Efficacy and safety of 12-weekly versus 4-weekly zoledronic acid for prolonged treatment of patients with bone metastases from breast cancer (ZOOM): a phase 3, open-label, randomised, non-inferiority trial.


Zoledronic acid reduces skeletal-related events in patients with breast cancer, but concerns have been raised about prolonged monthly administration. We assessed the efficacy and safety of a reduced dosing frequency of zoledronic acid in women treated previously with monthly zoledronic acid.


We did this non-inferiority, phase 3 trial in 62 centres in Italy. We enrolled patients with breast cancer who had one or more bone metastases and had completed 12—15 months of monthly treatment with zoledronic acid. Patients were randomly assigned with a permutated block (size four to eight) random list stratified by centre in a 1:1 ratio to zoledronic acid 4 mg once every 12 weeks or once every 4 weeks, and followed up for at least 1 year. Neither patients nor investigators were masked to treatment allocation. The primary outcome was skeletal morbidity rate (skeletal-related events per patient per year) in the intention-to-treat population. We used a non-inferiority margin of 0·19. The trial is registered with EudraCT, number 2005-004942-15.


We screened 430 patients and enrolled 425, of whom 209 were assigned to the 12-week group and 216 to the 4-week group. The skeletal morbidity rate was 0·26 (95% CI 0·15—0·37) in the 12-week group versus 0·22 (0·14—0·29) in the 4-week group. The between-group difference was 0·04 and the upper limit of one-tailed 97·5% CI was 0·17, which is lower than the non-inferiority margin. The most common grade 3—4 adverse events were bone pain (56 [27%] patients in the 12-week group vs 65 [30%] in the 4-week group), nausea (24 [11%] vs 33 [15%]), and asthenia (18 [9%] vs 33 [15%]). Renal adverse events occurred in one patient (<1%) in the 12-week group versus two (1%) in the 4-week group. One patient (<1%) in the 4-week group had grade 1 acute renal failure. Osteonecrosis of the jaw occurred in four patients in the 12-week group versus three in the 4-week group. No treatment-related deaths were reported. Median N-terminal telopeptide concentration changed from baseline more in the 12-week group than in the 4-week group after 12 months (12·2% vs 0·0%; p=0·011).


Our results raise the possibility of decreasing administration of zoledronic acid to a 12-weekly regimen to reduce exposure during the second year, while maintaining its therapeutic effects. However, the effects on N-terminal telopeptide should be investigated further before changing current practice.

Source: Lancet.


Integration of 3D digital mammography with tomosynthesis for population breast-cancer screening (STORM): a prospective comparison study.


Digital breast tomosynthesis with 3D images might overcome some of the limitations of conventional 2D mammography for detection of breast cancer. We investigated the effect of integrated 2D and 3D mammography in population breast-cancer screening.


Screening with Tomosynthesis OR standard Mammography (STORM) was a prospective comparative study. We recruited asymptomatic women aged 48 years or older who attended population-based breast-cancer screening through the Trento and Verona screening services (Italy) from August, 2011, to June, 2012. We did screen-reading in two sequential phases—2D only and integrated 2D and 3D mammography—yielding paired data for each screen. Standard double-reading by breast radiologists determined whether to recall the participant based on positive mammography at either screen read. Outcomes were measured from final assessment or excision histology. Primary outcome measures were the number of detected cancers, the number of detected cancers per 1000 screens, the number and proportion of false positive recalls, and incremental cancer detection attributable to integrated 2D and 3D mammography. We compared paired binary data with McNemar’s test.


7292 women were screened (median age 58 years [IQR 54—63]). We detected 59 breast cancers (including 52 invasive cancers) in 57 women. Both 2D and integrated 2D and 3D screening detected 39 cancers. We detected 20 cancers with integrated 2D and 3D only versus none with 2D screening only (p<0·0001). Cancer detection rates were 5·3 cancers per 1000 screens (95% CI 3·8—7·3) for 2D only, and 8·1 cancers per 1000 screens (6·2—10·4) for integrated 2D and 3D screening. The incremental cancer detection rate attributable to integrated 2D and 3D mammography was 2·7 cancers per 1000 screens (1·7—4·2). 395 screens (5·5%; 95% CI 5·0—6·0) resulted in false positive recalls: 181 at both screen reads, and 141 with 2D only versus 73 with integrated 2D and 3D screening (p<0·0001). We estimated that conditional recall (positive integrated 2D and 3D mammography as a condition to recall) could have reduced false positive recalls by 17·2% (95% CI 13·6—21·3) without missing any of the cancers detected in the study population.


Integrated 2D and 3D mammography improves breast-cancer detection and has the potential to reduce false positive recalls. Randomised controlled trials are needed to compare integrated 2D and 3D mammography with 2D mammography for breast cancer screening.

Source: Lancet.

Photodynamic therapy versus topical imiquimod versus topical fluorouracil for treatment of superficial basal-cell carcinoma: a single blind, non-inferiority, randomised controlled trial.


Superficial basal-cell carcinoma is most commonly treated with topical non-surgical treatments, such as photodynamic therapy or topical creams. Photodynamic therapy is considered the preferable treatment, although this has not been previously tested in a randomised control trial. We assessed the effectiveness of photodynamic therapy compared with imiquimod or fluorouracil in patients with superficial basal-cell carcinoma.


In this single blind, non-inferiority, randomised controlled multicentre trial, we enrolled patients with a histologically proven superficial basal-cell carcinoma at seven hospitals in the Netherlands. Patients were randomly assigned to receive treatment with methylaminolevulinate photodynamic therapy (MAL-PDT; two sessions with an interval of 1 week), imiquimod cream (once daily, five times a week for 6 weeks), or fluorouracil cream (twice daily for 4 weeks). Follow-up was at 3 and 12 months post-treatment. Data were collected by one observer who was blinded to the assigned treatment. The primary outcome was the proportion of patients free of tumour at both 3 and 12 month follow up. A pre-specified non-inferiority margin of 10% was used and modified intention-to-treat analyses were done. This trial is registered as an International Standard Randomised controlled trial (ISRCTN 79701845).


601 patients were randomised: 202 to receive MAL-PDT, 198 to receive imiquimod, and 201 to receive fluorouracil. A year after treatment, 52 of 196 patients treated with MAL-PDT, 31 of 189 treated with imiquimod, and 39 of 198 treated with fluorouracil had tumour residue or recurrence. The proportion of patients tumour-free at both 3 and 12 month follow-up was 72·8% (95% CI 66·8—79·4) for MAL-PDT, 83·4% (78·2—88·9) for imiquimod cream, and 80·1% (74·7—85·9) for fluorouracil cream. The difference between imiquimod and MAL-PDT was 10·6% (95% CI 1·5—19·5; p=0·021) and 7·3% (—1·9 to 16·5; p=0·120) between fluorouracil and MAL-PDT, and between fluorouracil and imiquimod was −3·3% (—11·6 to 5·0; p=0·435. For patients treated with MAL-PDT, moderate to severe pain and burning sensation were reported most often during the actual MAL-PDT session. For other local adverse reactions, local skin redness was most often reported as moderate or severe in all treatment groups. Patients treated with creams more often reported moderate to severe local swelling, erosion, crust formation, and itching of the skin than patients treated with MAL-PDT. In the MAL-PDT group no serious adverse events were reported. One patient treated with imiquimod and two patients treated with fluorouracil developed a local wound infection and needed additional treatment in the outpatient setting.


Topical fluorouracil was non-inferior and imiquimod was superior to MAL-PDT for treatment of superficial basal-cell carcinoma. On the basis of these findings, imiquimod can be considered the preferred treatment, but all aspects affecting treatment choice should be weighted to select the best treatment for patients.

Source: Lancet.



Plastic waste burns to give cooking gas.


A team of researchers from the National Institute of Technology, Calicut (NIT-C), has developed a technology that converts plastic waste into cooking gas, without causing pollution.

The team, led by Lisa Sreejith, associate professor, Department of Chemistry, NIT-C and N. Sitaraman, retired chemistry professor of the institute, told The Hindu that the cost-effective and eco-friendly breakthrough was achieved through a thermochemical decomposition of the shredded waste plastic at an elevated temperature in the absence of oxygen.

“As much as 750 ml of gas can be produced from a mere four grams of plastic waste using the technology (750 litre from 4 kg),” said Dr. Lisa. Apart from the gas, other costly chemicals including the plasticizers employed to make plastic more pliable, can also be extracted during the process, she said.

Unlike in the existing recycling system, no plastic item is rejected in the new method. “The trials have been successful in disintegrating all kinds of plastics including polythene, bottles, bags, tyres, charring plastics such as toffee covers and thermocol,” said Dr. Lisa.

According to Dr. Lisa, a plant for processing 100 tonnes of plastic waste daily can be set up at an estimated cost of Rs.2.5 crore. “This includes machinery and storage facilities for gas in liquid form as it is done in refineries,” she said.

Chief Minister Oommen Chandy has lauded Dr. Lisa and her team on their feat. “Mr. Chandy has also expressed his wish see the demonstration of the technology,” she said.

Dr. Sitaraman said that the technology could make a huge difference in the lives of millions of people if utilised effectively.

“We expect the government to respond positively to this development,” said Dr. Sitaraman.

According to Dr. Lisa, the team has submitted the project to various State and Central funding agencies, including the Department of Science and Technology of the Union government for approval. “The patent filing process also is in progress,” said Dr. Lisa.

The technology was demonstrated in front a group of invited guests including Kozhikode MLA A. Pradeepkumar on the NIT-C campus recently. Mr. Pradeepkumar said

the technology should be utilised with the help of local bodies and residential associations such as Niravu Vengeri, which systematically collect plastic wastes from residents and hand them over periodically to plastic recycling units.

Source: the Hindu.

How Birds Lost Their Penises?


How did the chicken lose its penis? By killing off the growing appendage in the egg.

That’s the finding of a new study, which reveals how most birds evolved to lose their external genitalia. Turns out, a particular protein released during the development of chickens, quail and most other birds nips penis development in the bud, according to the new research, published today (June 6) in the journal Current Biology.

The findings have implications for genital development in general, which is important because birth defects in the external genitalia are among the most common congenital defects in humans, said study researcher Martin Cohn, a developmental biologist at the Howard Hughes Medical Institute and the University of Florida.

“Comparative evolutionary studies of development allow us to understand not only how evolution works, but also gives us new insights into the possible causes of malformations,” Cohn told LiveScience.

Missing penises

About 97 percent of birds lack penises entirely. The exceptions are real odd ducks — literally. Some waterfowl have coiling penises that can exceed the length of the rest of their bodiesThe most primitive group of birds, paleognaths, which include emus, kiwis and ostriches, have well-developed phalluses, as well. Along the evolutionary line, two newer groups diverged: anseriformes, which include penis-wielding ducks, swans and geese, and galliformes, which make up most land-loving birds and lack penises.

To understand how this genital gap diverges in development, Cohn, along with research assistant Ana Herrera and their colleagues, grew embryos from chickens (galliformes) and ducks (anseriformes) and tracked their penis growth.

“It’s pretty surprising, actually,” Cohn said. “Chickens and ducks start to develop their genitalia in such a similar manner that they’re almost indistinguishable.”

A few days after a primitive penile swelling appears on chick embryos, however, development abruptly halts, and then regresses. By the time they’re born, chickens and their galliforme relatives are left with only an opening called the cloaca, rather than an external penis. In duck embryos, the penis continues to grow.

The disappearing phallus

Next, the researchers set out to find out what stops a chick’s penis from growing while allowing a duck’s to reach startling lengths. They expected to find something missing in chickens — some mysterious molecular factor that would have otherwise spurred the penises to greater lengths.

Instead, the found just the opposite. In chick embryos, penis development is halted by the release of bone morphogenetic protein 4, or Bmp4. This protein shows up along the whole length of the primitive genital swelling seen in early chick development; in ducks, it’s only seen at the base of the genitals.

To make sure Bmp4 was really doing the penis-stifling deed, the researchers applied the protein to duck penises. Sure enough, development halted. Likewise, when they blocked Bmp4’s expression in chick penises, the embryonic birds’ phalluses continued to grow.

It turns out that Bmp4 is a cell death factor, Cohn said. Its release encourages cells to self-destruct, turning a growing organ into a shrinking one. Cell death is normal in embryos, he said, but it’s more typical to see loss of embryonic growth factors in cases where limbs regress in the womb.

“There are many paths to reach the same morphological end,” Cohn said.

The new study reveals how birds lost their penises, but not why. It seems odd that birds would evolve to lose an organ so critical to reproduction, Cohn said. Evolutionary biologists have theorized that perhaps bird penises vanished because female birds preferred mates with smaller penises. In ducks and other species with phalluses, males frequently force females to copulate. By picking mates with small penises, female birds could have gained more control over the reproductive process.

Alternatively, penis loss could have been a side effect of other changes in the birds’ body. Bmp proteins are responsible for the origin of feathers in birds and their loss of teeth. Bmp4, in particular, is responsible for variations in beak size and shape, Cohn said.

“It’s interesting that so many of these little details of the bird body plan are associated with changes in Bmp activity,” he said.



Future warming narrowed down.


Australian scientists have narrowed the predicted range of global warming through groundbreaking new research.

Scientists from the University of Melbourne and Victoria University have generated what they say are more reliable projections of global warming estimates at 2100.

The paper, led by Dr Roger Bodman from Victoria University with Professors David Karoly and Peter Rayner from the University of Melbourne and published in Nature Climate Change, found that exceeding 6 degrees warming was now unlikely while exceeding 2 degrees is very likely for business-as-usual emissions.

This was achieved through a new method combining observations of carbon dioxide and global temperature variations with simple climate model simulations to project future global warming.

Dr Bodman said while continuing to narrow the range even further was possible, significant uncertainty in warming predictions would always remain due to the complexity of climate change drivers. “This study ultimately shows why waiting for certainty will fail as a strategy,” he said. “Some uncertainty will always remain, meaning that we need to manage the risks of warming with the knowledge we have.”

The study found 63% of uncertainty in projected warming was due to single sources – such as climate sensitivity, followed by future behaviour of the carbon cycle and the cooling effect of aerosols – while 37% of uncertainty came from the combination of these sources.

“This means that if any single uncertainty is reduced – even the most important, climate sensitivity – significant uncertainty will remain,” Dr Bodman said.

Professor Karoly said the study reinforced the importance of strong action on climate change.

“Our results reconfirm the need for urgent and substantial reductions in greenhouse gas emissions if the world is to avoid exceeding the global warming target of 2 degrees needed to minimise dangerous climate change,” he said.

Dr Bodman is Postgraduate Research Fellow at Victoria University’s Centre for Strategic Economic Studies. Professor Karoly and Professor Rayner are from the University of Melbourne’s School of Earth Sciences and the ARC Centre of Excellence for Climate
System Science.

Source: http://www.sciencealert.com.au

Salt: friend or foe?


Dietary guidelines advise against the consumption of too much salt. A high intake of sodium causes raised blood pressure—an established risk factor for heart disease, stroke, and kidney disease. But how much salt is too much? And could a very low salt intake also be detrimental?

The effects of salt consumption on health are controversial, but reduced salt intake is mostly believed to decrease the risk of cardiovascular disease. The 2010 Dietary Guidelines for Americans recommend a maximum daily consumption of 2300 mg salt for healthy adults and 1500 mg for people at raised risk of heart disease (eg, those older than 51 years, people with diabetes, and black people). The American Heart Association even advises that everyone adheres to the 1500 mg limit, irrespective of age or race. However, most people still eat too much salt—on average, US adults consume 3400 mg (about 1·5 teaspoons) daily.

In May, 2013, the Institute of Medicine reviewed recent evidence (39 studies) and reported that a very low salt intake might not be as beneficial as was previously thought, at least for those at increased risk of heart disease. Less than 2300 mg salt daily could even increase some cardiovascular risk factors, such as blood lipids and insulin resistance, potentially triggering heart problems. Moreover, no evidence suggested a benefit of an ultra-low sodium intake (<1500 mg daily) in any population.

High study heterogeneity, and the fact that the effects of reduced sodium intake on health outcomes cannot always be distinguished from those of overall diet changes, make accurate conclusions difficult. The report concludes that more trials are needed to address gaps in the data, especially studies of the effects of a 1500—2300 mg daily salt intake in different groups.

The report needs cautious interpretation—it does not suggest that people use salt freely. The Institute agrees that a link between high salt consumption and increased risk of cardiovascular disease persists, and that average intake needs to be reduced. However, the findings about very low sodium levels will help to clarify public health messages (eg, updated US dietary guidelines, due in 2015) and hopefully improve health outcomes.

Source: Lancet.



Intravenous and inhaled MgSO4 for acute asthma.


Asthma is one of the most common chronic disorders worldwide and symptom control is often elusive. Exacerbations are common in response to various triggers such as upper respiratory tract infections, air pollution,1 occupational irritants,2 and failure to adhere to appropriate management regimens. Mild exacerbations might be manageable by primary-care doctors; however, moderate-to-severe acute asthma attacks often need assessment in an emergency department. The accepted approach to acute asthma is to relieve acute bronchospasm, start treatments addressing airway oedema, identify the cause, and observe the patient for response or complications. Although most patients can be discharged home after assessment and treatment, some individuals require extended observation or hospital admission.

Numerous national and international guidelines exist to guide management of acute asthma.3—5 Most recommend short-acting β-agonists such as salbutamol with metered-dose inhalers or nebulisers,6 short-acting anticholinergics such as ipratropium, and systemic corticosteroids (either by oral or intravenous routes)7 for the treatment of acute asthma. In severe asthma, additional treatment such as intravenous magnesium sulphate (MgSO4),8 inhaled corticosteroids, and epinephrine (intramuscular or nebulised) can be considered. In the most severe cases, clinicians require interventions that reduce the risk of airway complications (ie, intubation), hospital admissions, and other serious sequelae.

The role of MgSO4 for treatment of asthma is evolving rapidly. Magnesium is an important intracellular and extracellular cation and is a cofactor of important intracellular enzymatic reactions.9 Magnesium may act in acute asthma through various mechanisms; for example, it can directly relax smooth muscles, and might be involved with inhibition of smooth-muscle contraction. It is also involved in acetylcholine release from cholinergic nerve terminals and histamine release from mast cells. Moreover, the effect of magnesium might be related to its ability to block the calcium ion influx to respiratory smooth muscles.10 Finally, an anti-inflammatory action has been shown.11 Overall, magnesium is an element with many complex functions in asthma; however, the precise mechanisms and their relative importance are unclear.

MgSO4 asthma treatment can be delivered via nebulised or intravenous routes. Two new trials12, 13 in The Lancet Respiratory Medicine expand our understanding of the efficacy of these modes of delivery. Although randomised controlled trials provide strong evidence, risk of bias means that not all trials are equally valid.14 In these two trials, however, the methodological rigour deserves special mention. Both trials were funded by unbiased sources, registered, and undertaken with the highest methodological quality (eg, appropriate sequence generation, randomisation, masking, outcome assessment, attention to loss to follow-up, and comprehensive reporting). In addition to their high-quality methods, the large sample sizes assessed suggests the evidence presented is at a low risk of bias. Although one trial should not generally result in practice change, incorporation of trial findings into systematic reviews and the totality of evidence clearly should lead to practice changes.

One of these trials, MAGNETIC,12 was a randomised trial of nebulised MgSO4 in children aged 2—16 years presenting with severe acute asthma to 30 hospital emergency departments in the UK.12 All patients received nebulised salbutamol and ipratropium bronchodilator treatments and either three nebulised treatments of isotonic MgSO4 or a saline placebo every 20 min. Overall, 227 patients received nebulised MgSO4, which resulted in significantly lower asthma severity scores in the adjusted primary analysis after 60 min than were noted in 243 children in the placebo group. This effect was largest in children with the severest asthma exacerbations. However, the investigators noted no differences in hospital admission, intravenous bronchodilator use, or length of inpatient stay for children treated with MgSO4 or placebo.

This new evidence for inhaled treatment needs to be interpreted in view of the systematic review of nebulised MgSO4 available in the present version of the Cochrane library.15 Overall, 16 studies (seven of adults, four of children, three mixed, and two unclear) of 896 patients examined the use of nebulised MgSO4 in acute asthma. Overall, seven studies examined the same comparison as the MAGNETIC trial, and the evidence failed to identify important differences (in pulmonary functions, admission, or symptom scores) in adults or children associated with inhaled MgSO4. Although reassurance was provided that the treatment was safe, the cumulative evidence fails to support the use of nebulised MgSO4, apart from perhaps in severe acute paediatric asthma.

The second trial, 3Mg, was a double-blind, randomised controlled trial enrolling adults with severe acute asthma undertaken in 34 hospital emergency departments in the UK.13 1084 patients received nebulised short-acting β-agonists, short-acting anticholinergics, and systemic corticosteroids at baseline and were then randomly allocated to receive 2 g of intravenous MgSO4, a cumulative dose of 1500 mg of nebulised MgSO4, or standard care. At 2 h, the investigators noted no difference for admission among the groups; however, there was a small difference between intravenous and nebulised magnesium groups with respect to breathlessness scores. The authors concluded there was no role for nebulised MgSO4 in the management of severe acute asthma in adults and at best only a limited role for intravenous MgSO4. However, the outcome assessment could be considered premature compared with many other emergency department studies and the trial included patients with less severe asthma than have been assessed in other MgSO4 trials. Moreover, the data do suggest a potential trend in favour of intravenous MgSO4, which when added to the systematic review evidence, supports its use in some situations.

The original systematic review8 of intravenous MgSO4 was published in the Cochrane Library in 2000 and uptake of use of intravenous MgSO4 was relatively rapid.16 That review, and other trials published since then, provided variable support for the role of intravenous MgSO4 in acute asthma. The original systematic review included 13 studies (eight in adults and five in children) of 965 patients and examined the addition of intravenous MgSO4 to short-acting β-agonists and systemic corticosteroids. A subsequent systematic review17 confirmed some of these earlier results but called for additional research to clarify others. Although the evidence in all severity groups was heterogeneous, intravenous MgSO4 reduced rates of hospital admission by about 40% and improved pulmonary function in severe acute asthma (ie, admission rates >30%). Nevertheless, the 3Mg trial reconfirms the absence of efficacy of intravenous MgSO4 in the treatment of moderate acute asthma. Notably, intravenous treatment was relatively safe in 3Mg and is inexpensive but until additional research is published, intravenous MgSO4 use should be restricted to adults with severe acute asthma.

Overall, the two trials need to be considered in view of all of the available evidence from systematic reviews. Both nebulised and inhaled MgSO4 seem efficacious in children with severe acute asthma. Conversely, the cumulative evidence of efficacy of inhaled MgSO4 in adults is limited. Although intravenous MgSO4 should be restricted to those patients who are unresponsive to bronchodilators or who have very severe asthma, these individuals are precisely the patients in whom aggressive management could prevent serious adverse events.



1 Villeneuve PJ, Chen L, Rowe BH, Coates F. Outdoor air pollution and emergency department visits for asthma among children and adults: a case-crossover study in northern Alberta, Canada. Environ Health 2007; 6: 40. CrossRef | PubMed

2 Beach J, Russell K, Blitz S, et al. A systematic review of the diagnosis of occupational asthma. Chest 2007; 131: 569-578. CrossRef | PubMed

3 British Thoracic Society, Scottish Intercollegiate Guidelines Network. British guidelines on the management of asthma—a national clinical guideline British Thoracic Society. http://www.brit-thoracic.org.uk/clinical-information/asthma/asthma-guidelines.aspx. (accessed May 10, 2013).

4 Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention. http://www.ginasthma.org. (accessed May 10, 2013).

5 Hodder R, Lougheed D, Rowe BH, Kaplan A, Fitzgerald M, McIvor A. Management of acute asthma in adults in the emergency department: nonventilatory management. CMAJ 2010; 182: E55-E67. CrossRef | PubMed

6 Cates CJ, Crilly JA, Rowe BH. Holding chambers (spacers) versus nebulisers for beta-agonist treatment of acute asthma. Cochrane Database Syst Rev 2006; 2. CD000052

7 Rowe BH, Spooner C, Ducharme FM, Bretzlaff JA, Bota GW. Early emergency department treatment of acute asthma with systemic corticosteroids. Cochrane Database Syst Rev 2001; 1. CD002178

8 Rowe BH, Bretzlaff JA, Bourdon C, Bota GW, Camargo CA. Systematic review of magnesium sulfate in the treatment of acute asthma. Cochrane Database Syst Rev 2000; 2. CD001490

9 Dominguez LJ, Barbagallo M, Di-Lorenzo G, et al. Bronchial reactivity and intracellular magnesium: a possible mechanism for the bronchodilating effects of magnesium in asthma. Clin Sci 1998; 95: 137-142. PubMed

10 Gourgoulianis KI, Chatziparasidis G, Chatziefthimiou A, et al. Magnesium as a relaxing factor of airway smooth muscles. J Aerosol Med 2001; 14: 301-307. CrossRef | PubMed

11 Cairns CB, Kraft M. Magnesium attenuates the neutrophil respiratory burst in adult asthmatic patients. Acad Emerg Med 1996; 3: 1093-1097. CrossRef | PubMed

12 Powell C, Kolamunnage-Dona R, Lowe J, et alon behalf of the MAGNETIC study group. Magnesium sulphate in acute severe asthma in children (MAGNETIC): a randomised, placebo-controlled trial. Lancet Respir Med 2013. http://dx.doi.org/10.1016/S2213-2600(13)70037-7. published online April 22.

13 Goodacre S, Cohen J, Bradburn M, Gray A, Benger J, Coats Ton behalf of the 3Mg Research Team. Intravenous or nebulised magnesium sulphate versus standard therapy for severe acute asthma (3Mg trial): a double-blind, randomised controlled trial. Lancet Respir Med 2013. http://dx.doi.org/10.1016/S2213-2600(13)70070-5. published online May 17.

14 Higgins JPT, Altman DG, Sterne JAC. Assessing risk of bias in included studies. In: Higgins JPT, Green S, eds. Cochrane handbook for systematic reviews of interventions, version 5.1.0. http://www.cochrane-handbook.org. (accessed June 15, 2011).

15 Powell C, Dwan K, Milan SJ, et al. Inhaled magnesium sulfate in the treatment of acute asthma. Cochrane Database Syst Rev 2005; 3. CD003898

16 Rowe BH, Camargo CAMulticenter Airway Research Collaboration (MARC) Investigators. The use of magnesium sulfate in acute asthma: rapid uptake of evidence in North American emergency departments. J Allergy Clin Immunol 2006; 117: 53-58. CrossRef | PubMed

17 Mohammed S, Goodacre S. Intravenous and nebulised magnesium sulphate for acute asthma: systematic review and meta-analysis. Emerg Med J 2007; 24: 823-830. CrossRef | PubMed

Source: Lancet.



Coronary artery bypass graft surgery versus percutaneous coronary intervention in patients with three-vessel disease and left main coronary disease: 5-year follow-up of the randomised, clinical SYNTAX trial.


We report the 5-year results of the SYNTAX trial, which compared coronary artery bypass graft surgery (CABG) with percutaneous coronary intervention (PCI) for the treatment of patients with left main coronary disease or three-vessel disease, to confirm findings at 1 and 3 years.


The randomised, clinical SYNTAX trial with nested registries took place in 85 centres in the USA and Europe. A cardiac surgeon and interventional cardiologist at each centre assessed consecutive patients with de-novo three-vessel disease or left main coronary disease to determine suitability for study treatments. Eligible patients suitable for either treatment were randomly assigned (1:1) by an interactive voice response system to either PCI with a first-generation paclitaxel-eluting stent or to CABG. Patients suitable for only one treatment option were entered into either the PCI-only or CABG-only registries. We analysed a composite rate of major adverse cardiac and cerebrovascular events (MACCE) at 5-year follow-up by Kaplan-Meier analysis on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT00114972.


1800 patients were randomly assigned to CABG (n=897) or PCI (n=903). More patients who were assigned to CABG withdrew consent than did those assigned to PCI (50 vs 11). After 5 years’ follow-up, Kaplan-Meier estimates of MACCE were 26·9% in the CABG group and 37·3% in the PCI group (p<0·0001). Estimates of myocardial infarction (3·8% in the CABG group vs 9·7% in the PCI group; p<0·0001) and repeat revascularisation (13·7% vs 25·9%; p<0·0001) were significantly increased with PCI versus CABG. All-cause death (11·4% in the CABG group vs 13·9% in the PCI group; p=0·10) and stroke (3·7% vs 2·4%; p=0·09) were not significantly different between groups. 28·6% of patients in the CABG group with low SYNTAX scores had MACCE versus 32·1% of patients in the PCI group (p=0·43) and 31·0% in the CABG group with left main coronary disease had MACCE versus 36·9% in the PCI group (p=0·12); however, in patients with intermediate or high SYNTAX scores, MACCE was significantly increased with PCI (intermediate score, 25·8% of the CABG group vs 36·0% of the PCI group; p=0·008; high score, 26·8% vs 44·0%; p<0·0001).


CABG should remain the standard of care for patients with complex lesions (high or intermediate SYNTAX scores). For patients with less complex disease (low SYNTAX scores) or left main coronary disease (low or intermediate SYNTAX scores), PCI is an acceptable alternative. All patients with complex multivessel coronary artery disease should be reviewed and discussed by both a cardiac surgeon and interventional cardiologist to reach consensus on optimum treatment.

Source: Lancet.



Consumers’ estimation of calorie content at fast food restaurants: cross sectional observational study.


Objective To investigate estimation of calorie (energy) content of meals from fast food restaurants in adults, adolescents, and school age children.

Design Cross sectional study of repeated visits to fast food restaurant chains.

Setting 89 fast food restaurants in four cities in New England, United States: McDonald’s, Burger King, Subway, Wendy’s, KFC, Dunkin’ Donuts.

Participants 1877 adults and 330 school age children visiting restaurants at dinnertime (evening meal) in 2010 and 2011; 1178 adolescents visiting restaurants after school or at lunchtime in 2010 and 2011.

Main outcome measure Estimated calorie content of purchased meals.

Results Among adults, adolescents, and school age children, the mean actual calorie content of meals was 836 calories (SD 465), 756 calories (SD 455), and 733 calories (SD 359), respectively. A calorie is equivalent to 4.18 kJ. Compared with the actual figures, participants underestimated calorie content by means of 175 calories (95% confidence interval 145 to 205), 259 calories (227 to 291), and 175 calories (108 to 242), respectively. In multivariable linear regression models, underestimation of calorie content increased substantially as the actual meal calorie content increased. Adults and adolescents eating at Subway estimated 20% and 25% lower calorie content than McDonald’s diners (relative change 0.80, 95% confidence interval 0.66 to 0.96; 0.75, 0.57 to 0.99).

Conclusions People eating at fast food restaurants underestimate the calorie content of meals, especially large meals. Education of consumers through calorie menu labeling and other outreach efforts might reduce the large degree of underestimation.


In this study of diners at fast food chain restaurants in four New England cities, we found that participants purchased large meals, and adults, adolescents, and (parents of) school age children underestimated the calorie content of those meals by 175 calories, 259 calories, and 175 calories, respectively. Nearly a quarter of adults, adolescents, and (parents of) school age children underestimated meal calorie content by 500 or more calories. Estimated calorie content was strongly associated with actual calorie content for each of the samples. Noticing calorie information in the restaurant had no effect on the accuracy of calorie estimations.

In a study of 147 fast food restaurant diners at food courts, Chandon and Wansink also found that people underestimated the calorie content of purchased meals, with larger underestimation for higher calorie meals and no association with recognition of nutritional information in the restaurants.2 Compared with that study and other previous research,1 4 our study has the advantages of a large sample size, comparison of diners at six restaurant chains across four cities, recruitment of a racially and ethnically diverse study population in three age groups, and investigation of predictors of underestimation.

Adult and adolescent diners at Subway restaurants estimated lower calorie content than diners at the other chains. These findings suggest a consistent “health halo” for Subway in these age groups. In a study of 518 participants eating meals with equivalent calorie content at McDonald’s and Subway, Chandon and Wansink found that participants estimated 151 fewer calories at Subway than at McDonald’s.3 Participants also ordered side dishes with more calories at Subway. Dieticians also falsely considered equivalent calorie meals to be lower calorie at Subway than McDonald’s.3Our study extends these findings by showing that this “health halo” is unique to Subway across the six chains and is present across age groups in a diverse sample.

Branding could be an important component of Subway’s “health halo.” Marketing researchers have found that brand positioning is particularly important in guiding consumer choices when specific information about products is not available.8 For example, simply labeling a food item as “heart healthy” led consumers in one experiment to conclude that the item conferred a lower risk of heart disease and stroke than similar unlabeled foods.9 Subway’s positioning as a “healthier” fast food option might lead consumers to view its food as lower calorie, especially when calorie information is not readily apparent.

The forthcoming US federal regulation on labeling calorie content on menus could alter this “health halo” by providing easily accessible information on menus and menu boards.10 11 Previous research has found that information can be most powerful when it contradicts previous expectations (in this case, improper estimation of calorie content of foods with a “health halo”).12 Unlike previous state and local regulations, the federal regulation will also require an anchoring statement that indicates recommended total daily calorie requirements. In our study, participants’ estimates of meal calories strongly correlated with their estimates of total daily requirements, supporting inclusion of daily requirements on menus as an “anchor.” Thus far, research about the effects of calorie menu labeling, in both real world and experimental settings, has been mixed.113 14 15 16 17 18 19 20 21 22 23 24 25 26 It is difficult to ascertain why these studies had inconsistent results, but differing study designs, demographic characteristics, the rare use of an anchoring statement, and weight status might be involved.

In addition to providing an anchoring statement on menus, policymakers could perhaps improve menu labeling by supporting social marketing campaigns to better explain the concept of calories. These efforts could bolster not only menu labeling but nutritional labeling of packaged foods.


In this study of over 3000 diners at six fast food restaurant chains across four diverse New England cities, we found that adults, adolescents, and parents of school age children generally underestimated the calories of meals, especially if the meal was large. Adults and adolescents dining at Subway underestimated calorie content more than diners at other chains. The forthcoming calorie menu labeling requirements of the US Patient Protection and Affordable Care Act might help to correct underestimation of calorie content.

What is already known on this topic

  • Consumers are known to underestimate the calorie content of restaurant meals, especially for large calorie meals
  • Previous studies have been conducted in experimental settings without monitoring consumer choices at actual fast food restaurants, have focused on a narrow range of fast food restaurants, or have enrolled samples with limited racial/ethnic or age group diversity
  • All age groups and racial/ethnic groups studied underestimated the calorie content of meals from fast food restaurants

What this study adds


Source: BMJ