Friday, April 29, 2016

The United Nations has chosen to keep the war on drugs going — but it can’t win.

NATURE | EDITORIAL

On a downer


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Readers of the Los Angeles Times last week received some unexpected news about a major shift in the attitude of the United Nations towards the decriminalization of cannabis. According to the paper, the UN Office on Drugs and Crime (UNODC) was set to announce a more tolerant approach at a major meeting in New York City. But although the meeting was real, the policy shift was not. The announcement was a hoax, and pointedly timed for 20 April (‘4/20’), a day on which cannabis users celebrate and promote their choice. The scam even included a well-constructed fake press release that quoted the (real) UNODC executive director Yury Fedotov as saying: “The science increasingly supports decriminalization and harm reduction over proscriptive, fear-based approaches.”
For those who advocate drug-law reform — a group that includes a sizeable number of scientists — the truth was a lot less encouraging. The comments that Fedotov made at last week’s UN General Assembly Special Session on Drugs (UNGASS) were certainly less quotable. In a tweet he noted: “#UNGASS outcome doc reaffirms joint responses to world drug problem based on agreed frameworks, #sharedresponsibility, intl cooperation”.
Despite hopes ahead of the meeting that nations would step back from the ‘war on drugs’ rhetoric that has defined international policy — and science — for decades, instead the UN blandly reformatted the existing status quo. Essentially, the message is still: ‘drugs are bad’.
This will disappoint the many readers of Nature who want to see a more evidence-based approach. And that disappointment is especially acute because hopes had been raised by a growing number of drug-policy experiments, such as legalization and decriminalization of cannabisin Uruguay and many US states.
If the overall message coming down from the highest levels remains the same, then so does the stance taken by those who fund research. Witness the struggles in the United States over cannabis studies: whereas some states permit citizens to openly smoke marijuana, researchers must wade through federal red tape to study it.

1 Minute of All-Out Exercise May Have Benefits of 45 Minutes of Moderate Exertion




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CreditiStock
DESCRIPTIONPhys Ed
PHYS ED
Gretchen Reynolds on the science of fitness.
The Well Guide: How to Start Running
Want to start a new running habit? We make it easy to get started, get inspired and stay on track. Are you ready? Let’s go!
For many of us, the most pressing question about exercise is: How little can I get away with? The answer, according to a sophisticated new study of interval training, may be very, very little. In this new experiment, in fact, 60 seconds of strenuous exertion proved to be as successful at improving health and fitness as three-quarters of an hour of moderate exercise.
Let me repeat that finding: One minute of arduous exercise was comparable in its physiological effects to 45 minutes of gentler sweating.
...
They began by recruiting 25 out-of-shape young men and measuring their current aerobic fitness and, as a marker of general health, their body’s ability to use insulin properly to regulate blood sugar levels. The scientists also biopsied the men’s muscles to examine how well their muscles functioned at a cellular level.
Then the researchers randomly divided the men into three groups. (The scientists plan to study women in subsequent experiments.) One group was asked to change nothing about their current, virtually nonexistent exercise routines; they would be the controls.
A second group began a typical endurance-workout routine, consisting of riding at a moderate pace on a stationary bicycle at the lab for 45 minutes, with a two-minute warm-up and three-minute cool down.
The final group was assigned to interval training, using the most abbreviated workout yet to have shown benefits. Specifically, the volunteers warmed up for two minutes on stationary bicycles, then pedaled as hard as possible for 20 seconds; rode at a very slow pace for two minutes, sprinted all-out again for 20 seconds; recovered with slow riding for another two minutes; pedaled all-out for a final 20 seconds; then cooled down for three minutes. The entire workout lasted 10 minutes, with only one minute of that time being strenuous.
Both groups of exercising volunteers completed three sessions each week for 12 weeks, a period of time that is about twice as long as in most past studies of interval training.
By the end of the study, published in PLOS One, the endurance group had ridden for 27 hours, while the interval group had ridden for six hours, with only 36 minutes of that time being strenuous.
But when the scientists retested the men’s aerobic fitness, muscles and blood-sugar control now, they found that the exercisers showed virtually identical gains, whether they had completed the long endurance workouts or the short, grueling intervals. In both groups, endurance had increased by nearly 20 percent, insulin resistance likewise had improved significantly, and there were significant increases in the number and function of certain microscopic structures in the men’s muscles that are related to energy production and oxygen consumption.
There were no changes in health or fitness evident in the control group.
The upshot of these results is that three months of concerted endurance or interval exercise can notably — and almost identically — improve someone’s fitness and health.
Neither approach to exercise was, however, superior to the other, except that one was shorter — much, much shorter.
Fig 2. Effect of SIT and MICT on insulin sensitivity.
The change in insulin sensitivity (CSI) over the 12-week intervention, measured from a 50-minute IVGTT in MICT, SIT and CTL. Closed circles denote individual responses. Values are means ± S.D. * p<0.05, PRE vs. POST.
Fig 1. Effect of SIT and MICT on VO2peak.
Measured at baseline (PRE), 6 weeks (MID), and 12 weeks (POST) in MICT, SIT and CTL. Values are means ± S.D. * p<0.05, vs. same group at PRE; # p<0.05, vs. same group at MID.



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Thursday, April 28, 2016

Researchers push for personalized tumour vaccines

NATURE | NEWS

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Steve Gschmeissner/Science Photo Library
Researchers are testing personalized vaccines to treat melanoma (shown here).
It is precision medicine taken to the extreme: cancer-fighting vaccines that are custom designed for each patient according to the mutations in their individual tumours. With early clinical trials showing promise, that extreme could one day become commonplace — but only if drug developers can scale up and speed up the production of their tailored medicines.
The topic was front and centre at the American Association for Cancer Research (AACR) annual meeting in New Orleans, Louisiana, on 16–20 April. Researchers there described early data from clinical trials suggesting that personalized vaccines can trigger immune responses against cancer cells. Investors seem optimistic that those results will translate into benefits for patients; over the past year, venture capitalists have pumped cash into biotechnology start-ups that are pursuing the approach.
But some researchers worry that the excitement is too much, too soon for an approach that still faces many technical challenges. “What I do really puzzle at is the level of what I would call irrational exuberance,” says Drew Pardoll, a cancer immunologist at Johns Hopkins University in Baltimore, Maryland.

Target practice

The concept of a vaccine to treat cancer has intrinsic appeal. Some tumour proteins are either mutated or expressed at different levels than in normal tissue. This raises the possibility that the immune system could recognize these unusual proteins as foreign — especially if it were alerted to their presence by a vaccine containing fragments of the mutated protein. The immune system’s army of T cells could then seek out and destroy cancer cells bearing the protein.
Decades of research into cancer-treatment vaccines have thus far yielded disappointing clinical trial results, but recent advances — including a suite of drugs that may amplify the effects of cancer vaccines — have rekindled hope for the field. And DNA sequencing of tumour genomes has revealed a staggering diversity of mutations, producing proteins that could serve as ‘antigens’ by alerting the immune system.
Last year, researchers reported that they had triggered an immune response in three patients with melanoma by administering a vaccine tailored to their potential tumour antigens1. The vaccines' effects on tumour growth are not yet clear, but by the end of 2015, several companies had announced their intention to enter the field. Gritstone Oncology, a start-up firm in Emeryville, California, raised US$102 million to pursue the approach, and Neon Therapeutics of Cambridge, Massachusetts, raised $55 million. A third company, Caperna, spun out of a prominent biotechnology company called Moderna Therapeutics, also in Cambridge.


Tuesday, April 26, 2016

Advisers to F.D.A. Vote Against Duchenne Muscular Dystrophy Drug

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Stacie Al-Chokhachi, second from right, and her son, Dalton, right, who has Duchenne muscular dystrophy, traveled from Memphis to Hyattsville, Md., to attend an F.D.A. meeting.CreditEric Kruszewski for The New York Times
In a confrontation between the hopes of desperate patients and clinical trial data, advisers to the Food and Drug Administration voted on Monday not to recommend approval of what would become the first drug for Duchenne muscular dystrophy.
The negative votes came despite impassioned pleas from patients, parents and doctors who insisted that the drug, called eteplirsen, was prolonging the ability of boys with the disease to walk well beyond when they would normally be in wheelchairs.
The problem was that the drug’s manufacturer, Sarepta Therapeutics, was trying to win approval based on a study involving only 12 patients without an adequate placebo control.
The advisory panel voted 7 to 3, with three abstentions, that the clinical data did not meet the F.D.A. requirements for well controlled studies necessary for approval. However, some of the panel members had trouble reconciling the often compelling patient testimony with the F.D.A. legal requirements.
“I was just basically torn between my mind and my heart,” said Richard P. Hoffmann, a pharmacist who was the consumer representative on the committee and who abstained.
Dr. Bruce I. Ovbiagele, chairman of neurology at the Medical University of South Carolina, voted against approval but said, “Based on all I heard, the drug definitely works, but the question was framed differently.”
On another question of whether the drug could qualify for so-called accelerated approval, a lower hurdle, the panel voted 7 to 6 against the drug.
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The F.D.A., which does not have to follow the advice of its advisory panels, is scheduled to decide whether to approve eteplirsen by May 26.
The controversy over eteplirsen is perhaps the most vivid example of how patients and patient advocates are playing a growing role in the F.D.A.’s evaluation of drugs. This can result in intense pressure on the agency to approve drugs.
The muscular dystrophy community is particularly well organized and has lobbied the agency for years to approve the drug, including getting members of Congress to write letters to the agency.
Hundreds of patients and family members showed up for the meeting, including more than 40 parents who came from Britain and said they would move their families to the United States if eteplirsen was approved.
So many people were expected that the F.D.A. had to change to a larger location, a hotel ballroom in Hyattsville, Md. Even that room was filled to capacity, including with some boys in wheelchairs.
The public testimony from patients, parents and doctors took more than three hours, much more than the one hour that is typical for advisory committee meetings.
“I’m not only not getting worse, I’m getting better,” Austin LeClaire, a teenager in a wheelchair said of the drug, which has allowed him to raise his arm above his head and to feed himself more easily. “It’s time to listen to the real experts,” he said.
The advocates said that since the drug appears to be safe, there is no reason not to make it available to boys and young men who have little to lose.
“The worst thing you can do is deny access to a drug and then find out it works – too late, after we have lost a generation of boys,” Debra Miller, chief executive of the advocacy group CureDuchenne told the panel.
Dr. Billy Dunn, the director of the F.D.A.’s division of neurology products, opened the meeting by saying that the agency was “highly sensitive to the urgency” of finding drugs for muscular dystrophy. Still, he said, the F.D.A. was bound by law to approve drugs only if there was “substantial evidence” of effectiveness.
“These words are not vague words to be defined according to whim or fashion,” he said. “Anecdote and emotion do not change the data with which we are confronted, no matter the attendance,” he added.
About 9,000 to 12,000 Americans, virtually all boys, are estimated to have Duchenne muscular dystrophy. Because of genetic mutations, people with the disease make little or no dystrophin, a protein that acts as a shock absorber to protect muscles from deterioration. Boys with Duchenne typically need wheelchairs by their teens and die by their late 20s.
Eteplirsen uses a novel technology, called exon skipping, which seeks to partially correct the genetic defect, allowing muscle cells to produce a somewhat functional form of dystrophin. If approved, the drug would be applicable to only 13 percent of Duchenne patients. But other exon-skipping drugs are being developed for patients with different mutations.
One reason Sarepta’s main clinical trial involved only 12 boys was apparently that the company lacked the ability to manufacture more when it started out.
A competitor, GlaxoSmithKline, which was developing a similar drug, did a randomized trial involving 186 boys, one third of whom were given a placebo. (That drug, now owned by BioMarin Pharmaceutical, did not prove effective in that study and failed to win F.D.A. approval.)
The F.D.A. strongly urged Sarepta to do a larger study with a placebo control to better determine whether the drug worked.
But the company, based in Cambridge, Mass., argued that it would be unethical and impractical to do so, since early hints of effectiveness meant that parents would no longer enroll their sons in a trial where they might not get the drug.
Instead, Sarepta compared the data from the 12 boys treated with eteplirsen to historical data from patients in Italy and Belgium who were as closely matched as possible in disease characteristics.
The main measure was how far the boys could walk in six minutes. After four years of weekly infusions of eteplirsen, the boys in Sarepta’s study could walk on average 162 meters further — almost two football fields — than the boys in Italy and Belgium. Ten of the 12 boys on the drug were still able to walk after four years, versus only three of 13 in the control group.
“Fifteen-year-old boys like Billy don’t maintain ambulation by accident,” Dr. Jerry Mendell, director of the center for gene therapy at Nationwide Children’s Hospital in Columbus and lead investigator in Sarepta’s study, told the committee, after showing a video of one 15-year-old on the drug.
The F.D.A. staff, however, said that comparisons to historical data can be misleading. There have been many cases, it said, in which drugs or medical devices looked good compared with historical data but were not effective in a randomized trial against a placebo.
The F.D.A. staff said the walking ability of the boys treated with eteplirsen was within the range of natural variation for that disease and did not show the drug worked. It also said that it was uncertain whether the drug led to increased dystrophin production, but even if it did, the boys still had only about 1 percent of normal levels, an amount unlikely to be beneficial.
Trading in shares of Sarepta was halted throughout the day.
Patients have long pressed for approval of drugs that the F.D.A. found only marginally effective, if at all. Critics say that approving drugs that do not really work is offering false hope to patients and removing an incentive for drug companies to develop better products.
But patient input has now been intensifying. This is partly because of social media, which makes it easier for patients to organize. In addition, the F.D.A., in response to a 2012 law, has become more systematic in considering patient input. It has been meeting with patients with different diseases and working to evaluate drugs partly based on outcomes that patients say are meaningful to them, not just those specified by the drug company.

Friday, April 22, 2016

U.S. Suicide Rate Surges to a 30-Year High

WASHINGTON — Suicide in the United States has surged to the highest levels in nearly 30 years, a federal data analysis has found, with increases in every age group except older adults. The rise was particularly steep for women. It was also substantial among middle-aged Americans, sending a signal of deep anguish from a group whose suicide rates had been stable or falling since the 1950s.
The suicide rate for middle-aged women, ages 45 to 64, jumped by 63 percent over the period of the study, while it rose by 43 percent for men in that age range, the sharpest increase for males of any age. The overall suicide rate rose by 24 percent from 1999 to 2014, according to the National Center for Health Statistics, which released the study on Friday.
The increases were so widespread that they lifted the nation’s suicide rate to 13 per 100,000 people, the highest since 1986. The rate rose by 2 percent a year starting in 2006, double the annual rise in the earlier period of the study. In all, 42,773 people died from suicide in 2014, compared with 29,199 in 1999.

A Growing, Widespread Toll

From 1999 to 2014, suicide rates in the United States rose among most age groups. Men and women from 45 to 64 had a sharp increase. Rates fell among those age 75 and older.
40
suicides per
100,000 people
Age 75+
30
45–64
65-74
25-44
20
15-24
Men
Women
45–64
10
25-44
65-74
15-24
75+
10-14
10-14
1999
2014
1999
2014
“It’s really stunning to see such a large increase in suicide rates affecting virtually every age group,” said Katherine Hempstead, senior adviser for health care at the Robert Wood Johnson Foundation, who has identified a link between suicides in middle age and rising rates of distress about jobs and personal finances.
Researchers also found an alarming increase among girls 10 to 14, whose suicide rate, while still very low, had tripled. The number of girls who killed themselves rose to 150 in 2014 from 50 in 1999. “This one certainly jumped out,” said Sally Curtin, a statistician at the center and an author of the report.
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“We have more and more effective treatments, but we have to figure out how to bake them into health care systems so they are used more automatically,” ... “We’ve got bits and pieces, but we haven’t really put them all together yet.”
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Wednesday, April 20, 2016

Marijuana Legalization in New England Is Stalled by Opiate Crisis

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Gov. Peter Shumlin of Vermont, a Democrat, has supported efforts to create a regulated market for recreational marijuana in the state. CreditJacob Hannah for The New York Times
MONTPELIER, Vt. — First came Colorado and Washington. Then Alaska, Oregon and Washington, D.C. Now advocates for legal marijuana are looking to New England, hoping this part of the country will open a new front in their efforts to expand legalization nationwide.
But this largely liberal region is struggling with the devastating effect of opiate abuse, which is disrupting families, taxing law enforcement agencies and taking lives. And many lawmakers and public officials are balking at the idea of legalizing a banned substance, citing potential social costs.
“The shadow of the heroin epidemic is something that people think about when they think about the legalization, and they ask themselves, ‘Are we sending the right message about legalization?’ ” said Shap Smith, the speaker of the House in Vermont, who is open to legalizing marijuana. “I think in the public’s mind, it’s making passage of this bill more difficult.”
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