Richard Lehman’s journal review—3 August 2015

richard_lehmanNEJM 30 July 2015 Vol 373
405 This week’s first paper has an interesting title: Therapeutic Hypothermia in Deceased Organ Donors and Kidney-Graft Function. It’s the first time I’ve seen the word “therapeutic” used to describe something done to a person who is already dead. The hypothermia they refer to here occurs in a newly deceased cadaver. The currently recommended alternative is to maintain heat in the cadaver until the kidneys are harvested. This is what it means when it says “after declaration of death according to neurologic criteria, donors were assigned by means of computer-generated block randomization to mild hypothermia (34 to 35°C) or normothermia (36.5 to 37.5°C).” So it’s the whole body and not just the kidneys: I’m labouring the point because it took me a few minutes reading the paper to work it out myself. The result of the trial shows that cooler is better. It was stopped early at the point when delayed graft function had developed in 79 recipients of kidneys from donors in the hypothermia group (28%) and in 112 recipients of kidneys from donors in the normothermia group (39%) (odds ratio, 0.62; 95% confidence interval, 0.43 to 0.92; P=0.02).

438 Now for Antisense Inhibition of Apolipoprotein C-III in Patients with Hypertriglyceridemia. Reading this title fills my brain with summer afternoon torpor. Let’s go through it backwards. A lot of people have levels of triglycerides in their blood above what is considered “normal,” usually as a result of some other metabolic disturbance, or sometimes for genetic reasons. Severe hypertriglyceridaemia can probably cause pancreatitis and may be a cardiovascular risk factor in its own right, though it is hard to tell. Apolipoprotein C-III (APOC3) is a regulator of lipoprotein metabolism, which lives in the liver and circulates in the plasma: the more of it you have, the higher your triglycerides. In fact, APOC3 levels correlate better with cardiovascular risk than TGs themselves. And now for antisense inhibition, and the new drug we’re talking about. “ISIS 304801 is a second-generation antisense oligonucleotide that is designed specifically to reduce levels of APOC3 messenger RNA (mRNA). Hybridization of ISIS 304801 to its cognate mRNA, through Watson–Crick base-pair interactions, causes ribonuclease H1–mediated degradation of the target mRNA to prevent production of the APOC3 protein.” Read that several times: I’m sure it makes perfect antisense. So on to the actual phase 2 trial of ISIS 304801. The highest dose produced an 80% drop in TG levels. This stuff certainly does what it set out to do: whatever else it does to the people who will take it for years, time and properly designed studies will tell. To say anything more at this stage would amount to antisense.

456 “Chagas’ disease is caused by the protozoan parasite Trypanosoma cruzi, which is transmitted when the infected feces of the triatomine vector are inoculated through a bite site or through an intact mucous membrane of the mammalian host.” That’s enough! I have heard all I need to about this gross and disgusting process. But please read on, especially if you are planning to visit South America. This is a really comprehensive and excellent review.

OL Dengue fever is another disease you might risk getting as a traveller to the hotter parts of South America, and an increasing number of other places. There is no effective vaccine. This paper describes the three to six year results of a trial of a CYT-TDV dengue vaccine by Sanofi Pasteur. In year three, there were actually more kids under the age of 9 needing hospital admission for dengue in the vaccinated group. In other years there were fewer. Not a resounding success then, as the editorial explains. Its tone is not entirely ecstatic: “There is some comfort in the fact that CYD-TDV vaccination did not increase the frequency of genuinely severe, life-threatening complications (e.g., dengue shock syndrome) . . . The CYD-TDV trials have been superbly conducted and are hugely informative; they have delivered major insights into disease burden, clinical epidemiology, and immunity. They have also highlighted knowledge gaps, since we still lack definitive immune correlates of protection or vaccine-associated disease risk. A lesson from these trials, and from our understanding of the natural history of dengue epidemiology, is that partial, waning immunity is a particularly unwelcome outcome after vaccination.”

JAMA 28 July 2015 Vol 314
355 In the Budget Speech of 1948, the Chancellor announced the imminent arrival of the National Health Service “with a song in his heart.” He had no money to pay for it and no idea of what it would cost. That did not matter: money could be borrowed from the US, and provision of universal free healthcare was a moral issue, not a financial one. In the US itself, no such thing occurred. The closest to universal federal cover it got was when Lyndon Johnson introduced Medicare for over 65s in July 1965. This week’s JAMA is devoted to celebrating its 50th birthday (plus that of Medicaid for the poor). Now we are used to thinking of the US healthcare economy as one of spiralling costs and stagnant outcomes. But of the Medicare population since 1999, this is not true. A masterly survey by Harlan Krumholz concludes: “Among Medicare fee-for-service beneficiaries aged 65 years or older, all-cause mortality rates, hospitalization rates, and expenditures per beneficiary decreased from 1999 to 2013. In the last 6 months of life, total hospitalizations and inpatient expenditures decreased in recent years. Health outcomes related to hospitalizations appear to have improved substantially in the last 2 decades.” But America should aspire for more. Perhaps in another 50 years, it could achieve the life expectancy, universal coverage, and cost/outcome ratio of the NHS.

JAMA Intern Med July-August 2015
OL The National Lung Screening Trial showed a reduction on mortality from lung cancer by using three annual screenings with low dose CT in high dose subjects. Even hardened screening sceptics had to take notice. We regrouped, and argued that this might not be replicable in a non-trial setting, and that the burden from overinvestigation of “intermediate” lesions might prove insupportable. Above all, most lung cancer is preventable by smoking cessation. Would the existence of a screening programme provide false reassurance and act as a disincentive to cessation? Here’s a qualitative study of 35 smokers, which seems to show that about half of them would be less likely to stop now that screening is available to “prevent” cancer. So without a transformation in public understanding, there is a risk that a screening programme might do more harm than good. Always bear in mind that screening is detection, not prevention. And smoking does a lot more harm than just causing lung cancer.

Ann Intern Med July-August 2015
OL About 15 years ago, I thought I might dabble with some kind of research to do with high blood pressure. But the more I looked, the more uncontrollable variables I seemed to find, operating over a timescale that would see me long in the grave. This study looks at just one of them, which is relatively neglected: visit to visit variability (VVV). It’s a post-hoc analysis of the ALLHAT trial and it shows that VVV in both systolic and diastolic pressure is an independent risk factor for fatal CHD or nonfatal CHD, all cause mortality, stroke and heart failure. Could this be mediated by aortic stiffness and/or compliance problems? What about pulse pressure? I could go on and on. It is an ouroboros. A snake that devours its own tail. And what’s the elephant in the room of “hypertension”? How to identify the 400 out of 405 who will never benefit from treatment.

OL A few weeks back, I tried to do a Zoroastrian moral analysis of the placebo effect. This time let’s stick to the science. Here’s a systematic review and network meta-analysis of different treatments for knee pain due to osteoarthritis, done in two different ways. Their “differential” model found that intra-articular and topical therapies were superior to oral treatments in reducing pain. But using a model that took no account of differences in treatment delivery, oral nonsteroidal anti-inflammatory drugs were superior. As the accompanying editorial says, Reaffirmation of ‘Needle Is Better Than Pill.’” At least in how your knee feels, which is the main thing.

Lancet 1 August 2015 Vol 386
452 Why do some drugs end in -cetrapib? And what exactly do they do? The answers lie in the cholesterol esterase transfer protein (CETP). The idea is to inhibit it and thus lower LDL cholesterol and raise HDL cholesterol. CE TRAnsfer Protein InhiBitors. The new superstatins? Not actually, since torcetrapib had to be withdrawn due to excess mortality, and dalcetrapib failed to deliver. The jury remains out on anacetrapib and evacetrapib. And yet, as rapidly as they disappear, new ones come along to replace them. This one is called TA-8995, and the Lancet has decided to print a short term phase 2 trial funded by the manufacturer, Dezima. In patients with mild dyslipidaemia, the drug did its job and showed great success in turning their LDL into HDL. Whatever else it might do, we will learn in due course. Perhaps TA-8995 should be called metucetrapib: after all, it’s clearly a me-too drug.

461 Lithium. Now there’s an enigma. Its nuclei were formed at the time of the Big Bang and it remained the only metal in the Universe until the stars began to form and explode. It’s abundant in a lake in Bolivia, and in the medicine cabinets of people with bipolar disorder. For a decade or more, all requests for lithium levels from my practice would arrive in the laboratory of Brian Shine, who is principal author of this study. Surprisingly, it’s the first long term study based on laboratory data. Brian’s go back to 1985 and tell us of what lithium does to renal function, thyroid function, and serum calcium levels over an extended time at various levels of dosage and monitoring. Unfortunately, though it remains the best mood stabiliser, lithium treatment is associated with a decline in renal function, hypothyroidism, and hypercalcaemia. Women younger than 60 years and people with lithium concentrations higher than median are at greatest risk.

The BMJ 1 August 2015 Vol 351
The first intervention to promote hand hygiene in hospitals was a short treatise by Alexander Gordon in 1795. Nobody read it and it had no effect. Wonderful, witty Oliver Wendell Holmes repeated the attempt with a privately published treatise in 1855. This merely provoked the response from his professor that “Obstetricians are gentlemen, and gentlemen have clean hands.” Ignaz Semmelweiss introduced caustic chlorinated lime handwashes on his maternity wards in the 1840s and raged at anyone caught entering without them. He called his fellow practitioners murderers. He published his own book in 1862. This also failed to popularise the procedure. So we can read this systematic review of the comparative efficacy of interventions to promote hand washing in hospitals knowing what definitely does not work: publishing obscure treatises, insulting colleagues, and using washes that take the skin off people’s hands. The 21st century approach recommended by the World Health Organization comprises system change, training and education, observation and feedback, reminders in the hospital, and a hospital safety climate. This network meta-analysis proves that these work. Now this would have really pleased John Haygarth of Chester, who first came up with something remarkably similar in his Fever Hospital Rules of 1783.

Now for a trial of balance training to prevent falls and injuries in women aged 75 and over. It is called Ossébo. In Ghana? Or Sweden? No, the accent is the giveaway: Ossébo is French. And actually it’s not a place at all: it’s an intervention used in a collaboration of 20 sites in 16 medium to large cities throughout France. The vielles de ces villes were randomised to a two year progressive balance retraining programme combining weekly group and individual sessions, or (in the control group) just advice brochures and six monthly reminders. In the course of the trial there were 305 injurious falls in the intervention group and 397 in the control group (hazard ratio 0.81, 95% confidence interval 0.67 to 0.99). So a modest benefit that just reached statistical significance, using a fairly intensive long term intervention. Probably a good idea, though.

Plant of the Week: Tamarix ramosissima

There’s a spring flowering tamarisk which carries sprays of pink flower on arching leafless branches—a lovely sight, but just one of many in late May. Besides, that tamarisk—tetrandra or parviflora—grows very large and can’t be cut back or it won’t flower.

We planted this late summer flowering one instead, ages ago. It was crowded by a tree in poor soil and never did much. But with a bit of pruning and feeding, it’s doing splendidly now. The feathery branches with their tiny green leaves are pleasant in themselves, and for weeks they are now interspersed with flower bearing wands. Their pink goes well with deeper crimsons and also with whites or blues. You can keep this shrub to the size you want, too, as it flowers on new growth.

August break: These reviews will be back in two or three weeks, when I’ve had a break.

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