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Dr Linda Calabresi

Ischaemic stroke patients are less likely to deteriorate mentally if they take ginkgo biloba extract in addition to low-dose aspirin in the acute phase, a new study suggests. “Cognitive decline after stroke can result in vascular cognitive impairment and Alzheimer’s disease,” the study authors wrote. Importantly then, this randomised controlled trial showed stroke patients who took ginkgo as well as aspirin had better memory function, executive functions, neurological function and daily life in the six months after experiencing their stroke than those patients who took aspirin alone. The Chinese study also showed that taking ginkgo was not associated with an increased incidence of adverse events. The results of the study, published in the journal, Stroke and Vascular Neurology support the long-held hypothesis that ginkgo protects against neuronal death caused by ischaemia, which had been demonstrated in animal stroke models. It has been suggested that the possible mechanism of ginkgo’s effectiveness may include anti-apoptosis and increasing cerebral blood flow. In the study, researchers randomised over 340 patients, from five hospitals who had had an ischaemic stroke in the previous seven days to receive either 450mg of ginkgo biloba extract with 100mg aspirin daily or only the 100mg of aspirin daily. Both groups were treated for six months and were various intervals over that period. From the very early assessments (at 12 days) and through until 180 days, the difference in the assessments of cognitive and executive function was statistically significant. Similarly neurological and global function was significantly better in the group that took ginkgo. “These data suggest that [ginkgo biloba extract] is effective and could be recommended in the treatment of acute ischaemic stroke,” the study authors concluded. Ref: Li S, et al. Stroke and Vascular Neurology 2017; 0:000104. doi:10.1136 /svn-2017-000104

Emeritus Prof Simon Chapman AO

Using prescription drugs or over-the-counter products like gums, mints or patches won’t increase your chances of quitting smoking a year later, according to a new study. The US researchers followed two groups of people 2002/03 and 2010/11 and found at the end of the 12-month period, those using varenicline (sold in Australia as Champix), bupropion (Zyban), or nicotine-replacement therapy (gums, mints or patches) were no more likely to have quit smoking for 30 days or more than those who didn’t use these drugs.
Read more – Weekly Dose: Champix’s effectiveness is questionable and safety record is concerning

Evidence based smoking cessation?

We’re told the best way to quit smoking is to use an “evidence-based” method: a strategy supported by high-quality research evidence. And for the last 30 or so years, this has been nicotine-replacement therapy, bupropion (Zyban) and varenicline (Champix), which claim to increase (and sometimes double) your chance of success. In the hierarchy of evidence, the lowest form is anecdote or case studies (“I smoked for 20 years, then an alternative therapist sprinkled magic powder on me, and the next day I stopped smoking!”). These cannot withstand the most elementary critical appraisal, starting with the basic question of how many similar smokers sprinkled with the powder kept smoking and how many who went nowhere it also stopped smoking. Far higher up the evidence pyramid is the double-blinded, randomised controlled trial (RCTs). In these, both the person taking the treatment and those delivering it are unware of who is taking the active drug and who is taking the comparison placebo or comparison drug. All enrolled in RCTs are randomly allocated to the active or placebo/comparison groups. The numbers of participants are sufficiently large enough to allow for an outcome to be declared statistically significant (or not) above a chance finding.
Read more – Randomised control trials: what makes them the gold standard in medical research?
Some have tried to dismiss earlier findings about the poor performance of nicotine-replacement therapy by emphasising “indication bias”. In the real world, those who opt to use medications to try to quit are likely to be more intractable smokers, more highly addicted to nicotine, and with histories of failure at quitting unaided. No one should therefore be surprised if they fail more often than those who try to quit on their own. In this new study, this issue was anticipated and all smokers were assessed by what the study authors called a “propensity to quit” score. This score accounts for factors such as smoking intensity, nicotine dependence, their quitting history, self-efficacy to quit, and whether they lived in a smoke-free home where quitting would likely be more supported. In the analysis, those who tried to quit with drugs and those who didn’t were matched on this propensity score, so “like with like” could be compared in the analysis. The findings held even when these “propensity” to quit factors were taken into account.

RCTs are very different to real world use

Critics have long pointed out that RCTs have many features which make them a pale shadow of how drugs are used in the real world. RCTs often exclude people with mental illness, poor English, and no fixed address. Excluding hard-to-reach and treat participants is likely to produce more flattering results. In the real world, people are not paid or otherwise incentivised to keep taking the drugs across the full period of the trial, so compliance is almost always far lower. In the real world, people do not get reminder calls, texts or visits from researchers highly motivated to minimise trial drop-out. There is no “Hawthorne effect”: when trial involvement and the attention paid to participants alters the outcomes. Nicotine-addicted people generally know very quickly if they have been allocated to the placebo arm in NRT trials because their brains feel deprived of nicotine. They invariably experience unpleasant symptoms. Knowing they have been allocated to the placebo undermines the integrity of the trial because it is important participants believe the drug might be effective. Large, real world studies like the one just published, which assess long-term success, not just end-of-treatment or short-term results, are therefore of most importance in assessing effectiveness. These new data ought to cause such rhetoric to cool right down. As for the evidence on e-cigarettes in quitting, neither the US Preventive Health Services Task Force, nor the UK’s National Institute for Health and Care Excellence or Australia’s National Health and Medical Research Council, have endorsed e-cigarettes as an effective way of quitting smoking.
Read more: Want to quit smoking? Switching to e-cigarettes no advantage
Quitting smoking is the single most important thing anyone can do to reduce the likelihood they will get heart or lung disease, and a whole string of cancers. It has been in the clear interests of the pharmaceutical and, more recently, the vaping (e-cigarette) industries, to promote the notion that anyone who tries to quit alone is the equivalent of someone with pneumonia refusing antibiotics. Hundreds of millions around the world have quit smoking without using any pharmaceutical intervention. Before nicotine-replacement therapies became available in the 1980s, many millions of smokers successfully quit smoking without using any drug or nicotine substitute. The same still happens today: most ex-smokers quit by going cold turkey. The ConversationThe problem is, in recent years, the government has moth-balled the national quit campaign, the megaphone for promoting this very positive message. Commercial interests are now commodifying something millions have always done for themselves. Simon Chapman, Emeritus Professor in Public Health, University of Sydney This article was originally published on The Conversation. Read the original article.
Dr Linda Calabresi

Breast cancer survival has improved dramatically over the last few decades. Courtesy of earlier diagnosis and better treatments, five year survival has increased from 70% in the 1980s to 90%, says Melbourne medical oncologist, Dr Jacqueline Chirgwin in the latest issue of the MJA. It is little wonder then that there is now increased focus on the ongoing general health in this ever-growing population of breast cancer survivors. “Although breast cancer is worldwide the most common cancer in women, many, perhaps most patients die from other causes,” she says. Dr Chirgwin’s comments are in relation to an Australian study, published in the same issue of the journal which showed comorbid conditions are more likely to develop in women who have been diagnosed with hormone-dependent breast cancer than in women without cancer. The South Australian researchers reached this conclusion after analysing a random sample of PBS data from a cohort of women who commenced endocrine therapy at some time in the eight years from 2004 and compared that with age and sex matched controls who weren’t taking anti-cancer treatment. Conditions significantly more likely to develop in the breast cancer women included depression, pain or pain-inflammation, osteoporosis, diabetes, cardiovascular disorders and gastric acid disorders. As the study authors point out there are a number of very logical reasons why these conditions are more likely in this particular group of women. For example it is hardly surprising that someone given a diagnosis of breast cancer might subsequently develop depression and be prescribed antidepressants. Similarly a number of the cancer medications may contribute to comorbidities such as cardiovascular disease, osteoporosis and musculoskeletal pain, in addition menopausal hormone therapy is contraindicated. In addition some risk factors for breast cancer are the same risk factors for other chronic conditions such as heart disease and diabetes, namely excessive alcohol consumption, obesity and physical inactivity. And while the findings might not be all that surprising, the researchers suggest that we are missing a major opportunity to target this at-risk group in a manner which will ultimately improve their health outcome, independent of the breast cancer. “As most women diagnosed with breast cancer in Australia can now be cured, the burden of non-cancer comorbidities is becoming a major health concern for these patients, but this is still largely unrecognised. Future breast cancer research should focus on strategies that effectively respond to the burden imposed by these comorbidities,” they concluded. Ref: MJA doi:10.5694/mja17.00006 doi:10.5694/mja17.00938

Dr Linda Calabresi

Taking fish oil supplements to prevent a heart attack has always been somewhat controversial. However, a new meta-analysis, involving almost 78,000 high risk individuals has provided the best evidence to date that the practice is not worthwhile. (1) The UK researchers analysed the data from 10 trials which had investigated whether taking omega-3 fatty acid supplementation reduced the risk of fatal and non-fatal coronary heart disease as well as other vascular events including stroke. According to the study findings, published in JAMA Cardiology, those individuals randomised to omega-3 fatty acid supplementation for a mean of 4.4 years experienced no significant benefit in terms of preventing adverse vascular outcomes compared with those who did not receive supplementation. “Importantly, this meta-analysis also demonstrated no significant effect on major vascular events in any particular sub-groups, including prior vascular disease, diabetes, lipid levels, or statin use,” the study authors wrote. They suggest that the results of this study provide no support for the recommendations to use approximately 1g/d of omega-3 fatty acids in patients with a history of coronary heart disease to prevent heart attacks or any other vascular disease, which is the current advice from American Heart Association. Our own Australian Heart Foundation guidelines have been a little more circumspect with regard omega-3 fatty acids. While they do suggest supplementation for people whose diet is lacking in fish sources of EPA and DHA, they do say the cardioprotective benefit may be only for some high-risk groups. “There is evidence omega-3 supplements can play a beneficial role in the treatment of patients with high triglyceride levels and patients with existing heart disease, specifically heart failure,” according to their website. (2) Whether this advice is set to change remains to be seen. However, while this latest study might seem like the nail in the coffin for the fish oil business there is an important caveat to consider. The trials included in the meta-analysis involved various doses of omega-3 fatty acid supplementation. All but one trial included combinations of EPA and DHA, with the one exception being a trial of EPA supplementation alone. Daily doses of EPA ranged from 226 to 1800 mg/day and DHA doses varied from 0 to 1700mg/day. Several large randomised controlled trials, involving over 50,000 participants are currently underway investigating whether much higher doses of omega-3 fatty acids will reduce the risk of major cardiovascular events. Even the authors of this latest meta-analysis concede “The results of the ongoing trials are needed to assess if higher doses of omega-3 fatty acids (3-4g/d) may have significant effects on risk of major vascular events.” Ref: 1. JAMA Cardiol. doi: 10.1001/jamacardio.2017.5205 2. https://www.heartfoundation.org.au/images/uploads/main/Programs/Health_Professional_QA_Fish_Omega3_Cardiovascular_Health.pdf

Dr Linda Calabresi

Skin abscesses are best treated with incision and drainage plus antibiotics, rather than just incision and drainage alone, recommends an international guideline panel in the BMJ. After critically appraising all the current evidence, the panel found adjuvant antibiotic therapy in addition to incision and drainage of uncomplicated skin abscesses reduced the risk of treatment failure and abscess recurrence by approximately 13% compared to treatment without additional antibiotics. In particular the randomised controlled trials included in the review, were evaluating the use of clindamycin or trimethoprim-sulfamethoxazole (TMP-SMX) in addition to incision and drainage. “TMP-SMX or clindamycin modestly reduces pain and treatment failure and probably reduces abscess recurrence, but increases the risk of adverse effects including nausea and diarrhoea,” they said. TMP-SMX is the more preferable option over clindamycin as it is less likely to cause diarrhoea, they added. The recommendation is in contrast to most of the current guidelines that generally advise uncomplicated skin abscesses be treated with incision and drainage alone except in cases where there is systemic illness, extensive tissue damage, immunocompromising conditions, an artificial joint or a high risk of endocarditis. And while the panel concedes that the benefit of adjuvant antibiotic therapy is modest, they anticipate that most fully informed patients would consider it large enough to choose it over incision and drainage alone. Of course, the major counter argument against increasing antibiotic use would be the possible increased risk of antimicrobial resistance. “From a societal perspective, it is possible that the modest benefits from adjuvant antibiotics in this scenario would not outweigh the risk of antimicrobial resistance in the community,” they said. However, the impact of a single course of antibiotics on this public health problem remains unknown, so any conclusion about net benefit versus net harm can only be speculative, they concluded, even though the issues are worth considering as part of the shared decision making. The panel also considered evidence for using cephalosporins for adjuvant treatment of skin abscesses, however they concluded that this class of antibiotics was unlikely to provide any benefit over incision and drainage in the majority of cases of skin abscesses, and therefore could not be recommended. Ref: BMJ 2018; 360: k243 doi.org/10.1136/bmj.k243

Dr Linda Calabresi

We know night shift work is not good for your health. Evidence shows night shift work is associated with an increased risk of sleep loss, occupational accidents, obesity and weight gain, type 2 diabetes, coronary heart disease, and breast, prostate and colorectal cancers, according to a review in the BMJ by two intensive care specialists. But what of strategies to help night shift workers mitigate these risks? What does the research say we should be advising these patients to do to optimise their health, remembering that many health professionals will be involved in this type of shift work? According to the review, there is a ‘paucity of adequately powered, well designed, randomised controlled trials’ on the subject however from what there was and with the addition of expert opinion the review authors recommended the following.
  • Try and make sure you’re not sleep-deprived before a night shift. Try and wake the morning before naturally (without an alarm) and, if possible have a daytime nap maybe taking advantage of that ‘circadian dip’ between 2 and 6pm the afternoon before you front up for night duty.
  • If you get the opportunity to nap during the night shift, try to limit the duration of these to less than 30 minutes, “to avoid slow wave sleep followed by grogginess on waking, known as ‘sleep inertia’”, the authors advise.
  • Caffeine reduces sleepiness and improves performance 20-45 minutes after taking it, with the effect lasting up to five hours.
  • There is evidence that drugs such as modafinil are effective in reducing sleepiness in night shift workers compared with placebo but these drugs have been associated with skin reactions and their long-term safety is yet to be established. Similarly, exposure to bright light has been proposed as a possible means of inhibiting melatonin, reducing sleepiness and perhaps reducing the cancer risk associated with shift work but neither these drugs nor bright light exposure is supported by sufficient evidence to be conclusively recommended.
  • Hunger and digestion are both affected by circadian rhythm. There is some evidence to suggest if you don’t eat you’ll perform better over the duration of the night shift than if you eat, however it is likely you will experience hunger and will be more likely to get GI symptoms leading the authors to recommend a main meal immediately before the shift and then small snacks as required to stave off hunger overnight.
  • And the big one. How to optimise sleep between night shifts? Well- the recommendations are fairly predictable – avoid bright light on the way home (wear sunglasses), employ blue screens on your computer and phone, use eye masks and ear plugs and develop a predictable pre-bed routine. Avoid caffeine for at least six hours before sleep time and perhaps consider taking melatonin the morning after a night shift –some evidence suggests that this increases sleep duration by up to 24 minutes.
“A meta-analysis of 66 studies concluded that regular exercise leads to improvement in sleep quantity and quality, but the optimum timing, duration, and type of exercise for sleep promotion have yet to be determined,” they said. In addition, the review authors didn’t recommend any other sleeping tablets due to a lack of quality evidence of their effectiveness and the risk of dependency. Finally, the researchers advised night shift workers to be aware their performance is likely to be reduced especially in that particularly vulnerable time between 3 and 5am and therefore they should seek support when required to do critical tasks at this time. They also warned workers to be aware of their vulnerability when driving home after night shift and referred to a patient, the inspiration for this review, who experienced the life-changing consequences of being involved in a road traffic accident while on a set of night shifts in 2005. Ref: BMJ 2018; 360:j5637 doi: 10.1136/bmj.j5637

Dr Linda Calabresi

Infants receiving acid suppressive medications are more than twice as likely to develop food allergies later in life, US researchers say. Findings from a large retrospective study, analysing data from almost 800,000 children, showed that being prescribed either an H2 receptor antagonist or a proton pump inhibitor in the first six months more than doubled the risk of developing a food allergy (hazard ratios of 2.18 and 2.59 respectively) when they got older. Similarly, the use of these medications was also found to associated with an increased risk of other allergies as well, including medication allergy (HR 1.70 and 1.84), anaphylaxis (HR 1.50 and 1.45) and, to a lesser extent, allergic rhinitis and asthma. As part of the same study, the researchers also looked at antibiotics in the first six months and, perhaps unsurprisingly found a link between this type of medication and developing an allergic condition. In the case of antibiotics, children were more likely to develop allergic respiratory conditions such as asthma and allergic rhinitis than food allergies. The findings have biological plausibility, the researchers said in JAMA. Acid suppressive medications inhibit the breakdown of ingested protein which, in turn facilitates IgE antibody production increasing the sensitivity to ingested antigens. The medications also, by definition, interfere with histamine which researchers now believe has a greater role in modulating immune system functioning than previously thought. The association between increased allergy and antibiotics, on the other hand supports findings from previous studies, and is thought to be related to the effect of the antibiotics on the gut bacteria or microbiome. It is one of a number of reasons why there has been growing pressure on clinicians to try to avoid prescribing antibiotics to infants. “While there has been increasing recognition of the potential risks of antibiotic use during infancy, H2 [receptor antagonists] and PPIs are considered to be generally safe and are commonly prescribed for children younger than a year,” the study authors say. Among the almost 800,000 children included in the study, 7.6% had been prescribed a H2 receptor antagonist in infancy and 1.7% had had a PPI. The researchers did concede that a limitation of this study could be ‘the potential bias from reverse causality’. Namely an infant’s symptoms of a food allergy could have originally been misdiagnosed as gastro-oesophageal reflux necessitating acid suppression, or early symptoms of asthma could have mistakenly been thought to be an indicator of a bacterial respiratory infection. However, the authors say, this is unlikely to be the whole story. Such scenarios cannot explain the increased rates of anaphylaxis or urticaria or medication allergy. And many food allergies don’t develop until well after the first six months so it would be unlikely that allergy would have caused the symptoms experienced by an infant. All in all, best practice, according to these researchers is to minimise the use of acid suppressive medications and antibiotics in children, particularly in children less than six months old. “This study provides further impetus that antibiotics and anti-suppressive medications should be used during infancy only in situations of clear clinical benefit,” they concluded.

Prof Adam Watkins

ON THE PILL: In this seven-part series we explore the history, myths, side-effects and alternatives of the pill, and why it’s the most popular form of contraception in Australia.
The female contraceptive pill has helped millions of women take control of their fertility and reproductive health since it became available in 1961. Yet a male equivalent has yet to be fully developed. This effectively leaves men with only two viable contraceptive options: condoms or a vasectomy. The idea of creating a male contraceptive has been around almost as long as the female contraceptive. In theory, targeting the production of sperm should be a simple process. The biology of sperm production and how they swim towards the egg are well understood. Yet, studies aimed at developing an effective male pill have been dogged by issues such as severe side effects. Most recently, a study that injected men with the hormones testosterone and progestogen – similar to hormones found in the female pill – had to be stopped early.
Read more: Why the male 'pill' is still so hard to swallow
The study, from 2016, showed pregnancy rates for female partners of men receiving the injections fell below that typically seen for women on the pill. But the study was cut short due to reports of adverse side effects including acne, mood disorders and raised libido. For the men taking part, these side effects proved too severe for them to continue, despite the desired drop in sperm production. However, many people may see these side effects as relatively minor compared to those suffered by women on the pill, which include anxiety, weight gain, nausea, headaches, reduced libido and blood clots. Male contraceptives have been under development for at least 50 years. However, the drive to bring a male contraceptive onto the market has stalled for two main reasons. First, there is a general pessimism of men towards taking a contraceptive pill, especially in countries such as India. Second, the global success of the female pill provides little incentive for pharmaceuticals to invest in a male pill. Globally, the female pill is the third most-used form of contraception, with a projected market value of nearly US$23 billion by 2023. Despite these setbacks, a new way of thinking about male contraception is taking shape. Here, the focus has shifted from stopping sperm production to stopping the sperm being able to fertilise the egg.

The clean sheet pill

The clean sheet pill effectively works as its name suggests: preventing the release of sperm. The clean sheet pill has two main selling points. First, by preventing the release of sperm and the fluid they are carried in, the clean sheet pill simultaneously prevents unwanted pregnancy and the spread of sexually-transmitted infections. Second, because the pill does not affect the feeling of orgasm, there is no reduction in male sexual pleasure. Unfortunately, the clean sheet pill has so far only been tested in animals. As such, a version for human use is probably ten years away from being developed.

Vasalgel

One of the downsides of a vasectomy is that it can render a man permanently sterile. However, the recent development of a product call Vasalgel may offer men a serious alternative to a vasectomy. Vasalgel is a long-term, non-hormonal yet reversible form of contraception. This offers benefits over both hormonal contraceptives with their side effects as well as the permanency of a vasectomy. Vasalgel is polymer that is injected into the vas deferens, the tube that carries sperm from the testes. This allows the movement of fluid, but stops the passage of sperm.
Read more: A new male contraceptive could help men bear the family planning burden
In a trial in monkeys, Vasagel was found to be 100% effective at preventing conception. In separate studies in animals, the effect of Vasagel was easily reversed with a simple second injection to dissolve the polymer. If these effects are replicated in men, this could offer a low-cost, minimally invasive and effective contraceptive that is also reversible.

Heart-stopping poisons

A deadly, heart-stopping poison might not sound like a good starting point for a new male contraceptive. However, researchers have shown that a toxic compound call oubain can be be used to slow down the swimming of sperm. Researchers already knew that oubain could affect male fertility. But the cardio toxic effects of oubain prevented scientists from exploring its effects on male reproduction in any detail. By modifying the structure of the oubain molecule, researchers showed it can be used to reduce the motility (ability to swim) of rat sperm while being non-toxic to the heart.

Research and development

While research into male contraceptives have been ongoing for nearly 50 years, we still seem to be at least “five to ten years away” from an effective male pill.
Read more: We won't have a male contraceptive until we change our understanding of risk
Potential new targets for male contraceptives are being developed and tested scientifically all the time. However, without the significant input and push from big pharmaceutical companies, these discoveries may never see the light of day. The ConversationWith the cost of developing a new drug to market estimated at US$2.6 billion, the burden of family planning looks to remain firmly on the shoulders of women for now. Adam Watkins, Assistant Professor, University of Nottingham This article was originally published on The Conversation. Read the original article.
Dr David Palmer

The importance of eosinophils and neutrophils infiltrating oesophageal squamous epithelium as markers for reflux, eosinophilic oesophagitis, and infection are well entrenched, although traditionally less attention has been paid to lymphocytes. Small numbers of lymphocytes are normally seen in oesophageal epithelium including CD4 helper and CD8 positive cytotoxic lymphocytes. However, isolated increases in lymphocytes in the oesophageal epithelium, outside the context of entities such as lichen planus and graft versus host disease, have been less well recognised until recently. The criteria for a diagnosis of lymphocytic oesophagitis, where lymphocyte numbers are markedly increased with few or no eosinophils, is not strictly defined since this is still a reaction pattern and not a specific diagnosis per se, and thresholds vary from study to study. The strictest definition requires at least 50 intraepithelial or peripapillary lymphocytes per HPF with few or no granulocytes. The term lymphocytic oesophagitis was originally coined in 2005 by Rubio et al to describe a histological reaction pattern in the oesophagus of a series of 20 patients. The patients had a high number of peripapillary lymphocytes and a lack of neutrophils and eosinophils. The papillae are projections of lamina propria, containing capillaries, which project a short distance into the epithelium of the normal oesophagus. The pattern of lymphocytic oesophagitis showed an association with Crohn’s disease, though not a completely specific one. Of the 20 patients, 11 were age 17 or younger and of these, eight (40%) had Crohn’s disease; 20% had manifestations of reflux and the remainder a mixture of conditions including coeliac, gastroduodenitis, and Hashimoto’s thyroiditis. A similar study of 40 patients in 2008 was unable to confirm these findings. Looking at it from a different angle, Ebach et al studied 60 paediatric patients with known Crohn’s disease and control groups and found an association. Lymphocytic oesophagitis  which was found in 28% of patients with Crohn’s disease (mean age 13.3) but in only 2/30 patients with ulcerative colitis. A 2014 study of 580 paediatric patients confirms the association with Crohn’s disease, but also shows the non-specific nature of lymphocytic oesophagitis. This found 31 patients with lymphocytic oesophagitis and 49 with Crohn’s disease. Six of the 31 lymphocytic oesophagitis patients (19%) and 43 of the 514 non- lymphocytic oesophagitis patients (8.4%) had Crohn’s disease. The remaining lymphocytic oesophagitis patients had other diagnoses with no significant clinical correlates. Conversely, lymphocytic oesophagitis was identified in 12.2% of the patients with Crohn’s disease. Thus, there were still more lymphocytic oesophagitis patients without Crohn’s disease than with Crohn’s disease. In adults, the association with Crohn’s disease is not seen but there appears to be an association with oesophageal dysmotility. A 2011 study of over 129,000 patients from a large outpatient private GI pathology lab service revealed lymphocytic oesophagitis in only 119 patients, 60% female. Most patients had symptoms of oesophageal disease such as dysphagia or odynophagia, with dysphagia being the most common complaint, and around 20% complaining of reflux. Endoscopically, around a third of patients were suspected of having eosinophilic oesophagitis (including ‘feline oesophagus’ where the oesophagus has rings resembling that of a cat’s oesophagus), around 20% were normal, 18% had features suggestive of reflux, and 10% had stricture. However, none had Crohn’s disease or an association with Helicobacter gastritis. Although this study drew no firm conclusions as to the nature of lymphocytic oesophagitis in adults, the prevalence of dysphagia as a presenting complaint, and the number of patients with findings reminiscent of eosinophilic oesophagitis were noted. The association with dysmotility is enhanced by the finding that in adult patients, a lymphocytic oesophagitis with a complete absence of granulocytes was mostly seen in older female patients who presented with dysphagia and had an oesophageal motility disorder. CD4- and CD8-predominant lymphocytic oesophagitis occurs with roughly equal frequency. However, patients with CD4-predominant lymphocytic oesophagitis are more likely to be female (71%), and have a motility disorder (90% of those tested). This suggests a new entity of ‘dysmotility lymphocytic oesophagitis’. In summary, the reaction pattern of lymphocytic oesophagitis appears to be real, however, the term cannot be used as a wastebasket and true increased numbers of intraepithelial lymphocytes must be seen. Clinical and endoscopic correlations determine the significance of any pathologist comment on increased numbers of lymphocytes in the epithelium.
General Practice Pathology is a new regular column each authored by an Australian expert pathologist on a topic of particular relevance and interest to practising GPs. The authors provide this editorial, free of charge as part of an educational initiative developed and coordinated by Sonic Pathology.

Dr Jo Marchant

Is there real science in the spiritualism of meditation? Jo Marchant meets a Nobel Prize-winner who thinks so. It’s seven in the morning on the beach in Santa Monica, California. The low sun glints off the waves and the clouds are still golden from the dawn. The view stretches out over thousands of miles of Pacific Ocean. In the distance, white villas of wealthy Los Angeles residents dot the Hollywood hills. Here by the shore, curlews and sandpipers cluster on the damp sand. A few metres back from the water’s edge, a handful of people sit cross-legged: members of a local Buddhist centre about to begin an hour-long silent meditation. Such spiritual practices may seem a world away from biomedical research, with its focus on molecular processes and repeatable results. Yet just up the coast, at the University of California, San Francisco (UCSF), a team led by a Nobel Prize-winning biochemist is charging into territory where few mainstream scientists would dare to tread. Whereas Western biomedicine has traditionally shunned the study of personal experiences and emotions in relation to physical health, these scientists are placing state of mind at the centre of their work. They are engaged in serious studies hinting that meditation might – as Eastern traditions have long claimed – slow ageing and lengthen life.

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Elizabeth Blackburn has always been fascinated by how life works. Born in 1948, she grew up by the sea in a remote town in Tasmania, Australia, collecting ants from her garden and jellyfish from the beach. When she began her scientific career, she moved on to dissecting living systems molecule by molecule. She was drawn to biochemistry, she says, because it offered a thorough and precise understanding “in the form of deep knowledge of the smallest possible subunit of a process”. Working with biologist Joe Gall at Yale in the 1970s, Blackburn sequenced the chromosome tips of a single-celled freshwater creature called Tetrahymena (“pond scum”, as she describes it) and discovered a repeating DNA motif that acts as a protective cap. The caps, dubbed telomeres, were subsequently found on human chromosomes too. They shield the ends of our chromosomes each time our cells divide and the DNA is copied, but they wear down with each division. In the 1980s, working with graduate student Carol Greider at the University of California, Berkeley, Blackburn discovered an enzyme called telomerase that can protect and rebuild telomeres. Even so, our telomeres dwindle over time. And when they get too short, our cells start to malfunction and lose their ability to divide – a phenomenon that is now recognised as a key process in ageing. This work ultimately won Blackburn the 2009 Nobel Prize in Physiology or Medicine. In 2000, she received a visit that changed the course of her research. The caller was Elissa Epel, a postdoc from UCSF’s psychiatry department. Psychiatrists and biochemists don’t usually have much to talk about, but Epel was interested in the damage done to the body by chronic stress, and she had a radical proposal. Epel, now director of the Aging, Metabolism and Emotion Center at UCSF, has a long-standing interest in how the mind and body relate. She cites as influences both the holistic health guru Deepak Chopra and the pioneering biologist Hans Selye, who first described in the 1930s how rats subjected to long-term stress become chronically ill. “Every stress leaves an indelible scar, and the organism pays for its survival after a stressful situation by becoming a little older,” Selye said. Back in 2000, Epel wanted to find that scar. “I was interested in the idea that if we look deep within cells we might be able to measure the wear and tear of stress and daily life,” she says. After reading about Blackburn’s work on ageing, she wondered if telomeres might fit the bill. With some trepidation at approaching such a senior scientist, the then postdoc asked Blackburn for help with a study of mothers going through one of the most stressful situations that she could think of – caring for a chronically ill child. Epel’s plan was to ask the women how stressed they felt, then look for a relationship between their state of mind and the state of their telomeres. Collaborators at the University of Utah would measure telomere length, while Blackburn’s team would measure levels of telomerase. Blackburn’s research until this point had involved elegant, precisely controlled experiments in the lab. Epel’s work, on the other hand, was on real, complicated people living real, complicated lives. “It was another world as far as I was concerned,” says Blackburn. At first, she was doubtful that it would be possible to see any meaningful connection between stress and telomeres. Genes were seen as by far the most important factor determining telomere length, and the idea that it would be possible to measure environmental influences, let alone psychological ones, was highly controversial. But as a mother herself, Blackburn was drawn to the idea of studying the plight of these stressed women. “I just thought, how interesting,” she says. “You can’t help but empathise.” It took four years before they were finally ready to collect blood samples from 58 women. This was to be a small pilot study. To give the highest chance of a meaningful result, the women in the two groups – stressed mothers and controls – had to match as closely as possible, with similar ages, lifestyles and backgrounds. Epel recruited her subjects with meticulous care. Still, Blackburn says, she saw the trial as nothing more than a feasibility exercise. Right up until Epel called her and said, “You won’t believe it.” The results were crystal clear. The more stressed the mothers said they were, the shorter their telomeres and the lower their levels of telomerase. The most frazzled women in the study had telomeres that translated into an extra decade or so of ageing compared to those who were least stressed, while their telomerase levels were halved. “I was thrilled,” says Blackburn. She and Epel had connected real lives and experiences to the molecular mechanics inside cells. It was the first indication that feeling stressed doesn’t just damage our health – it literally ages us.

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Unexpected discoveries naturally meet scepticism. Blackburn and Epel struggled initially to publish their boundary-crossing paper. “Science [one of the world’s leading scientific journals] couldn’t bounce it back fast enough!” chuckles Blackburn. When the paper finally was published, in the Proceedings of the National Academy of Sciences in December 2004, it sparked widespread press coverage as well as praise. Robert Sapolsky, a pioneering stress researcher at Stanford University and author of the bestselling Why Zebras Don’t Get Ulcers, described the collaboration as “a leap across a vast interdisciplinary canyon”. Mike Irwin, director of the Cousins Center for Psychoneuroimmunology at the University of California, Los Angeles, says it took a lot of courage for Epel to seek out Blackburn. “And a lot of courage for Liz [Blackburn] to say yes.” Many telomere researchers were wary at first. They pointed out that the study was small, and questioned the accuracy of the telomere length test used. “This was a risky idea back then, and in some people’s eyes unlikely,” explains Epel. “Everyone is born with very different telomere lengths and to think that we can measure something psychological or behavioural, not genetic, and have that predict the length of our telomeres? This is really not where this field was ten years ago.” The paper triggered an explosion of research. Researchers have since linked perceived stress to shorter telomeres in healthy women as well as in Alzheimer’s caregivers, victims of domestic abuse and early life trauma, and people with major depression and post-traumatic stress disorder. “Ten years on, there’s no question in my mind that the environment has some consequence on telomere length,” says Mary Armanios, a clinician and geneticist at Johns Hopkins School of Medicine who studies telomere disorders. There is also progress towards a mechanism. Lab studies show that the stress hormone cortisol reduces the activity of telomerase, while oxidative stress and inflammation – the physiological fallout of psychological stress – appear to erode telomeres directly. This seems to have devastating consequences for our health. Age-related conditions from osteoarthritis, diabetes and obesity to heart disease, Alzheimer’s and stroke have all been linked to short telomeres. The big question for researchers now is whether telomeres are simply a harmless marker of age-related damage (like grey hair, say) or themselves play a role in causing the health problems that plague us as we age. People with genetic mutations affecting the enzyme telomerase, who have much shorter telomeres than normal, suffer from accelerated-ageing syndromes and their organs progressively fail. But Armanios questions whether the smaller reductions in telomere length caused by stress are relevant for health, especially as telomere lengths are so variable in the first place. Blackburn, however, says she is increasingly convinced that the effects of stress do matter. Although the genetic mutations affecting the maintenance of telomeres have a smaller effect than the extreme syndromes Armanios studies, Blackburn points out that they do increase the risk of chronic disease later in life. And several studies have shown that our telomeres predict future health. One showed that elderly men whose telomeres shortened over two-and-a-half years were three times as likely to die from cardiovascular disease in the subsequent nine years as those whose telomeres stayed the same length or got longer. In another study, looking at over 2,000 healthy Native Americans, those with the shortest telomeres were more than twice as likely to develop diabetes over the next five-and-a-half years, even taking into account conventional risk factors such as body mass index and fasting glucose. Blackburn is now moving into even bigger studies, including a collaboration with healthcare giant Kaiser Permanente of Northern California that has involved measuring the telomeres of 100,000 people. The hope is that combining telomere length with data from the volunteers’ genomes and electronic medical records will reveal additional links between telomere length and disease, as well as more genetic mutations that affect telomere length. The results aren’t published yet, but Blackburn is excited about what the data already shows about longevity. She traces the curve with her finger: as the population ages, average telomere length goes down. This much we know; telomeres tend to shorten over time. But at age 75–80, the curve swings back up as people with shorter telomeres die off – proof that those with longer telomeres really do live longer. “It’s lovely,” she says. “No one has ever seen that.” In the decade since Blackburn and Epel’s original study, the idea that stress ages us by eroding our telomeres has also permeated popular culture. In addition to Blackburn’s many scientific accolades, she was named one of Time magazine’s “100 most influential people in the world” in 2007, and received a Good Housekeeping achievement award in 2011. A workaholic character played by Cameron Diaz even described the concept in the 2006 Hollywood film The Holiday. “It resonates,” says Blackburn. But as evidence of the damage caused by dwindling telomeres piles up, she is embarking on a new question: how to protect them.

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At first, the beach seems busy. Waves splash and splash and splash. Sanderlings wheel along the shoreline. Joggers and dog walkers amble across, while groups of pelicans hang out on the water before taking wing or floating out of sight. A surfer, silhouetted black against the sky, bobs about for 20 minutes or so, catching the odd ripple towards shore before he, too, is gone. The unchanging perspective gives a curious sense of detachment. You can imagine that the birds and joggers and surfers are like thoughts: they inhabit different forms and timescales but in the end, they all pass. There are hundreds of ways to meditate but this morning I’m trying a form of Buddhist mindfulness meditation called open monitoring, which involves paying attention to your experience in the present moment. Sit upright and still, and simply notice any thoughts that arise – without judging or reacting to them – before letting them go. For Buddhists this is a spiritual quest; by letting trivial thoughts and external influences fall away, they hope to get closer to the true nature of reality. Blackburn too is interested in the nature of reality, but after a career spent focusing on the measurable and quantifiable, such navel-gazing initially held little personal appeal and certainly no professional interest. “Ten years ago, if you’d told me that I would be seriously thinking about meditation, I would have said one of us is loco,” she told the New York Times in 2007. Yet that is where her work on telomeres has brought her. Since her initial study with Epel, the pair have become involved in collaborations with teams around the world – as many as 50 or 60, Blackburn estimates, spinning in “wonderful directions”. Many of these focus on ways to protect telomeres from the effects of stress; trials suggest that exercise, eating healthily and social support all help. But one of the most effective interventions, apparently capable of slowing the erosion of telomeres – and perhaps even lengthening them again – is meditation. So far the studies are small, but they all tentatively point in the same direction. In one ambitious project, Blackburn and her colleagues sent participants to meditate at the Shambhala mountain retreat in northern Colorado. Those who completed a three-month course had 30 per cent higher levels of telomerase than a similar group on a waiting list. A pilot study of dementia caregivers, carried out with UCLA’s Irwin and published in 2013, found that volunteers who did an ancient chanting meditation called Kirtan Kriya, 12 minutes a day for eight weeks, had significantly higher telomerase activity than a control group who listened to relaxing music. And a collaboration with UCSF physician and self-help guru Dean Ornish, also published in 2013, found that men with low-risk prostate cancer who undertook comprehensive lifestyle changes, including meditation, kept their telomerase activity higher than similar men in a control group and had slightly longer telomeres after five years. In their latest study, Epel and Blackburn are following 180 mothers, half of whom have a child with autism. The trial involves measuring the women’s stress levels and telomere length over two years, then testing the effects of a short course of mindfulness training, delivered with the help of a mobile app. Theories differ as to how meditation might boost telomeres and telomerase, but most likely it reduces stress. The practice involves slow, regular breathing, which may relax us physically by calming the fight-or-flight response. It probably has a psychological stress-busting effect too. Being able to step back from negative or stressful thoughts may allow us to realise that these are not necessarily accurate reflections of reality but passing, ephemeral events. It also helps us to appreciate the present instead of continually worrying about the past or planning for the future. “Being present in your activities and in your interactions is precious, and it’s rare these days with all of the multitasking we do,” says Epel. “I do think that in general we’ve got a society with scattered attention, particularly when people are highly stressed and don’t have the resources to just be present wherever they are.”

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Inevitably, when a Nobel Prize-winner starts talking about meditation, it ruffles a few feathers. In general, Blackburn’s methodical approach to the topic has earned a grudging admiration, even among those who have expressed concern about the health claims made for alternative medicine. “She goes about her business in a cautious and systematic fashion,” says Edzard Ernst of the University of Exeter, UK, who specialises in testing complementary therapies in rigorous controlled trials. Oncologist James Coyne of the University of Pennsylvania, Philadelphia, who is sceptical of this field in general and describes some of the research on positive psychology and health as “morally offensive” and “tooth fairy science”, concedes that some of Blackburn’s data is “promising”. Others aren’t so impressed. Surgeon-oncologist David Gorski is a well-known critic of alternative medicine and pseudoscience who blogs under the name of Orac – he’s previously described Dean Ornish as “one of the four horsemen of the Woo-pocalypse”. Gorski stops short of pronouncing meditation as off-limits for scientific inquiry, but expresses concern that the preliminary results of these studies are being oversold. How can the researchers be sure they’re investigating it rigorously? “It’s really hard to do with these things,” he says. “It is easy to be led astray. Nobel Prize-winners are not infallible.” Blackburn’s own biochemistry community also seems ambivalent about her interest in meditation. Three senior telomere researchers I contacted declined to discuss this aspect of her work, with one explaining that he didn’t want to comment “on such a controversial issue”. “People are very uncomfortable with the concept of meditation,” notes Blackburn. She attributes this to its unfamiliarity and its association with spiritual and religious practices. “We’re always trying to say it as carefully as we can… always saying ‘look, it’s preliminary, it’s a pilot’. But people won’t even read those words. They’ll see the newspaper headings and panic.” Any connotation of religious or paranormal beliefs makes many scientists uneasy, says Chris French, a psychologist at Goldsmiths, University of London, who studies anomalous experiences including altered states of consciousness. “There are a lot of raised eyebrows, even though I’ve got the word sceptic virtually tattooed across my forehead,” he says. “It smacks of new-age woolly ideas for some people. There’s a kneejerk dismissive response of ‘we all know it’s nonsense, why are you wasting your time?’” "When meditation first came to the West in the 1960s it was tied to the drug culture, the hippie culture,” adds Sara Lazar, a neuroscientist at Harvard who studies how meditation changes the structure of the brain. “People think it’s just a bunch of crystals or something, they roll their eyes.” She describes her own decision to study meditation, made 15 years ago, as “brave or crazy”, and says that she only plucked up the courage because at around the same time, the US National Institutes of Health (NIH) created the National Center for Complementary and Alternative Medicine. “That gave me the confidence that I could do this and I would get funding.” The tide is now turning. Helped in part by that NIH money, researchers have developed secularised – or non-religious – practices such as mindfulness-based stress reduction and mindfulness-based cognitive therapy, and reported a range of health effects from lowering blood pressure and boosting immune responses to warding off depression. And the past few years have seen a spurt of neuroscience studies, like Lazar’s, showing that even short courses of meditation can forge structural changes in the brain. “Now that the brain data and all this clinical data are coming out, that is starting to change. People are a lot more accepting [of meditation],” says Lazar. “But there are still some people who will never believe that it has any benefit whatsoever." Blackburn’s view is that meditation is a fair topic to study, as long as robust methods are used. So when her research first pointed in this direction, she was undaunted by concerns about what such studies might do to her reputation. Instead, she tried it out for herself, on an intensive six-day retreat in Santa Barbara. “I loved it,” she says. She still uses short bursts of meditation, which she says sharpen her mind and help her to avoid a busy, distracted mode. She even began one recent paper with a quote from the Buddha: “The secret of health for both mind and body is not to mourn for the past, worry about the future, or anticipate troubles but to live in the present moment wisely and earnestly.” That study, of 239 healthy women, found that those whose minds wandered less – the main aim of mindfulness meditation – had significantly longer telomeres than those whose thoughts ran amok. “Although we report merely an association here, it is possible that greater presence of mind promotes a healthy biochemical milieu and, in turn, cell longevity,” the researchers concluded. Contemplative traditions from Buddhism to Taoism believe that presence of mind promotes health and longevity; Blackburn and her colleagues now suggest that the ancient wisdom might be right.

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I meet with Blackburn in Paris. We’re at an Art Nouveau-themed bistro just down the road from the Curie Institute, where she is on a short sabbatical, arranging seminars between groups of scientists who don’t usually talk to one another. In a low, melodious voice that I strain to hear through the background clatter, the 65-year-old tells me of her first major brush with Buddhist thinking. In September 2006, she attended a conference held at the Menla Mountain Buddhist centre, a remote retreat in New York’s Catskill mountains, at which Western scientists met with Tibetan-trained scholars including the Dalai Lama to discuss longevity, regeneration and health. During the meeting, the spiritual leader honoured Blackburn’s scientific achievements by inducting her as a “Medicine Buddha”. If Epel’s psychiatry research had been another world, the scholars’ Eastern philosophy seemed to Blackburn more alien still. Over dinner one evening, while explaining to the other delegates how errors in the gene for telomerase can cause health problems, she described genetic mutation as a random, chance event. That’s dogma for Western scientists but not for those trained in the Tibetan worldview. “They said ‘oh no, we don’t regard this as chance’,” says Blackburn. For these holistic scholars, even the smallest events were infused with meaning. “I suddenly thought, whoa, this is a very different world from the one I’m on.” But instead of dismissing her Eastern counterparts, she was impressed, finding the Dalai Lama to have “a very good brain”, for example. “They’re scholarly in a very different way, but it is still good-quality thinking,” she explains. “It wasn’t ‘God told me this’, it was more ‘let’s see what actually happens in the brain’. So there are certain elements of the approach that I am quite comfortable with as a scientist.” Blackburn isn’t tempted to embrace the spiritual approach herself. “I’m rooted in the physical world,” she says. But she combines that grounding with an open mind towards new ideas and connections, and she seems to love breaking out of established paradigms. For example, she and Epel have shown that the effects of stress on telomeres can be passed on to the next generation. If women experience stress while pregnant, their children have shorter telomeres, as newborns and as adults – in direct contradiction of the standard view that traits can only be passed on via our genes. In the future, information from telomeres may help doctors decide when to prescribe particular drugs. For example, telomerase activity predicts who will respond to treatment for major depression, while telomere length influences the effects of statins. In general, however, Blackburn is more interested in how telomeres might help people directly, by encouraging them to live in a way that reduces their disease risk. “This is not a familiar model for the medical world,” she says. Conventional medical tests give us our risk of particular conditions – high cholesterol warns of impending heart disease, for example, while high blood sugar predicts diabetes. Telomere length, by contrast, gives an overall reading of how healthy we are: our biological age. And although we already know that we should exercise, eat well and reduce stress, many of us fall short of these goals. Blackburn believes that putting a concrete number on how we are doing could provide a powerful incentive to change our behaviour. In fact, she and Epel have just completed a study (as yet unpublished) showing that simply being told their telomere length caused volunteers to live more healthily over the next year than a similar group who weren’t told. Ultimately, however, the pair want entire countries and governments to start paying attention to telomeres. A growing body of work now shows that the stress from social adversity and inequality is a major force eroding these protective caps. People who didn’t finish high school or are in an abusive relationship have shorter telomeres, for example, while studies have also shown links with low socioeconomic status, shift work, lousy neighbourhoods and environmental pollution. Children are particularly at risk: being abused or experiencing adversity early in life leaves people with shorter telomeres for the rest of their lives. And through telomeres, the stress that women experience during pregnancy affects the health of the next generation too, causing hardship and economic costs for decades to come. In 2012, Blackburn and Epel wrote a commentary in the journal Nature, listing some of these results and calling on politicians to prioritise “societal stress reduction”. In particular, they argued, improving the education and health of women of child-bearing age could be “a highly effective way to prevent poor health filtering down through generations”. Meditation retreats or yoga classes might help those who can afford the time and expense, they pointed out. “But we are talking about broad socioeconomic policies to buffer the chronic stressors faced by so many.” Where many scientists refrain from discussing the political implications of their work, Blackburn says she wanted to speak out on behalf of women who lack support, and say “You’d better take their situations seriously.” While arguments for tackling social inequality are hardly new, Blackburn says that telomeres allow us to quantify for the first time the health impact of stress and inequality and therefore the resulting economic costs. We can also now pinpoint pregnancy and early childhood as “imprinting periods” when telomere length is particularly susceptible to stress. Together, she says, this evidence makes a stronger case than ever before for governments to act. But it seems that most scientists and politicians still aren’t ready to leap across the interdisciplinary canyon that Blackburn and Epel bridged a decade ago. The Nature article has engendered little response, according to a frustrated Epel. “It’s a strong statement so I would have thought that people would have criticised it or supported it,” she says. “Either way!” “It’s now a consistent story that the ageing machinery is shaped at the earliest stages of life,” she insists. “If we ignore that and we just keep trying to put band-aids on later, we’re never going to get at prevention and we’re only going to fail at cure.” Simply responding to the physical symptoms of disease might make sense for treating an acute infection or fixing a broken leg, but to beat chronic age-related conditions such as diabetes, heart disease and dementia, we will need to embrace the fuzzy, subjective domain of the mind. This article first appeared on Mosaic and is republished here under a Creative Commons licence.

Dr Linda Calabresi

Low density lipoprotein cholesterol is the well-known culprit in terms of cardiovascular risk. Courtesy of a large meta-analysis of statin trials done in 2010 (the Cholesterol Treatment Trialists Collaboration), we know that for people starting with higher LDL-C levels (approximately 3.4 mmol/L), they can lower their risk of having a major adverse vascular event by 22%, every time they lower their LDL-C level by 1mmol/L. But what happens once your LDL level is lower? Can you continue to increase your protection by lowering your LDL levels further? Or does the beneficial effect plateau at a certain level? Or, worse still can very low LDL levels actually cause harm? A new meta-analysis just published in JAMA Cardiology has gone some way in answering these questions. The researchers analysed data from the 26 statin studies in the CTTC as well as three large trials of non-statin, cholesterol-lowering therapy looking at those patients who had an LDL-C level of 1.8 mmol/L or less at baseline. They found the cardioprotective benefits continued as LDL-C levels declined to even lower levels. “We found consistent clinical benefit from further LDL-C lowering in patient populations starting as low as a median of 1.6 mmol/L and achieving levels as low as a median of 0.5 mmol/L”. What’s more, the incremental benefit was of an almost identical magnitude to that seen when the LDL-C levels were higher - 21% relative risk reduction per 1-mmol/L reduction in LDL-C through this range. “This relative risk reduction is virtually the same as the 22% reduction seen in the overall CTTC analysis in which the starting LDL-C was nearly twice as high,” they said. And even though very low cholesterol levels have been rumoured to be associated with everything from cancer to dementia, across all these studies there were no offsetting safety concerns with LDL-C lowering, even when extremely low levels were recorded, levels that were lower than those seen in newborns. Given the weight of benefit over risk, the study authors suggest the current targets for LDL-C could be lowered further, to even as low as 0.5 mmol/L to reduce cardiovascular risk. This suggestion is supported by an accompanying editorial, in which the author, Dr Antonio Gotto, a New York cardiologist, predicts the findings will be included as part of the revision of the American Heart Association National Cholesterol guidelines which is currently underway. He said the study findings would provide much needed evidence to help clinicians manage patients with these extremely low achieved cholesterol levels, that until recently have been very rare. “Whether one calls it a target or a threshold, practicing physicians need some guidance as they venture into achieved levels of LDL-C levels that are as foreign as travel to outer space. I have confidence that the new guidelines will be closer to a global positioning system map rather than just a compass and the stars”, he concluded. Ref: JAMA Cardiol. Published online August 1, 2018. doi:10.1001/jamacardio.2018.2258

Dr Linda Calabresi

Salt may have been unfairly targeted as a killer in the healthy heart stakes, according to newly published research. The observational study of over 90000 people in 300 communities across 18 countries, found that sodium consumption was not associated with an increase in health risks unless the average daily consumption was excessive – more than 5g/day or 2.5 teaspoons of salt. And, this average high daily sodium intake was mostly seen in China, with only about 15% of communities outside of China exceeding this 5g a day limit. As part of this ongoing Prospective Urban Rural Epidemiology (PURE) study, participants aged 35-70 were assessed initially at baseline and then followed for an average of 8.1 years, over which time the occurrence of any major cardiovascular events or death was recorded. What the researchers found was that the risk of hypertension and strokes was only increased in communities where the average daily sodium intake was greater than 5g. Perhaps unexpectedly, this higher sodium intake was actually found to be also associated with lower rates of myocardial infarction and total mortality. Furthermore, the research found that very low levels of sodium intake were harmful, being associated with an increased risk of cardiovascular disease and mortality. The findings fly in the face of the current WHO guidelines that recommend, as a global approach we should be aiming for populations to reduce their sodium intake to below 2g/day. However, no communities in the study came close to achieving this target. In fact, no communities in the study had an average sodium intake of less than 3g/day, based on morning fasting urine samples from the participants. “Sodium intake was associated with cardiovascular disease and strokes only in communities where mean intake was greater than 5g/day. A strategy of sodium reduction in these communities and countries but not in others might be appropriate,” the Canadian study authors said. But before we all go and stock up on our Saxa, an accompanying editorial sounds a word of caution. While acknowledging the findings that ‘normal’ salt intake appeared to be at least health-neutral if not beneficial, the editorial authors remind us that the study is observational and has not taken into consideration a number of potential confounders such as diet. Without taking these confounders into account, one can’t assume that just decreasing salt intake in people at high risk of stroke or increasing it in people at risk of a heart attack will work, they said. “Nevertheless the findings are exceedingly interesting and should be tested in a randomised controlled trial,” they concluded, adding that such a trial, to be conducted in a US federal prison population had been proposed.   Ref: Lancet Vol 392 No 10146 pp:496-506 Vol 392 No 10146 pp: 456-458