News in brief

Large study shows BMI link to cancer risk
A LARGE UK population cohort study has found associations between body mass index (BMI) and the risk of developing some common cancers, although effects varied substantially by cancer type. The research, published in The Lancet, used data from GP records to identify more than five million people aged 16 years and older who were cancer free at baseline, who were followed for an average of 7.5 years for associations with 22 common cancers, adjusting for individual risk factors such as sex, menopausal status, smoking and age. A total of 166 955 people developed one of the 22 cancers over the follow-up period, and BMI was associated with 17 of these cancers. With BMI included as a linear effect and adjusting for all potential confounders, the researchers found that for each 5 kg/m² increase in BMI there was a large increased risk of cancer of the uterus, gallbladder, kidney and liver, and smaller increases for colon, cervical, thyroid, ovarian and postmenopausal breast cancers and leukaemia. “Even within normal BMI ranges, higher BMI was associated with increased risk of some cancers, accentuating the public health implications in view of the overall increase in population BMI distributions in several countries”, the researchers wrote. They found BMI had a net inverse association with risk of premenopausal breast and prostate cancers, and in lung and oral cavity cancers. An accompanying commentary said there was now sufficient evidence that obesity was “an important cause of unnecessary suffering and death from many forms of cancer”, as well as the well recognised increased risks of mortality and morbidity from many other causes. “More research is not needed to justify, or even demand, policy changes aimed at curbing overweight and obesity”, the commentary said.

Salt blamed for 1.65 million deaths
A MODELLING study, published in the New England Journal of Medicine, has estimated that there were 1.65 million global deaths from cardiovascular (CV) causes in 2010 that could be attributed to sodium consumption above a reference level of 2.0 g per day. The authors used systematic searches for previously conducted national or subnational surveys on individual-level sodium consumption based on urinary excretion, estimated dietary intake, or both. They estimated that in 2010, the mean level of sodium consumption worldwide was 3.95 g per day, with substantial variations across individual countries ranging from 2.18 g to 5.51 g a day. “Overall, 181 of 187 countries — 99.2% of the adult population in the world — had estimated mean levels of sodium intake exceeding the World Health Organization recommendation of 2.0 g per day, and 119 countries — 88.3% of the adult population in the world — exceeded this recommended level by more than 1.0 g per day”, they wrote. The researchers used the dose–response effects on blood pressure (BP) and cardiovascular mortality, and cause-specific deaths to estimate the effect of current sodium intake on worldwide mortality. They wrote that although there was debate on whether the effects of sodium on BP could be directly extrapolated to CV risk, “the effect on cardiovascular disease is supported by extensive experimental and ecologic evidence, data on cardiovascular events from some trials of reduced sodium intake, and evidence of the cardiovascular benefits of blood-pressure lowering across multiple interventions”. In another study, published in the same issue of the NEJM, based on morning fasting urine samples from 101 945 participants in 17 countries and estimated 24-hour sodium and potassium excretion, researchers found an estimated sodium intake between 3 g and 6 g per day was associated with a lower risk of death and CV events than was either a higher or lower estimated level of intake. An accompanying editorial said the results from the articles “highlight the need to collect high-quality evidence on both the risks and benefits of low-sodium diets”.

Cancer benefits of bisphosphonates questioned
POST-HOC analyses of two large randomised clinical trials (RCTs) assessing the relationship between bisphosphonate use for osteoporosis and postmenopausal breast cancer incidence have found 3‒4 years of treatment with either alendronate or zoledronic acid did not decrease the risk of invasive breast cancer. The results of the trials, published in JAMA Internal Medicine, differed from earlier reports of a protective effect in several observational and case-control studies, and a meta-analysis of those results, which suggested postmenopausal women taking bisphosphonate, particularly alendronate, had a 32%‒39% decreased risk of breast cancer. The Fracture Intervention Trial (FIT) randomly assigned 6459 women aged 55‒81 years to alendronate or placebo for a mean follow-up of 3.8 years, and the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly–Pivotal Fracture Trial (HORIZON-PFT) randomly assigned 7765 women aged 65‒89 years to annual intravenous zoledronic acid or placebo for a mean follow-up of 2.8 years. The researchers found no significant difference in the rate of breast cancer in FIT with 1.5% (n = 46) in the placebo group and 1.8% (n = 57) in the alendronate group. HORIZON-PFT also showed no significant difference in breast cancer rates with 0.8% (n = 29) in the placebo group and 0.9% (n = 33) in the zoledronic acid group. “Our analyses found that treatment with neither alendronate nor the more potent zoledronic acid reduced the risk of breast cancer”, they wrote. “The discrepancy between the observational studies and our randomized trial results may represent an example of confounding by indication.” An accompanying editorial said while the findings from the trials highlighted why it was important for new therapies to be evaluated using RCTs, “they also reinforce the importance of assessing the methodological rigor of observational studies before interpreting real-world effects”.

Limit to exercise benefits
ANALYSES to test whether more exercise is associated with progressively lower mortality after a cardiac event suggest that the benefits of running or walking do not accrue indefinitely. The research, published in the Mayo Clinic Proceedings, found that above a certain level, which the authors estimated as running more than 7.1 km a day or briskly walking more than 10.7 km a day, there was a significant increase in cardiovascular (CVD) mortality and ischaemic heart disease (IHD) deaths. The researchers used Cox proportional hazard analyses to examine mortality versus estimated energy expended by running or walking measured as metabolic equivalents (3.5 mL O2/kg per minute per day or metabolic equivalent of task-h/d [MET-h/d]) in 2377 self-identified heart attack survivors, where 1 MET-h/d was the energy equivalent of running one km/day. A total of 526 deaths occurred during an average prospective follow-up of 10.4 years, of which 376 (71.5%) were related to CVD. “The reason for the increased mortality among the most active exercise cohort … is unclear”, the researchers wrote. “It occurred despite lower CVD risk factors in this group, suggesting that the risk was not due to more or accelerated atherosclerosis. However, the increased risk appears to be specific to IHD-related deaths, rather than dysrhythmia related deaths.” An accompanying editorial said that exercise was “unparalleled for its ability to improve CV health, quality of life, and overall longevity”. However, as with any powerful therapy, “establishing the safe and effective dose range is fundamentally important — an insufficiently low dose may not bestow full benefits, whereas an overdose may produce dangerous adverse effects that outweigh its benefits”.

Concerns for soldiers in PTSD criteria changes
A COMPARISON of screening questionnaires for post-traumatic stress disorder (PTSD), published in The Lancet Psychiatry, shows a high percentage of soldiers who met the diagnostic criteria of PTSD in the Diagnostic and Statistical Manual of Mental Disorders — fourth edition (DSM-IV) did not meet the criteria in DSM-5, released in 2013. The researchers compare the new 20-item PTSD checklist in DSM-5 with the original validated 17-item specific stressor version to assess 1822 US infantry soldiers, including 946 soldiers who had been deployed to Iraq or Afghanistan. An analysis of all soldiers found 224 (13%) screened positive for PTSD by DSM-IV criteria and 216 (12%) by DSM-5 criteria. In soldiers exposed to combat, 177 (19%) screened positive by DSM-IV and 165 (18%) by DSM-5 criteria. Of 221 soldiers with complete data who met DSM-IV criteria, 67 (30%) did not meet DSM-5 criteria, and 59 additional soldiers met only DSM-5 criteria. The researchers wrote that from a clinical and policy perspective, their findings raised “fundamental concerns as to whether changing the PTSD definition (a definition proven to be highly useful in guiding treatment for more than 25 years) will enhance diagnosis and clinical care, and what this means for current and future generations of veterans”. An accompanying commentary by Professor Alexander McFarlane, from the Centre for Traumatic Stress Studies, University of Adelaide, said the findings drew attention to the hazards that changes in diagnostic criteria could have on the administration of veterans’ benefits and access to care. “We think there should be a period of transition between legal use of DSM-IV and DSM-5 so that potential effects of these changes can be examined and that deserving individuals are not denied their legal rights”, Professor McFarlane wrote. “There is an obligation not to let this unintended consequence of a fashion of psychopathological formulation prevail.”

Drugs used by shift workers lack evidence
A COCHRANE review has found only low-quality evidence on the effects of pharmacological interventions used by shift workers to reduce sleepiness or to improve alertness and decrease sleep disturbances both during and off work. The review included 15 randomised placebo-controlled trials with 718 participants. Nine trials evaluated the effect of melatonin and two the effect of hypnotics for improving sleep problems. One trial assessed the effect of modafinil, two assessed the effect of armodafinil, and one examined caffeine plus naps to decrease sleepiness or to increase alertness. The researchers found low-quality evidence that melatonin might improve sleep length (mean increase 24 minutes) after a night shift but not improve other sleep parameters. There was moderate-quality evidence to show modafinil and armodafinil increased alertness and reduced sleepiness to some extent during the night shift in employees who experienced shift work sleep disorder but both drugs were associated with adverse events. Pre-shift caffeine plus pre-shift naps increased alertness during the night shift, but this was based on just one small trial. One low-quality trial of hypnotic medication, zopiclone, was included but it was not shown to significantly affect daytime sleep length. “Based on the available evidence, it is unclear whether or not hypnotics improve sleep length and quality after a night shift”, the researchers wrote. “Melatonin may improve sleep length after a night shift but may not improve other sleep parameters … Given the low quality evidence, additional placebo-controlled trials of melatonin are needed. Trials should use objective electrophysiological monitoring of sleep length and quality.” They also called for more randomised control trials on the use of caffeine for shift workers under field conditions, which should also measure adverse effects. Long-term adverse effects of modafinil and armodafinil should be studied in cohort and case–control studies, they wrote.