Journal Watch - February 2012

JAMA 22 Feb 2012 Vol 307

813 When an Italian team of physicists reported that they had detected neutrinos travelling faster than light, the televisual physicist Jim Al-Khalili promised to eat his boxer shorts if it proved to be true. It turns out to have been a measurement error due to faulty wiring. Unbelievable results either shatter the laws of the known universe, or else they are wrong. So if a study tells us that 42% of women and 31% of men presenting with myocardial infarction do not have chest pain (or even pain in the arm or jaw), this either overturns clinical medicine as we know it - from experience and from several other large cohort studies - or else it is due to lousy recording. Guess which. This retrospective study is based on a single tick in a box completed by busy physicians looking after over a million patients coming into American hospitals with heart attacks between 1994 and 2006. It could be that they had better things to do than record the obvious. If these figures are true, then I will eat my elegant black Marks & Spencer long johns. These thermal underpants have proved very effective at protecting my lower parts from the ravages of winter on the eastern seaboard of America, and I just wish journal editors were as effective at protecting us against the ravages of bad data.

823 It's a while since I was a proper GP, with a consulting room of my own and an obligation to endure baby clinics every so many weeks. As a result, I've completely lost track of what the standard infant immunization schedule now is in the UK. The poor mites seem to suffer an ever-increasing bombardment of antigens, but I no longer have to listen to them squawk somewhere down the corridor. So I will leave it to you to judge whether you need to know that "DTaP-IPV-Hib vaccination was associated with an increased risk of febrile seizures on the day of the first 2 vaccinations given at 3 and 5 months, although the absolute risk was small. Vaccination with DTaP-IPV-Hib was not associated with an increased risk of epilepsy."

832 There was once an editorial in Gut which began, "The liver is a stupid organ. It can only grunt." The point that this witty hepatologist was making is that estimating liver health from enzymes and ultrasound is like taking a history from a pig. Veterinary experts can no doubt pick up some diagnostic clues from the noises of their porcine clients, but it probably goes little beyond "oh dear, something's the matter." In this paper, the Rational Examination series revisits the question Does This Patient With Liver Disease Have Cirrhosis? In the best tradition of this generally wonderful series, 86 studies of patients referred to liver clinics are analysed in great detail and the findings are written up clearly and comprehensively. Astonishingly, alcohol history has no useful predictive value. The gold standard is liver biopsy, though even this can miss its target. All in all, this is a great contribution to the science of gruntology, but the end result is just a better kind of guessing.

NEJM 23 Feb 2012 Vol 366

687 This long-term report from the National Polyp Study made newspaper headlines the world over, which just shows that if you do lots of colonoscopies to remove colorectal adenomas for a period of up to 23 years, you may eventually get your 15 minutes of fame. More importantly, those you have treated will have half the rate of colorectal cancer of the general population. Since they were at greatly increased risk to start with, this is quite an achievement, and shows that a single colonoscopy per lifetime might reduce the population rate of colorectal cancer by up to 53%.

697 But the next paper brings us down to earth. A randomized non-inferiority trial of once-only colonoscopic screening compared with faecal immunochemical testing every two years has been going on in 8 regions of Spain since 2008. It seems that Spaniards are no different from the rest of us in their aversion to collecting poo (34.2% uptake) or having lengthy instruments introduced into their bottoms (24.6% uptake). The preliminary results seem to show a similar detection rate of cancers using the two methods, but a much higher rate of adenoma detection with colonoscopy. How to make screening more acceptable is the fundamental (sic) problem.

707 For patients with disseminated melanoma and their families, this is a tormenting period. Real advances are being made but they remain short of a cure; and they are also hideously expensive. Vemurafenib can extend the life of patient with metastatic melanoma by about a year, if it is one of the 60+% of tumours that has a mutation in the gene encoding the serine-threonine protein kinase B-RAF (BRAF). But the cost of a year's vemurafenib is $113,000. And even if combination chemotherapy using this drug was developed which extended life beyond a year, there would be a high risk of developing other skin tumours. This phase 2 trial, paid for by Hoffmann-La Roche with company involvement at every stage, illustrates so much that is right and wrong with the current process of targeted drug development in cancer. If survival in advanced cancer is ever going to move beyond the prerogative of the wealthy, we need a whole new model of collaborative, global, not-for-profit cancer therapy research.

723 There is something deeply irritating about the names of skin conditions, which mix up Latin and Greek and seldom tell you anything useful. Lichen planus, for example. Moreover, we haven't a clue what causes most skin diseases, and the treatment tends to be with local corticosteroids in the first instance, and oral corticosteroids if desperate. Lichen planus, for example. However, learned reviews of skin disease do tend to have elaborate accounts of molecular mechanisms and lots of sharp and lurid illustrations. Lichen planus for example; as reviewed in this article.

Lancet 25 Feb 2012 Vol 379

713 The Lancet, you may have noticed, is a seriously weird journal. One of the things it likes to do is publish the results of cutting-edge human experiments before they have any clear outcomes. Two subjects - one nearly blind with Stargardt's macular dystrophy and the other nearly blind from age-related macular degeneration - underwent subretinal transplantation of retinal pigment epithelium cells derived from human embryonic stem cells. Four months later, not much happened. A great breakthrough, the editorial announces.

721 A few minutes after the Big Bang, when the Universe had cooled to two trillion degrees C, the first protons and neutrons formed out of the gluon-quark plasma and formed the nuclei of hydrogen and helium, together with tiny numbers of lithium nuclei. Wind on 360,000 years, when the Universe had cooled sufficiently for electrons to form stable orbits, and lithium as we know it came about. A certain amount has since been made - or recycled - by stellar nucleosynthesis. So what happens if you put lithium into people? This meta-analysis of 385 studies shows that it can be an effective mood stabiliser but carries the risk of reduced urinary concentrating ability, hypothyroidism, hyperparathyroidism, and weight gain. The risk of renal failure is very small but the risk of hyperparathyroidism is 10% and of the rate of hypothyroidism is increased more than fivefold. The authors recommend that TSH and calcium should be checked before starting lithium therapy and annually thereafter. They also cast doubt on the need for 3-monthly monitoring of serum levels. "Because few patients spontaneously develop toxic effects without a precipitating illness, yearly monitoring plus monitoring of one-off lithium concentrations in high-risk circumstances might be more clinically relevant and cost effective." But this means better education of patients and doctors.

BMJ 25 Feb 2012 Vol 344

So if protons are of such ancient cosmic pedigree, what happens if we put proton pump inhibitors into people? By and large, they are happy: their gastric symptoms disappear and they want to keep taking them. But as an increasing proportion of the population take them, hidden harms begin to emerge. One of these is increased risk of fracture. This analysis of data from the Nurses' Health Study shows that regular use of PPIs is associated with a 30% increase in incident hip fracture - increasing to over 50% in women who smoke.

For the 14 years I have been writing weekly reviews, Scandinavians have been engaged in furious argument about breast cancer screening and its contribution to the rise and subsequent decline of invasive breast cancer in those hardy regions. Here a group of Norsemen from Oslo, Bergen and Trondheim try to promote our understanding of breast cancer trends in Norway, and conclude that "Changes in incidence trends of invasive breast cancer since the early 1990s may be fully attributed to mammography screening and hormone treatment, with about similar contributions of each factor." But in a formidable editorial from Harvard, Karin Michels points out that "the authors do not discuss artefacts that can arise in ecological data and age-period-cohort analyses when non-linearities are present". No doubt she is right, but I'm afraid I gave up at that point.

On to the whole question of hormone replacement therapy. It's now ten years since the Women' Health Initiative Study published its findings and reversed our notions of HRT and cardiovascular risk. The subsequent mass cessation of HRT caused endless hot flushes in doctors and women alike; but has the dust now settled sufficiently for us to take a balanced view of the immediate benefits versus the longer-term risks? Perhaps: and the verdict of this review is that HRT taken for five years at the onset of menopause is reasonably safe. It also confirms my feeling that we know too little about the risk/benefit ratio of hormone combinations other than the conjugated equine oestrogen/medoxyprogesterone acetate combination used in the WHI study.

Ann Intern Med 21 Feb 2012 Vol 156

I can't think of many studies from British primary care that have appeared in the Annals, and this one receives a rave review in the editorial: "That this study was done at all speaks to the better support for high-quality research in primary care in the United Kingdom; finding support for a study like this would be extraordinarily difficult in the United States." It's not that easy in the UK either, and the praise is deserved: a 4-university collaborative did a cluster-randomized trial of cardiovascular family history taking by patient-completed questionnaire. It had a 98% uptake and showed that this is useful and practicable and resulted in a 4.5% increase in patients categorized as high risk.

Plant of the Week: Prunus cerasifera "Pisardii Nigra"

The earth is beginning to stir and buds are swelling imperceptibly on shrubs and trees. Among the first to open - maybe even as I write, in the gentler regions of England - will be those of this flowering cherry. It was an Edwardian favourite and is often abundant in the suburbs of that era, usually as a thirty-foot tree with an untidy trunk and dark purple leaves throughout the season. I would not recommend it for small gardens where every subject has to earn its place throughout the year, but it is a lovely sight in flower for a couple of weeks at the very end of winter.

There are plenty of these trees in the town where I used to practise, and I would look forward to their abundant pink blossom as I drove on my rounds. Wonderful when underplanted with snowdrops, or better still with scillas or blue chionodoxas. To make the tree less gloomy later in the season, train a vigorous white clematis into it - montana "Wilsonii" for May, or viticella Alba for August.

JAMA 15 Feb 2012 Vol 306

669 This week's star Viewpoint piece is about The Unintended Consequences of Conflict of Interest Disclosure. It seems to me that twenty-first century medicine operates on roughly the same principle as the court of the Grand Vizier of the Ottoman Empire - prestige is judged by the number of bribes you are offered. Far from being a source of shame and reluctance to publish, these are routinely flaunted at the end of most interventional trials in the leading medical journals. I once counted 63 for a single individual; and perhaps he would argue that once you enter double figures, they begin to cancel each other out. How did we reach a state where the default setting of our medical culture is conspicuous corruption? As the authors here point out, this cannot go on: "Conflicts of interest, including fee-for-service arrangements, are at the heart of the astronomical increases in health care costs in the United States, and transparency is no substitute for more substantive reform." And just as the US health system thinks of ways to get out of this hole, our British political masters are determined to push us into it.

674 One way in which JAMA lags behind other journals is in flagging up the role of the funder in interventional trials. It would have helped if we were told right at the beginning that Abbott paid for this study of paracalcitol in patients with an estimated glomerular filtration rate of less than 60 and echographic evidence of left ventricular hypertrophy. The title of the paper tells you little about the contents and the whole study (PRIMO) is a wonderful exercise in futility. It is completely free of clinical outcomes - a closed loop of nearly meaningless surrogate end-points relating to cardiac and renal function: and even on this basis it was a dud. Why on earth did JAMA think this worth publishing?

685 It took 60 centres in 11 countries to recruit 227 subjects for that PRIMO trial of paracalcitol ("Zemplar", Abbott). This is not at all unusual in trials run by pharmaceutical companies on products still under patent, when the prize might be a large extension of indication. For good old amoxicillin this scarcely applies, and so for this placebo-controlled trial in acute rhinosinusitis, ten community clinics in St Louis proved perfectly sufficient to garner 166 subjects, and to prove that this particular antibiotic provides no symptomatic benefit at 3 days. There was some benefit at 7 days into the ten-day course given. This is not particularly new news, but the proximity of these two trials offers a nice demonstration of the marked difference between a pharma-funded study aimed at increasing market penetration, and a publicly-funded trial aiming to inform clinical practice. Tens of millions of dollars versus tens of thousands - and all ultimately from the pockets of the public.

713 There have been lots of recent studies linking short term air pollution and myocardial infarction and this systematic review and meta-analysis usefully combines the results of 34 of them. Small but statistically significant increases in MI can be traced to atmospheric pollution with carbon monoxide, nitrogen dioxide, sulphur dioxide and particulate matter. Another small item on the list of reasons why we need to end our dependence on carbon-based fuels.

NEJM 16 Feb 2012 Vol 366

591 Old- fashioned British general practice used to involve occasional bouts of physical exertion, such as wrestling with a patient in status epilepticus in order to give intravenous diazepam. I thought that this unique form of physical combat with an unconscious opponent had died out, but evidently it remains popular in America. This trial in older American children and adults in the pre-hospital setting shows that intramuscular midazolam given by paramedics is at least as effective as intravenous lorazepam. Worth knowing in all health care settings, as an alternative to the rectal, buccal and intranasal routes.

601 It's a familiar pattern: a pharma company (Sanofi in this case) pays for a trial based in 395 centres across 47 countries, in order to study the effect of its new drug semuloparin on the outcomes of 3172 patients receiving chemotherapy for solid tumours. The duration of the trial is 3.5 months and the end-points are venous thromboembolism, bleeding and overall survival: the comparator is not a different low molecular heparin, but placebo. Sanofi writes up the study, with the bottom-line conclusion: "Semuloparin reduces the incidence of thromboembolic events in patients receiving chemotherapy for cancer, with no apparent increase in major bleeding." Result: semuloparin continues to be used in most of the 395 centres and Sanofi is free to buy shed-loads of reprints from the NEJM in order to encourage clinicians to believe that their product is the one best proven to prevent VTE in chemo patients. The NEJM is free to sell these reprints without disclosing this to anyone (for "commercial reasons"), but can salve its conscience by printing an editorial criticizing the study for undue commercial bias. Both parties are winners, and cancer patients can now be treated on the basis of 3.5 months' worth of outcome data, most of which will not even be in the public domain. This is nothing exceptional - it is the standard model of evidence-based medicine in 2012.

619 I've come across surgeons who were daunted at the size of their patients, but I didn't realize that genomic scientists could be similarly affected, until I read here that "TTN, the gene encoding the sarcomere protein titin, has been insufficiently analyzed for cardiomyopathy mutations because of its enormous size." I like the idea of thousands of gene gnomes swarming to tie down the Titin gene, like the famous illustration in Gulliver's Travels. And this could turn out to be genuinely useful: "TTN truncating mutations are a common cause of dilated cardiomyopathy, occurring in approximately 25% of familial cases of idiopathic dilated cardiomyopathy and in 18% of sporadic cases." Anything that brings some order and understanding into this perplexing group of disorders must be welcome, even if it takes decades to translate into therapy.

Lancet 18 Feb 2012 Vol 379

617 In the world of competitive science, it has been said that there are no prizes for coming second. It is high time we got rid of this way of thinking, especially in the clinical sciences, where collaboration needs to become the core value, where everybody should share data and where nobody should value precedence for its own sake. So let's give a big cheer for this study of the new group B meningococcal vaccine, 4CMenB, which proves that it is immunogenic - just like last week's study in JAMA.

633 If I'm sounding tetchy about pharma-funded trials this week, that's because I particularly hate the kind that threaten enormous costs to health systems for tiny marginal benefits - especially where they play on our wish to do our best for patients with cancer. The logic for this GlaxoSmithKline trial is given thus: "The anti-HER2 monoclonal antibody trastuzumab and the tyrosine kinase inhibitor lapatinib have complementary mechanisms of action and synergistic antitumour activity in models of HER2-overexpressing breast cancer. We argue that the two anti-HER2 agents given together would be better than single-agent therapy." A hypothesis worth testing, though at current US prices, trastuzumab can cost $6K per month and lapatinib an extra $2.9K.: fine while GSK are paying, and if there are robust benefits. The end-point measured, however, was purely histological - so-called pathological complete response meaning absence of invasive tumour in the breast or lymph nodes in surgery conducted after 18 weeks of treatment (with paclitaxel added for the last 12 weeks). The conclusion, written without help from GSK this time, is suitably modest: "Dual inhibition of HER2 might be a valid approach to treatment of HER2-positive breast cancer in the neoadjuvant setting." And if it is - which can only be determined by long-term follow up for all-cause mortality - how shall we make it affordable?

648 A very nice seminar on atrial fibrillation by Greg Lip and colleagues provides an excellent map of what has become quite a complex subject. Generalists as well as cardiologists will learn a lot from this painstaking account of the latest evidence on the treatment of a highly prevalent condition which most of us encounter at least once a day. As we gain more knowledge, treatment is becoming more patient-focussed, and more may sometimes mean less: "Lenient or strict rate control strategies might not provide great differences in outcomes, whereas the availability of non-pharmacological approaches has allowed additional possibilities for the management of atrial fibrillation in patients who are unsuitable or intolerant of pharmacological therapy."

662 Fans of Sherlock Holmes will remember the passage in The Dying Detective where Holmes fakes delirium and attacks his dear friend Watson for being an ignorant general practitioner: "What do you know of the Tapanuli fever? Or the Black Formosa Corruption?" he rants. Modern GPs wishing to escape the opprobrium of Benedict Cumberbatch would therefore do well to read Chikungunya: a re-emerging virus.

"Ah, Watson, what are the vectors of this infection?"
"Species of the mosquito Aedes, I believe, Holmes."
"Very good. I observe that you have been reading The Lancet, Watson. And which is the particular mosquito that may have caused the death in London of the man who lies on the carpet before us?"
"Aedes albopictus
in all likelihood, Holmes. They say it may be carrying Chikungunya virus to temperate regions."
"Watson, you excel yourself! We must away to Baker Street for breakfast. I believe that Mrs Hudson has obtained some particularly fine kippers."

BMJ 18 Feb 2012 Vol 344

Why are newspapers so bad at reporting the results of medical research articles? We are all very happy to blame the innate stupidity of reporters, their bias towards pharma, their bias against pharma, the dreadful state of scientific education in the UK, Rupert Murdoch, homeopaths, in fact anything other than ourselves; but might some of the fault actually lie with the poor quality of press releases from medical journals? Lisa Schwartz and Steven Woloshin have been examining these issues for many years, and one of their earliest papers was a lucid explanation of the difference between odds ratios and hazard ratios following widespread misreporting of a race-sensitive paper in the NEJM. As most doctors still struggle with this, I attach it here. Small wonder that reporters also struggle when we give them too little guidance - and here is a retrospective study which proves that bad press releases lead to bad newspaper articles.

Just because the BMJ hosts these remarks on its website does not stop me being beastly when the occasion demands. But this week (at the risk of sounding like a creep) I will say that the BMJ leads all the medical journals in providing debate and information about topical issues in medicine. This week it covers obesity treatments, commitment contracts, and new recreational drugs. Let's take these in turn. Geoff Watts runs through obesity treatments present and future with a light touch. We have no effective drugs and we don't really know how surgery works. But it does - and that's a dilemma when most of the population is drifting towards overweight and obesity and the knife or the gastric band can scarcely be a general solution. Slimming clubs may have been the first to offer commitment contracts - money laid down against fulfilment of a health objective. The pros and cons are weighed up with no firm conclusion. As for new recreational drugs, you could scarcely wish for a better account of their effects and the treatment of their medical consequences. This is a must-keep article if your clientele includes the young and experimental.

Arch Intern Med 13 Feb 2012 Vol 172

209 Last year, Peter Rothwell and colleagues published a celebrated meta-analysis based on individual patient data from randomized controlled trials which showed that daily low-dose aspirin reduces total cancer mortality. This meta-analysis used summary patient data from a somewhat different set of trials and concludes: "Despite important reductions in nonfatal MI, aspirin prophylaxis in people without prior CVD does not lead to reductions in either cardiovascular death or cancer mortality. Because the benefits are further offset by clinically important bleeding events, routine use of aspirin for primary prevention is not warranted and treatment decisions need to be considered on a case-by-case basis." I wish I could take you through the merits and faults of each analysis, but I am afraid you will have to do this for yourselves. The Invited Commentary by Samia Mora (p.217) provides no help in resolving the clash of conclusions about cancer mortality.

219 Back to the issue of air pollution. The JAMA meta-analysis of particulate pollution showed an increased risk in the acute situation of less than 1% for MI, but a long-term study of cognitive decline in women in relation to particulate exposure indicates a stronger effect. Live in the country, and avoid tractors.

229 The same applies if you want to avoid acute ischaemic stroke. Even "safe" levels of particulate air pollution increase your risk. Move to Vermont.

Plant of the Week: Iris reticulata

It's hard to gain inspiration to write about plants in New England in February, but when I resorted to giving you a Hardy poem instead a couple of weeks ago, at least it climaxed with an iris. And you may well be able to enjoy the odd iris in flower during February in England, if you have planted the bulbs of the Near Eastern species reticulate. I've done this from time to time in the drier, more Mediterranean spots of our garden, but they have never thrived. It's certainly a lovely thing to see their flowers - I like the light blues best - unfolding fragrantly amongst the mire and frost of an English winter; but they do have a poor, shivery look about them, and I cannot blame them for giving up.

JAMA 8 Feb 2012 Vol 307

565 There are signs that JAMA is gradually improving under its new editor, although moving its perspective pieces to the beginning of the journal doesn't really count as progress. The BMJ has also tinkered with its order of contents, almost as if to hide the fact that they are improving at the same time. And it will certainly take a lot more than swapping chairs around to improve The Lancet. Anyway, here is a Viewpoint piece that is well worth reading if you are interested in screening and shared decision-making with patients. In a clear and well-structured piece, the authors trace the gradual path of disillusionment from the "spotting cancer early is always good" mindset to "there are harms and costs" attitudes of the present. They point out that dumping these issues on to individual clinicians to share with patients is a dubious strategy (not least in health systems where patients are called for screening independently of their normal health care provision). "Expert groups may dispute the 'facts'; the science can be difficult for physicians to communicate and for patients to understand; some patients demure [sic] and want the physician to decide; physicians may lack the time, reimbursement, or motivation to engage in long discussions; and social attitudes and medicolegal pressures may influence the decision." I particularly like their concluding sentences: "However, society's first concern should be to confirm that screening is a net good for public health. This requires harms to be considered independently of costs. Until the reality of harms becomes more palpable to clinicians and the public, concerns about the safety of screened populations will continue to be mistaken for frugality."

567 The next Viewpoint piece also raises an important issue in shared decision-making with patients. When we mention the potential harms of the treatment we propose - as we often must - can this interfere with its effectiveness? Again I would recommend everyone to read this article on Nocebo Effects, Patient-Clinician Communication, and Therapeutic Outcomes. This is not as coherent a piece as the previous one, but it's good to see this discussion coming out into the open. So much simplistic talk about shared decision making ignores the extraordinary power of clinicians to instill fear and hope in their patients by the words they use and the attitudes they convey. We need to be realistic and indeed scientific about this. We have a duty to be honest, but we also have a professional and ethical duty to understand the effect we have on people in situations where they are vulnerable and we have the power to help them or harm them.

573 This study of a new polyvalent vaccine against serotype B meningococcus may mark a great moment in medical history - final victory over a horrible killer and maimer of mostly young people. The science behind it is certainly awesome: it deploys a fusion protein made up of various newly discovered antigens from different strains of type B meningococci. In this European trial the 4CMenB vaccine proves safe and moderately antigenic in infants, but how the antibody responses relate to protection from invasive disease remains to be seen. We now seem to be within sight of vaccination to neutralize the full range of pathogenic meningococci. Rejoice!

583 Bacteriologists and public health physicians in the UK try to dissuade us from using ciprofloxacin as first-line treatment for uncomplicated cystitis in young women, but in the USA the battle is already half-lost and urinary pathogens are increasingly showing resistance to fluoroquinolone antibiotics. This study examines an alternative - a third-generation cephalosporin called cefpodoxime, which seems to have been around for long enough to be available as a generic (in the UK, used by vets more than doctors). And it works: 100mg of the proxetil ester daily for 3 days works as well for simple UTI as 250mg b.d. of cipro. Possibly worth knowing.

598 Now let us praise another vaccine, this time against rotavirus. We know that this works, and saves many young lives in the developing world and hospital admissions in the USA, where it is now routinely given. What we weren't quite sure of was whether there would an increase in intussusception following vaccination with the new pentavalent vaccine, such as caused the withdrawal of the previous trivalent vaccine. This cohort study rules that out: there was no increase in intussusception after nearly 800 000 shots given to American babies and toddlers.

NEJM 9 Feb 2012 Vol 366

489 The New England Journal alone has shown no urge to shift its contents around in the 14 years I have been reviewing it. I don't often mention the opening Perspective pieces, but they are usually interesting and sometimes outstanding. This week you can read about the threat of untreatable gonorrhea, Medicaid battles in the Supreme Court ("All Heat, No Light" - I didn't read further), and Preparing for Precision Medicine. The piece is co-signed by no less than Lord Darzi, once Czar Omnipotent of our humble health system, since he alone knew how to improve it. Here he sets forth a vision of medicine so perfectly guided by improved diagnostics and genomics that every intervention will achieve complete success with no harms worth speaking of. Together, we can do it! All that it will take is a little time and endless wealth. Replacing the human race would also be a good step, because as Kant said, "Out of the crooked timber of humanity, no straight thing was ever made."

493 Neonatal screening for hypothyroidism has relegated the word 'cretin' to an archaic term of abuse, but an association persists between high levels of thyrotropin (TSH) in pregnancy with impaired cognitive development in children. This largely British trial looked at the effect of screening for high TSH and low free T4 at less than 16 weeks' gestation, and giving levothyroxine at a starting dose of 150 mcg to half of the mothers with evidence of hypothyroidism and matched placebo to the other half. The (questionable) end-point was IQ in the offspring at the age of 3. There was no difference between the groups.

511 As a coffee-drinker with little interest in alternative therapies, I was under the impression for several years that tai chi was some kind of herbal tea, but apparently it is another of those things where you put your legs apart and wave your arms about, often to the accompaniment of an out-of-tune bamboo flute. Here it was compared with resistance training or stretching exercises for mild-to-moderate Parkinson's disease. Tai chi was better than either at improving balance and reducing falls. Perhaps in Western cultural settings, it should next be compared with slow disco dancing. Like bamboo flute music, this has also been shown to foster supportive relationships, particularly amongst those trying to escape.

520 Another week, another therapy which prolongs progression-free survival in advanced breast cancer. This time it is everolimus, a derivative of what used to be called rapamycin and is now called sirolimus; and the subgroup of patients in this trial (BOLERO-2) are those with hormone receptor positive cancer who are taking exemestane. The Abstract gives two figures for the primary end-point, indicating a benefit of either 4 months or 6.5 months according to who judged "progression-free" survival. The end-point that really matters, which is overall survival, is not yet "mature", according to the investigators: so far the absolute difference between groups is less than 2%, with far more adverse effects in the everolimus group. I think the sentences you need to read here are "In summary, we report a phase 3 trial in patients with HR-positive advanced breast cancer showing that the addition of everolimus to endocrine therapy results in an improved clinical outcome." Note the singular use of "outcome" - these patients has 8 times the rate of stomatitis, 4 times the rate of anaemia and fatigue and ran a risk of pneumonitis which was absent with exemestane alone. The second sentence you need to read is: "Supported by Novartis, including funding for medical editorial assistance with the manuscript."

Lancet 11 Feb 2012 Vol 379

521 This analysis of birth outcomes following assisted conception looks at 124,128 cycles of IVF that resulted in 33,514 live births, and the results are intriguing: women aged over 40 have the best outcomes. This seems counter-intuitive, and if this is a subject that interests you, you definitely need to get hold of this paper and pore over the figures. Here the bottom line will have to suffice: "Transfer of three or more embryos at any age should be avoided. The decision to transfer one or two embryos should be based on prognostic indicators, such as age."

547 Many years ago, I put off a 3 a.m. visit to a 3-day old baby who was sleepy and reluctant to feed. Two days later he was dead from fulminating group B streptococcal disease. Hardly a day has gone by since when I have not thought of that mistake which may have cost a baby's life, and which could and perhaps should have ended my medical career. Most general practitioners in the UK will never encounter this disease, especially in neonates, since antibiotic prophylaxis before birth is now the rule. But those who do have one chance to get it right: so any child with a hint of sepsis in the first three months of life must go straight to the paediatricians. This systematic review tries to determine the incidence of disease due to Streptococcus agalactiae in this age group, from wherever there are data: it is probably around 0.53 per 1,000 live births. The investigators add the rider that "A conjugate vaccine incorporating five serotypes (Ia, Ib, II, III, V) could prevent most global group B streptococcal disease." I hope so.

BMJ 11 Sep 2012 Vol 344

Antibiotic prescribing in British primary care is the subject of endless debate and investigation, much of which I have found quite unpersuasive. Here is a notable exception: a real-life cluster-randomized trial of an educational intervention which really worked, albeit modestly. It is called STAR, which stands for Stemming the Tide of Antibiotic Resistance. In fact past interventions which have reduced antibiotic prescribing in primary care have shown little effect on antibiotic resistance, and it is not even a secondary end-point in this trial. Introducing the STAR programme in Welsh practices resulted in a 4.2% reduction in antibiotic dispensing. This is discussed in an outstandingly useful editorial by James McCormack and Michael Allan, which should be discussed in every training practice in the UK - and elsewhere. I particularly like the last paragraph, advising that patients should stop their antibiotics as soon as they feel better, and also that they should be told what to do if they don't.

In my recent experience of general practice (increasingly geriatric on both sides), about half of gout is brought on by diuretics. So it's no surprise that this trawl through the UK GP Research Database to find associations between blood pressure lowering drugs and gout points the finger most clearly at thiazides. What is slightly less expected is that beta-blockers increase the risk of gout by around a half and ACE inhibitors blockers and angiotensin II blockers increase it by about a quarter. Except for losartan, which decreases gout risk by about 20%, as do calcium channel blockers.

Surgery is like violin-playing: most people can learn how to scratch out a tune; many can learn enough to play in a band; a few learn to sound nice all the time; and a tiny handful become great musicians. Most of the great ones, like Heifetz and Milstein, did a lot of practice every day; others like Kreisler and Busch did not, and you can tell the difference technically, though they were arguably greater musicians. We all also know there are great surgeons, good surgeons and bad surgeons: also perfectly hopeless non-surgeons, such as ourselves, who are reduced to joking about the rest. And we know perfectly well - by analogy and instinct - that this is not just a matter of case-load and experience. All learning curves do not eventually rise to the same line. This study of French thyroid surgeons does not tackle this problem of individual variation head-on, but instead related rates of damage to the parathyroids and the recurrent laryngeal nerve with number of years in post. The middle years see fewest mistakes. "Optimum individual performance in thyroid surgery cannot be passively achieved or maintained by accumulating experience. Factors contributing to poor performance in very experienced surgeons should be explored further." Mais non: c'est la vie, mon ami. Laissez tranquilles les pauvres vieillards. Add Gallic shrug and outstretched hands.

The generally high standard and practical focus of the BMJ's Clinical Review series is well exemplified in this week's offering on Raynaud's Phenomenon. It's great to see a team of young trainee doctors coming up with a product of such quality.

Ann Intern Med 7 Feb 2012 Vol 156

173 Rooting about in the library of the Robert Wood Johnson Scholars at Yale, I was surprised to come across a copy of Epidemiology in Country Practice (1937) by William Pickles. This is the founding text of British academic general practice, though it comes from a world that has now disappeared, where a pair of doctors watched day and night over a whole Yorkshire dale. In John Pemberton's Will Pickles of Wensleydale (1970), you can read how Pickles and his taciturn Scottish partner kept track of every case of infectious disease in their rural domain, cut off from the outside world but for a railway line to the end of the valley. When influenza struck, Pickles and his wife plotted a great chart of its progress on their kitchen wall: he had his wife drive him to the village school (he hated driving himself) and ordered that classes be suspended immediately. Alas, too late: a teacher had already spread the contagion, which moved inexorably up the dale. Most of the schoolchildren went down with it: I can't remember how many dalesmen died. Now let's switch to Canada, some 80 years later. An epidemic of H1N1 flu strikes Alberta, and schools are closed. Infection rates in children drop quickly. Then schools are reopened; and infection rates show a second peak. Somewhere from a moorland grave, I can hear Pickles muttering, "I bloody told you so."

Violinist of the Week: Fritz Kreisler (1875-1962)

Many doctors are excellent violinists, but there is only one doctor amongst the greatest. As a teenager, Kreisler showed outstanding ability as a violinist and toured Europe and even America, but when he failed to get a place in the Vienna Philharmonic Orchestra, he decided to train as a doctor. He qualified, and sought career advice from one of the faculty. "Well, my boy, you can progress and become a third rate doctor, or go back and carry on being a great violinist," he was told. Sound advice.

Kreisler was a complete natural, and his mode of playing was unique. He introduced the practice of almost continuous vibrato to his playing, which had a magical tonal and expressive power in his own hands. Unfortunately it had a generally disastrous effect on most twentieth century violinists. Because he never strove to keep up his technique (saying that "practice is just a bad habit"), his playing deteriorated with age. To get a full idea of his musicianship and mastery, listen to his recordings of the Beethoven and Brahms concertos with Blech and the Berlin Philharmonic from the earliest years of electrical recording, together with the Bach G minor Adagio (which served as a fill-up side on the 78s). To understand why nobody could resist his charm, go for the many recordings he made of his own salon pieces and imitation Baroque movements, prior to 1930. Magical, inimitable.

JAMA 1 Feb 2012 Vol 307

467 We of a physicianly disposition may not like to admit it, but throughout history surgeons have been well ahead of physicians at looking critically at their outcomes. For example, rates of re-operation have appeared in case series reports for well over a hundred years, so this paper on re-excision in breast-conserving cancer surgery is less innovative than it might seem, except that it goes further and looks at variability between centres and surgeons. And actually that is nothing new either - James Simpson and Florence Nightingale were doing it in the 1860s. I'm not sure we have got all that much further in understanding this wild variation: in this survey of 4 US centres it isn't associated with case-load at all, and isn't even all that much to do with completeness of excision. For example, reoperation rates on patients with negative margins varied from 0% to 70% (?!) among individual surgeons, and from 1.7% to 20.9% among institutions. What is going on?

483 Shock horror: Americans are not getting fatter. We can no longer console ourselves that however bad the obesity epidemic may be in the UK, it will always be worse in the USA. Mind you, we are quite a way behind; and Americans still cherish their obesogenic environment by never serving portions that are less than twice the amount required. It's just that nowadays in middle class circles it tends to contain a lot of unidentifiable greenery and some grated carrot. A plateau has been reached at every age group in the US, according to the latest figures from NHANHES. The 2010 obesity level was 17% overall in children and adolescents, and 36% in adults, with higher levels in black and Mexican Americans. The awful fact is that for those already obese, this is virtually irreversible by any non-surgical intervention, individual or societal.

NEJM 2 Feb 2012 Vol 366

399 Hodgkin's lymphoma in its earlier stages became a curable cancer several decades ago, through a combination of combined chemotherapy and radiotherapy. Now we are witnessing a gradual finessing of treatment aimed at minimizing the harms of curative therapy: a noble effort, where success is measured in small differences in outcome at 12 years' follow-up. This trial was initiated in 1994 and proves by the narrowest of statistical margins that using modern staging and chemotherapy, stage IA and IIA non-bulky Hodgkin's lymphoma survival is better if you omit the radiotherapy. Great news for people with early Hodgkin's and a great example of patient research, in both senses of the word.

409 And now to two trials on fibroids. I don't know why that should seem vaguely odd in the NEJM, but the editorial seems to feel the need to apologize (Uterine Fibroids and Evidence-Based Medicine - Not an Oxymoron, p.471). I suppose the point is that although there are plenty of evidence-based treatments for fibroids, most women still end up with a hysterectomy. These trials looked at the effect of ulipristal acetate, an orally available progesterone receptor modulator,in women waiting for fibroid surgery; in the second trial ulipristal was pitted against leuprolide, a GnRH agonist already in use for shrinking fibroids prior to surgery. Ulipristal certainly shrinks fibroids and may have fewer side-effects than leuprolide: "Both the 5-mg and 10-mg daily doses of ulipristal acetate were noninferior to once-monthly leuprolide acetate in controlling uterine bleeding and were significantly less likely to cause hot flashes." I recently caused hot flashes in Neville Goodman by using the term "non-inferior", for which there is unfortunately no technically suitable alternative in the English language. Alas, Nev, the medical world has few places left for us ageing pedants and purists. It is heartening to see Jeff Aronson's learned letter on the word "surrogate" in this week's BMJ; but the reprinted JAMA piece on Fossil Medical Words (1912) is full of the most beastly howlers in Greek spelling. The rot may have set in 100 years ago - in America, of course.

Lancet 4 Feb 2012 Vol 379

Fuddy-duddies wishing to enjoy hot flashes of rage at bad English generally go to two places in the medical literature: the poetry section in JAMA and Offline by Richard Horton. The JAMA offering this week is beyond human endurance, while Offline reverts to being merely dotty, with the odd bum note that most readers would hardly notice, such as "his stunning musical career took off - aged 8." While praising Donizetti, Horton begins his section by disparaging a plate of brains he saw in an Italian restaurant. This is most unfair. Brains are a great delicacy and the Italian way of preparing them in batter is delicious. And those over 60 need hardly worry about Creutzfeldt-Jakob disease with its incubation period of around 50 years (possibly shorter if you eat squirrel brains).

413 The Bill and Melinda Gates Foundation funded this study of malaria mortality between 1980 and 2010 - all part of the noble effort that we Microsoft users put into global disease eradication (what have you trendy Apple users got to say for yourselves? Eh?). As you will have read by now, the adult death rate may be around twice what we previously thought, hovering around a million a year. Previous attempts at global malaria eradication foundered on Cold War competition to produce genocidal weaponry and land a man on the moon. Now it might be worth addressing this before sending a man to Mars.

432 Here is another massive effort: Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100 000 women in 123 randomised trials. The conclusion of the editorial sums it up perfectly: "The EBCTCG meta-analyses continue to show that polychemotherapy saves lives (and that it can, on average, reduce breast cancer mortality by about a third). Clearly, the actual benefit and harm of polychemotherapy will be determined by the individual future risk of relapse and coexisting comorbidities. The challenge now is not only to save more lives, but to reduce the number of women given polychemotherapy unnecessarily. It is with such hope that the results of ongoing oncomolecular trials are awaited. We look forward to the day when treatment of fewer women with a personalised approach achieves more."

453 Even better is the editorial on this study of cardiovascular magnetic resonance and single-photon emission computed tomography for diagnosis of coronary heart disease (CE-MARC). State-of-the-art cardiac MRI is pretty amazing at spotting coronary atheroma, and better than state-of-the-art CT (SPECT); but that is no reason to rush to adopt the new technology. Robert Bonow's words have resonances far beyond cardiac imaging: "Enhanced diagnostic accuracy of CMR must be balanced against availability and cost-effectiveness, and there is a need for evidence of measurable improvements in patient outcomes. Diagnosis of coronary artery disease alone is not sufficient to determine the need for revascularisation. To show value, advances in imaging must be coupled with enhanced patient well-being or a reduction in unnecessary downstream testing and procedures."

461 For your further intellectual nourishment this week The Lancet offers seminars on Lyme borreliosis, hereditary angio-oedema and low back pain. Hereditary angio-oedema is caused by C1 esterase deficiency, and if you have a patient with it the chances are that he or she will be able to tell you all you need about it (including tales of relatives who died from laryngeal involvement). About low back pain you already know as much as anyone else. This seminar on Lyme disease, however, has already come in handy as it was already on the Lancet website last July, when my wife and I hired a car and passed through Old Lyme, Connecticut on our way to a highly recommended coastal nature reserve. This consisted of reedy marshland and woodland areas full of bracken and stagnant pools of water. After two hours we emerged covered from head to toe in insect bites which became gross and sometimes haemorrhagic, spreading out in large erythematous circles over several days. But we took no antibiotics, and after a few hot nights, rendered sleepless from itching, the spots settled. I don't think we have Lyme disease, though thousands of Americans believe that they have the chronic form and rage incessantly at anyone who disbelieves them. If we eventually become delusional, you'll all regret we didn't just take some tetracycline in good time.

BMJ 4 Feb 2012 Vol 344

Three papers in this week's BMJ examine the decline in mortality from myocardial infarction in European countries. The first is England, a part of the United Kingdom which was oddly missing from the European MONICA study in the 1980s and 1990s. This record linkage study shows an astonishing fall in standardized mortality from myocardial infarction of one half between 2002 and 2010. This is unevenly spread across England, as most things are, but in this case there is no evidence of a clear North/South divide. Nearly half of the drop is attributed to improved survival at 30 days. Most deaths from MI in England are now sudden deaths outside hospital.

In Denmark, a similar decline has occurred, but measured over 25 years rather than 8.

The investigators from Poland prefer to measure their halving of cardiac mortality from 1991: "Over half of the recent fall in mortality from coronary heart disease in Poland can be attributed to reductions in major risk factors and about one third to evidence based medical treatments" they conclude. By means of different kinds of modelling, they attribute this to "socioeconomic transformation", i.e. liberation from the yoke of socialism. Perhaps we in England should attribute ours to Tony Blair, though I would rather not.

A somewhat worrying report from five Scandinavian countries suggests that taking serotonin reuptake inhibitors during pregnancy may double the risk of persistent pulmonary hypertension in the newborn. This is billed as a population cohort study but is really a case-control study. The risk seems greatest when SRIs are taken in the last weeks of pregnancy - unfortunately just when one would least wish to discontinue them.

Plant of the Week: Rubus cockburnianus

Basking in temperatures of 5 degrees and more here in New England, we think anxiously about you left in old Britain as it snows and freezes. Often the plants that look best in such conditions are the brambles that we love to hate all the rest of the year. Covered in rime, their stems and even their leaves can take on a sort of hoary magic. Once the ice has melted, you can go back to cursing and bleeding as you struggle to extirpate them. Here in New England there are curiously few wild brambles, or even nettles, making its woods a delight to wander in (so long as you avoid poison ivy).

If you want a bramble that looks good all the year round, this one is worth trying - but only if you are prepared to give it about fifty square yards of ground, or fight a losing battle to contain it. The white stems look wonderful all winter, and there are various varieties with goodish leaves for the rest of the year. R cockburnianus is not quite as invasive as the common bramble, and when we finally decided to extirpate our bank of it, it only took about five goes and less than a pint of blood.








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Page last edited: 06 March 2012