Folic Acid Supplements During Pregnancy and Child Psychomotor Development After the First Year of Life.

Importance  Folate intake during pregnancy has been associated with improved neuropsychological development in children, although the effects of high dosages of folic acid (FA) supplements are unclear.

Objective  To examine the association between the use of high dosages of FA supplements during pregnancy and child neuropsychological development after the first year of life.

Design, Setting, and Patients  The multicenter prospective mother-child cohort Infancia y Medio Ambiente (INMA) Project recruited pregnant women from 4 areas of Spain (Asturias, Sabadell, Gipuzkoa, and Valencia) between November 2003 and January 2008. Pregnant women completed an interviewer-administered questionnaire on the usual dietary folate intake and FA supplements at 10 to 13 weeks and 28 to 32 weeks of gestation. The main analyses were based on a sample of 2213 children with complete information on neuropsychological development and FA supplement intake during pregnancy. Multiple linear and logistic regression analyses were used to explore the effects of FA supplements on child neuropsychological development.

Main Outcomes and Measures  Neuropsychological development was assessed using the Bayley Scales of Infant Development. We calculated mental scale and psychomotor scale scores. One SD below the mean established a delay in neurodevelopment (score <85).

Results  A high proportion of women (57.3%) did not reach the recommended dosages of FA supplements (400 μg/d), but 25.2% women took more than 1000 μg/d of FA supplements (3.5% consuming >5000 μg/d). In multivariate analysis, we observed that children whose mothers used FA supplement dosages higher than 5000 μg/d during pregnancy had a statistically significantly lower mean psychomotor scale score (difference, −4.35 points; 95% CI, −8.34 to −0.36) than children whose mothers used a recommended dosage of FA supplements (400-1000 μg/d). An increased risk of delayed psychomotor development (psychomotor scale score <85) was also evident among children whose mothers took FA supplement dosages higher than 5000 μg/d, although the association was not statistically significant (odds ratio = 1.59; 95% CI, 0.82-3.08).

Conclusions and Relevance  To our knowledge, this is the first time a detrimental effect of high dosages of FA supplements during pregnancy on psychomotor development after the first year of life has been shown. Further research from longitudinal studies is warranted to confirm these results.

Plants make their own sunscreen

A new study has revealed how plants protect themselves from getting sunburnt – by producing special molecules that block harmful ultraviolet rays.


Plants spend their whole day sunbathing, and while they need sunlight for photosynthesis, overexposure to the Sun’s rays can cause serious damage to their DNA that can disrupt their development. So how do they protect their luscious leaves and shoots from burning to a crisp? A new study has discovered that plants produce a natural “sunscreen”.

This plant sunscreen isn’t like the white lotion that we use to protect ourselves from the Sun – it’s a concoction of special molecules, called sinapate esters, that plants produce and then send to the outer layers of their leaves to form an invisible barrier.

Researchers from Purdue University in the US have now discovered that these molecules block ultraviolet-B (UVB) radiation whilst absorbing the light needed for photosynthesis. The team identified the various wavelengths of light that a type of sinapate ester called sinapoyl malate blocks, by converting the sinapoyl malate from a liquid to a gas, and then zapping it with UVB radiation from a laser. Interestingly, they found that the sinapoyl malate was able to soak up radiation at every wavelength across the UVB spectrum.

“Plants do not usually show signs of UV damage in sunlight, so the mechanisms they’ve evolved for UV protection, which include sunscreen production, evidently work pretty well,” Gareth Jenkins, plant biologist at the University of Glasgow in the UK, who was not involved in the study, told Andy Coghlan from New Scientist. 

The team says that the discovery could be useful for making plants that are even more resistant to UVB in the case of heatwaves which are becoming increasingly common with climate change.

With such an efficient mechanism for absorbing harmful radiation, it’s not surprising that unlike us, plants only need a thin coating of sunscreen to protect themselves from sunburn.

‘Sponge on a string’ test for cancer



Cancer of the gullet could be diagnosed with a cheap and simple sponge-on-a-string test, latest trial results show.

Swallowed and then retrieved from the mouth by pulling on the string, the Cytosponge capsule expands in the body to collect cells on its way out.

In tests on more than 1,000 UK patients, it was found to be well tolerated, safe and accurate at diagnosing Barrett’s oesophagus.

One in 10 people with this condition later develops cancer of the food pipe.

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Death rates are unacceptably high in oesophageal cancer, so early diagnosis is vital”

Dr Julie SharpCancer Research UK

In Barrett’s, acid comes back up the food pipe from the stomach, which can cause symptoms such as indigestion and heartburn as well as changes in the normal cells that line the gullet.

Conventionally, doctors have diagnosed and monitored these patients for signs of cancer using biopsy – taking a small sample of cells – during a procedure called endoscopy, where a long, flexible tube with a camera is inserted down the throat.

But researchers from the Medical Research Council Cancer Unit at the University of Cambridge say the Cytosponge could replace this test.

Unlike endoscopy, Cytosponge can easily be used in GP surgeries and doesn’t require any sedation, say Prof Rebecca Fitzgerald and colleagues.

As well as being less invasive, Cytosponge is also cheaper, costing £25 compared with the £600 cost of a traditional endoscopy.

The trial invited more than 600 patients with Barrett’s to swallow the Cytosponge and to undergo an endoscopy. Almost 500 more people with symptoms like reflux and persistent heartburn did the same tests.

Many patients in the trial said they preferred it to endoscopy. More than nine in 10 patients were able to successfully swallow the capsule. Larger studies are now planned.

Dr Julie Sharp, of Cancer Research UK, the charity that funded the trial, said: “These results are very encouraging and it will be good news if such a simple and cheap test can replace endoscopy for Barrett’s oesophagus.

“Death rates are unacceptably high in oesophageal cancer, so early diagnosis is vital.”

Jacqui Graves, of Macmillan Cancer Support, said a less invasive test that hastened diagnosis would be welcome, but she said it would be some time before any such test would be available across the UK on the NHS.

The trial findings will be presented at the National Cancer Research Institute’s annual conference in Liverpool this week.

Shift work dulls your brain .

Woman working

Working antisocial hours can prematurely age the brain and dull intellectual ability, scientists warn.

Their study, in the journal Occupational and Environmental Medicine, suggested a decade of shifts aged the brain by more than six years.

There was some recovery after people stopped working antisocial shifts, but it took five years to return to normal.

Experts say the findings could be important in dementia, as many patients have disrupted sleep.

The body’s internal clock is designed for us to be active in the day and asleep at night.

The damaging effects on the body of working against the body clock, from breast cancer to obesity, are well known.

Graphic on sleeping

Now a team at the University of Swansea and the University of Toulouse has shown an impact on the mind as well.

Three thousand people in France performed tests of memory, speed of thought and wider cognitive ability.

The brain naturally declines as we age, but the researchers said working antisocial shifts accelerated the process.

Those with more than 10 years of shift work under their belts had the same results as someone six and a half years older.

The good news is that when people in the study quit shift work, their brains did recover. Even if it took five years.

‘Substantial decline’

Dr Philip Tucker explains how shift work impairs cognitive performance

Dr Philip Tucker, part of the research team in Swansea, told the BBC: “It was quite a substantial decline in brain function, it is likely that when people trying to undertake complex cognitive tasks then they might make more mistakes and slip-ups, maybe one in 100 makes a mistake with a very large consequence, but it’s hard to say how big a difference it would make in day-to-day life.”

He said he would not do night shifts “if I could possibly help it” but they were a “necessary evil” that society could not do without.

“There are ways to mitigate the effects in the way you design work schedules and regular medical check-ups… should include cognitive performance tests to look for danger signs,” he added.

Eating on a night shift

Dr Michael Hastings, from the UK Medical Research Council’s Laboratory of Molecular Biology, told the BBC: “The reversibility is a really exciting finding because no-one else has shown it and no matter how compromised a person may be there’s always hope of recovery.”

He said the findings may have important consequences in dementia, which is known to damage sleeping patterns in a similar way to shift work.

“If you can keep the sleep-wake cycle as solid as possible you’re unlikely to reverse neurodegeneration, but you can ameliorate one of the consequences.

“In nursing homes one thing you can do to help is to set a very clear daily routine to encourage a sensible 24-hour pattern of activity; it needs bright lights in the day, resting at night and appropriate medication such as melatonin before bed.”

Prof Derk-Jan Dijk, from the Surrey Sleep Centre, cautioned that retired shift workers still had lower sleep quality than people who had never done nights.

“So some of these effects may not be so readily or rapidly reversed.”

He added: “We now accept that shift work may not be good for your physical health, but this shows your brain function is affected, and I think that finding will surprise many people.”

Coating makes batteries child-safe

button batteries

In 2013 more than 3,000 cases of battery ingestion were reported across the US

Engineers in the US have produced child-safe batteries with a special coating that stops them causing harm if they are swallowed.

Small, button-shaped batteries can be easy to swallow and cause thousands of injuries every year, some fatal.

The new coating only conducts electricity when squeezed – such as when a battery is inside its spring-loaded compartment.

The rest of the time it insulates the battery, making it inactive and safe.

The process is described in the science journal PNAS. The insulation is critical, because the injuries and deaths happen when batteries get wet and release current after they are swallowed.

“Current is released and this breaks down the water, producing hydroxide ions which are caustic,” explained senior author Dr Jeff Karp, a biomedical engineer at the Brigham and Women’s Hospital in Boston.

The battery effectively makes caustic soda, which can eat through tissue and damage the oesophagus or the vocal cords, and sometimes reaches major blood vessels.

‘Horrific’ injuries

Two years ago, one of Dr Karp’s colleagues saw the statistics on the problem – more than 3,000 ingestions per year in the US – and his team started looking for a solution.

Their new pressure-sensitive design makes use of a property called quantum tunnelling, which is also used in touch pads and screens.

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“That would be superb, if something this simple could solve a major problem”

Dr Kate ParkinsNorth West Paediatric Transport Service

The negative terminal of a battery was covered with a 1mm-thick layer of a material called a “quantum tunnelling composite” (QTC). It is mostly silicone, but is laced with tiny particles of metal.

When it is squeezed firmly, the metal particles get closer together which allows electrons to “tunnel” between them: a process that can only be explained by quantum mechanics.

“Quantum tunnelling is a wild phenomenon,” said Dr Karp. “It essentially achieves the impossible.”

Baffling though their details may be, QTCs are already found in many applications. A Yorkshire-based company, Peratech, developed QTCs and licensed them to smartphone manufacturers and to Nasa.

So Dr Karp’s team didn’t have to look far once they hit upon the idea of making batteries touch-sensitive.

“As a first attempt, we thought, what if we just purchased some of this from a catalogue and place it onto the battery and see if it works?” he told the BBC.

“And it worked quite well!”

With QTC stuck on one side, the edges of the battery were then covered with a sealant, so that the whole thing was waterproof.

Now, the battery would only deliver current if it was under pressure. The rest of the time it was completely inert.

two batteries after testing
After 25 hours in stomach fluid, a normal battery (left) leaked badly but the coated design (right) was intact

Together with colleagues from the Massachusetts Institute of Technology and Harvard University, Dr Karp set about thoroughly testing the new design.

When placed on samples of gut tissue or inside the intestines of live pigs, the armoured batteries did no damage at all.

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We hope to work with battery manufacturers in the near future”

Dr Jeff KarpBrigham and Women’s Hospital, Boston

Even dropped into simulated stomach fluid and left for 24 hours, they remained intact. The same test caused a normal, uncoated battery to short-circuit and leak badly.

Dr Kate Parkins has seen several small children suffer terribly after swallowing batteries, including two recent deaths. She specialises in intensive care and is the lead consultant for the North West and North Wales Paediatric Transport Service.

She said it was “pretty horrific” to see internal bleeding that doctors can’t stop, no matter what they try.

“You’re throwing the kitchen sink at things to try and control it,” Dr Parkins told BBC News.

“You’re following all of the stuff about major haemorrhage that we’ve learned from places like Camp Bastion. Even with all of that and, in one case, surgical intervention, we still couldn’t get control.”

Patent pending

The only solutions Dr Parkins had seen proposed, until now, were ideas such as making the batteries taste bad, or painting them with dye so that parents would notice if a child had swallowed one.

She said the protective coating idea was “fantastic”.

“That would be superb, if something this simple could solve a major problem.”

X-ray of a battery lodged in a child's throat
Small “button” batteries are easily swallowed and can cause severe burns or permanent damage

Dr Paul Shearing studies battery technology at University College London, where he is a Royal Academy of Engineering research fellow. He agreed the design was an “exciting possibility”, as long as it could be widely applied.

“These things are made at such enormous scale that you need quite widespread adoption, in order to bring in something new,” Dr Shearing said, adding that the coating design “does seem relatively scalable and inexpensive”.

Dr Karp and his team in Boston have filed a patent on the design, and have already had “a few conversations” about putting it into practise.

They expect the cost impact would be “in the order of pennies, and certainly not dollars” per battery.

“We hope to work with battery manufacturers in the near future, to help prevent these injuries from happening,” he said.

FDA Panel Endorses Endoxaban as Fourth NOAC

Edoxaban (Savaysa) should be approved for stroke and systemic embolism prevention in nonvalvular atrial fibrillation, an FDA advisory panel recommended Thursday.

The panel voted 9-1 in favor of approval for that indication despite dissension over what doses to approve and for which patient populations.

While the FDA usually follows the recommendation of its advisory committees, it doesn’t have to do so, and there were clear rifts in opinion within the agency over the drug.

“No FDA speaker has argued for non-approval,” said Martin Rose, MD, JD, cross-discipline team leader in the FDA’s Division of Cardiovascular and Renal Products, in presenting the discussion issues to the panel.

However, almost every other option was proposed.

The Controversy

Drugmaker Daiichi Sankyo requested approval of a 60-mg, once-daily dose as well as a 30-mg, once-daily dose for patients with moderate to severe renal impairment (creatinine clearance 15 to 50 mL/min), body weight under 132 lbs, or on P-glycoprotein inhibitors except amiodarone (Cordarone) as was used in the pivotal ENGAGE-AF trial.

None of the speakers or panelists questioned the main results of the trial, which showed noninferiority of both doses of edoxaban versus well-managed warfarin (Coumadin, median time in therapeutic range 66%).

But differences in efficacy when patients were stratified according to renal function in a post-hoc analysis complicated the assessment and were a major topic of discussion at the committee meeting.

And, for once, it was normal renal function rather than renal impairment being discussed as a potential contraindication.

In ENGAGE-AF, the overall stroke hazard ratio with edoxaban at the higher 60-mg dose versus warfarin was 1.41 (95% confidence interval 0.97-2.05) with normal kidney function but 0.51 (95% CI 0.38-0.69) in the mildly-impaired renal subpopulation.

The same pattern was seen for ischemic stroke: the hazard ratio for stroke was “markedly superior” with 60-mg edoxaban versus warfarin in the mildly impaired renal function group (HR 0.62, 95% 0.43-0.87) but worse with the factor Xa inhibitor in normal renal function (HR 1.58, 95% 1.02-2.45).

The entire trial was likely under-dosed, suggested Melanie Blank, MD, a medical officer, Division of Cardiovascular and Renal Products.

Bumping the dose up to 75 mg for normal renal function patients would have cut the event hazard ratio to an estimated 1.26, and 90 mg was projected to have a hazard ratio of 1.15, Justin Earp, PhD, an FDA pharmacometrics reviewer, reported.

Because about one-third of the study population had normal renal function, “you can imagine the public health impact of approving a dose that’s ineffective,” Blank said.

Mahmoud Ghazzi, MD, PhD, executive vice president and global head of development for Daiichi Sankyo, argued for the company’s perspective that the difference by renal subgroup was not due to inadequate exposure in the renal sufficient group but driven by warfarin variability.

The event rate was nearly identical with 60-mg edoxaban between the renally sufficient and impaired subgroups, at about 1%; whereas warfarin showed a lower rate that varied by renal function and was lower than average in other NOAC trials, company presenters noted.

The slope of the curve for major bleeding versus edoxaban exposure is steeper than the one for event prevention, Glenn Gormley, MD, PhD, global head of research and development at Daiichi Sankyo, pointed out.

Increasing edoxaban exposure by considering a dose over 60 mg will not increase efficacy but will result in more significant bleeds, he argued.

The Options for Approval

The FDA statistical reviewer supported approval with dosing based on the high exposure regimen used in the pivotal ENGAGE-AF trial plus approval of a 15-mg dose for those with severe renal impairment, although not studied.

The FDA clinical reviewer recommended an indication only for patients with renal impairment, 60-mg once daily for those with mild renal impairment. The company should establish the benefits and risks of a higher dose for those with normal renal function in a postmarketing clinical trial.

The FDA pharmacometrics reviewer also proposed approving the 60-mg dose for those with mild renal impairment but also a higher never-tested dose, projected as between 75 and 90 mg based on exposure matching, for those with normal renal function.

The 30-mg tablet seemed off the table as a starting dose, perhaps just to be used for dose reduction.

FDA reviewers pointed out that the lower dose trended toward inferiority, with a hazard ratio of 1.13 for stroke or systemic embolism versus warfarin (P=0.10).

“As there was no marked bleeding excess and bleeding rates were still well below warfarin, it seems hard to support use of a dose less than 60 mg,” the briefing documents noted.

Linda Fried, MD, MPH, a nephrologist and chief of peritoneal dialysis for the VA Pittsburgh Healthcare System, said clinicians use estimated glomerular filtration rate (eGFR), not creatinine clearance.

“None of us use creatinine clearance clinically any more,” she said.

Some FDA staffers called the two well-correlated, suggesting that clinicians could get eGFR on labs to guide the initial dose determination.

However, John Lawrence, PhD, senior statistical reviewer in the FDA’s Division of Biometrics I, argued for approval of only the 60-mg dose in part because of the potential for confusing eGFR and estimated creatinine clearance.

If a higher untested dose is approved, there is a possibility of dosing errors such that people who should be getting the 60 mg dose would get the higher, untested dose instead, he posited.

Involvement of a cross-discipline team leader in an FDA advisory panel meeting is a highly uncommon move, highlighting the discord within the agency.

Norman Stockbridge, MD, PhD, director of the FDA’s Division of Cardiovascular and Renal Products, had predicted from the outset that it would be a tough panel.

“Our internal discussions [at FDA] have been spirited and divergent,” he said in opening the meeting.

If it were not for the proposal by the FDA to increase the dose of edoxaban for patients with normal renal function, “we probably would not be taking the fifth NOAC [novel oral anticoagulant] to committee,” Stockbridge noted.

The Vote

Discussion among the advisory panel members about their “yes” votes on approval of edoxaban largely (five of nine) supported approval of the 60-mg dose for both patients with normal renal function and those with mild renal impairment.

Two favored approval of a dose greater than 60 mg for patients with normal renal function — one saying she would chose non-approval if this was not an option.

Two suggested approval of edoxaban only for patients with mild or moderate renal impairment.

“Most are concerned and very cautious about the idea of using a higher dose empirically based on pharmacokinetics … but it has been pointed out that we could assure we achieved the levels we intended with a relatively [short] study,” said the panel chair, A. Michael Lincoff, MD, of the Cleveland Clinic.

Most of the panelists said they felt some sort of patient education beyond the label regarding a higher than 60-mg dose was feasible but likely to be challenging. A range of dose adjustments could be put in the label, they suggested.

Half of the 10 voting members on the panel said they thought the finding of lower efficacy in the normal renal function group was real, whereas two said it was likely a play of chance.

“There is some division,” the panel chair summarized. “Given the size of the subgroup, the biological plausibility, …and the fact that other NOACs exist, the potential clinical impact if this is real is important.”

Putting an untested higher dose on the market, Stockbridge added, “is not without some precedent. Marketed Pradaxa [dabigatran] results in ~10% higher exposure than you got with the formulation used in the RE-LY study. For at least some of us, the proposal to adjust the dose of edoxaban is not unprecedented.”