Richard Lehman’s journal review—25 July 2016

richard_lehmanNEJM  21 July 2016  Vol 375

MenB vaccination for students
220    We’ve been waiting for decades to get a vaccine against Neisseria meningitidis serogroup B. But now that it’s arrived, it’s hardly the kind of thing that gets people looking for champagne bottles in the fridge. It’s an expensive way to prevent a rare disease, and it’s actually quite hard to prove that it has saved any lives so far. This report from its use during an outbreak at “University A in New Jersey” illustrates the problem. Although this paper (and another in Pediatrics) has input from Princeton University, neither actually mentions this august institution by name. I guess this coyness is because it would prefer to be linked in the public mind with Albert Einstein rather than the outbreak of meningococcal disease that began there in December 2013. Nine students were affected and one died. Nearly 6000 were then given meningitis B vaccination and none of the vaccinated students got the disease. In fact, one fifth of the students already had antibodies to menB, and one third of those vaccinated failed to develop any. We are never going to have accurate quantification of its protective effect. As the accompanying editorial says, “4CMenB will not be the last vaccine for which a traditional, pivotal, double-blind, randomized, controlled trial with hard clinical end points is difficult, if not impossible, to generate.”

Proopiomelanocortin Deficiency
240   No, I’d never heard of it either. But as this week’s is a rather sparse issue of the NEJM, I decided to take a look at a case report of two patients with this rare syndrome who were treated with setmelanotide, a new melanocortin-4 receptor agonist. “The patients had a sustainable reduction in hunger and substantial weight loss (51.0 kg after 42 weeks in Patient 1 and 20.5 kg after 12 weeks in Patient 2).” Blimey! This is hot. I think you can safely skip reading about rare defects in the gene encoding proopiomelanocortin (POMC), which cause extreme early-onset obesity, hyperphagia, and hypopigmentation. This drug will move on. I guess Prader-Willi syndrome may be the next target. And then, if it’s the safe appetite suppressant the world has been waiting for, who knows?

JAMA  19 July 2016  Vol 316

Buprenorphine implants
282   I like the idea of an implant that will stop opioid addicted people craving for opioids. Buprenorphine is a good opioid replacement when given in sufficient doses, and it tends to block the effect of other opioids at the same time. Here’s a trial designed to determine whether six month buprenorphine implants are noninferior to daily sublingual buprenorphine as maintenance treatment for opioid dependent people with stable abstinence. It had a double-blind, double-dummy design and 177 participants were randomised to receive sublingual buprenorphine plus four placebo implants or sublingual placebo plus four 80 mg buprenorphine hydrochloride implants. Ninety three per cent of these completed the trial. So this is about as far as you could get from the “honest doc, I dropped my bottle of methadone” clientele of coming and going opioid addicts that many of us are familiar with. And yet I think it is these patients who could benefit most from regular buprenorphine implants. As things stand, this method is most likely to be licensed for people who have good outcomes anyway. Over six months, 72 of 84 participants (85.7%) receiving buprenorphine implants and 64 of 89 participants (71.9%) receiving sublingual buprenorphine maintained opioid abstinence.

Ovarian stimulation & breast cancer
300    Sometimes observational research can deliver a nice clean answer: “Among women undergoing fertility treatment in the Netherlands between 1980 and 1995, IVF treatment compared with non-IVF treatment was not associated with increased risk of breast cancer after a median follow-up of 21 years. Breast cancer risk among IVF-treated women was also not significantly different from that in the general population.”

Diabetes drugs & outcomes
313    Other times observational research cannot deliver a nice clean answer. Last week I tweeted about the Nottingham observational study on diabetes drugs and cardiovascular outcomes, saying that we seemed to be getting something right. This week a systematic review and network meta-analysis of these drugs concludes that “Among adults with type 2 diabetes, there were no significant differences in the associations between any of nine available classes of glucose lowering drugs (alone or in combination) and the risk of cardiovascular or all-cause mortality.” The authors then suggest that beginning with metformin makes sense and that additional treatment can be “based on patient-specific considerations.” In the absence of evidence about long term outcomes, this will have to mean selection according to convenience and adverse effects.

Ann Intern Med  18 July 2016  Vol 165

Tai Chi v physio for knee OA
Physiotherapy, or physical therapy, grew up as a therapeutic discipline based on real anatomy and physiology, from small beginnings in the 19th century to huge prevalence in the 20th century. Tai Chi is a martial art, which was systematised in the 16th century and is based on ancient ideas of yin and yang incorporated in 2500 years of Confucian and Taoist teaching. A Canadian trial pits one against the other in the treatment of chronic knee pain due to osteoarthritis. “At 12 weeks, the WOMAC score was substantially reduced in both groups . . . The between-group difference was not significant. Both groups also showed similar clinically significant improvement in most secondary outcomes, and the benefits were maintained up to 52 weeks. Of note, the Tai Chi group had significantly greater improvements in depression and the physical component of quality of life. The benefit of Tai Chi was consistent across instructors. No serious adverse events occurred.”

Lancet  23 July 2016  Vol 388

Take the aspirin right away
365   You may already have read about this study, which first appeared on The Lancet website two months ago; but if not, better late than never. Common wisdom says that if you think you’re having a transient ischaemic attack (TIA) or a stroke, you should take an aspirin right away. And this study indicates that this is true. Peter Rothwell and colleagues looked at individual data for 15 778 participants from 12 trials of aspirin versus control in secondary prevention. They dug deep and covered a number of questions, but the clear message that emerged was that aspirin is the key intervention and substantially reduces the risk of early recurrent stroke after TIA and minor stroke. It also reduces the severity of early recurrent stroke by 80-90%.

Polonium-210 poisoning
OL   Somehow I never thought of polonium-210 poisoning as a topic for the Easily Missed series, and yet it nearly was missed in the notorious killing of Alexander Litvinenko by Russian agents in London in 2006. It’s an extremely expensive murder method, but it’s quite possible that it has been used on other occasions, since it requires gamma-ray spectroscopy of a urine sample to make the diagnosis. When did you last order that test? “Early symptoms of 210Po poisoning are indistinguishable from those of a wide range of chemical toxins. Hence, the diagnosis can be delayed and even missed without a high degree of suspicion. Although body surface scanning with a standard Geiger counter was unable to detect the radiation emitted by 210Po, an atypical clinical course prompted active consideration of poisoning with radioactive material.” Weird fact: the first deliberate administration of polonium to human subjects took place in the US between 1943 and 1947, when tiny amounts produced by the Manhattan atomic weapons project were given to five terminally ill people in hospital to measure its human excretion.

Behavioural activation v CBT
OL   Ironically, polonium got its name as a gesture of defiance towards Russia by its Polish discoverer Marie Curie-Skłodowska, who was officially classed as a subject of the Russian Tsar and therefore forbidden to speak Polish in public. For this and numerous other reasons she was prone to depression, which she countered with an obsessive regimen of mental and physical work. I guess this might count as a kind of “behavioural activation,” something which was compared with cognitive behavioural therapy (CBT) in this trial in Devonshire people with major depressive disorder. It isn’t really clear from the text what behavioural activation actually is: this is a common problem in studies of complex interventions. Whatever it may be, it seemed to be as effective as CBT and cheaper.

The BMJ 23 July 2016  Vol 355

Meniscus surgery v exercise
“I’ll go in there with a telescope and trim your torn cartilage” sounds an eminently sensible offer to most patients who’ve been a bit hobbled by knee pain and locking, and who’ve been told their MRI shows a partial meniscal tear. And operations like this clock up billions of dollars of income for orthopaedic surgeons around the world. But when a Norwegian centre randomised 140 patients aged around 50 with cartilage tears to receive arthroscopic surgery or just do exercises, they found no difference in outcomes at two years. Here’s a procedure that can be taken off the NHS menu, however popular it may remain elsewhere.

Specialism or volume?
The volume-outcome debate in surgery has been going on for at least 30 years, but a simple fact seems to have escaped attention until this study of surgeon specialisation and mortality in the US. Looking at the outcomes of Medicare patients after eight surgical procedures, the investigators discovered that surgeon specialisation was an important predictor of operative mortality independent of volume in that specific procedure. “No mechanism was identified for this relation, and the study was limited by potential unobserved choices and characteristics of surgeons.” This carefully and modestly written paper is one of the best outcomes research articles that The BMJ has published. Somebody should replicate this study in the UK.

Plant of the Week: Clematis viticella “Alba Luxurians”

 We’ve been to three great gardens in the past two weeks—Coton Manor, Hidcote, and Kiftsgate—and in all of them the late summer flowering clematis species were star performers, and they will carry on beautifully as July turns to August.

Our own small garden brings death to most clematis varieties, but the viticellas are relatively resistant to slugs and wilt, so we’ve put them everywhere. Since very few trees or shrubs flower after the end of June, you must give each one its clematis for summer interest, either viticella or jackmanii. Fortunately, these come in a pretty wide range of colours. The one I mention here, “Alba Luxurians” comes with green tips at the end of its white petals and can look very fetching when it has grown to proper size.

Success with these viticella species comes when the stems are about one centimetre in diameter. By then they will mostly climb to three to six metres if you let them: it depends where you want the flowers to end up. This will usually be about a metre above where you cut them back to in late autumn. They are tough plants but even so we seem to be able to lose them from time to time. The books suggest that regular feeding with tomato fertiliser helps them to maintain vim and vigour. We will give it a try.