Richard Lehman’s journal review – 6 June 2011

Richard LehmanJAMA  1 June 2011  Vol 305
2184   Diabetes is a state of increased risk for many things, including fractures. The most striking thing I learnt from this study is that a man on insulin treatment has double the fracture risk for any given level of bone mineral density. The additional risk is less dramatic in women, whether you measure it against a BMD measurement by dual energy X-ray absorptiometry or against the FRAX score. The data were obtained from three prospective studies of older adults with type 2 diabetes. I guess this should lead us to have a lower threshold for prescribing bisphosphonates to elderly men who use insulin, though I am not aware of any hard data about DEXA screening and fracture prevention in this group.

2193   I’m about to leave these shores for several months attached to America’s leading outcomes research unit, who in the past have found that hospital mortality rates for some conditions can show a definite diurnal and weekly pattern according to staffing levels. This study by a different team looks at whether the same applies to thoracic organ transplants. It doesn’t. Should I find myself in need of a new heart or lungs on a Sunday evening in the USA, I can relax.

2200   The lure of new biomarkers can be irresistible: I should know. As I’ve told you before, I suggested to a GP partner in the mid-1990s that he should do a study of coeliac disease in primary care using the newly available endomysial antibody test, so that forever after people would quote Hin et al. as a landmark paper. And it came to pass even as I spake. I, on the other hand, decided to work on the newly available marker for “heart failure”, B-type natriuretic peptide. People (including David Sackett) do still quote my little paper with its simple 2×2 table, but just to show how you cannot validate a diagnosis of treated HF in the community using a single random sample of BNP. Now it so happens that EMA is a test for coeliac disease that has ideal predictive properties – 100% against duodenal biopsy in Harold Hin’s original cohort, where the immunoassay for antibody was created from fresh monkey oesophagus. Subsequent studies have found sensitivities and specificities in the high 90% region, probably because the substrate for the assay is less refined in normal practice. By contrast BNP is highly variable according to minute-to-minute loading conditions in either ventricle and nobody has yet found a dependable clinical use for it.  Now we can turn to this article, a comparative study of effect sizes for biomarkers. You should not be surprised to learn that it finds a consistent overestimation of the predictive value of these surrogates in highly cited original articles as compared with subsequent meta-analyses. The associated editorial is called ” The Thin Line Between Hope and Hype in Biomarker Research”  and it points out that ” No new major cancer biomarkers have been approved for clinical use for at least 25 years.” Most discouraging: if you have been reading the Daily Mail, you will have been told that British scientists have discovered an infallible diagnostic test for cancer every week over this entire period.

NEJM  2 June 2011  Vol 364
2111   Now the context in which the predictive values of a diagnostic test come under greatest pressure is whole population screening. Think PSA: and then consider this new polymerase chain reaction saliva test for cytomegalovirus in the newborn. The “gold standard” against which PCR was assessed is rapid viral culture from fresh saliva, and its sensitivity was 100% and its specificity 99.9%. The prevalence of CMV in these newborns was 5 per thousand. The point of detecting it is to make sure that these babies are carefully followed up for sensorineural deafness, which will eventually affect 10-15% of them. So this saliva PCR is a great screening test which, combined with regular audiometry and early speech therapy, may help to improve outcomes in one child in 30,000.

2119   Another study of an innovative treatment for advanced cancer here illustrates (a) that progress is slow and incremental and (b) that a month of additional life generally costs £1-5K, though the amount is hard to calculate in this trial of gp100 Peptide Vaccine and Interleukin-2 in Patients with Advanced Melanoma. The principle here is that melanomas are usually immunogenic and we can use interleukin-2 to boost the immune response: maybe we can boost it even further by means of a vaccine that results in very high levels of circulating T-cells. And so it was: patients of mean age 50 with advanced melanoma (but no brain metastases) of the commonest HLA type lived six months longer if given the vaccine in addition to IL-2.

2128   I shall try not bore you with too much US hospital outcomes research, but all those of us who refer patients for high-risk surgery need to keep abreast of the volume-quality debate and I think there are generalisable lessons from this study. I’ll let the authors sum up: “Wide variations in outcomes across hospitals suggest further opportunities for improvement. For a small number of procedures associated with particularly strong direct volume–outcome relationships, such as pancreatectomy and esophagectomy, referral to high-volume centers should continue to be encouraged. For most high-risk procedures, however, strategies such as operating-room checklists, outcomes-measurement and feedback programs, and collaborative quality-improvement initiatives are likely to be more effective than volume-based referral.”

2138   “During breakfast at 8 a.m. his wife saw him slump over and fall from the chair to the floor. He was unable to speak and could not move his right arm or leg.” The patient in this vignette is 81 and he is used to illustrate the topic of Intravenous Thrombolytic Therapy for Acute Ischemic Stroke. If he receives intravenous tissue plasminogen activator, he is perhaps 10% more likely to make a better recovery. But if this were me in 20 years’ time, and I had the ability to choose what I wanted as an intravenous bolus, I doubt whether it would be tPA. 

Lancet  4 June 2011  Vol 377
1929    It’s in The Lancet; it was paid for by Sanofi-Aventis; so what hype can we look forward to in the Abstract of this trial? “Interpretation: TAMARIS provided no evidence that non-viral 1 fibroblast growth factor is effective in reduction of amputation or death in patients with critical limb ischaemia. Thus, this group of patients remains a major therapeutic challenge for the clinician.” So an honestly reported RCT with a negative outcome – sad for the company, sadder for the patients, but good news for the integrity of this journal.

1938   Of course The Lancet has other virtues – half this week’s is taken up with global issues that rarely feature in the leading US journals – but it does like a good tabloid story about high-tech advances of dubious importance. An exceptionally fit young man with paraplegia receives exceptionally intense treatment for an exceptional length of time and manages to stand for 4.25 minutes with assistance for balance. This can only happen when a 16-electrode array stimulates his spinal dura. We have seen it on the telly: we believe, but it’s hardly the Miracle at the Pool of Bethesda. 

BMJ  4 June 2011  Vol 342
1249    In patients with chronic back pain, don’t mess with the spine unless you really have to. That is the message of the editorial accompanying this Norwegian study comparing the insertion of a disc prosthesis with rehabilitation in patients with degenerate discs. The two year results failed to reach clinical significance, and the operation is potentially hazardous. As Jeremy Fairbank points out in his commentary, this is unsurprising since 75% of people with low back pain have degenerate discs, whereas among people without back pain, 80% have degenerate discs. Degeneracy is rife, and always has been.

1250   More hospital outcomes research from North America: the relation between emergency department waiting times and short term mortality and hospital admission following discharge from the ED in Ontario, Canada. In other words, what happens to patients who either discharge themselves or get sent home after assessment at very busy times in A&E. They fare distinctly worse, as you might expect; and although this study deserves points for originality, it is crudely observational and more analytical prospective work is needed to tease out the exact reasons why.

1251    This excellent account of the assessment and management of insomnia in primary care is written by four New Zealanders, reminding us that the kiwi is a nocturnal bird, noted for its natural modesty and long beak. We are also reminded of the possibility of secondary insomnia (e.g. depression, obstructive sleep apnoea) and the need to take a proper history. There is a useful chart of the half-lives of common benzodiazepines and a reminder that it is wrong to prescribe sedative antidepressants merely to avoid the obloquy of being labelled an easy dispenser of benzos.

Plant of the Week: Campanula persicifolia

As I look out at our little back garden in Oxfordshire, I wonder which plants I shall most miss while in New England. The problem is that I have no idea what grows best in New England, though I shall learn quickly enough since our apartment overlooks a botanical garden.
The plots that surround our English house are ever in danger of wildness and neglect, and our best friends are the plants that sow themselves wherever there is bare earth: Labrador violets, oriental hellebores and primroses in the spring, and thereafter valerians, opium poppies, evening primroses, white mallows, meadow geraniums and these lovely peach-leaved campanulas. They are welcome wherever they chance to take root, waving long stems of pure white or clear blue open bells. These will continue to liven the garden right until the autumn, or, as I must learn to call it, fall.