All you need to read in the other general journalsBMJ 2012; 344 doi: http://dx.doi.org/10.1136/bmj.e700 (Published 01 February 2012) Cite this as: BMJ 2012;344:e700
First two patients given retinal cells derived from human embryonic stem cells
Two women with severe macular disease have been given transplants of retinal pigment epithelium derived from human embryonic stem cells. Four months on, neither patient has signs of rejection, teratoma formation, or ectopic tissue, according to a preliminary safety report. All are potential dangers with transplants derived from embryonic stem cells, which can migrate, proliferate, and differentiate into unwanted cell types. The retinal pigment epithelial cells must be completely free from contaminating stem cells before transplantation, say the authors. These adults were given submacular injections of a pure suspension, with the primary intention of assessing safety.
The human retina is immunologically privileged, protected to some extent by the blood-ocular barrier. So it is a good anatomical site for early tests of a treatment derived from cells foreign to the recipient and grown using mouse fibroblasts. These are essentially xenotransplants, say the authors. The patients took immunosuppressants for at least 12 weeks, but they will not be immunosuppressed long term.
They were carefully selected for treatment, which took place in the US. One had dry age related macular degeneration. The other, who was younger, had Stargardt’s macular dystrophy. Both had severely impaired vision at the time of the procedure. Visual acuity improved slightly over four months in the treated eye of both patients. The authors also report slight improvement in the untreated eye of the patient with age related macular degeneration.
Visual improvements were subjective, say the authors. It is too early to say whether this treatment works. For now, all we can say is that the treatment is possible and seems to be well tolerated in the short term.
Dutasteride for men with low risk prostate cancer?
Inhibitors of 5α-reductase, such as GlaxoSmithKline’s dutasteride, are best known as treatments for benign prostatic hyperplasia. These agents can shrink the prostate gland and reduce serum concentrations of prostate specific antigen, and GlaxoSmithKline is currently exploring the possibility that dutasteride might also help men with small, low risk, prostate cancers, particularly those who opt for active surveillance⇑.
A daily dose of 0.5 mg dutasteride did slow the progression of low risk cancers in their first trial, which was placebo controlled, double blind, and lasted for three years (38% (54/144) progressed v 48% (70/145); hazard ratio 0.62, 95% CI 0.43 to 0.89). But a linked editorial (doi:10.1016/S0140-6736(12)60066-X) cautions against an overenthusiastic interpretation. Although dutasteride seemed to delay progression defined by the need for further treatment (surgery or radiotherapy), results from the trial’s most objective outcome—disease progression confirmed by prostate biopsies—were less clear cut. Blinding was difficult because the drug reduces prostate specific antigen concentrations, and the editorial insists that objective outcomes carry more weight. The trial was small and relatively short term compared with the natural course of low risk prostate cancer. Dutasteride can’t be recommended as a routine add on to active surveillance.
The ultimate goal should be to stop diagnosing low risk cancers, so we are not tempted to treat them, says the editorial. Risk calculators, better imaging, and a selective approach to prostate biopsies are all steps in the right direction.
Oral HPV is more prevalent in men
Human papillomavirus (HPV) causes oral and anogenital cancers. Almost 7% of US adults had oral infections in the latest round of regular national survey (6.9%, 95% CI 5.7% to 8.3%). One in 100 people were infected with the riskiest subtype, HPV-16 (1.0%, 0.7% to 1.3%)⇑.
Men were more likely to have oral HPV infections than women (10% v 3.6%; P<0.001) in this cross sectional survey. Overall prevalence went up in line with the number of sexual partners and the number of cigarettes smoked per day in fully adjusted analyses. Vaginal sex and oral sex were both implicated, although the significantly higher prevalence among men persisted after adjustments for sexual behaviour.
Prevalence varied with age, and the authors report a bimodal distribution in men, with the largest peak in men aged 55-64 when tested. The peak wasn’t explained by sexual behaviour or smoking, so infections may persist longer, or reactivate more often, in older men.
More than 5000 men and women aged 14-69 provided oral samples for HPV testing and answered questions about their sex lives. The authors hope their data will help explain why the US has seen a significant rise in oral cancers associated with HPV during the past three decades. The prevalence figures are also a baseline for future surveys tracking the effect of HPV vaccines and should help inform debates about whether to vaccinate boys and men, as well as girls and women.
Measuring cardiovascular risk over a lifetime
Diabetes, smoking, serum cholesterol concentrations, and blood pressure all contribute to a person’s risk of cardiovascular disease and death, which is usually measured over 10 years or less. These factors also dictate cardiovascular risk over a lifetime, say researchers, and have a similar impact on all age groups, from mid-life onwards⇑.
Data from 18 separate cohorts confirm that lifetime risk of a death from cardiovascular disease (or a non-fatal myocardial infarction) climbs steadily with every extra risk factor, measured in any age group. Among 55 year old men, for example, those (few) who did not smoke, did not have diabetes, and had “optimal” blood pressure and cholesterol concentrations had a 4.7% risk of dying from cardiovascular disease before the age of 80. This figure rose to 29.6% for men of the same age with at least two major risk factors. Risk factors seemed to have a comparable influence in men and women, both black and white, born earlier or later in the last century.
In other words, these four risk factors are more important than age, sex, race, or birth cohort, say the researchers. The lifetime chance of cardiovascular disease and death starts to climb as soon as risk factors become suboptimal—an untreated systolic blood pressure between 120 and 139, for example. Efforts to control cardiovascular disease should aim to prevent risk factors, not just treat them.
Exercise helps some adults with chronic illnesses and depressive symptoms
A new meta-analysis of 90 trials suggests that exercise can help lift the depression that often accompanies chronic illness. Exercise seemed to work best for adults with worse symptoms at baseline and for those who met recommended exercise targets. It also seemed to work better when patients’ functional abilities or related quality of life improved at the same time. The authors weren’t able to tell whether depression lifted before or after the functional improvements. Both are possible.
Overall though, the effect of exercise was modest in these trials (mean effect size 0.30, 95% CI 0.25 to 0.36). The trials were a mixed bag, testing a variety of interventions in adults with cardiovascular disease, chronic pain, fibromyalgia, cancer, or neurological diseases. Only three were designed primarily to look at depressive symptoms. None of the included patients had a clinical diagnosis of depression, although 34 trials included some people with highly suggestive symptom scores.
The authors weren’t able to identify the most effective exercise regimen, or the lowest “dose” likely to be effective, so the picture remains incomplete, despite the many dozens of trials in their review. Even more trials are needed to help fill the gaps, they write. Such trials should recruit more adults with clinical depression, use more objective outcome measures, and compare different intensities of exercise.
Lady health workers can manage severe pneumonia too, say researchers
Pakistan’s “lady health workers” already manage some young children with pneumonia, and the programme works particularly well in poor rural areas where parents have limited access to a clinic or hospital. These community health workers should also be allowed to treat more severe cases, say researchers. Young infants and children identified and treated at home by lady health workers did no worse than children referred to a local health facility, in a cluster randomised trial. The risk of treatment failure in the first week was slightly but not significantly lower in the intervention clusters (8% (187/2341) v 13% (273/2069); risk difference −5.2% (−13.7% to 3.3%)). Risk of relapse in the first two weeks was also comparable. There were just three early deaths in 4691 children under 5 years.
Lady health workers identified all cases of severe pneumonia. Those working within intervention districts gave children a short course of oral amoxicillin. In control districts they prescribed one dose of oral co-trimoxazole, before arranging referral and transport (current recommended practice). The lady health workers referred all children with danger signs, including those who were difficult to wake, vomiting repeatedly, or too ill to drink.
They were good at diagnosing severe pneumonia. About a fifth of the diagnoses were checked by a doctor. Agreement was more than 95% in the first 24 hours.
Carotid scans do not help smokers to quit
It is hard to quit smoking, and researchers recently tried to motivate smokers by showing them an ultrasound scan of their carotid arteries. More than half the smokers had carotid plaques, but after a seven minute tutorial spent looking at the scans and learning about the implications of carotid atherosclerosis, they were no more likely to quit smoking than controls who were not scanned (24.9% v 22.1%; P=0.45). The trial comprised 536 long term smokers, who were ready to give up. All participants received a comprehensive package to help them quit, including nicotine replacement and regular counselling. The trial lasted a year.
It was worth a try, says a linked editorial (doi:10.1001/archinternmed.2011.1948), but technological quick fixes are no substitute for human interaction. We should focus our efforts on improving the motivational content of doctors’ consultations instead. It may be harder to do, and trickier to evaluate, but there are probably no shortcut solutions to a complex addiction such as smoking. Communication skills in general, and motivational interviewing in particular, are sidelines in many medical training programmes. Both should be given more prominence at all levels, says the editorial. We have the tools to help all doctors master motivational interviewing, and we should deploy them. Relying on technology to change harmful behaviour is an expensive waste of scarce healthcare resources.
Cite this as: BMJ 2012;344:e700