Richard Lehman reviews the latest research in the top medical journals
NEJM 18 Jan 2018 Vol 378
A Neglected Epidemic
“Imagine a global epidemic with more than 10 million new cases and 1.7 million deaths in a single year, far greater than the 28,600 cases and 11,315 deaths that were caused by Ebola virus disease in West Africa in 2014 and 2015.” So begins a trenchant short commentary called “A Neglected Epidemic” by Barry Bloom which accompanies an Australian trial report demonstrating the superiority of active over passive case-finding for tuberculosis in Vietnam. The White Death* is still with us, and now exceeds HIV/AIDS and malaria as the largest cause of mortality from an infectious disease in the world. It’s entirely predictable that by going into households and finding cases you will achieve better control than if you simply wait for people to come to clinics. Anyone who has watched Ken Burns’ harrowing history of the Vietnam War can’t help thinking that if the USA had its priorities right, it might be righting a historic wrong by eliminating TB from Vietnam: it’s entirely doable with the right health system and affordable drugs. But o silly me: such things are not to be found in present America.
*Title of a wonderful polymathic history of TB by Thomas Dormandy, 1999.
Hot chemo for ovarian cancer
Over three decades, tumour reduction surgery for stage III ovarian cancer has been combined with chemotherapy given before or after resection, and the chemo regimens of carboplatin and paclitaxel have been given either intravenously or intraperitoneally, or by both routes. Sadly there is no sign of this being about to change; but this Dutch trial does clearly demonstrate a useful advance in deploying combined treatment. The trial tested the relatively new technique of hyperthermic intraperitoneal chemotherapy (HIPEC), which consists of extra carboplatin put into the peritoneum during surgery, delivered under hyperthermic conditions. Heat enhances the toxic effects of the chemo on tumour cells but surprisingly did not increase adverse effects for the patients. In this complex open-label trial, median overall survival was 33.9 months in the surgery group and 45.7 months in the surgery-plus-HIPEC group.
It’s a MGUS game
Monoclonal gammopathy of uncertain significance is what it says on the can. This observational study addresses some of the “uncertain significance” bit but leaves quite a lot behind. MGUS is an excess of gamma globulin which may or may not progress to malignancy (mostly myeloma). In this cohort of 1384 cases from Olmsted County the median age at diagnosis of MGUS was 72, and the median follow-up was 34 years. So these data are as good as you are likely to get for a mainly white middle-American population. Having MGUS reduced life expectancy by a little over 4 years, and most of this reduction was not attributable to disease progression.
In ancient cultures, each human pleasure tended to be allocated its own deity. The Aztec goddess Cihuacoahuatl took care of tobacco: indeed her body was made of it. That tobacco causes pleasure is indisputable, and I was delighted when “electronic cigarettes” were introduced as a method of rendering it less harmful. Smoking tobacco is a terribly dangerous way of enjoying it: vaping tobacco may not be completely harmless but it is vastly safer. Yet when e-smoking was introduced, it was immediately frowned on in the USA and in some circles within the UK. Fortunately Public Health England, supported by Action on Smoking and Health and the Royal College of Physicians, saw the potential for harm reduction and came out in favour in 2015. Here for the first time was a way of safely delivering nicotine by the traditional route and the little bursts which smokers enjoy. And despite their enjoyment, most use it as a way of breaking their addiction altogether. The English attitude is praised in a short article in the NEJM, and I’m pleased to see that The BMJ has at last reversed its censorious stance and published an excellent evidence-based review of electronic cigarettes for smoking cessation. The coming of these devices is a huge leap forward for two reasons: first, it helps people to get a nicotine hit without killing themselves, and secondly it removes any excuse for combustible tobacco products to remain legally available.
JAMA 16 Jan 2018 Vol 319
Eating is another human pleasure that used to be deified and is now demonised. Here is an issue of the Journal of the American Medical Association devoted to obesity. There is no sadder sight in America than a huge poorly dressed mother with three hugely obese preadolescent children outside Dunkin Donuts. Life has never had any comfort to offer them but this. Life will never offer them anything else but a cycle of this. Forget behavioural interventions administered by healthy people with nice homes; forget bariatric surgery, which would have to be offered free to a third of the US population to make any difference. I think the commonest cause of obesity is despair.
Everyone is programmed to seek a way out of despair, and one route is acceptance. Once you put on fat, mammalian physiology is overwhelmingly tuned to keep it there. After a few cycles of trying to lose it by painful effort, most people give up. When a whole society becomes fat, fatness is the new normal. Since the threshold year of 1980, it has gradually become almost unAmerican not to be overweight. Fortunately the President has managed to stay overweight but not obese, thanks to growing a half-inch. In general height, I mean. But this is not a route available to most Americans, who are left having to try and embrace their inner fatness: the subject of a nice commentary piece in this exceptional issue of JAMA.
The one intervention that definitely works for obesity is bariatric surgery, and most of the issue is taken up with trials and observational studies of it. I challenge any reader with the time and the graphic skills to summarize all this (including the surgical differences and uncertainties) into a decision aid for people of different ages and levels of glycaemia. Impossible? And yet this is the “shared decision making” we are told to do in every consultation. Clinicians need a great deal more help if that is to become a reality.
The bariatric procedure with the best long-term results is Roux-en-Y gastric bypass. Now that gastric banding has become discredited, the main competing procedure is sleeve gastrectomy. Both procedures can be done laparoscopically and the sleeve procedure is somewhat easier to do. A randomised trial (SLEEVEPASS) shows that loss of excess weight with either procedure is about 50% at five years.
Comparisons from Israel
In this retrospective cohort study of 8385 patients who underwent bariatric surgery and 25 155 matched patients who received usual care, the mortality rate over approximately 4.5 years was 1.3% among surgical patients compared with 2.3% among nonsurgical patients.
Sleeve gastrectomy was associated with the lowest all-cause mortality, but the low absolute numbers preclude reliable comparison.
Roux-en-Y for diabetes
This is a follow-up study of 120 people with type 2 diabetes and obesity who were randomised to surgery or intensive non-surgical care. It measured the surrogates of BMI, HbA1c, lipid profile, and systolic BP. The surgical group showed better control of these but the effect diminished over 5 years.
The acronym of this Swiss trial suggests some form of strict discipline, but in fact it’s another comparative trial of sleeve gastrectomy vs Roux-en-Y bypass for morbid obesity. Once again the two provide very similar 5-year weight reduction.
Norway and the down side
Observational data from 1888 very obese Norwegians who sought surgery: those who had it had 16% higher rates of further GI surgery, 4.7% more peptic ulcers and 14% more iron deficiency anaemia. On the other hand, they had better control of weight, BP and glycaemia.
I’ve given you this very brief run-down, but now for the spoiler: you’d do much better to read the excellent commentaries which cover these papers in JAMA itself.
The Lancet 20 Jan 2018 Vol 391
Slaying the eyeworm with moxidectin
My memories of student lectures on tropical diseases are populated by people with huge legs and testicles, missing noses, worms in their bowels and skin, and by starving blind beggars sitting by mud roads. None of this should still be happening in 2018, but a lot of it still does. River blindness, for example, which is one manifestation of onchocerciasis, a disease caused by the helminth Onchocerca volvulus. It used to exist in pockets of Central and South America but has been virtually eradicated using ivermectin. But it still badly affects some of the world’s most disadvantaged communities, 99% of which are in remote, rural areas in sub-Saharan Africa. It might be possible to eliminate onchocerciasis in these communities, but ivermectin is not an ideal drug for the job, partly because it can cause severe reactions in people co-infested with Loa loa. Now there is an alternative drug, moxidectin, which proved superior at eliminating filarial worms from the skin when given as a single oral dose in this trial.
Bring it on. The only point of money and human existence is to make the world a better place.
The BMJ 20 Jan 2018 Vol 360
How to cause opioid addiction after surgery
Somehow these reviews have got dominated by lethal comfort-seeking addictions and their associated gods. Morpheus, son of the sleep-god Hypnos, is an obscure Greek deity known only from a reference in Ovid’s Metamorphoses. He was in charge of dreams, and had thousands of offspring. But in the early nineteenth century his name was given to an alkaloid of poppy isolated by the German pharmacist Friedrich Wilhelm Adam Sertürner, which he called morphium. In English it was generally called morphia, and in a purer form it became morphine. From the start it became obvious that if you took more than a few doses, you were likely to crave more and to get withdrawal effects if you couldn’t get any. And you got all the thousand dreams which Morpheus was fabled for. This had been known of opium for centuries, but became a literary sensation when described by Sertürner’s contemporaries Coleridge and de Quincey. And now here’s a study which rediscovers the obvious.
Post-operative patients in the USA given opioids for the first time become addicted in direct proportion to the duration of opioid use. In keeping with The BMJ‘s light-touch editing of American copy, we are told that “The analysis quantifies the association of prescribing choices on opioid misuse and identifies levers for possible impact.” Identifies levers for possible impact. Oh for a person from Porlock.
Why can’t diagnostic research address reality?
Reader, have you ever made a diagnosis? How did you manage it? Did you listen to the patient? Examine her/him? Did you do any tests? Sequentially, or a whole bunch at a time? Yes, you did all these things, singly or in combination, often with ten or twenty people a day, sometimes getting the patient to come back for another go. It’s so complex and so fast that it’s miraculous we can do it at all. We function as rapid Bayesian machines, with a lot more thrown in. You’d think a science of diagnosis would take this into account. A few noble people have tried, but mostly we’re stuck in the old sensitivity/specificity/predictive value territory with a single test at a time, compared with something called a gold standard (if such exists). This is usually done badly, and when people try to do more, it often gets worse. “We show that increasing the number of tests used to define a composite reference standard can worsen its accuracy, leading to underestimation or overestimation of the new test’s accuracy. Further, estimates based on composite reference standards vary with disease prevalence, indicating that they may not be comparable across studies.”
Plant of the Week: Galanthus nivalis
Flowering snowdrops signal new life and promise the delight of a new season. They are the first fruits of them that sleep.
Perhaps fittingly, we saw our first open snowdrops this year in the garden of a crematorium. In real life, snowdrops form multitudinous clumps, promiscuous, exuberant and generous during their short woodland glory. But here among the low brick buildings, the lawns and dignified advertisements for headstone masons, they were set in pairs in tiny round beds among tastefully chosen winter pansies. They were temporary, manageable and impoverished, like the short life stories, clipped poems and little pieces of music that form modern goodbye rituals in the surrounding buildings.
Best so, perhaps. I had known Doug and Judy Gray for 49 years. The music and the tributes in their short leave-taking were entirely in keeping with the love and simple decency they showed throughout their long lives. Doug welcomed me to read English when I came to Oxford and had become fazed at the thought of doing a degree in Human Physiology, a subject which made even less sense in 1969 than it does now. Hidden in his room among fan heaters and books, he rarely offered an opinion but instilled in me a lasting adoration of English medieval literature, the people of New Zealand and self-effacing scholarship. He was elevated to create a new professorship at Oxford, but he never learnt the least pomposity and continued to live his life in a small terraced cottage where he would dispense wine at all times of day and Judy would cook sublime meals in the evenings. He even introduced me to his mushroom picking haunts (rarest of gifts!) and every year for many autumns in succession we would snuffle among the undergrowth together.
Let there be many snowdrops where his ashes are scattered with Judy’s.