Richard Lehman’s journal review—8 February 2016

richard_lehmanNEJM 4 Feb 2016 Vol 374
Renal altruism
411 Greater love hath no man than this, that a man lay down his life for his friends. Failing that, consider live kidney donation. In fact, the risk of you laying down your life by getting end stage failure of the other kidney is really low, especially if you are “white” rather than “black”, in the parlance of this paper. If you are a black man of 40 in the general US population with two intact kidneys, your 15 year risk of end stage renal disease is 0.24%, whereas if you are a white woman, it is 0.04%. Donating a kidney increases the risk by a factor of 3.5 to 5.3. So the extremes would be: maximum 1.72% risk for a black man donating a kidney versus minimum 0.14% for a white woman over 15 years. Quite a range, but reassuring figures for anyone thinking of being altruistic.

150 Shades of AML
422 Pathologists have always been classifiers, and the new genomics has sent them into pathology heaven. Let’s take a peep at their paradise: “We used a reverse-transcriptase quantitative polymerase-chain-reaction assay to detect minimal residual disease in 2569 samples obtained from 346 patients with NPM1-mutated acute myeloid leukemia who had undergone intensive treatment in the National Cancer Research Institute AML17 trial. We used a custom 51-gene panel to perform targeted sequencing of 223 samples obtained at the time of diagnosis and 49 samples obtained at the time of relapse. Mutations associated with preleukemic clones were tracked by means of digital polymerase chain reaction.” They identified 150 subtypes, which, considering there were 346 patients, was not very helpful. But then they dug down and looked instead for persistence of NPM1-mutated transcripts in blood, as an indicator of residual disease after two cycles of chemotherapy. And this really did predict both relapse and death in the 15% of patients affected: 24% survival at three years rather than 75% for the rest. So we have a new prognostic marker, and maybe targeted treatment will follow. This can only happen through data sharing and the not for profit design of individualised therapy. Anything else would, I’m afraid, have to be called parasitism.

Metformin for mothers
434 The safety of metformin in pregnancy is well established, so it seemed reasonable to do a randomised trial of the drug in pregnant women with a BMI of 35 or greater, to see if it would reduce the incidence of gestational diabetes, large for gestational age neonates, or adverse neonatal outcomes. It did none of these things. Mothers who took the drug put on less extra weight, and that was it.

Amoxicillin for starved kids?
444 Another good idea trial with a negative result. Go to places where children still have to be rescued from the brink of death from malnutrition, and see if the common practice of giving them amoxicillin with their feeding regimen helps them to recover. “Nutritional recovery occurred in 65.9% of children in the amoxicillin group (790 of 1199) and in 62.7% of children in the placebo group (752 of 1200).” Makes you wonder: what is the fate of the third of children who have not shown “nutritional recovery” by week eight?

Long hours for junior docs
OL In the US, the New England Journal paper most discussed lately is a covertly randomised trial involving 117 general surgery residency programs. Programs were randomly assigned to current Accreditation Council for Graduate Medical Education duty hour policies or more flexible policies that waived rules on maximum shift lengths and time off between shifts. There was no difference in patient outcomes and, more surprisingly, there was none in residents’ satisfaction with overall wellbeing and education quality. The NEJM carries an editorial from John Birkmeyer concluding, “The FIRST Trial effectively debunks concerns that patients will suffer as a result of increased handoffs and breaks in the continuity of care. Rather than backtrack on the ACGME duty hour rules, surgical leaders should focus on developing safe, resilient health systems that do not depend on overworked resident physicians.” There is also a Perspective piece by Lisa Rosenbaum, which takes the opposite view, and spends a lot of time attacking those who have alleged that this trial lacked the consent of its participants. “The allegations, focused primarily on ‘serious health risks’ to residents from long shifts, are dizzyingly tautological.” I shall not comment further on this US issue. Things are different over there.

JAMA 2 Feb 2016 Vol 315
Sniffing big money
469 “The ‘super jab’ that is a breath of fresh air for allergy sufferers.” Should you chance not to have read the Daily Mail on 21 June 2014, you may need to be told that the product being puffed here is dupilumab. This is an antibody which binds to the alpha subunit of the interleukin-4 receptor, still awaiting US and European approval but lined up to be a blockbuster. Its makers are not letting the grass pollinate under their feet: they want people to use it for nasal polyps too.
“Sanofi and Regeneron Pharmaceuticals Inc, in collaboration with the academic clinical investigators, provided input on the design and conduct of the study; oversaw the collection, management, and statistical analysis of data; and contributed to the interpretation of the data and the preparation, review, and submission of the manuscript.” And they conclude: “Among adults with symptomatic chronic sinusitis and nasal polyposis refractory to intranasal corticosteroids, the addition of subcutaneous dupilumab to mometasone furoate nasal spray compared with mometasone alone reduced endoscopic nasal polyp burden after 16 weeks. Further studies are needed to assess longer treatment duration, larger samples, and direct comparison with other medications.”

Fish and Alzheimer’s
489 It was the monthly fish day in our little town yesterday. Jack from Selsey came with his overnight catch and I bought a fine turbot, three crabs, and a lobster. It has become a ritual for us to share pickings from his stall over white Burgundy with a friend or two. Sounds awfully middle class, I know, but this is a village in England and we are old. If I knew that this led to Alzheimer’s disease, I would still go ahead, because it is part of the essence of life to eat good fish in good company. Here is a brain pathology study (open access), which suggests that fish actually protects against Alzheimer’s. As investigators sliced through brains of deceased participants in the Memory and Aging Project and compared them with self-reported fish consumption, they found that moderate seafood intake correlated with lesser Alzheimer disease neuropathology. And if you are worried about mercury, note that “although seafood consumption was also correlated with higher brain levels of mercury, these levels were not correlated with brain neuropathology.” So maybe our chief medical officer should urge us to eat fish, while always remembering the cancer risk that comes with each glass of Chablis.

Smoking & collapsing airways
498 It’s easy to see how constantly inhaling smoke can damage the smaller airways and alveoli, but smoking affects the function of the central airways too, making them more likely to collapse on breathing out. This very macroscopic observation was made as investigators recruited participants to the COPDGene study across 21 centres in the US and examined CT images of their airways during inspiration and expiration. Central airway collapse greater than 50% of luminal area during exhalation was found in 5% and, not surprisingly, it correlates with worse respiratory quality of life.

JAMA Intern Med Feb 2016 Vol 176
My whatsit’s gone to pot
OL Verbal memory. That’s the expression. Sorry I couldn’t put my finger on it. This study finds that past exposure to marijuana is associated with worse verbal memory but does not appear to affect other domains of cognitive function. This is not the explanation in my case. It must be mercury from fish.

Adhering to the text
OL If you were doing a trial to improve medication adherence in people with chronic illness, what do you think would be the mean age of your participants? 67? 76? 80? In this meta-analysis of an intervention, the mean age was 39. Perhaps that’s because the intervention was mobile text messaging. There comes a certain age beyond which the pinging of a mobile phone simply produces short expletives. In these (mainly short) trials, phone text reminders doubled the odds of medication adherence by 50%, producing an absolute increase of 17.8%. Perhaps they also produced expletives, like “Sh*t, I’ve forgotten to take my gabapentin.”

Lancet 6 Feb 2016 Vol 387
OL I’m having to go to the Lancet website for material this week, as I’ve already commented on the relevant articles in the printed issue. I will go to work with a phase 2 trial of daratumumab in multiple myeloma. “As a result of this study, daratumumab was the first monoclonal antibody approved by the US Food and Drug Administration [FDA] for the treatment of refractory myeloma.” But it was a half-completed phase 2 study—can this possibly be right, or is it yet another example of the FDA’s rush to fast track everything in sight? Let’s read this from the perspective of the recruited patients with myeloma. They’ve been through severe pain and debility and a median five lines of previous therapy, including autologous stem cell stem transplantation in 80% of cases. They really are at the last ditch and they know it. The structure of this open label trial is complex and difficult to summarise. Of 106 patients who ended up getting 16mg/kg of daratumumab, 32 showed some response. I cannot completely decipher the reporting of outcomes in the text, but there was certainly a trend towards better survival in those who carried on with the drug. If I had myeloma, I think I would try it if I knew the alternative was certain death. But we’re told that 60% of non-responders were still alive at some unspecified time point over a year later, as opposed to 94% of responders. Elsewhere, presumably at a later point, we read that 29% of treated patients were dead. Please, please authors give us some meaningful flow charts and graphics that make some sense of all this. Was the FDA decision the right one? I really have no idea. I just don’t think the trial should have been reported at this point and in this way.

The BMJ 6 Feb 2016 Vol 352

Ben Goldacre’s terrific COMPare project tracks how trial outcomes are often switched in publication to make results appear more interesting/different/ significant, or indeed to produce results about things that the trial was never designed to examine in the first place. It’s simply amazing that the editors of a first rank journal like Annals of Internal Medicine when confronted with this replied that it was part of their job to select interesting outcomes and they knew best. Here is how honest outcome reporting should look:
“Despite being the largest and longest trial of physical activity in older people, the LIFE Study only had sufficient power to detect relatively large reductions in serious fall injuries. For the comparison of physical activity versus health education, the hazard ratio was 0.90 for serious fall injuries, which was a prespecified secondary outcome in the LIFE Study, and the rate ratio was 0.87. These null results were accompanied by a statistically significant 34% reduction in falls leading to persistent restricted activity, a finding that did not differ significantly between men and women.
In contrast to women, who showed no benefit, men randomized to physical activity experienced a 46% reduction in all serious fall injuries, including a 53% reduction in the rate of fall related fractures and a 59% reduction in the rate of fall injuries leading to admission to the hospital. Because the analyses were not prespecified, these sex specific results should be interpreted with caution and warrant replication in future studies.”
Apart from the relative rather than absolute percentages, this is close to perfect.

Benzodiazepines have been in the doghouse for decades, while we blithely prescribe psychotropic drugs with equally bad or worse effects. A prospective cohort study from Seattle puts to rest the idea that benzos cause dementia: “Over a mean follow-up of 7.3 years, 797 participants (23.2%) developed dementia, of whom 637 developed Alzheimer’s disease. For dementia, the adjusted hazard ratios associated with cumulative benzodiazepine use compared with non-use were 1.25 (95% confidence interval 1.03 to 1.51) for 1-30 total standardised daily doses; 1.31 (1.00 to 1.71) for 31-120 TSDDs; and 1.07 (0.82 to 1.39) for ≥121 TSDDs. Results were similar for Alzheimer’s disease. Higher benzodiazepine use was not associated with more rapid cognitive decline.”

Plant of the Week: Skimmia japonica “Magic Marlot”

A long time ago I was quite interested in skimmias, because they are absolutely undemanding, attractive little shrubs that will grow in the driest shade. Having found a favourite, Kew Green, I left them alone for a couple of decades, during which Dutch nurserymen have been busy creating new ones.

I came across “Magic Marlot” a few weeks ago and bought it at sight. Like most skimmias, it has a compact tight habit. This one is a dwarf that will probably never get to more than half a metre high and across. Its evergreen leaves have creamy white margins and it is covered in attractive conical heads of pink flower-bud. It will be a while before these open but they already hold promise of weeks of beauty and pervasive scent.

I have no doubt that somewhere you can already see rows of them along well tended bungalow drives. I don’t care. This is a beautiful, versatile plant that you can put anywhere you like. Any bit of it that ever breaks off can be made into a new plant. You can hide them invisibly under the darkest deciduous tree or shrub and they will reappear to cheer you through the winter and delight you in the spring. No one has a right to ask for anything better.