Richard Lehman’s journal review—30 November

richard_lehmanNEJM 26 Nov 2015 Vol 373
“Artificial cell” for diabetes
2129 “Home use of an artificial beta cell in type 1 diabetes” conjures up a vision of some huge cellular blob taken home in a glass tank and connected up with the circulation, probably by Peter Cushing in a white coat and half-moon spectacles. In fact the artificial beta cell is just a fanciful name for a closed loop insulin pump driven by a glucose sensor. It’s the device we’ve been waiting for for decades. The trial recruited 33 adults from the UK, Germany, and Austria, and 25 children and adolescents from the UK. The comparator was a sensor augmented pump. The closed-loop system produced overall better control and less nocturnal hypoglycaemia over 12 weeks, provided it was connected properly with a working battery: when not, it caused three episodes of significant hypoglycaemia. So a promising start for a device that would be used for a whole lifetime, and a great opportunity to do an international collaborative follow-up study, in which all the data and device modifications are shared in real time to achieve the quickest route to an effective, safe, and affordable system. Come on guys, you can do this.

Progesterone flops for miscarriage
2141 The temptation to use some kind of placebo for people suffering the repeated anguish of failed pregnancy is great, and the very name “progesterone” has a ring of promise about it. But it’s a false promise, as this British trial confirms. In a large trial, 400mg daily of micronised progesterone used vaginally from confirmation of pregnancy up to 12 weeks made no difference to the live birth rate in women who had experienced previous recurrent miscarriages, compared with placebo. The good news though is that the live birth rate in the groups was 63-67%.

Velpatasvir, hepatitis C and dollars
OL You’ve heard of sofosbuvir. Or if you haven’t, you should at least pretend to have, because it’s become an essential part of drug regimens to cure hepatitis C, and is also at the centre of a storm about international drug patents. To achieve a cure, it needs to be used with an inhibitor of the HCV NS5A protein, and Gilead Sciences have developed one called velpatasvir. On the NEJM website you can find three papers reporting the comprehensive success of a sofusbuvir velpatasvir regimen in every genotype and clinical stage of HCV infection, including the end stage of decompensated cirrhosis. But the end of HCV as a threat to health and life is some way off, as conveyed in the title of a trenchant editorial: “Simple, effective, but out of reach? Public health implications of HCV drugs.” Do read it. “At a population level, the effect of HCV medications will be determined by affordability and equitable access to HCV testing, care, and treatment.” How can we even think of achieving that on a global scale when the current cost of curative regimens is $83,000 to $153,000 per course of treatment? And what can anyone do about it?

JAMA 24 Nov 2015 Vol 314
Busy with mabs and lasers
2137 When you last heard of ranibizumab, it was probably in the context of comparative trials in macular degeneration, showing that it is no more effective than the much cheaper bevacizumab. Here’s another trial of ranibizumab—this time for diabetic proliferative retinopathy—which received only limited funding from the manufacturers, though most of its investigators had received other payments from Novartis/Genentech. They report this non-inferiority trial with admirable restraint. In most respects, ranibizumab produced better results than the standard treatment, which is panretinal photocoagulation. Lasering the whole retina is bound to cause some damage, whereas the signal from this trial is that ranibizumab injections do not. But the authors content themselves with saying that, “Although longer term follow-up is needed, ranibizumab may be a reasonable treatment alternative, at least through two years, for patients with proliferative diabetic retinopathy.”

Lancet 28 Nov 2015 Vol 386
More rads going radial?
2129 Here’s a systematic review of the evidence about comparative radiation doses to people undergoing cardiac catheterisation by the transradial rather than the transfemoral route. On the whole, they get a bit more ionizing radiation but not enough to carry any definable risk, while the transradial approach is associated with lower bleeding and vascular complications.

LEAN week in the journals
OL If it wasn’t such a lean week in the journals, I’m not sure I’d be writing about the LEAN trial, which is a phase 2 study of the effect of liraglutide on “non-alcoholic steatohepatitis.” This nasty sounding condition is a triumph of disease mongering, taking the well known association between obesity and a fatty looking liver and turning it into a life threatening illness. “Non-alcoholic steatohepatitis is now the most common cause of chronic liver disease worldwide and incurs a significantly increased risk of both liver related and cardiovascular disease related morbidity and mortality.” In fact the association between fat deposition in the liver and cardiovascular disease is exactly the same as fat deposition in the neck and cardiovascular disease. The prevalence of both went up steadily over two decades (it may have plateaued now) while the incidence of cardiovascular disease went steadily down. The absolute risk of liver morbidity and mortality “incurred by” having the NASH label is tiny among the 30-50% of the adult population given this label in Western countries. The absolute risk from a bleeding complication from repeated liver biopsies would probably be greater, were you to inflict them on everyone with a fatty-looking liver on ultrasound. Anyway, enter liraglutide. NovoNordisk, the Wellcome trust and the NIHR funded this tiny 48 week trial in 52 people with a histological diagnosis of NASH. Nine people in the active group and two in the placebo group showed histological resolution at the end of the trial. Larger studies are sure to follow, and perhaps one day every fat person in the world, myself included, will be offered regular injections of liraglutide.

Good germs fail tiny babies
OL The adult large bowel contains between 500 to 1,000 different species of bacteria, whereas the bowel of premature infants tends to contain just a few Enterobacteriaceae, with relatively few of the lactobacilli and bifidobacteria which are typical of the term breast fed infant. So there was clear logic in this trial of the probiotic Bifidobacterium breve BBG-001 to reduce necrotising enterocolitis, late-onset sepsis, and death in preterm infants. It was carried out in 24 hospitals across southeast England and recruited 1315 infants born between 23 and 30 weeks’ gestational age. Unfortunately the trial showed that if there is any merit in this approach, Bifidobacterium breve BBG-001 is not the right germ for the job. Outcomes were the same as for placebo.

BMJ 28 Nov 2015 Vol 351
Be born on a Tuesday
If you are born on Tuesday, not only will you be full of grace, but you will also be more likely to survive than if you are born on a Thursday. There are some fascinating summary statistics charts in this paper about the association between day of delivery and measures of quality and safety of maternity services. The authors from Imperial College chose Tuesday as their reference day, and their conclusion concentrates on the “weekend effect.” “The results would suggest approximately 770 perinatal deaths and 470 maternal infections per year above what might be expected if performance was consistent across women admitted, and babies born, on different days of the week.” But the magic intervention which will eliminate all stochastic variability has yet to be described.

Put in the bread supply
A study of long term trends in prevalence of neural tube defects in Europe finds a random wiggle of results with nothing to suggest any decrease. This really is disappointing, since we’ve known for over 30 years that most of them are preventable through the preconceptual use of folic acid supplements. It is surprising that no European country has followed the USA in mandating the fortification of flour with folate, because we know that works.

Cochrane on Ritalin
Enjoying an advisory role in Cochrane UK, I had advance sight of this systematic review and sequential trial analysis of methylphenidate for attention deficit/hyperactivity disorder in children and adolescents, and even as a case hardened trial watcher, I was shocked. The authors found “high quality data” gathered from just 183 participants in six trials, out of a potential 12 245 participants in the 185 trials included. The authors were unable to draw any firm conclusions about the risks and benefits associated with methylphenidate—not helped by a median duration of treatment of less than two months. It’s hard to get dependable figures, but several million American children are currently taking this drug, usually for several years: years which are crucial to their brain development. To call it incredible is no hyperbole.

Plant of the Week: Spinacia oleracea

I like my spinach big and slightly chewy. I was reminded of this when I bought some at a farmers’ market this weekend. Its big crinkly dark green leaves bore little resemblance to the smooth anaemic spinach in supermarket packets, and its taste was deep and wonderful when cooked in cream. It also kept some of its texture rather than vanishing into slime the second it reached the boiling point of cream.

Its presence as a local winter vegetable in Oxfordshire is rather remarkable. It probably arrived in the High Middle Ages, via Spain and France. It features in the first known English recipe book, the Forme of Cury (1390), where it is referred to as “spinnedge” and/or “spynoches.” But its ultimate origin is from the original paradise of food, Persia, from which it had long before spread to China via Nepal, gaining popularity with Arabs and Indians on the way. Sag curries may be over a thousand years old. The Arabs then brought it to Sicily and Spain and referred to it as raʼīs al-buqūl, “the chieftain of leafy greens.” One wonders if when Robert Burns hailed haggis as ” Great chieftain o’ the pudding-race!” he was alluding to this coinage by the great Arab agronomist Ibn al-ʻAwwām. But somehow I doubt it.

Catherine de’ Medici introduced good food to France when she became its queen in 1531, and to her the French owe both petits pois and those lovely dishes combining fish, eggs, cheese and cream sauces with spinach. They are known as Florentine in her honour. It is said that she insisted on being served with spinach at every meal. Whether you wish to call this the Medici diet or the Popeye diet, it has much to commend it.