JAMA  21 July 2010  Vol 235

This issue of JAMA is devoted to human immunodeficiency virus infection  in resource-poor countries and as usual I won't attempt to comment on issues such as preventing mother-to-child transmission in Africa (p.293) and the benefits and limitations of using generic antiviral drugs in resource-poor settings (pp.303,313). We're talking here about individuals who are HIV positive of course: but when might it be a good thing to be HIV positive? Answer: when it is an indicator of successful vaccination against HIV. We don't yet have a vaccine of proven efficacy, but several large field trials are going on and inevitably they depend on inducing the very antibodies that we normally use to diagnose HIV infection. Fortunately there are ways around this: in the unlikely event of your being faced with the problem, see Figure 1on p.277.
http://jama.ama-assn.org/cgi/content/abstract/304/3/275

NEJM  22 July 2010  Vol 363

311    Insulin pumps have been around for a long time, and so has the idea that they could one day be linked with continuous sensor measurements of blood glucose, creating an automated feedback system for treating type 1 diabetes. This study doesn't go quite that far: although the implanted sensor measures blood sugar every five minutes, the patient has to adjust the insulin pump accordingly. The results are also beamed off to the patient's physician. The trial (STAR 3) was a modest success in that the children and adults randomised to the device achieved a reduction in glycated haemoglobin (7.5 v 8.3%) compared to those randomised to multiple daily insulin injections, without any increase in hypoglycaemia. However, we are still some way from a high-tech fix for type 1 diabetes using a closed feedback system, for reasons set out in the thoughtful editorial on p.383.
http://www.nejm.org/doi/full/10.1056/NEJMoa1002853

331    "The optimal management of a torn anterior cruciate ligament (ACL) of the knee is unknown", is the mince-no-words first sentence of this paper. You might have thought it was obvious that early ACL reconstruction was bound to prove superior to a policy of rehabilitation plus optional delayed reconstruction, but not so. This admirable Swedish study pushes the boundaries of evidence-based orthopaedics to prove that fit young adults do equally well with either approach. Operative treatment will only be needed in a third of patients if you first wait to see how much rehabilitation improves the situation.
http://www.nejm.org/doi/full/10.1056/NEJMoa0907797

365    Functional hypothalamic amenorrhea is the rather grand name given to stoppage of periods due to stress, weight loss, or exercise. Stress doesn't get much mention in this single-author review, which is also keen to avoid discussing anorexia nervosa. That mostly leaves girls who are keen athletes and/or excessive slimmers, and these will generally recover with less exercise and more food. Except that most of them would rather not go those routes, and so end up oestrogen deficient. We don't really know if bisphosphonates are safe in this age group. Most interventions are laughably under-researched (16 subjects in a CBT trial, 12 in a hypnotherapy study, 3 and 12 in two trials of naltrexone). For me this review was most useful just for its list of hormone tests to rule out other disorders.
http://www.nejm.org/doi/full/10.1056/NEJMcp0912024

Lancet  24 July 2010  Vol 376

235    Two studies seek to prove that a new drug called olaparib can have a targeted effect on cancers associated with BRCA1 and BRCA2 mutations. These mutations were amongst the first to cancer predisposition genes to be identified and they remain the most important, even though they only account for 5-10% per cent of breast and ovarian cancers. The thing about olaparib that excites investigators is that it specifically targets the repair mechanisms of BRCA mutated cancer cells by inhibiting poly(ADP)-ribose polymerase (PARP). The thing that will appeal to patients is that olaparib is orally available and has little severe toxicity. In these observational studies it was used as a last-ditch treatment for BRCA-related cancers that had recurred after several rounds of standard chemotherapy. The median progression-free survival for both breast and ovarian cancers was about 6 months. I think we shall hear more about this drug for earlier treatment in this subgroup of patients.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60892-6/abstract
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60893-8/abstract

BMJ  24 July 2010  Vol 341

185    I am too much of a coward to think of jumping off a viaduct, though perhaps under extreme circumstances I might jump off a river bridge: less of a splat factor for all concerned. I have little idea why the BMJ decided to publish this study of "jump rates" in Toronto following the erection of a protective barrier at Bloor Street Viaduct: I suppose it's the sort of thing that gets it cited in newspapers. The barrier prevented Bloor St splats but had no effect on the overall jump rate in Toronto.
http://www.bmj.com/cgi/content/full/341/jul06_1/c2884

186   The Swedish study which follows is a great deal more interesting, though the data are pretty ancient - people who attempted suicide between 1973-82 followed up to 2003. In the 70s Sweden was famous for sex and suicide; and it remains a very violent and fairly sexy place if Wallander is to be believed, quite the equal of St Mary Mead, the fabled county of Midsomer, or Morse's Oxford, and a great deal gloomier. The hazard ratios for a repeat suicide attempt range from 1 for self-poisoning or cutting to 6.5 for hanging or strangulation, with shooting, jumping and drowning half way between. Except that in Kurt Wallander's Ystad, such happenings are always the result of a drug gang or a religious cult. Watch it every Saturday and learn Swedish the easy way. Helvete!
http://www.bmj.com/cgi/content/full/341/jul13_1/c3222

188   I've spent a lot of years musing on the assessment of diagnostic tests, and have reached the conclusion that for all practical purposes the predictive value of a test depends on just two things - what it actually measures, and its prevalence in the population you are looking at. Faecal calprotectin is a good teaching example, or would be if we had enough studies in different presenting populations. Calprotectin is a complex of two proteins that is released from the inflamed bowel lining as part of the initial innate response, and it is distributed throughout the stool, or skit as it is known in Sweden. It can be detected by a standard enzyme linked immunoabsorbent assay (ELISA). So, readers, what does a faecal calprotectin ELISA measure? That's right, inflammation of the bowel. And what causes the bowel to become inflamed? Miscellaneous infections which usually resolve quickly, and inflammatory bowel disease, which does not. So which population would we use this test for? Yes, people with persistent bowel symptoms. In this study, it was used in people referred for such symptoms to secondary care in the Netherlands, and it had a sensitivity of 93% and a specificity of 96% for the diagnosis of IBD. So how should we use it in primary care? Answer: in a study setting which replicates as nearly as possible the way it would be used by GPs to sort out their patients, most of whom will not have IBD. That's the only way we will know how useful this test may be in the patients we actually deal with.
http://www.bmj.com/cgi/content/full/341/jul15_1/c3369

190    The area of diagnostic research I was particularly interested in 15 years ago was chronic heart failure, the subject here of a good review under the older adjective "congestive". I was the first to investigate the correlation between primary care diagnoses of "heart failure" and levels of BNP - and found that there wasn't much. Gradually it dawned on me that the certainties that were being proclaimed about the condition were all wrong - half of people with heart failure have a normal systolic ejection fraction, and even in those with a low EF, titrating up ACE inhibitors is of little benefit, as shown by three negative trials and two that produced a minimal reduction in hospital admission for an 8-fold increase in dose. BNP is great for proving there is something straining the heart, and if it's normal then the heart is not being strained. It's also great for estimating prognosis, whereas the EF is nearly useless. And so on. Some of this revisionism - but not all - is reflected in this review, which also scores marks for knowing the literature about end-of-life care for HF.
http://www.bmj.com/cgi/content/extract/341/jul14_2/c3657

Plant of the Week: Kniphofia "Timothy"

The issue of red-hot pokers in the garden once divided opinion in this household, but I am glad to say that over the years a solid appreciation of their merits has replaced the deprecation which was once sadly observable in certain quarters. Much of the credit for this belongs to Bob Brown - the flamboyant owner of the almost unfindable Cotswold Garden Flowers nursery in Badsey, near Evesham. He keeps an unrivalled stock which he claims can provide a poker for almost every month of the year, and while he hymns the beauties of many in his quirky catalogue ("Like a blue octopus after rigor mortis has set in" he quotes of one poker, approvingly), he is not afraid to fulminate against others , e.g. 'Kniphofia "Tuckii" : Coarse plant. (Destroyed - not good enough). Bobs Score=2.0.'
Of "Timothy" Bob writes, 'Soft salmon-peach flowers lined with deeper colour from dark buds, bronze stems Jul-Sep, 70cm. Easy and a most beautiful and unusual colour. Selected by Carlisles. (Plant thriving). Bobs Score=8.5.'
To get Timothy, you may only need to visit your local garden centre. However, to ensure a succession of good pokers, you need to make the pilgrimage to Badsey. I would suggest "Wol's Red Seedling" to precede Timothy (Bobs score 8.0) and "Bitter Chocolate" to succeed him (no Bobs score yet). There are scores of others, and some even have a maximum Bobs score of 10; but these are generally sold out. You can't beat a good poker.

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JAMA  14 July 2010  Vol 304

163    The classic hero of palliative care used to be the personal doctor who turned up in the middle of the night to administer symptom relief and consolation. Most doctors have done that from time to time, and found it immensely satisfying and immensely tiring. So what, by contrast, is the effect of centralised telephone-based care management coupled with automated symptom monitoring on pain and depression in patients with cancer? Also good, is the verdict of this randomised trial from Indiana, where there are lots of scattered rural communities, making heroism less practical. It resulted in better pain control and relief of depression than "usual care". Yet palliative care ideally comprises not only such routine systems for averting symptom crises, but also good systems of immediate care, and always the availability of human comfort.
http://jama.ama-assn.org/cgi/content/abstract/304/2/163

172    Most childhood cancers are now followed by long term survival, but at a high cost. Here is the latest report from the cohort of nearly 18,000 British children followed up after cancer treatment from 1940 onwards. Overall, there were 11 times the expected number of deaths in these survivors. Of these nearly two-thirds were due to recurrent or progressive initial malignancy, but that still leaves an awful excess of second cancers and cardiovascular disease. Even after thirty years, the death rate is tripled.
http://jama.ama-assn.org/cgi/content/abstract/304/2/172

194    It's often stated that before antiretroviral treatment, HIV infection was uniformly fatal, but that is not quite true. About one infected person in 200 failed to develop progressive disease while remaining untreated. These people (LTNPs - long-term non-progessors) are intensively studied, of course, for what they might be able to tell us about mechanisms to protect everybody from this virus. They fall into two broad categories according to their detectable viral load and CD-4 counts but most remain healthy without any treatment for 20 years. Read on.
http://jama.ama-assn.org/cgi/content/abstract/304/2/194

NEJM  15 July 2010  Vol 363

211    ANCA-associated vasculitis is nasty: in the days before it was called that, it killed most people who had it, by causing renal failure and respiratory tract inflammation and necrosis complicated by infection. Cyclophosphamide and high-dose corticosteroids are effective treatments, but mortality in the first year still exceeds 15%. Then along came rituximab, a monoclonal antibody aimed at knocking out B-cells expressing CD20. It was hoped that this would be a magic bullet treatment that would avoid all the dangerous effects of cytotoxic drugs and steroids. Here are two trials in patients with newly presenting Wegener's granulomatosis, Churg-Strauss syndrome and other ANCA-associated diseases. The first demonstrates non-superiority; the second (p.221) demonstrates non-inferiority. In other words, rituximab treatment is still associated with a 15%+ first year mortality and similar adverse effects to existing standard regimens using cyclophosphamide and prednisolone. The niche use of rituximab will be for patients who fail to respond to these - see editorial on p.285.
http://content.nejm.org/cgi/content/abstract/363/3/211
http://content.nejm.org/cgi/content/abstract/363/3/221

233    By now, most of you should be aware that ACCORD was a big trial of various interventions in type 2 diabetes that was stopped early because of excess mortality in the group randomised to tight control of glycaemia. Death is generally agreed to be the most important and definite end-point in any study. Diabetic retinopathy is not quite in the same league, and a good deal harder to define. ACCORD used a definition based on three points in a visual acuity scale and/or the need for intervention (laser photocoagulation or vitrectomy). Just as in UKPDS and other studies, tighter glycaemic control achieved a small but significant reduction in these end-points. But the biggest reduction (about 40%) was seen in patients randomised to receive fenofibrate in addition to statins. This is seized upon with enthusiasm by an ophthalmologist writing on p.287 . Reading this editorial and last week's Lancet review, I'm beginning to worry that diabetic retinopathy can cause tunnel vision.
http://content.nejm.org/cgi/content/abstract/363/3/233

245    If anything can cause a company's profits to BLOOM, it's a new obesity drug. The BLOOM (Behavioural Modification and Lorcaserin for Overweight and Obesity Management) trial was funded by Arena Pharmaceuticals, who will be hoping for vast returns on the latest drug to target the serotonin receptor. Those with supernaturally good memories and profound knowledge of clinical pharmacology (OK, you can put your hand down, Jeff Aronson) will remember that there are actually three such receptors and that previous anti-obesity drugs such as fenfluramine and dexfenfluramine targeted them non-specifically. They worked fairly well for appetite suppression but were withdrawn because they could cause valvular heart defects and pulmonary hypertension. This is because cells around the heart valves and in the pulmonary vasculature contain 5HT2B receptors whereas the receptor you need to hit for appetite suppression is 5HT2C. Lorcaserin is powerfully specific for this receptor and Arena went out of their way to check their trial subjects regularly with echocardiograms which prove that it doesn't cause heart valve problems in the first two years. Whereas it certainly does help people lose weight and will be advertised as blooming wonderful if and when it gets it licence.
http://content.nejm.org/cgi/content/abstract/363/3/245

266    In reviews of acute pulmonary embolism I look for two things: mention of it as a common cause of exacerbations in heart failure and COPD, and guidance about which patients need long-term anticoagulation. This article by two Italian authors doesn't fully satisfy either criterion. There's little mention of HF or COPD and although they say that "extended treatment requires a reassessment of the patient's risk-benefit ratio at periodic intervals" they fail to tell us how to calculate these risks and benefits.
http://content.nejm.org/cgi/content/extract/363/3/266

Lancet  17 July 2010  Vol 376

163   Droves of healthy people come to see doctors all year round to have blood pressure checks. If it's off target, their GP sees them every few weeks to make adjustments. Neither the timing, the place nor the health professional involved reflects any real logic. This ground-breaking study (TASMINH2) addresses these realities by passing management to the patient whose blood pressure is monitored at home with a reliable automatic device linked by an automated modem to the GP practice. If it remains high, the patient is given advice and if necessary additional drug treatment to reduce it. The group randomised to this intervention showed usefully better control of systolic BP at the end of a year. If this technology became widespread, we would save many GP appointments and improve control in most of our hypertensive patients.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60964-6/abstract

173    Recently we were urged by our prescribing adviser to change everyone possible from celecoxib to a cheaper combination of NSAID with omeprazole if gastric protection is needed. This was largely cost-driven; but there is also an appreciable difference in cardiovascular risk between celecoxib and naproxen and ibuprofen, for example. Both celecoxib and diclofenac carry approximately the same twofold risk of cardiovascular events, which may be why Pfizer chose this NSAID as the comparator in the CONDOR study looking at the risk of gastrointestinal events. They have demonstrated to their own satisfaction that celecoxib is a safer choice than diclofenac plus omeprazole in patients with a history of GI bleeding. But for most patients needing NSAIDs, neither celecoxib nor diclofenac would be the best choice for overall long-term safety.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60673-3/abstract

180    Most of us are vitamin D deficient for at least part of the year, some more than others. The overriding determinant is skin exposure to sunlight, followed way behind with diet, and some way behind that with genetic determinants. This genome-wide study was even more labour-intensive than most, covering 34 000 subjects in five discovery cohorts, plus five "in-silico replication cohorts" (I think this quaint term refers to stored samples)  and five de-novo replication cohorts. Unlike many of these prodigious exercises in gene gnomery, this one produced results: variants at three loci reached genome-wide significance, and together they can account for a 2.7-fold difference in the risk of vitamin D deficiency. However, this brings no nearer the day when we will get round to detecting and treating this important and ubiquitous condition. These gene gnomes need to get out more, and so probably do the rest of us.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60588-0/abstract

BMJ  17 July 2010  Vol 341

135    This interesting observational study discovers that opioid addicts who regularly take prescribed methadone are less likely to die than those who do not, even though they continue to inject street opioids. This is purely an artefact of the way we criminalise drug addiction. Addicts who remain in regular contact with health professionals by supplementing their street use with methadone are displaying a less risky behaviour pattern than those who don't.
http://www.bmj.com/cgi/content/full/341/jul01_1/c3172

139    The latest in Michael Goldacre et al's regular analysis of early career choices by doctors compared with their eventual specialties. The pico format kills this sort of thing stone dead. You can't loll in an armchair squinting at the tables one by one, then flicking back and forth to make sense of them. All you're given in the printed BMJ is a bare little summary table showing that the longer you've been a doctor, the more likely you are to have found your eventual specialty.
http://www.bmj.com/cgi/content/full/341/jul06_1/c3199

140   Thank goodness the BMJ still allows readers the full text of its Clinical Reviews. Obstetric anal sphincter injury is an important topic which I haven't ever read a good review about, but I fear that this one may suffer from some over-enthusiasm on the part of its expert authors. On the basis of another review published in 2003, they declare that "A thorough clinical examination of the perineum and vagina, including a digital rectal examination, should be performed after every vaginal delivery to improve the detection rate of anal sphincter injury". Following every vaginal delivery? Not just that, but "Visual inspection should be combined with palpation, including a pill rolling movement using the index finger in the rectum and the thumb over the anal sphincter to assess muscle bulk." I do hope they have some evidence that all this anal fixation can result in better outcomes.
http://www.bmj.com/cgi/content/extract/341/jul09_1/c3414

146   It's always a source of pleasure to me when one of my original suggestions for a BMJ series to be called "Commoner than you think?" appears under the eventual series title of Easily Missed, and this week it's bronchiectasis. As with many of these topics, the reason we have become more aware of its prevalence is better imaging - no more horrible endoscopic contrast bronchograms, just a nice CT scan. But  the patient may still be in constant danger of misdiagnosis by unfamiliar doctors, especially when the basal crackles are bilateral. Some should be protected by a tattoo over a marked area of their backs, reading "These crackles are always here: I do not need furosemide".
http://www.bmj.com/cgi/content/extract/341/jul14_3/c2766

Arch Intern Med  12 July 2010  Vol 170

1135    Vitamin D again. The InCHIANTI cohort study finds a small but significant relationship between vitamin D levels and the risk of dementia. The average MMSE score in these 70+ year olds in Tuscany began surprisingly low at under 25 and declined slightly faster according to quartile of serum 25-hydroyvitamin D. It's interesting to note that 80% of these D-deficient Tuscans were the black-clad women who stay at home to cook meals for the men. The vitamin-rich men sit with their friends in the sun on benches dressed in dark suits with open neck white shirts, uttering the odd word every half hour.
http://archinte.ama-assn.org/cgi/content/abstract/170/13/1135

Plant of the Week: Eryngium alpinum

This Sea Holly is an old favourite, introduced to England from Europe in 1597. It can be one of the best things in the garden at this time of year, if you give it a good start in well-drained soil in full sun. Once established it will grow in limy rubble quite happily.

The flowers are large and look prickly, but unlike all other sea holly flowers, they are not. Their excellent blue makes a nice contrast to the yellows and oranges of the day-lilies which provide most of the garden colour at this time of the year.

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JAMA  7 July 2010  Vol 304

45     Glucosamine is the doctor's best friend. It doesn't do anything, but people believe it might, and so if you have trouble treating their joint symptoms you can always say "have you tried glucosamine?". Note that you are not obliged to lie: the most you have to say is that it seems to work for some people. In this Norwegian double-blinded trial for chronic low back pain and degenerative lumbar osteoarthritis it was as good as placebo, with slightly fewer adverse effects.
http://jama.ama-assn.org/cgi/content/abstract/304/1/45

61    As part of the ongoing upturning of the Sacred Truths of Diabetes, this analysis of data from the INVEST study shows that tight control of blood pressure in diabetic patients with coronary artery disease does not improve outcomes. And so another unwarranted extrapolation from UKPDS crumbles into dust: in fact the whole edifice of British diabetology, built up on this slender foundation, is looking a bit like the work of Ozymandias. I must say that this has come as a slight shock even to a hardened and vocal sceptic like me; but this subgroup analysis of 6400 participants in the randomised controlled trial is consistent with last week's meta-analysis in the Archives and with the data from ACCORD. Treating to a target of <130/85 produced the same outcomes as treating to 140/85.
http://jama.ama-assn.org/cgi/content/abstract/304/1/61

69    We speak of lives cut short by cancer, but in an odd way it works the other way round, according to this study of telomere length and cancer incidence and cancer mortality. The opening sentences of the paper describe the significance of  telomere length: "Telomeres are nucleoprotein complexes at the extreme ends of linear chromosomes implicit in the maintenance of chromosomal integrity. Telomeres shorten with each cell cycle and therefore reflect organism aging at a cellular level." Thus the shorter your telomeres, the less time you have to live. This is demonstrated here in a population study from Bruneck, a German-speaking South Tyrolean town which belongs to Italy. Those with short telomeres had the highest risk of cancer. Now in a German town this would be attributed to the shears of the three Norns, whereas further south it would be attributed to shears of the three Fates.
http://jama.ama-assn.org/cgi/content/abstract/304/1/69

76   The Rational Clinical Examination series assumes a very high degree of literacy, intelligence and education on the part of its readers; and perseverance, too, as most of these excellent articles set out the evidence in unsparing detail. Why, I even know people who have had resort to skim-reading in some cases. "Can This Patient Read and Understand Written Health Information?" is a great question for this series to address, because it's one we fail to ask so often. We fail to elicit the physical signs of incomprehension or reading difficulty because we are not looking for them or the patient wants to hide them from us. Just ask "How confident are you in filling out medical forms by yourself?"
http://jama.ama-assn.org/cgi/content/abstract/304/1/76

NEJM  8 July 2010  Vol 363

109    The TOM trial recruited 209 New England men with a mean age of 74 and limitations in mobility plus low testosterone. Given that there is a definite association between low testosterone and inability to perform vigorous activity (see next paper), might transdermal testosterone restore youthful litheness to these tardy vieillards? Alas, we shall never really know, as the trial was stopped early due to an excess of cardiovascular events in the treatment group within the first six months. Half of the 23 events in this were relatively unimportant but the other half were not, and this study certainly does raise concern that we might be promoting myocardial infarcts and strokes when we try to treat male hypogonadism in the elderly.
http://content.nejm.org/cgi/content/abstract/363/2/109

123    So should we be trying to identify late-onset hypogonadism in middle-aged and elderly men? This excellent definition-seeking study shows that there is a definite clustering of low testosterone, poor morning erection, low libido, and erectile dysfunction, associated with fatigue and depression. Whether you go looking for it is another matter: I suppose it all depends on what you want to achieve. In monastic circles, the avoidance of wet dreams was a constant anxiety, even mentioned in the great Compline hymn Te lucis ante terminum:

Procul recedant somnia                          May dreams recede afar
et noctium phantasmata;                         And phantoms of the night;
hostemque nostrum comprime,               And hold back our enemy
ne polluantur corpora.                             That our bodies may not be polluted.

So for these monks, a low testosterone accompanied by few erections would have been considered a blessing. Whereas for poor Anton Bruckner, the celibate Catholic composer, testosterone levels must have remained painfully high to the end: in his seventies he wore large flannel shorts at night and when he was not climbing bell-towers he would roam the parks proposing marriage to young ladies at random. Finally a young housemaid from Hamburg accepted him, though he died before consummation. Perhaps we old chaps should simply accept whatever falls to our lot in terms of gonadal luck.
http://content.nejm.org/cgi/content/abstract/363/2/123

136    Now what did I promise you next in the Stent Wars? I do believe it was a battle between zotarolimus and everolimus, though to be honest I am too bored to remember. Anyway, battle has been joined between stents eluting these particular olimusses and so far the result is an exciting draw.
http://content.nejm.org/cgi/content/abstract/363/2/136

147    Recovery from severe burns to the cornea is limited by the number of stem cells in the limbus, a narrow zone between the cornea and the bulbar conjunctiva. Happily a team of Italians from Milan and Modena has devised a method of harvesting these precious cells and cultivating them on fibrin, so restoring good vision to 77% of the 112 patients they treated with this technique.
http://content.nejm.org/cgi/content/abstract/363/2/147

156    Mitral regurgitation due to degenerative mitral valve disease isn't just a topic for exam swots, but a frequent clinical problem well worth updating yourself about with the help of this excellent review. Mitral valve repair is now usually the treatment of choice, with excellent long term success: this largely abolishes the risk of chorda tendina rupture but not of atrial fibrillation. Surgery for the mitral valve reflux of left systolic heart failure has a ten-year mortality of 57%, but that is probably quite low compared with medical treatment alone.
http://content.nejm.org/cgi/content/extract/363/2/156

166    In the course of these reviews I've taken you through (though perhaps 'past' would be a better word) many genomewide association studies and I'm sure that you are finding how much they have improved your assessment of the risk of disease. I certainly am. And so does this article on the subject: we are all agreed that they do not help at all. The author takes us patiently through all the technical details and ends in the plaintive hope that some day all of this may help clinicians. I applaud him for being honest and the New England Journal for letting everybody have this article without charge.
http://content.nejm.org/cgi/content/full/363/2/166

Lancet  10 July 2010  Vol 376

91    A study which would have delighted Sir Geoffrey Keynes (1887-1982) who first tried out limited radiotherapy for breast cancer in the early 1920s. Ninety years later, post-operative radiotherapy is usually delivered in small doses of external beam treatment to the whole breast over several weeks. This trial looked at the effect of a single dose of targeted intraoperative radiotherapy to the immediate environs of the removed early breast cancer, and produced non-inferior outcomes at four years.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60837-9/abstract

103   The CANOE trial was designed by GlaxoSmithKline at a time when rosiglitazone was still a popular drug, and no doubt GSK will point with relief to the fact that at low dosage (2mg) it didn't do any measurable harm to the 103 Canadians assigned to it in this study. On the contrary, when combined with metformin 500mg b.d. it stopped a good many of them from getting type 2 diabetes. These Canadians were selected for their high risk of crossing the arbitrary threshold of 7mmol/L fasting glucose, so giving them drugs which lowered sugar naturally helped to postpone this. But did it help to postpone anything else? We know that cardiovascular disease and retinopathy refuse to recognise the existence of a glycaemic threshold anyway, and that pushing down sugar of itself can make no difference to these, or even do harm. Metformin is fortunately one drug we know tends to improve real outcomes, but the same can certainly not be said of rosiglitazone. And oddly enough this combination did nothing to preserve beta-cells - as far as we can measure that process. Get out and take a walk: it may do you more good.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60746-5/abstract

112   Exercise will also help you avoid a stroke; alcohol alas will not. Most of the other risk factors for stroke identified by the INTERSTROKE study are the ones you might expect, and the ten main ones account for nearly 90% of the risk. The oddest feature is the role of body mass index: when corrected for other factors, a high BMI actually seems protective, whereas a high waist-to-hip ratio is a substantial risk factor.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60834-3/abstract

124    The two most salient things I've learnt from looking into diabetic retinopathy over the last couple of years is (a) that it shows a linear relationship to glycaemia from well below the "diabetic" threshold and (b) it doesn't greatly matter exactly when you start treating it, provided that visual damage has not occurred. This seminar, by contrast, emphasises the importance of early detection. It discusses the largely negative evidence for tight glycaemic control in relation to eye complications but still comes down heavily in favour of this approach. I am confused.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)62124-3/abstract

BMJ  10 July 2010  Vol 341

82    The rotator cuff is one of those body parts which normally works brilliantly well but is a perfect beast when it starts going wrong. This Australian trial tried the effect of a 10-week exercise programme and failed to improve pain while improving function a little bit. If you want all the evidence we have on treating rotator cuff disease, you'd be better off turning to the Annals of Internal Medicine website, where they've just posted a big (free) meta-analysis.
http://www.bmj.com/cgi/content/full/340/jun08_2/c2756
http://www.annals.org/content/early/2010/07/01/0003-4819-153-4-201008170-00263.full?aimhp

83    This study of transdermal and oral hormone replacement therapy and the risk of stroke should boost sales of transdermal HRT, especially low doses. I use the "should" more in a predictive than an advisory way, because I don't think one can place 100% reliance on case-control studies based the UK GP Research Database. On the other hand, it is reassuring that there seems to be no observed increase in stroke at all with low dose transdermal oestrogen, opposed or not, whereas for high doses and for all oral preparations there is an added risk of 30-40%.
http://www.bmj.com/cgi/content/full/340/jun03_4/c2519

Ann Intern Med  6 July 2010  Vol 153

23    This meta-analysis looks at the trials which have changed practice in recent years towards a lower target haemoglobin in renal patients receiving erythropoietin. It doesn't matter what stage of renal failure they are at: outcomes are better if you aim for an Hb around 10 rather than one around 13. This doesn't seem right, but then lots of things in medicine (and real life) are counter-intuitive.
http://www.annals.org/content/153/1/23.abstract

Poem of the Week: Ozymandias by Percy Bysshe Shelley

I met a traveller from an antique land
Who said: "Two vast and trunkless legs of stone
Stand in the desert. Near them on the sand,
Half sunk, a shattered visage lies, whose frown
And wrinkled lip and sneer of cold command
Tell that its sculptor well those passions read
Which yet survive, stamped on these lifeless things,
The hand that mocked them and the heart that fed.
And on the pedestal these words appear:
`My name is Ozymandias, King of Kings:
Look on my works, ye mighty, and despair!'
Nothing beside remains. Round the decay
Of that colossal wreck, boundless and bare,
The lone and level sands stretch far away".
pub. Jan 1818

---

NEJM  1 Jul 2010  Vol 363

11    So far, the trials of carotid stenting versus endarterectomy have sent out mixed messages, but the CREST study sends out a message of equipoise. The triallists decided to recruit asymptomatic patients mid way through, to bump numbers up to 2502, but the main population was fairly homogeneous and had stenoses of 70% or more which were symptomatic. In the periprocedural period those who had endarterectomy had more strokes, and the stent group had more myocardial infarcts. But at a median follow-up of 2.5 years, there was no difference in major outcomes and a pleasingly low incidence of ipsilateral stroke at 2-2.4%.
http://content.nejm.org/cgi/content/abstract/363/1/11

24    Most of the 200 human papillomaviruses are harmless, but type 16 can get nasty and is found in many genital and oropharyngeal cancers. This study looks at the influence of HPV-16 on survival in treated oropharyngeal cancer. If you adjust for other factors, tumours are much more likely to respond to radiotherapy and platinum-based chemotherapy if they contain HPV-16 DNA.
http://content.nejm.org/cgi/content/abstract/363/1/24

36    I'm no great fan of implantable cardioverter-defibrillators, not least because they often go wrong due to lead failure, and they can lead to shockingly bad ends in heart failure. This trial assesses a new type of ICD which does not rely on venous access but is entirely subcutaneous, delivering shocks to the thorax close to the heart. Its success depended a lot on accurate positioning, and over the ten months of the trial it worked well and appropriately, though it's too soon of course to say anything about long-term reliability, let alone long-term mortality benefit.
http://content.nejm.org/cgi/content/abstract/363/1/36

63    If you get regular migraine, you probably use a triptan from time to time. I was delighted when sumatriptan injections first became available about 25 years ago but rather disappointed by the results, on myself particularly. Since then there have been many more triptans with better oral availability, but surprisingly little evidence to guide any choice, or even to prove that they work better than analgesic/metoclopramide combinations. Although I no longer need to take triptans myself, I know many others who do and I fell upon this review article with keen interest. But I'm afraid I learnt very little.
http://content.nejm.org/cgi/content/extract/363/1/63

Lancet  3 July 2010  Vol 376

20    I don't normally comment on the letter pages, but the letter here from Mike Clarke, Sally Hopewell and Iain Chalmers is the most important thing in this week's Lancet, and may even have achieved a change in the policy of this august publication (see editorial on p.10). The Cochrane stalwarts simply restate a truth that all researchers should always heed; clinical trials should begin and end with systematic reviews of the evidence. That's the main part of the title of their letter: the other bit is 12 years and waiting. They have gone through the same journals as I go through each week and state that "there is no evidence of progress between 1997 and 2009 in the use of updated systematic reviews in discussing the findings of trials published in these five medical journals." And these are the best journals: when I wander into the rest I am dismayed and appalled at the even greater extent of repetition, muddle and futility. At least The Lancet promises to pull its socks up. I'll believe it when I see it.

23    Tranexamic acid has been around for ages and is mostly used in gynaecological and urological practice, though it's recently also been used to reduce bleeding in elective surgery. The CRASH-2 trial tests the hypothesis that it might reduce bleeding and improve outcomes in trauma victims with significant haemorrhage. Over 20 000 such patients were recruited in 40 countries, and the result is a very narrow win for tranexamic acid over placebo: a 9% reduction in mortality which just reaches significance.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60835-5/abstract

49    Antiviral therapy and management of HIV infection. That's a nice straightforward (if ambitious) title for a seminar. And a very good seminar it is: one every doctor should read, since as the opening sentence states, "Advances in understanding of HIV biology and pathogenesis, an in application of that knowledge to reduce morbidity and mortality, rank among the most impressive accomplishments in medical history." Not just that but the story continues to be largely optimistic, despite the awesome adaptability of the virus.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60676-9/abstract

63    As I said a couple of weeks ago, no child should die of diarrhoea, and in many European countries none do, but worldwide the death toll is 1.5 million. The treatment is usually nothing more than an appropriate oral rehydration solution, with added zinc. I was quite unaware that zinc has marked benefits in the acute phase and even months later, and that added to the standard sugar and electrolyte solution in the poor world it can halve overall mortality from diarrhoea.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60356-X/abstract

BMJ  3 July 2010  Vol 341

30    Steroid injections remain popular with patients who have moderate to severe shoulder pain, and the figure from this study shows why: there is substantial added relief beyond the effect of exercise alone in the first three months. Thereafter there is no significant difference.
http://www.bmj.com/cgi/content/full/340/jun28_1/c3037

31    A team of epidemiologists and statisticians has worked on national databases of childhood cancer and found that there is no relation between these and proximity to mobile phone radio masts. This should logically put an end to such claims, but I wouldn't put any money on it.
http://www.bmj.com/cgi/content/full/340/jun22_1/c3077

32   Proton pump inhibitors are associated with an increased risk of postoperative pneumonia in elderly patients. These people then have to have antibiotics and get Clostridium difficile. Hence naughty doctors should prescribe fewer PPIs. So runs the usual logic: but it isn't quite right. This Canadian study found that elderly people taking acid suppressants (mainly PPIs) had more major risk factors for pneumonia than those who did not at the time of operation. Adjust for those, and it seems that acid suppressants confer no extra pneumonia risk at all.
http://www.bmj.com/cgi/content/full/340/jun21_1/c2608

34   A Clinical Review article about Huntington's disease maintains the generally very high standard of current BMJ reviews, as it should, since it comes from the UK's leading centre for treating the condition. It's well worth reading through for general interest, and keeping if you have a family with the condition in your practice. There is also a readable and rather chilling historical account of Huntington's discovery and early medical attitudes to it in this week's Lancet (Stigma, history, and Huntington's disease by Alice Wexler, p.18).
http://www.bmj.com/cgi/content/extract/340/jun30_4/c3109

41    A short piece in the much more variable Rational Testing series deals with investigating symmetrical polyarthritis of recent origin. Its main virtue is in emphasising the urgency of referring such patients (especially with hand joint involvement) to a rheumatologist straight away, since the diagnostic tests available in primary care can be entirely misleading. The 32 year old woman in the vignette has a normal CRP, ESR and negative rheumatoid factor but nevertheless has markedly elevated anticyclic citrullinated peptide antibodies which are highly predictive of progressive rheumatoid arthritis. Rheumatoid factor is negative in 38% of patients with RA, especially in early disease: conversely 20% of healthy over 65s have a positive RF. It's a bad test and anti-CCP looks set to replace it.
http://www.bmj.com/cgi/content/extract/340/jun30_4/c3110

Arch Intern Med  28 Jun 2010  Vol 170

1013   Last week I grumbled that the Archives and Annals had yielded me nothing to write about for three weeks: well this week the Archives take their revenge. I was trying to take a break from thinking about medicine, and here is more thinking matter than a week can easily contain. Let's begin with diagnostic adverse effects. Looking back over your distinguished career, how many patients have you harmed by late diagnosis or wrong diagnosis? OK, let's not go there. And how many systematic papers have you read about this topic? None at all, in my case, if you exclude essentially anecdotal material like Lesson of the Week in the BMJ and similar. Well, here is a rare and exemplary example of the genre, based on a review of nearly 8 000 patient records randomly gathered from Dutch hospitals. This is extraordinarily labour-intensive work with a low yield: the team found that only 4 hospital patients in every thousand were harmed by diagnostic errors, and in almost every case the error was caused by human judgement. The mortality from these misjudgements was 29%. For those with time enough, and a big project grant, the entire field of primary care lies open for further studies. They need to be done.
http://archinte.ama-assn.org/cgi/content/abstract/170/12/1015

1024    Next on to statins, my favourite drugs, which I have defended against all comers. If in doubt, prescribe, said I. Among patients with known cardiovascular disease, I was right, although it is very hard to find any benefit once heart failure has set in. But prescribing statins to high-risk patients for primary prevention may be futile, according to this literature-based meta-analysis. It is a very hard paper to follow, however, with a fairly heterogeneous mix of studies which are not adequately characterised or analysed in these six pages: to do that would require twice the length, or ideally an entire database, which could then be analysed on an individual patient basis...
http://archinte.ama-assn.org/cgi/content/abstract/170/12/1024

1032    The JUPITER trial of rosuvastatin was stopped early and has been a source of controversy ever since. The acronym stands for Justification for the Use of Statins in Primary Prevention, but when JUPITER's data are fed into a meta-analysis like the one we've just seen, there is no such Justification. In fact the data of this trial are internally contradictory in a way that strongly suggests manipulation, according to this critical reappraisal, which suggests that Jove's ire should be directed at the role of commercial sponsors. I can hear the distant peal of thunder across the Atlantic: Jupiter tonans.
http://archinte.ama-assn.org/cgi/content/abstract/170/12/1032

1037   The well-conceived new Archives series called LESS IS MORE here lives up to its radical credentials: we are giving diabetic patients too many drugs for cardiovascular protection. Again, this flies in the face of what we have been taught over the last few years. It also seems to fly in the face of the calculation done by these authors that treating to targets for LDL-cholesterol and blood pressure results in gains of 1.5 and I.35 quality-adjusted years respectively. But they demonstrate that these overall gains are largely accounted for by the treatment of a small number of very high-risk individuals, and that the more drugs you put in, the more you are likely to achieve minimal benefit or actual harm. A key paper in the continuing debate about targets in type 2 diabetes.
http://archinte.ama-assn.org/cgi/content/abstract/170/12/1037

Plant of the Week: Oenothera odorata

Last year our small back garden was made even smaller by building work and had to have large parts dug over and replanted: an ideal opportunity, you might have thought, for a careful reshaping of the whole. Well, it didn't quite happen like that: we bought nearly a hundred new plants, but dug in most of them in a hurry as they threatened to die in their pots.

We now have a miscellaneous riot of bought-in perennials in flower, but they don't dominate the scene. The masters of the garden are self-sown beauties that we can't find the heart to pull up: white mallows, great flopping opium poppies in shades of pink and red; but above all, beautiful pale yellow evening primroses, fading to coral pink on long red stems. By day they look like weeds, but as evening falls they come out like a forest of creamy lamps.

They are scented, as their correct botanical name implies; but often sold as "sulphurea" or "stricta". I have no idea where our first one came from, but once you have this plant, you are likely to enjoy its descendants in perpetuity, since it seeds itself freely. By day, you will be tempted to pull these children out of the ground as they appear randomly; but by evening you will wonder how you could ever have harboured such strange and cruel thoughts.

 

 

 

 

 

 

 

 

 

 

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Page last edited: 29 July 2010

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