Richard Lehman’s journal reviews—26 March 2018

Richard Lehman reviews the latest research in the top medical journals

richard_lehmanNEJM 22 Mar 2018

H pylori eradication and metachronous stomach cancer

Metachronous—what does that mean? The trouble is that like a lot of Greek prepositions, μετα can indicate a whole range of things, and there is no modern word beginning in “meta-” which would not be clearer with a different prefix. A metachronous cancer is one of the same type that is diagnosed more than three months after the first, according to some sources. So: some of the early ones are probably synchronous but hadn’t been detected, while others appearing later are new cancers of the same type. How about using the simpler word “subsequent”? Both occurrences are frequent in stomach cancer, which used to be the commonest cancer in the West but declined swiftly and is now most prevalent in the Far East. The reason for this is one of the unsolved mysteries of epidemiology. Could it be something to do with subtypes of Helicobacter pylori? Evidence that this ubiquitous bug plays a role comes from a trial in South Korea, which randomised 470 patients who had undergone endoscopic resection of early gastric cancer or high-grade adenoma to receive either H. pylori eradication therapy with antibiotics or placebo. The treated group had lower rates of metachronous—i.e. subsequent—gastric cancer and more improvement from baseline in the grade of gastric corpus atrophy than patients who received placebo. 

High flow oxygen for infant bronchiolitis

Oxygen makes the sky blue and burns things up. Generally speaking, we are best to breathe it diluted with nitrogen. One exception is in severe bronchiolitis up to the age of 12 months. The standard treatment to keep oxygen saturation levels between 92-98% is to use a standard nasal cannula delivering 2L of pure oxygen per minute. If that doesn’t work, babies have traditionally been admitted to intensive care to receive higher doses of oxygen by intubation. However, it’s now possible to deliver a higher flow of oxygen mixed with heated, humidified air through nasal cannulae, providing a degree of positive airways pressure in addition to more O2. A large Australia-New Zealand trial shows that used as first-line treatment, this can spare some babies with bronchiolitis and hypoxia from ICU admission and intubation.

Autoimmune polyendocrine syndromes

I have always been a dabbler, and expect I shall die one. Most of medicine is quite interesting, but to confuse it with life is a basic category error. When I was newly qualified in the mid-1970s, one of the few clinical topics which really intrigued me was the new science of immunology, and in particular how this played out in a few individuals that I came across with multi-endocrine disease. This review shows how far we have(n’t) got in 40+ years: “Autoimmune polyendocrine syndromes are insidious and are characterized by circulating autoantibodies and lymphocytic infiltration of the affected tissues or organs, eventually leading to organ failure. The syndromes can occur in patients from early infancy to old age, and new components of a given syndrome can appear throughout life. There is marked variation in the frequencies and patterns of autoimmunity in affected patients and their families, and the risk of the development of various organ-specific autoimmune diseases is most likely due to a combination of genetic susceptibility and environmental factors.” Ah, yes, quite so: I was right to go into general practice instead. But maybe this new classification indicates some progress: “We have now come to appreciate that these syndromes can be broadly categorized as rare monogenic forms, such as autoimmune polyendocrine syndrome type 1 (APS-1), and a more common polygenic variety, autoimmune polyendocrine syndrome type 2 (APS-2).”

JAMA 20 Mar 2018

Honey, I shrunk the P value

Being a lazy-minded dabbler, I have never really been able to engage with statistics. My problem with maths has always been that I need to understand what the end-goal is before I can engage with the process. P-values and confidence intervals are easy to understand, if one is a believer in a one-in-twenty standard of disproof of the null hypothesis. But I’ve always felt that it’s crazy to apply this across all types of hypothesis tested by a variety of methods. For this reason, the P-value has fallen into wide disfavour in the last three years or so. Why was it ever so popular in the first place? And would we be better off to demand a test of proof that is ten times stronger? In fact this would make surprisingly little difference, as John Ioannidis explains in this classic essay, which is open-access and well worth downloading.

JAMA Intern Med Mar 2018

Treating postmenopausal vulvovaginal symptoms

I can’t do better than quote the Key Points section of this trial

“302 postmenopausal women with moderate-to-severe vulvovaginal symptoms, vaginal 10-μcg estradiol tablet plus placebo gel and vaginal moisturizer plus placebo tablet were not more efficacious than dual placebo at reducing symptom severity or improving sexual function.

Meaning: Shared decision making for treatment of postmenopausal vulvovaginal symptoms can be based on cost and patient formulation preference; vaginal estradiol tablets appear not to add benefit beyond vaginal gel or moisturizer.”

But as the accompanying editorial comments:

women and their physicians may want to take this one step further and conclude that postmenopausal women experiencing vulvovaginal symptoms should choose the cheapest moisturizer or lubricant available over the counter—at least until new evidence arises to suggest that there is any benefit to doing otherwise.”

Ann Int Med 20 Mar 2018

America declines

“Cardiovascular health has declined in the United States, racial/ethnic and nativity disparities persist, and decreased disparities seem to be due to worsening cardiovascular health among whites rather than gains among African Americans and Mexican Americans.” So concludes an analysis of data from the NHANES (National Health and Nutrition Examination Survey). We can’t just blame the Republicans: this survey covered 1998 to 2014. We can’t blame pre-existing cardiovascular disease either, because these adults didn’t have any. And as we’ve seen from the wording, we can’t blame institutional racism, because the decline is worst in the poorer white population. As with all the problems arising from decreasing demand for unskilled labour, neither American party has a policy for addressing this.

The Lancet 24 Mar 2018

Sirolimus for SLE

Another underpowered, open-label phase 1/2 trial in The Lancet this week; but at least it addresses a clinical dilemma in what can be a horrible disease. It took from 9 March 2009 to 8 December 2014 to enroll 43 patients, three of whom did not meet eligibility criteria. 11 of the 40 eligible patients discontinued study treatment because of intolerance (n=2) or non-compliance (n=9). However, patients with treatment-resistant systemic lupus erythematosus who stuck with sirolimus treatment showed clear signs of improvement in the course of a year and were able to reduce their doses of steroid. This is the stuff of hope, but nowhere near to proof.   

Atraumatic adoption

I began this week’s reviews by proposing the abolition of meta- as a prefix. I include meta-analysis; a clumsy cacophonous word which was adopted because it once seemed new and clever. It isn’t really. It often disguises a pointless exercise in combining evidence about a variety of end-points arising from different procedures done in different contexts. Not so this one: the population consists of anyone undergoing lumbar puncture and the choice is simple and binary. You either have it done with a conventional needle or an atraumatic needle. 110 trials were done between 1989 and 2017 from 29 countries, including a total of 31 412 participants. These are just the better ones. For about a couple of decades it’s been perfectly clear that atraumatic needles produce fewer post-LP headaches and hospital admissions. So why isn’t everyone using them? A good question for your next EBM class. Evidence reaches a tipping point and becomes proof (discuss), but that does not equate with adoption (discuss).

The BMJ 24 Mar 2018

Dipeptidyl peptidase-4 inhibitors and IBD

Like everyone else, I keep having to look up the difference between pharmacokinetics and pharmacodynamics, but I have no problem with pharmacovigilance. Except that it should be done much better. For uncommon associations, like dipeptidyl peptidase-4 inhibitors and inflammatory bowel disease in this instance, there should be an alarm cohort and a replication cohort, as in genome-wide association studies. There should be a special set of statistical tests. Maybe someone is already on to this—I am making it up as I go along. But I’m struck by how many papers on emerging drug harms have conclusions like this one: “In this first population based study, the use of dipeptidyl peptidase-4 inhibitors was associated with an increased risk of inflammatory bowel disease. Although these findings need to be replicated, physicians should be aware of this possible association.” Is that really good enough, when there are so many replication databases around for comparison? This study was based on the UK Clinical Practice Research Dataset: in 2018 it really shouldn’t need more than a Skype call to Taiwan or Denmark to check if it’s happening over there too. Physician awareness is a poor substitute for actual data.

Plant of the Week: Teucrium fruticans “Compactum”

The ordinary form of the shrubby germander is a big tousled thing which can get to 2m high and across. It needs full sun and preferably a bit of wall protection. It has aromatic grey leaves and blue flowers almost the whole year round. We’ve always had one because it is such a delightful thing for leaf and flower, but they’ve been a devil to keep under control and often sulk after pruning and die in cold winters.

But now a more desirable form has appeared, which is nowhere near so large and not at all straggly. It is just about the prettiest thing in the garden at the moment, with lots of emerging clear blue flowers which sit perfectly next to the pinks of a young Daphne bholua. It would also be lovely next to daffodils.

Ours was planted last year but has proved perfectly hardy through a bitter winter by a low wall. This form of T fruticans might well be a good substitute for lavender if grown as an edging shrub in the open. But at the slightest brush-past it will shed some broken stems. Turn this to your advantage and stick them carefully in compost or soil: they will all strike, and soon you will have dozens of new plants to use or give away.