Richard Lehman’s journal review: Christmas issues

Richard Lehman

NEJM  19 Dec 2013  Vol 369

2379   The BMJ is alone among the journals in making any concession to festive frivolity. By contrast, the NEJM seems determined to prove that it can maintain stony-faced intellectualism at all times: its seasonal offerings begin with “Somatic Mutations of Calreticulin in Myeloproliferative Neoplasms” and “Somatic CALR Mutations in Myeloproliferative Neoplasms with Nonmutated JAK2.”

Let me try and explain in a few words what this is about: if you want the real detail, go to the editorial. The patients looked at here had the deadly condition of myelofibrosis, or else they had primary thrombocythaemia. Stay with me here, because this work has implications well beyond haematological oncology. “Approximately 50 to 60% of patients with essential thrombocythemia or primary myelofibrosis carry a mutation in the Janus kinase 2 gene (JAK2), and an additional 5 to 10% have activating mutations in the thrombopoietin receptor gene (MPL). So far, no specific molecular marker has been identified in the remaining 30 to 45% of patients.” So maybe if we can find which genomic changes determine the rest, we can find a new treatment.

The investigators succeeded: “Most patients with essential thrombocythemia or primary myelofibrosis that was not associated with a JAK2 or MPL alteration carried a somatic mutation in CALR. The clinical course in these patients was more indolent than that in patients with the JAK2 V617F mutation.”

Now that is real medical progress. Real social progress will come when we can take this work and use it to cure these patients, without taking a commercial route that demands an unaffordable price for their ransom.

2391   The next paper provides confirmation of these findings from a wider group of patients with myeloproliferative disorders: “Somatic mutations in the endoplasmic reticulum chaperone CALR were found in a majority of patients with myeloproliferative neoplasms with nonmutated JAK2.

2406   You can get anything you want in Denmark’s data restaurant. “Studies have raised concern about an association between the use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy and an increased risk of autism spectrum disorders in the offspring.” So let’s wander down to Alice’s restaurant. “Using Danish population registries, we linked information on maternal use of SSRIs before and during pregnancy, autism spectrum disorders diagnosed in the offspring, and a range of potential confounders.” Nice. “We did not detect a significant association between maternal use of SSRIs during pregnancy and autism spectrum disorder in the offspring.” Nicer. Coffee and a Danish please, Alice.

2424   And now it’s time to sit back for the Shattuck Lecture. You can literally do this, because the video link is here, and you can slump back in your armchair among the fairy lights, sipping the drink you didn’t really mean to pour, while you and the odd cat get a wonderful update on Chronic Infectious Disease and the Future of Health Care Delivery. Naturally it mostly about TB and HIV, and Paul Farmer’s lecture has some great lines. “It is not clear that any disease is helpfully termed ‘untreatable’ . . . ‘Untreatable’ often really means difficult or costly to treat, just as ‘resistant’ sometimes means resistant to our best efforts to deliver care . . . All five lessons from tuberculosis treatment apply to HIV disease. Many diseases affecting the world’s poor are treatable, including those that are considered untreatable because of delivery, rather than clinical, failures.”

JAMA  18 Dec 2013  Vol 310

2499   The research in this week’s JAMA is of negligible value, but the commentaries contain some real Christmas treats. This first piece, by Christakis and colleagues, isn’t the best of them. The message seems to be “you guys who want open data, be careful what you wish for.” They praise the Yale Medtronic project (which I was closely involved with), but point out that data can also be used for vexatious purposes–it can set legal hares running, confuse people, be mined by competitors, and so forth. We at YODA spent many days and nights meditating upon such things. But at the end of the day, if you want the truth to guide clinical decisions, you have to have the full data, and if people want to argue about it, that’s part of what we call science, and the only way to sort out bias and fraud.

2503   Which brings us nicely to the first sentence of a terrific article by Victor Montori and colleagues: “Research evidence is necessary but insufficient for making patient care decisions.” Everybody needs to read this open access piece, because it deals with the central challenge of the medical endeavour, the essence of what we need to aspire to whenever we tried to help individuals with illness or anxiety about their health. Ostensibly it is about guidelines, but let’s forget about those: they are false gods and graven images. “Patients may have preferences when it comes to defining the problem, identifying the range of management options, selecting the outcomes used to compare these options, and ranking these outcomes by importance.” That is where to begin. And where to end. Use guidelines if you think they are helpful, but generally they are a stumbling block. And under no circumstances just stick a label on the patient and then collect what money you can by following the rule book. QOF has done terrible damage to the essence of personal care.

2507   Now of course lots of very smart people have made heaps of money by sticking labels on patients and then writing the rule book themselves. We call this “industry”. Industry spreads far beyond the mere manufacture of pharmaceuticals. It pays academic units to base their research on the mechanistic models and products that it generates, and it infiltrates guideline committees to base their recommendations on that kind of research. Industry dominates continuing medical education throughout the world. Steven Woloshin and Lisa Schwartz unpick some of this in a typically delicious piece with the subtitle “Clouding the Sunshine.” Read it and applaud  their patient, witty, determined fight-back.

2510    Ah, and now for some industry based research. The mechanistic model that industry loves is that coronary arteries are like blocked pipes. You put in a device to unblock them, and people get better. Then you add an agent to thin the blood and stop the stent blocking. Now consider all the different kinds of stent, and all the different kinds of blood thinning agents, and all the doses you can use them at, and all the different durations you can devise, and every comparison you could make between each. I doubt whether you could actually do all the possible trials before the sun burns itself up and the human race becomes extinct. Consider then the importance of the OPTIMIZE trial, comparing Three versus Twelve Months of Dual Antiplatelet Therapy After Zotarolimus-Eluting Stents. I would suggest that in the context of eternity (sub specie aeternitatis) this trial is not worth the time it takes you to read about it; but as a source of reprint income it may have some importance to JAMA.

2523   If you look at a medical textbook from the 1920s, you’ll find that a lot of chronic illness is explained on the basis of “septic foci” which leach out toxins and poison the body. This was before antibiotics, so the answer was to look for these foci and remove them – hence the vogue for dental clearance and tonsillectomy. This study is a faint echo from that misguided age: somebody evidently thought that gum disease might impair glucose control in type 2 diabetes, and did a trial of non-surgical periodontal treatment to see if it improved levels of HbA1c. But it didn’t.

2533   The acutely failing heart is not much good at maintaining a circulation, but it is very good at pumping out large amounts of natriuretic peptides. That’s why I’ve always thought it a bizarre idea that adding extra natriuretic peptide analogues would make any difference to the treatment of acute heart failure; and in fact the BNP analogue nesiritide all but fell out of use when a properly conducted trial showed that it did nothing. But still they try. In this trial, nesiritide was compared with dopamine or placebo in patients admitted with acute HF and renal dysfunction, who were given diuretics as needed. Decongestion was measured by urine output and renal function by cystatin C. There was no difference between groups.

Lancet  21 Dec 2013  Vol 382

2069   The idea that patients and their carers can be trained to manage chronic conditions at home by the use of suitable programmes is a beguiling one, but it keeps being disproved. I wonder why. This account of a failed programme for carers of stroke patients discharged from hospital does not say how the intervention was devised, but the authorship may hold some clues. Everyone comes from academe or the hospital sector. Was the intervention designed in careful dialogue with patients, carers, GPs, and community nurses? Perhaps. Or perhaps not. If I were the MRC, I would have liked to know before funding this trial. As it is, the investigators are driven to conclude: “It is possible that the immediate post-stroke period, when potential caregivers are coming to terms with their new situation, might not be the ideal time for the delivery of structured training. The intervention approach might be more relevant if delivered after discharge by community-based teams.” Did it really warrant years of work and millions of taxpayer pounds to reach that conclusion?

2077   For the next three months, the happy islands of New Zealand will be awash with low hanging fruit. Lemons lie scattered on public lawns, people put boxes of misshapen avocados out for anyone to take, peaches the size of small melons hang by the million in sun drenched orchards. There is sweet low hanging fruit to be had in the neonatal research units of New Zealand too. “Neonatal hypoglycaemia is common, and a preventable cause of brain damage. Dextrose gel is used to reverse hypoglycaemia in individuals with diabetes; however, little evidence exists for its use in babies.” So they tried it, and it worked. “Treatment with dextrose gel is inexpensive and simple to administer. Dextrose gel should be considered for first line treatment to manage hypoglycaemia in late preterm and term babies in the first 48 h after birth.”

BMJ  21 Dec 2013  Vol 347

The Christmas BMJ this year is a classic. It begins with three good (serious) editorials, on resistance to patient-centredness in the NHS, poverty and health in the UK, and the Cochrane Collaboration at 20. There is an outrageously good Nativity spoof called “A born again Christian” which will probably halve the BMJ‘s American circulation at a stroke. It’s a shame that people who call themselves by that title don’t generally share the vital Jewish insight that God has a sense of humour. I’m afraid that the BMJ rather rubs it in by discovering that many pregnant American adolescents claim to be virgins

Much publicity has attended the semi-serious article comparing an apple a day with a statin. The references are really helpful and I intend to use them in a decision tool. Chocolate survival on wards seems to have changed little in the past 40 years, but James Bond’s alcohol intake reflects the pattern of a bygone age. In truth the classy boozers of those days really would consume about 20 units a day, and then take amphetamines if they needed to stay awake: see Fear and Loathing in Fitzrovia, a biography of Julian McLaren-Ross by Paul Willetts.

“Nominative determinism” is a wonderful spoof of data-mining and false association; some of the haikus are even good; Darzi as a hospital porter learns lessons; and “Growing up over the shop” is a fabulous recollection of a bygone Wales where doctors’ sons could perform post-mortems before they reached puberty. And so it goes on, there are no duds. There is even a passable Christmas Minerva on the website.


Painting of the Week: Adoration of the Magi by Fra Angelico and Fra Filippo Lippi c 1440-1460

Wandering through the Early Italian rooms in the National Gallery of Art in Washington DC, you will be stopped  in your tracks by this astonishing round painting on a block of wood from fifteenth century Florence. Nobody is quite sure whether it was painted by Fra Angelico or Filippo Lippi: nowadays it is attributed to both. Il beato Angelico was a model of virtue: “it is impossible to bestow too much praise on this holy father, who was so humble and modest in all that he did and said and whose pictures were painted with such facility and piety.” Lippi, though also a monk, was his exact opposite, who is said to have been locked in an upstairs room to finish his painting so that he did not run off after women or get drunk. His son, Filippino Lippi, was also a considerable artist and was the product of his liaison with a novice nun of noble birth.

Do not be deceived by the apparent naivety of this picture, with its impossible perspective, its seemingly random detail, its air of chaotic benignity and its exquisite use of colour. It is a very complex and profound meditation on a theme from Christian mythology which actually goes much further back than Christianity. To me it is a Zoroastrian picture. But never mind that, and never mind about theistic notions at all. If there is one thing that this picture tells us, it is about the infinite beauty and fertility of the human imagination when given great themes to dwell on.

N.B. Right in the middle of the picture, there is a crumbling pagan building from which several thin men emerge, almost naked, with white loin cloths. Who are these? And why is there a dead pheasant lying on the roof of the cattle shed, entirely out of scale?