Thursday, April 17, 2008

Researchers chart how new flu strains travel

South Korean health officials walk to bury chickens at the infected chicken farm in Gimje, 162 miles south of Seoul on April 4, 2008. South Korea has started culling thousands of chickens after an outbreak of bird flu was confirmed to be the deadly H5N1 strain, officials said.
They emerge in Asia and eventually disappear in South America. The findings should help improve vaccines.

Solving a 60-year-old mystery, researchers have concluded that new flu strains emerge in eastern and southeastern Asia, move to Europe and North America six to nine months later, then travel to South America where they disappear forever.

The new findings should help researchers pick the correct flu strains for each year's vaccine, a process that must be carried out a year ahead of time and that is now analogous to making a long-term weather forecast supported by only limited data.

The group charged with making the decisions about vaccines has been right about 80% of the time, said Dr. Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases, and the new findings should lead to an even higher success rate.

"If we have competing candidates, this will help to pick which virus should go in a vaccine," added Dr. Arnold S. Monto, an epidemiologist and flu specialist at the University of Michigan.

Influenza strikes up to 15% of the world's population each year, killing, on average, about 250,000 to 500,000 people, according to the World Health Organization. About 300 million people annually are protected by an influenza vaccine, but producing the vaccine is something of a crapshoot because its ingredients are typically chosen nearly a year before the flu season to allow time for production.

The problem is that the flu virus mutates rapidly, particularly the gene for a surface protein called hemagglutinin that plays a key role in interacting with the human immune system. Those mutations reduce the efficacy of the immune response to the virus, limiting vaccine protection.

For more than a half a century, researchers have debated where these mutations occur. One idea, discredited only about a year ago, suggested that a background infection of the virus remained in each country outside the flu season, allowing mutations to occur.

Other hypotheses were that the virus migrated back and forth between the northern and southern hemispheres following the seasons, that the viruses circulated continuously in the tropics, or that new mutations occurred in China and spread to the rest of the world from there.

The new results, appearing today in the journal Nature and Friday in Science, suggest that there is a little bit of truth in each of those scenarios.

In the Science paper, an international team led by geneticists Colin A. Russell and Derek J. Smith of the University of Cambridge studied more than 13,000 samples of influenza A virus collected on six continents between 2002 and 2007.

They studied physical differences in the hemagglutinin molecules on the surfaces of the viruses by measuring how strongly each one bound to an antibody. They also determined the DNA sequence of the hemagglutinin gene for about 10% of the viruses.

The team found that once the viruses leave Asia, they don't change much and rarely return. The areas outside Asia are "evolutionary graveyards," Russell said.

In the Nature report, biologist Edward Holmes of Pennsylvania State University and his colleagues sequenced the entire genome of 1,302 influenza A viruses collected over a 12-year period.

Holmes' results were very similar to Russell's findings. Holmes' team was able to conclude that the viral mutations originated in only one area in the tropics but could not pinpoint the area.

Several factors contribute to Asia's role in the mutations. While flu season in the Western world typically occurs in winter, flu season in Asia generally is the rainy season. Because of the wide geographic variations in the region, there is generally a rainy season somewhere, allowing the viruses to propagate continuously.

Add to that the high population density, and the conditions are ripe for a high transmission rate and accompanying mutations.

The large rate of air travel from Asia to Europe and North America then carries the mutated viruses to a new environment where there is little resistance to them. Much less direct traffic occurs between Southeast Asia and South America, so the virus must travel via North America, delaying its passage.

Some of the virus is undoubtedly carried back to Asia via air travel, Smith said, but by that time widespread immunity to it has built up in the population and it cannot gain a foothold.

Although the new information will be useful in producing vaccines, Monto said, even more important is the proliferation of new influenza monitoring stations throughout Asia in response to fears of a bird flu pandemic.

Too often, he said, researchers have known which strain should be included in a vaccine but have not been able to obtain a good isolate of the virus. The new monitoring stations should be able to provide those strains, he said.

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Peanut Butter and Deadly Taunts

Late last spring, 14-year-old Sarah VanEssendelft of Mastic, N.Y., experienced bullying worthy of a teen movie.

Peanut allergies
The number of reported peanut allergies has doubled in recent years. Taunting kids with food now may turn into medical school yard problems.
(iStock/ABC News)

"There was a group of five girls ... and they decided they didn't want me sitting at their lunch table anymore," said VanEssendelft. To get her to leave, they all brought in peanut butter and jelly sandwiches.

For VanEssendelft, it might as well have been arsenic.

Two weeks later, a boy in the back of her class opened up a peanut butter cup. The smell was enough to trigger VanEssendelft's peanut allergy and send her to the emergency room with breathing problems.

"My throat felt tight and my lips were getting really swollen, really fast," said VanEssendelft. "I looked like Angelina Jolie."

On the one hand, mean tricks or sneaking candy looks like mild behavioral problems to school administrators. On the other hand, given VanEssendelft's serious peanut allergy, those sandwiches might very well have been weapons.

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More airports to use 'whole body imaging' machines

WASHINGTON (CNN) -- Some travelers at key airports in New York and Los Angeles may be put through machines that see through clothing and provide a detailed image of a person's body beginning later this week.

The TSA says the screener who reviews the images is in a booth, unable to see the travelers.

It's the first expansion of the program since the machines were first put to the test in Phoenix, Arizona.

The "whole body imaging" machines have sparked complaints from privacy advocates.

But the Transportation Security Administration says that it has taken steps to protect individuals' privacy and that 90 percent of the travelers in Phoenix preferred the imaging machine to a pat-down.

The millimeter wave machines will be rolled out at John F. Kennedy International Airport in New York and Los Angeles International Airport in California later this week, TSA Administrator Kip Hawley told Congress on Tuesday.

The TSA will be purchasing at least 30 more machines for use at other U.S. airports this year, he added.

The TSA will use two different methods at JFK and LAX as they study the most effective way to use the machines.

At JFK, passengers sent to secondary screening will be given the option of a pat-down or a trip through the body imager. To protect the traveler's privacy, the screener who reviews the image is in a booth, unable to see the traveler, according to the TSA. The traveler's face is pixilated and the image is not stored, the TSA said.

At LAX, the millimeter wave machine will be located just beyond the checkpoint magnetometers.

Travelers will continuously and randomly be selected to go through the machine. While signs will inform them of the pat-down option, screeners will not announce that choice. But passengers electing not to go through the millimeter wave machine will be given the option of the pat-down.

A TSA spokesman said the agency is still exploring backscatter, another imaging technology in use at Phoenix's Sky Harbor International Airport.

Millimeter wave machines are already in use at airports in Britain, Spain, Japan, Australia, Mexico, Thailand and the Netherlands, as well as at some court and corrections facilities in Virginia, Colorado, Pennsylvania, California and Illinois.

Sky Harbor began using the machines last October.

Hawley also announced Tuesday the TSA is purchasing another 580 multi-view X-ray machines that are used to screen passengers' carry-on bags, bringing the total to 830 machines. The machines give screeners a clearer, more detailed view. Some 600 machines will be deployed by year's end, he said.

The technology is a "powerful platform" that can be adjusted to include software capable of detecting liquid explosives, he said.

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HPV-related oral cancers rise among younger men

Dr. Maura Gillison

Dr. Maura Gillison, a Johns Hopkins oncologist, found that HPV causes some head and neck cancers, as well as cervical cancer. (Sun photo by Kim Hairston / April 11, 2008)

The sexually transmitted virus that causes cervical cancer in women has now been linked to an uptick of throat, tonsil and tongue cancers - in a younger and healthier group of patients than doctors have ever seen before.

These head and neck cancers were once the scourge of older men - mostly the result of lifetimes of heavy smoking and drinking. The treatments often left victims disfigured.

But with those cases on the decline, doctors are seeing a new group of victims. They're men in their 40s, and even 30s, whose cancer is brought on by the increasingly common human papillomavirus (HPV). It's an infection that more than half of Americans will encounter during their lifetimes. And researchers now believe that the increase in certain oral cancers can be traced to the spread of the virus through oral sex.

New studies suggest that HPV-related oral cancer cases are on pace to eventually surpass cases of cervical cancer in the United States, which strikes about 11,000 women each year. And many doctors do not realize that they should be on the lookout for oral cancer in younger patients.

Doctors are familiar with this progression because pre-cancerous lesions are often caught during Pap tests. But they don't know much about how progression occurs in the throat and mouth.

Gillison and her colleagues say HPV-related oral cancers appear to be distinct from those not associated with the sexually transmitted infection and appear to respond differently to treatment.

Two years after diagnosis, 95 percent of those with HPV-positive head and neck cancers were alive compared with 62 percent with HPV-negative cancers, research shows.

Even so, the treatment can have serious and long-lasting side effects. Some patients end up disfigured; others have difficulty speaking or swallowing. Gillison said those with HPV-positive tumors might be able to survive with less-damaging treatments.

Meanwhile, the HPV vaccine has been a financial boon for Merck & Co., the maker of Gardasil, the three-dose vaccine approved in the United States in 2006 for females ages 9 through 26. Doctors recommend vaccinating girls before they become sexually active and can be exposed to the virus.

Merck sold $1.5 billion worth of Gardasil last year around the world. GlaxoSmithKline is seeking U.S. approval for a competing drug called Cervarix.

Neither vaccine is approved for males. Both companies are studying whether it is safe in boys and whether it would prevent genital warts and rare cancers of the penis and anus. But neither has plans to study whether the vaccine would play any role in the prevention of HPV-linked oral cancers.

"Cervical cancer is really the focus," said Liad Diamond, a GlaxoSmithKline spokeswoman.

Experts said they think researchers will find the vaccine works on HPV throughout the body.

"The way the vaccine works, there's no reason to think it wouldn't protect against oropharanyx [tonsil, tongue and throat] cancer as it does cervical cancer," Sturgis said.

Dr. Aimee Kreimer, an epidemiologist at the National Cancer Institute in Bethesda, said that, theoretically, the vaccine should work on HPV anywhere in the body but such discussion is premature.

"Before recommending the vaccine to men, it's crucial to determine if the vaccination works to prevent infection in men," she said.

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Medicine's Secret Stat

Researchers can gather all the hard-nosed evidence they want about the effectiveness of a particular drug or treatment. But there's one figure doctors don't much talk about despite its importance. It's called number needed to treat, or NNT, a new measure developed in the past 20 years that's one of the best-kept statistical secrets in medicine.

The idea of NNT is simple enough. Most clinical trials look at how much better people do on a particular medicine compared with how they would do without it or whether they should be on a different medicine. Take statins, drugs that aim to reduce bad cholesterol. A typical trial might give one group of men a statin for, say, five years and give a second group a placebo, or fake pill.

Generally, you will see fewer heart attacks in the statin group (about 30% fewer in one real-world trial). Reducing the risk by a third sounds like a lot, which is one reason many hundreds of thousands of men with no sign of heart disease take statins. But that number is meaningless unless you take into account the percentage of men in both groups who have heart attacks in the first place. If those people represent only a tiny fraction of the two populations, an improvement of 30% isn't much--maybe one heart attack fewer in a group of thousands.

The effort to handicap those odds is where NNT comes in. It answers the question, How many people have to take this drug to avoid one heart attack? The same principle can be applied to avoiding one recurrence of cancer or stroke or whatever end point you choose to measure. In healthy men, the NNT for statins is about 50 (depending on which of dozens of statins is taken, age, family history, lifestyle and so on). So 50 men have to take these drugs in order to prevent a single--not necessarily fatal, heart attack.

Presented that way, taking statins sounds like less of a no-brainer--especially given that the drugs cost hundreds of dollars a year, side effects could include liver and muscle damage and you have to take twice-yearly blood tests just in case. Still, factored out over the entire U.S. population, even a 1-in-50 figure means many thousands of heart attacks are avoided every year.

Since public-health officials want to save lives, they focus on the thousands and avoid the NNT. Since pharmaceutical companies are in business to sell drugs, they do the same. Those two forces have kept NNT from being a big part of medical education. We could all help change that by doing nothing more than asking for the number up front the next time we're handed a prescription.

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Vitamin supplements may increase risk of death

Vitamin supplements taken by millions of people do not increase life expectancy and may raise the risk of a premature death , according to a review of 67 studies with more than 230,000 subjects.

The review, by the Cochrane Collaboration which regularly pools data from trials to evaluate drugs and treatments, found supplements vitamin A, vitamin E and beta-carotene are detrimental to health. In 47 trials with 180,938 people and a low risk of bias, the "antioxidant supplements significantly increased mortality", the authors wrote. When the antioxidants were assessed separately and low risk of bias trials were included and selenium excluded, vitamin A was linked to a 16% increased risk of dying, beta-carotene to a 7% increased risk and vitamin E to a 4% increased risk.

Evidence for vitamin C and selenium was more equivocal, suggesting there was no benefit to taking these pills compared with a placebo.

"The bottom line is current evidence does not support the use of antioxidant supplements in the general healthy population or in patients with certain diseases," said Goran Bjelakovic, who performed the review at Copenhagen Universityhospital in Denmark. "There was no indication that vitamin C and selenium may have positive or negative effects. So regarding these we need more data from randomised trials."

All the supplements are categorised as antioxidants; research has suggested these chemicals underlie some of the beneficial effects of eating fruit and vegetables because they soak up harmful byproducts of metabolism which can damage cells and cause aging.

While the evidence of a beneficial effect of a diet rich in fruit and veg is solid, the Cochrane data suggest antioxidant supplements are either useless or detrimental.

Bjelakovic's team evaluated 67 randomised clinical trials with 232,550 subjects; 21 of the trials were on healthy subjects, while the rest tested patients with a range of diseases. The evidence suggests it would be safer to obtain the chemicals not as supplements but by eating plenty of fruit and vegetables.

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Why There Aren't More Googles

Umair Haque wrote recently that the reason there aren't more Googles is that most startups get bought before they can change the world.

Google, despite serious interest from Microsoft and Yahoo—what must have seemed like lucrative interest at the time—didn't sell out. Google might simply have been nothing but Yahoo's or MSN's search box.

Why isn't it? Because Google had a deeply felt sense of purpose: a conviction to change the world for the better.
This has a nice sound to it, but it isn't true. Google's founders were willing to sell early on. They just wanted more than acquirers were willing to pay.

It was the same with Facebook. They would have sold, but Yahoo blew it by offering too little.

Tip for acquirers: when a startup turns you down, consider raising your offer, because there's a good chance the outrageous price they want will later seem a bargain. [1]

From the evidence I've seen so far, startups that turn down acquisition offers usually end up doing better. Not always, but usually there's a bigger offer coming, or perhaps even an IPO.

Of course, the reason startups do better when they turn down acquisition offers is not necessarily that all such offers undervalue startups. More likely the reason is that the kind of founders who have the balls to turn down a big offer also tend to be very successful. That spirit is exactly what you want in a startup.

While I'm sure Larry and Sergey do want to change the world, at least now, the reason Google survived to become a big, independent company is the same reason Facebook has so far remained independent: acquirers underestimated them.

Corporate M&A is a strange business in that respect. They consistently lose the best deals, because turning down reasonable offers is the most reliable test you could invent for whether a startup will make it big.


So what's the real reason there aren't more Googles? Curiously enough, it's the same reason Google and Facebook have remained independent: money guys undervalue the most innovative startups.

The reason there aren't more Googles is not that investors encourage innovative startups to sell out, but that they won't even fund them. I've learned a lot about VCs during the 3 years we've been doing Y Combinator, because we often have to work quite closely with them. The most surprising thing I've learned is how conservative they are. VC firms present an image of boldly encouraging innovation. Only a handful actually do, and even they are more conservative in reality than you'd guess from reading their sites.

I used to think of VCs as piratical: bold but unscrupulous. On closer acquaintance they turn out to be more like bureaucrats. They're more upstanding than I used to think (the good ones, at least), but less bold. Maybe the VC industry has changed. Maybe they used to be bolder. But I suspect it's the startup world that has changed, not them. The low cost of starting a startup means the average good bet is a riskier one, but most existing VC firms still operate as if they were investing in hardware startups in 1985.

Howard Aiken said "Don't worry about people stealing your ideas. If your ideas are any good, you'll have to ram them down people's throats." I have a similar feeling when I'm trying to convince VCs to invest in startups Y Combinator has funded. They're terrified of really novel ideas, unless the founders are good enough salesmen to compensate.

But it's the bold ideas that generate the biggest returns. Any really good new idea will seem bad to most people; otherwise someone would already be doing it. And yet most VCs are driven by consensus, not just within their firms, but within the VC community. The biggest factor determining how a VC will feel about your startup is how other VCs feel about it. I doubt they realize it, but this algorithm guarantees they'll miss all the very best ideas. The more people who have to like a new idea, the more outliers you lose.

Whoever the next Google is, they're probably being told right now by VCs to come back when they have more "traction."

Why are VCs so conservative? It's probably a combination of factors. The large size of their investments makes them conservative. Plus they're investing other people's money, which makes them worry they'll get in trouble if they do something risky and it fails. Plus most of them are money guys rather than technical guys, so they don't understand what the startups they're investing in do.

What's Next

The exciting thing about market economies is that stupidity equals opportunity. And so it is in this case. There is a huge, unexploited opportunity in startup investing. Y Combinator funds startups at the very beginning. VCs will fund them once they're already starting to succeed. But between the two there is a substantial gap.

There are companies that will give $20k to a startup that has nothing more than the founders, and there are companies that will give $2 million to a startup that's already taking off, but there aren't enough investors who will give $200k to a startup that seems very promising but still has some things to figure out. This territory is occupied mostly by individual angel investors—people like Andy Bechtolsheim, who gave Google $100k when they seemed promising but still had some things to figure out. I like angels, but there just aren't enough of them, and investing is for most of them a part time job.

And yet as it gets cheaper to start startups, this sparsely occupied territory is becoming more and more valuable. Nowadays a lot of startups don't want to raise multi-million dollar series A rounds. They don't need that much money, and they don't want the hassles that come with it. The median startup coming out of Y Combinator wants to raise $250-500k. When they go to VC firms they have to ask for more because they know VCs aren't interested in such small deals.

VCs are money managers. They're looking for ways to put large sums to work. But the startup world is evolving away from their current model.

Startups have gotten cheaper. That means they want less money, but also that there are more of them. So you can still get large returns on large amounts of money; you just have to spread it more broadly.

I've tried to explain this to VC firms. Instead of making one $2 million investment, make five $400k investments. Would that mean sitting on too many boards? Don't sit on their boards. Would that mean too much due diligence? Do less. If you're investing at a tenth the valuation, you only have to be a tenth as sure.

It seems obvious. But I've proposed to several VC firms that they set aside some money and designate one partner to make more, smaller bets, and they react as if I'd proposed the partners all get nose rings. It's remarkable how wedded they are to their standard m.o.

But there is a big opportunity here, and one way or the other it's going to get filled. Either VCs will evolve down into this gap or, more likely, new investors will appear to fill it. That will be a good thing when it happens, because these new investors will be compelled by the structure of the investments they make to be ten times bolder than present day VCs. And that will get us a lot more Googles. At least, as long as acquirers remain stupid.

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Road Safety: The Uncrashable Car?

Look in your blind spot, too! The 'uncrashable car' is part of basic research undertaken by the largest research initiative into road safety ever undertaken in Europe. (Credit: PReVENT, Volvo)

The largest road safety research project ever launched in Europe will usher in a series of powerful road-safety systems for European cars. But, in the long term, its basic, experimental research could lead to a car that is virtually uncrashable.

A truck exits suddenly from a side road, directly into your lane only dozens of metres ahead. Suddenly, your car issues a warning, starts applying the brakes and attempts to take evasive action. Realising impact is unavoidable; in-car safety systems pre-tension the safety belts and arm the airbag, timing its release to the second before impact.

Such is the promise of the uncrashable car, coming to a dealer near you in the perhaps not-too-distant future. The system is part of the basic research undertaken by the largest research initiative into road safety ever undertaken in Europe.

PReVENT has a budget of over €50 million and 56 partners pursuing a broad, but highly complementary programme of research. A dozen sub-projects focus on specific road-safety issues, but all projects support and feed into each other in some way.

PReVENT is studying relatively cheap, even simple, technologies – such as parking sensors and existing satellite navigation – that can be retooled to enhance driver safety. But as part of its broad and deep approach to car safety, it is also diving into more experimental and medium- to long-term systems, innovations that could appear in five-to-ten years.

The uncrashable car is a theoretical construct that concerned a handful of PReVENT’s sub-projects. But it could become far more of a reality than anyone expected.

Of course, it is impossible to stop all car collisions, but the technology could be pushed to make it increasingly unlikely and mitigate crashes when they do occur.

For example, PReVENT project WILLWARN uses wireless communication with other vehicles to alert the driver about potentially dangerous situations ahead, while MAPS&ADAS reads sat-nav maps to track approaching hazards, like bends, dips or intersections. SASPENCE looks at safe driving distances and speed, while LATERALSAFE finally brings active sensing to the blind spot.

All have their role in the uncrashable car, as do many others within the broader project. But two projects, APALACI and COMPOSE, take this a step further, actively tracking the speed and trajectories of surrounding vehicles and other road users in real time. If one vehicle suddenly stops, or a pedestrian suddenly steps onto the road, they swing into action to rapidly calculate the implications.

Predictive collision detection

APALACI is an advanced pre-crash mitigation system built round the registration of other motorists and cyclists. In the APALACI system, sensors monitor the street or road immediately around the vehicle and collect as much information about a collision as possible, before it even starts to take place.

The system uses this data to decide on the ideal safety reaction strategy. Examples include controlled braking manoeuvres, controlled activation of the occupant restraint systems or pre-arming airbag systems. The car can react far faster than the driver, cutting speed by crucial amounts to ensure unavoidable accidents are less severe.

APALACI also developed a so-called ‘Start Inhibit System’ for trucks. It surveys the blind spot immediately in front of a truck and protects pedestrians or cyclists by preventing dangerous manoeuvres.

APALACI was tested in a series of vehicles like the Fiat Stilo, the Volvo FH12 truck, the Alfa Romeo 156 and Mercedes E350. It used laser sensors, radar, software decision assistance and a variety of other technologies to achieve the goal.

Tiny changes have a huge impact

COMPOSE, on the other hand, aims more specifically to keep others, as well as its driver, safe. It can apply the brakes if a pedestrian steps onto the road, or extend the bumper, and raise the bonnet to enhance occupant protection.

Tiny differences have a huge impact on car safety. Dropping speed by 1km/h can reduce accidents with injury by 3 per cent, while braking fractions of a second sooner is enough to reduce the damage caused dramatically.

The systems were tested in the BMW 545i and the Volvo FH12 truck, and they do appreciably enhance safety. But, for all their potential, these systems remain, for now, the preserve of the future.

“The teams developed sophisticated algorithms to track all these elements in the landscape,” explains Matthias Schulze, coordinator of the EU-funded PReVENT project and Senior Manager for ITS & Services at Daimler AG. “But they require enormous computer power to keep track of all the various elements, so this work is aimed at basic research, establishing how it could be done. It will be a while before in-car computers are sophisticated enough to use these systems.”

Nonetheless, they do provide tools that automakers can use to mitigate the potential for accidents, and they provide a clear research roadmap for the uncrashable car of the future.

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