Richard Lehman reviews the latest research in the top medical journals

NEJM  14 Jun 2018

Fluid for kids’ DKA

Diabetic ketoacidosis in children should be a never event, because it can lead to brain damage. But it happens. In this trial across 13 centres, a total of 1389 episodes of DKA were reported in 1255 children, but fortunately clinically apparent brain damage occurred in just 0.9% of these. The trial tested fluid replacement strategies in a 2×2 factorial design: 0.9% or 0.45% sodium chloride solutions given rapidly or slowly, and the primary outcome measure was a dip in the Glasgow Coma score. There was no difference between the four strategies: but then there weren’t many dips in the Glasgow coma score.

Double-edged dengue vaccine

For methodologists, this paper is a beauty: “In a case–cohort study, we reanalyzed data from three efficacy trials. For the principal analyses, we used baseline serostatus determined on the basis of measured (when baseline values were available) or imputed (when baseline values were missing) titers from a 50% plaque-reduction neutralization test (PRNT50), with imputation conducted with the use of covariates that included the month 13 anti-NS1 assay results. The risk of hospitalization for virologically confirmed dengue (VCD), of severe VCD, and of symptomatic VCD according to dengue serostatus was estimated by weighted Cox regression and targeted minimum loss–based estimation.” Now if you didn’t actually read that bit, read this: “CYD-TDV (the vaccine) protected against severe VCD and hospitalization for VCD for 5 years in persons who had exposure to dengue before vaccination, and there was evidence of a higher risk of these outcomes in vaccinated persons who had not been exposed to dengue.” Now read it again, substituting “but” for the “and”. Yes, the message is that this dengue vaccine worsens outcomes in those who have never previously had dengue. Ah. This is not really what you want from a vaccine.

Mediterranean diet study: wrong but right?

Strange things are happening in the NEJM these days. The latest is a republication of a corrected “landmark” Mediterranean diet paper after a British sceptic had called it out for statistical impossibility. It turns out that there had been some cross-contamination at one site, where recipients of olive oil were jealous of recipients of nuts, or vice versa, but the conclusion of the study remains unchanged in its second New England Journal appearance: “In the intention-to-treat analysis including all the participants and adjusting for baseline characteristics and propensity scores, the hazard ratio was 0.69 (95% confidence interval [CI], 0.53 to 0.91) for a Mediterranean diet with extra-virgin olive oil and 0.72 (95% CI, 0.54 to 0.95) for a Mediterranean diet with nuts, as compared with the control diet.” I’m no statistician, but I’m baffled by the appearance of adjustment for baseline characteristics and propensity scores. Aren’t these supposed to be rendered unnecessary by proper randomization and trial size? Which raises the basic question: is it actually possible to conduct a meaningful dietary trial in a free-living population?

JAMA 12 Jun 2018

Negative pressure negative

By applying continuous negative pressure to a wound, you can stop blood and fluid accumulating and encourage granulation tissue. What’s not to like? Well, the fact that according to this British trial, it makes no difference to self-rated healing at 12 months. This was in 226 people with severe lower limb fractures, compared with 234 who received standard dressings. So the use of continuous negative pressure devices for severe trauma will probably be discouraged in the NHS. But I wouldn’t be surprised if they continue to sell briskly in other settings. A medical device with a plausible sales pitch is a very hard thing to counter with mere evidence.

Depressed by all these pills

“Too Many Pills” is the title of a new book by James Lefanu, whose thoughtful analysis of medical news is usually bestowed on readers of the Daily Telegraph. Although I am not myself a Telegraph reader (surprise), I am enjoying his stylish prose and forthright condemnation of overprescribing driven by five factors: hypertension, raised cholesterol, diabetes, osteoporosis and the cardiac cocktail, all of which should be in quotation marks. Although “depression” does not appear in the book’s index, a number of the drugs he mentions have depression as a known adverse effect. Had this paper on depression caused by polypharmacy arrived in time, I am sure he would have cited it. The estimated prevalence of depression in over 29,000 people was 15% for those reporting use of 3 or more medications (with depression as a potential adverse effect) vs 4.7% for those not using such medications. These patterns persisted in analyses restricted to adults treated with antidepressants, among hypertensive adults, and after excluding users of any psychotropic medication.

JAMA Intern Med June 2018

Contaminated by humans

Are you, or have you ever been, a vector? In both the bacteriological and physical senses of this strange word, the answer has to be yes. Vector in Latin just means carrier. We move around in a cloud of billions of personal microbes, but only rarely do these harm other people. In houses of the sick (Gk: nosokomoi), however, we can be vectors for some pretty deadly nosocomial organisms. Strangely, this principle of personal infectivity appears to have been recognised long before the germ theory of disease. Hence the quarantining of ships in the lagoon of medieval Venice; the isolation of the village of Eyam in the English plague year of 1665; the astonishing success of Haygarth’s strictly governed fever hospital in Chester in the 1780s. Yet the lesson has to be learned anew in every generation. “This qualitative study of 325 patient rooms with precaution signage found frequent and varied active failures in infectious agent transmission (sic) precaution practices by hospital personnel, including violations, mistakes, and slips.” This study calls itself qualitative, but it is just as much quantitative: it is full of numbers, but also full of insights derived from watching people and talking to them. Call this what you will, but it is exactly the sort of paper which not only identifies a problem, but analyzes it in a way that clinicians can identify with. Would that The BMJ would take note and actively seek articles like this instead of relegating them to the bottom of its heap.

A magnificent editorial by Leora Horwitz drives home how vitally important such insights can be.

Ann Intern Med 12 Jun 2018

Retroviral suppression and cancers

A prospective cohort study of American military veterans (98% male) sought to find out the effect of long-term HIV suppression on the incidence of cancers. In men these are Kaposi sarcoma and non-Hodgkin lymphoma, with invasive cervical cancer thrown in for women. In this context, these are called “AIDS-defining cancers” (ADC) though this seems misleading to me. All other cancers are pooled as NADC. Based on a comparison of 42,441 HIV positive veterans v 104,712 who were HIV negative, followed up for 25 years, antiretroviral therapy resulting in long-term viral suppression may contribute to cancer prevention, to a greater degree for ADC than for NADC. But people with long-term viral suppression still had excess cancer risk.

The Lancet 16 Jun 2018

AAA and the delusive effect of screening

Screening for abdominal aortic aneurysm in old men makes a lot of sense. Repair of leaking AAA carries a mortality of about 30% which hasn’t changed since I last felt blood trickle into my surgical boots 40 years ago. Elective repair, on the other hand, has become much safer. Of course, with the numbers involved, you couldn’t expect a screening programme to affect all-cause mortality, but it would be certain to improve AAA-specific mortality. Except that it doesn’t. In places where screening was introduced, such as some counties of Sweden, AAA-specific mortality fell from 36 to 10 men per 100,000. In the counties where it was not introduced, the fall was the same.

And a similar story came out of Western Australia two years ago.

“Screening was associated with increased odds of AAA diagnosis (aOR 1·52) and an increased risk of elective surgery (aOR 1·59), such that for every 10 000 men offered screening, 49 men (95% CI 25–73) were likely to be overdiagnosed, 19 of whom (95% CI 1–37) had avoidable surgery that increased their risk of mortality and morbidity.” Stop it. It causes harm. Don’t offer it, unless you want to start a half-hour conversation about the counterintuitive harms of screening, which most people find impossible to understand.

Upadacitinib for RA

Rheumatoid arthritis isn’t quite the drug market it used to be. It can often be aborted by early conventional treatment, and if not, there is a range of “biological” treatments on offer, principally tumour necrosis factor α blockers. And then what? A lifetime of chronic disabling illness may follow, and there are some other drugs worth trying, but with unpredictable success. The latest is upadacitinib, an orally available selective Janus kinase 1 (JAK1) inhibitor made by AbbVie who designed, conducted and analyzed two trials which are on the Lancet website. Mean duration of disease in the first was 13.2 years, and the placebo-controlled trial lasted 12 weeks. 

“Both doses of upadacitinib led to rapid and significant improvements compared with placebo over 12 weeks in patients with refractory rheumatoid arthritis.” Bingo! But, “During the placebo-controlled phase of the study, one case of pulmonary embolism, three malignancies, one major adverse cardiovascular event, and one death were reported in patients receiving upadacitinib; none were reported in patients receiving placebo.” Considering the patients had already had the disease 55 times longer than the duration of the trial, that’s a bit worrying, isn’t it? But in fact fears are somewhat allayed by the second trial, in which patients continued their previous treatment and took added upadacitinib. There was still an increased incidence of serious infection and malignancy in the active groups but it was much less striking. But again, the duration of treatment was a mere 12 weeks. Longer trials should be mandatory before widespread use of this drug.

The BMJ 16 Jun 2018

COPD and telephone coaching

I’ve only been in the Institute of Applied Health Research at the University of Birmingham for a few months, and already it has produced two outstanding negative trials of well-intentioned public health interventions. The first was a schools-based obesity control programme, and now comes this study of self management of patients with mild chronic obstructive pulmonary disease in primary care. This was based on telephone health coaching intervention delivered by nurses, underpinned by Social Cognitive Theory. Now Social Cognitive Theory would have us believe that people will follow plans that they themselves have a part in formulating; but the finding that struck me most when I heard the principal investigator present the results was that the majority of people with COPD resisted the idea of coming up with any sort of plan. In the context of the trial, with its sequence of telephone calls, they improved their inhaler technique and became more active, but there was no improvement in their health-related quality of life over the course of a year.

Paternal antidepressants and kids’ outcomes

The idea that the drugs that dads take when they impregnate mums can affect their offspring is worth testing. In the case of antidepressants, Swedish registry analysts came up with a reassuring blank: paternal intake of antidepressants during the period around conception is safe with respect to the risk of the four major adverse outcomes in offspring—preterm birth, malformation, autism, or intellectual disability.

Plant of the Week: Campanula cochlearifolia “Tubby”

This is one of those plants you just have to buy for its name. Its tubbiness consists in having slightly fatter flowers than your average Campanula cochlearifolia. We love these little fellows, which should decorate the edges of every garden border and wall.

The transparent blue flowers of Tubby are almost identical to those of the harebell (Campanula rotundifolia) which grows in the walls of Rievaulx Abbey and other sacred (and secular) walls of northern England. In fact it grows everywhere in a circumpolar belt around the Northern Hemisphere, and it is a tough perennial, though I have never tried it in a garden. Tubby looks smaller and stronger, but that’s deceptive: he can sulk and die in bad years. Probably due to slugs.

There is a white version of Tubby as well.