-severe COPD, so any tin mug can pass for the Holy Grail. Roflumilast in combination with salmeterol or ipratropium can improve FEV₁ by all of 49ml and improve some patient-reported outcomes at the expense of diarrhoea, nausea and weight loss. A Holy Grail from Monty Python rather than Parsifal. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)61252-6/abstract

704   But what we label COPD is a life-shortening disease, and if we are to classify it more intelligently and treat it more effectively, we need better prognostic scoring systems. In themselves, these achieve nothing, but at least they can point the way to a better analysis of the disease process. But I don’t much like the ADO index which is promoted in this study from Spain and Switzerland. It performs better than the BODE index but that is because it incorporates data about drug treatment and hospital admissions. In other words, it depends on a mixture of objective characteristics such as BMI and airflow obstruction, and doctor behaviour in the shape of treatment decisions. This may predict prognosis but it doesn’t help us to understand the determinants of mortality. I fear it’s a case of much ADO about nothing. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)61301-5/abstract

712    At one time, our local chest physician (one of the best and kindest doctors I have ever met) advised us to try out a course of oral steroids on patients with bad COPD to see which ones responded, and then convert them to inhaled steroids at high dosage. Then things went quiet as studies seemed to show that this increased the rate of community-acquired pneumonia. Several meta-analyses of the randomised trials of inhaled steroids in COPD have confirmed this, but this meta-analysis of individual patient data in trials using budesonide finds no additional risk. In fact the data concerning mortality and inhaled steroids are reassuring and if your patient functions better when using them, I personally wouldn’t stop them. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)61250-2/abstract

721   Earlier in the year I had a go at the Quality and Outcomes Framework for diabetes, and one respondent who defended the QOF pointed out plaintively that there were many sillier targets in it than the HbA_1c of less than 7. Indeed there are, and some of them concern the detection and monitoring of COPD using spirometry. Because we get paid according to our prevalence figures, this amounts to an incentive to screening, though it doesn’t feature in the “British experience” section of this article about screening for COPD. The main argument in this rather diffuse paper is that objective proof of lung damage is an incentive to people to stop smoking. Fair enough: but beyond getting them to stop, we have no disease-altering interventions to offer them. Though we might have in the future, perhaps, according to a wide-ranging survey of new drugs for exacerbations on p.744. Arise, Sir Perceval, for yonder gleam may be the Holy Grail, I wot.

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)61290-3/abstract
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)61342-8/abstract

733   Then again, not all COPD is related to cigarette smoke: dung smoke will do nearly as well, if you live in a house full of it. This is politely referred to in this article as the burning of biomass fuel. There are other environmental associations with COPD in non-smokers too, and in many ways this review of COPD in non-smokers is the most interesting paper in this week’s Lancet. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)61303-9/abstract

BMJ  29 Aug 2009  Vol 339

488   If you’ve ever had a sleepless night with a raging sore throat, gagging on your own saliva, then next time you might do well to take a handful of corticosteroids. Although a specific dosage isn’t given in the printed text of this meta-analysis of the RCTs, the trials typically used generous amounts like 8mg of dexamethasone or 60mg of prednisolone. Nobody knows how safe this strategy is from a clutch of small studies, but I think I’ll do this for my next patients with really horrible, raging pharyngitis. Twenty-four hours of relief are worth a lot in this situation. http://www.bmj.com/cgi/content/full/339/aug06_2/b2976

491   As readers of Easily Missed will know, I’m keenly interested in timely diagnosis in general practice, as indeed every GP should be. But there is so little literature to guide us in a practical way. This interesting paper about alarm symptoms in general practice again needs to be read in the full text version rather than the printed one, which is hard to follow due to compression. Most patient s with haematuria, dysphagia, haemoptysis or rectal bleeding do not have a cancer diagnosis, but that should not lessen our alarm. Some of them do, and many others have diagnoses that need timely intervention. We need further, and more up-to-date, database studies of this kind. http://www.bmj.com/cgi/content/full/339/aug13_2/b3094

494    As an old lag GP living on the margins of academic life, I found this paper about novel methods to deal with publication biases inordinately difficult to follow. From reading the full text, I think I can divine what these new shaded funnel plots are meant to do. To me, though, it’s more interesting that the analysis of FDA data from RCTs of antidepressants confirms that these drugs are very effective indeed, more rather than less so once you have done the proper correction for publication bias. Or have I completely misunderstood? It’s always a lively possibility. http://www.bmj.com/cgi/content/full/339/aug07_1/b2981

498   It’s a truism of orthopaedics and general practice alike that radiographic features of osteoarthritis and patient symptoms often bear little relation to each other. That applies strongly to backs, less so to hips, and according this study, hardly at all to knees. In fact radiographic features of knee OA, especially loss of joint space, are highly associated with knee pain, according to this pair of cohort studies.

http://www.bmj.com/cgi/content/abstract/339/aug21_1/b2844

502   It’s the smoke that kills; the tobacco itself is harmless, is what we often think. Except for oropharyngeal cancer. But here’s a systematic review showing that smokeless tobacco increases the risk of stroke and myocardial infarction. There should be a worldwide ban on the planting of Nicotiana species except for their evening scent in private gardens. http://www.bmj.com/cgi/content/abstract/339/aug18_2/b3060

506    After tobacco smoke, the most dangerous twentieth-century threat to the lung was asbestos. On p.511, Kieran Sweeney, professor of General Practice at Exeter, gives a heart-rending account of what it is like to be dying of mesothelioma with a young family and full knowledge of the disease process. Asbestos, that magically heat-resistant mineral, can cause lung cancer as well as pleural cancer, and of course progressive interstitial lung disease too. Yet a lot of asbestos-related lung disease is benign. Here’s a nice clear guide to all of it. http://www.bmj.com/cgi/content/extract/339/aug24_1/b3209

Ann Intern Med  18 Aug 2009  Vol 151

229    I seem to remember that about 10 years ago, a team from Hong Kong looked through 10,000 papers about traditional Chinese remedies and found them all to be worthless. The papers, that is: and that probably applies to most of the remedies, though I think the study was prompted by the introduction at that time of phenomenally effective artemisinin-based treatment for malaria, based on Chinese folk practice. Will this now be followed by trypteriginin-based treatment for rheumatoid arthritis? Apparently the herb Tryperygium wilfordii Hook F has long been used by the Chinese for a variety of inflammatory conditions, and in this study it proved better than sulfasalazine in the treatment of RA. Interesting, but then a whole lot of drugs are better than sulfasalazine for rheumatoid. http://www.annals.org/cgi/content/abstract/151/4/229

264    Systematic reviewing is boring work, and hard work if you want to do it well. Bad systematic reviews appear by the score every week, often in the most prestigious journals, lumping or splitting in a random fashion to achieve their unconvincing conclusions. The Chief of Police in this field is Doug Altman who has helped to develop the PRISMA statement promulgated here in the Annals. Read, mark, learn and inwardly digest before starting your systematic review, or Doug will be on to you. http://www.annals.org/cgi/content/abstract/151/4/W-65

274   “But I have so much left to do!” was Mozart’s despairing cry as he realised he was dying at the age of 35 in 1791. Imagine what music we would have had Mozart lived another 40 years. And Weber, and Schubert, and Keats and Shelley. The world would be a different, kinder, infinitely more beautiful place. Ah me, I fondly dream. So, less fondly, do the many doctors who set about giving Mozart’s last illness a modern diagnosis. Here’s the latest attempt, based on an analysis of the official death register of Vienna between 1791 and 1793. Mozart died of “oedema” and so did an unusual number of young Viennese men that winter. Did they all have post-streptococcal nephritis? We will never know. Perhaps we will never care. Better to get out Bruno Walter’s pre-war performance of the Requiem and hear Anton Dermota cry “Recordare!” with the help of Elisabeth Schumann and Alexander Kipnis. I go faint even thinking about it.  http://www.annals.org/cgi/content/abstract/151/4/274