National Academy of Sciences

How Gaming Could Help ER Doctors Save More Lives

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A video game called
A video game called “Night Shift” helps doctors practice real-world emergency scenarios.

No one masters a skill without mistakes, but when you’re a health care provider, screw ups can be deadly.

In 2016, the National Academy of Sciences found that every year up to 30,000 civilian and military deaths of trauma patients could be prevented if the injured people had received optimal care.

A new video game developed by a critical care doctor at the University of Pittsburgh aims to help emergency medicine physicians build trauma expertize in a low-stakes environment.

“Night Shift” isn’t super flashy – think mid-’80s Nintendo – but the story is very “Grey’s Anatomy.” It stars Andy Jordan, a young emergency department doctor who favors v-neck shirts.

Andy spends the game trying to solve a mystery surrounding his grandfather while also treating trauma patients, such as Steven who has just arrived at the hospital with a gunshot wound.

“We intubated him. We put in large bore IVs. We’re going to him a couple liters of fluid,” said UPMC critical care doctor Deepika Mohan as she demonstrated the game she designed with the help of Pittsburgh-based Schell Games. “And then we’re going to give him some blood. We’re going to tell the nurse to go get me as much blood as they’ll give me from the blood bank. We saved him.”

That game is geared towards improving the trauma triage skills of emergency department doctors. Mohan said she got the idea from research showing people learn through stories.

In fact, during pre-testing, Mohan found that the game’s clinical lessons resonated more strongly the more people identified with Andy. The plot line with the grandfather fleshes out Andy’s character, which makes easier to empathize with him.

“So, it turns out there was a military base in the town, and you found that his grandfather worked for the military for a while,” she said. “It was all very hush-hush.”

To test its effectiveness, Mohan compared physicians who played “Night Shift” to those who studied traditional educational materials on triage. She found that, six months after these enrichments, when both groups participated in a simulation, the group that did the traditional education were 17 percent more likely to underestimate the seriousness of a patient’s injury or illnesses.

“Where my eyes kind of light up at this is the idea that this could supplement our residents’ education in a variety of ways, not just for trauma,” said Dr. Megan Ranney, who directs the Emergency Digital Health Innovation Program at Brown University’s Alpert Medical School in Providence, RI.

Ranney said since most triage is performed by nurses or emergency medical services workers, physicians might actually be the wrong audience for “Night Shift.”

But based on the results of Mohan’s study, Ranney’s excited by the possibility of video games. For example, she thinks games could help young doctors hone their medical judgment, especially because residency programs now limit the hours someone can work.

“Our trainees are having less time in the clinical environment,” she said. “Particularly for some rare diseases or rare procedures, those duty-hour restrictions mean they may not be seeing as many cases as they would have back in the days when we worked 120-hour weeks as residents.”

“Night Shift” still has a few kinks. Physicians who played reported the game was buggy. And the jury’s still out on whether it helps doctors treat real people, or if the game’s success is limited to training simulations.

Gene Editing: Report Calls for Caution, No Outright Ban

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National Academies panel outlines ‘stringent’ criteria for human germline editing

Every year at this time, MedPage Today‘s writers select a few of the most important stories published earlier in the year and examine what happened afterward. One of those original stories, which first appeared Feb. 14, is republished below; click here to read the follow-up.

WASHINGTON — Clinical trials involving “heritable germline editing” are not yet ready for prime-time, according to a report from the National Academy of Sciencesand the National Academy of Medicine.

However, heritable germline editing — genetic manipulations that can be passed down to offspring — could potentially be allowed in the future for “serious disease or conditions” and with strict oversight, provided certain criteria are met, according to a committee of science, healthcare, and legal experts that made up the Committee on Human Gene Editing.

The report is the result of a year-long examination of the science and policy of human gene editing and its ethical ramifications.

In weighing the benefits and risks of these techniques, the committee decided that “caution is absolutely needed, but being cautious does not mean prohibition,” said R. Alta Charo, JD, committee co-chair and bioethics scholar at the University of Wisconsin Law School in Madison.

According to Charo, the committee agreed to six “strict” and “stringent” criteria under which germline editing could begin to be considered:

  • Lack of reasonable alternatives
  • Limiting to genes “convincingly demonstrated to cause or predispose” one to serious illness
  • “Credible pre-clinical and/or clinical data” regarding the potential risks and benefits
  • Strong and continuous oversight during clinical trials
  • A broad plan for long-term, multi-generational follow-up
  • Extensive and continued review of “health and societal benefits and risks” that involves public engagement

“If those conditions are met, it was the committee’s conclusion that germline heritable editing clinical trials would be permissible — not obligatory, but permissible,” she said, adding that “we are not even close to the amount of research we need before you could actually move forward at a technical level, in terms of the precision and safety, in this particular technique.”

The committee also weighed in on non-heritable clinical trials or the editing of somatic cells.

Basic scientific trials in this category of genome editing are underway, and are in the nascent stages of clinical trials and applications. Treatments that enable “corrected” genes to implant themselves in cells, often using a virus, have shown promise in research studies of cystic fibrosis, HIV, and Duchenne muscular dystrophy.

Since these changes cannot be inherited by future generations, they should be allowed to continue only when the research or therapy aims to treat or prevent disease or disability, and not for the purpose of genetic enhancement, according to the committee.

New technologies such as the CRISPR-Cas9 — an enzyme that can slice DNA at targeted points — offer the possibility of altering an individual’s genome, or even a generation’s genome. CRISP-CAS9 is easy, efficient, and relatively cheap, as committee members noted, and with its introduction, the risk of off-target events or “mistaken edits” is shrinking.

Instead of worrying “it’s too risky,” stakeholders are now beginning to shift their focus to the ethical ramifications of germline editing, said committee Jeffrey Kahn, PhD, MPH, director of the Johns Hopkins Berman Institute of Bioethics in Baltimore.

Rather than fully opening a door that was previously closed for germline editing, Kahn told MedPage Today that the report is more “like a knock on the door. The door’s not open yet.”

He pointed out that the committee’s criteria are “pretty rigid,” and not necessarily easy to meet. In addition, in the U.S., the NIH Recombinant DNA Advisory Committee and the FDA also have regulations regarding germline editing.

The NIH committee previously stated that it will “not entertain proposals for germline alterations,” so those restrictions still need to be relaxed, Kahn noted, describing the NIH stance as “more than a door — that’s a locked door.”

Rules about germline editing are not necessarily as strict in other countries. For instance, in 2015, scientists at Sun Yat-sen University in Guangzhou, China, were the first to use CRISPR-CAS9 on human embryos, according to Nature.

While the embryos were defective and could not have led to a live birth, the experiment was likely tied to a call for a moratorium by an international group of scientists on gene editing that could cause “inheritable changes to the genome,” according to The New York Times.

Former Director of National Intelligence James Clapper expressed concern that CRISPR could be used as a weapon of mass destruction, according toScience.

In the current report, the committee issued guiding principles “that should be used by any nation in governing human genome editing research or applications.” These are:

  • Promote well-being
  • Transparency
  • Due care
  • Responsible science
  • Respect for persons
  • Fairness
  • Transnational cooperation

“These overarching principles, and the responsibilities that flow from them, should be reflected in each nation’s scientific community and regulatory processes,” said committee co-chair Richard Hynes, PhD, of Massachusetts Institute of Technology in Boston, in a press release.

Charo noted that the guidelines set forth in the report, including its criteria, might be weighted differently in different jurisdictions.

“In some countries, [germline editing] is entirely illegal,” she noted, adding that some states have made embryo research unlawful.

“The bottom line is that there is no planetary government with enforcement power, but the goal of the human genome initiative [and] the goal of this study committee is to help develop international norms that will be influential, with the policymakers, with physicians, with researchers, with patient groups … so that to the greatest extent possible, there is some global agreement” on a set of guiding principles that aim toward beneficial purposes, Charo stated.

Obama Signs Controversial GMO Food Label Law

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AUG 1 2016

President Obama has signed a new law that would require all food labels to declare for the first time whether the item contains genetically modified ingredients.

Just how clear those labels are, however, is up for debate.

The new law, signed Friday and supported by the food industry, pre-empts a recently passed — and stricter — Vermont ruling that requires food to say “produced with genetic engineering.” Instead, companies will be allowed to either say that in plain words on the package, or provide a QR code, 1-800 number, or website for consumers to visit for more information.

Image: Milk is displayed on shelves in a Brooklyn supermarket on June 9 in New York City. Milk prices for Americans have been on the rise recently with a 7.5% price increase for a gallon of fortified whole milk from last year.
Milk is displayed on shelves in a Brooklyn supermarket on June 9 in New York City. Milk prices for Americans have been on the rise recently with a 7.5% price increase for a gallon of fortified whole milk from last year. 

Opponents argue that this type of labeling discriminates against lower-income families who may not have access to the technology required to learn further details.

Plus — when you’ve got a grabbing toddler in the stroller and you’re snagging crates of mac n’ cheese off the shelves, you probably won’t have time to be scanning bar codes.

A recent review of two decades of research and over 900 studies by the National Academy of Sciences has not found any evidence that genetically modified organisms pose a hazard to human health. But advocates say not enough is known about GMOs — and consumers want to know exactly what’s in their food.

Men and women ‘wired differently’

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Men and women’s brains are connected in different ways which may explain why the sexes excel at certain tasks, say researchers.

A US team at the University of Pennsylvania scanned the brains of nearly 1,000 men, women, boys and girls and found striking differences.

brain networksThe “connectome maps” reveal the differences between the male brain (seen in blue) and the female brain (orange)

Male brains appeared to be wired front to back, with few connections bridging the two hemispheres.

In females, the pathways criss-crossed between left and right.

These differences might explain why men, in general, tend to be better at learning and performing a single task, like cycling or navigating, whereas women are more equipped for multitasking, say the researchers in the journal Proceedings of the National Academy of Sciences (PNAS).

The same volunteers were asked to perform a series of cognitive tests, and the results appeared to support this notion.

But experts have questioned whether it can be that simple, arguing it is a huge leap to extrapolate from anatomical differences to try to explain behavioural variation between the sexes. Also, brain connections are not set and can change throughout life.

In the study, women scored well on attention, word and face memory, and social cognition, while men performed better on spatial processing and sensori-motor speed.

To look at brain connectivity, the researchers used a type of scan called DTI – a water-based imaging technique that can trace and highlight the fibre pathways connecting the different regions of the brain.

Study author Dr Ruben Gur said: “It’s quite striking how complementary the brains of women and men really are.

“Detailed connectome maps of the brain will not only help us better understand the differences between how men and women think, but it will also give us more insight into the roots of neurological disorders, which are often sex related.”

Complex organ

Prof Heidi Johansen-Berg, a UK expert in neuroscience at the University of Oxford, said the brain was too complex an organ to be able to make broad generalisations.

“We know that there is no such thing as ‘hard wiring’ when it comes to brain connections. Connections can change throughout life, in response to experience and learning.

“Often, sophisticated mathematical approaches are used to analyse and describe these brain networks. These methods can be useful to identify differences between groups, but it is often challenging to interpret those differences in biological terms.”

Dr Michael Bloomfield, Clinical Research Fellow at the Medical Research Council Clinical Sciences Centre in London, said: “It has been known for some time that there are differences between the sexes when it comes to how our bodies work and the brain is no exception.

However, he said care must be taken in drawing conclusions from the study, as the precise relationships between how our brains are wired and our performance on particular tasks needed further investigation.

“We cannot say yet that one is causing the other.

“Furthermore, the measure used in the study, called “connectivity”, is only one aspect of how our brains our wired.

“We think that there can also be differences in certain chemicals in the brain called neurotransmitters, for example, and so we need more research to fully understand how all these different aspects of brain structure and function work together to answer fundamental questions like “how do we think?”.

“One thing that remains unknown is what is driving these differences between the sexes. An obvious possibility is that that male hormones like testosterone and female hormones like oestrogren have different affects on the brain.

“A more subtle possibility is that bringing a child up in a particular gender could affect how our brains are wired.”

 

Three-dimensional carbon goes metallic.

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A theoretical, three-dimensional (3D) form of carbon that is metallic under ambient temperature and pressure has been discovered by an international research team.

The findings, which may significantly advance carbon science, are published online this week in the Early Edition of the Proceedings of the National Academy of Sciences.

3-dimensional carbon goes metallic

Carbon science is a field of intense research. Not only does carbon form the chemical basis of life, but it has rich chemistry and physics, making it a target of interest to material scientists. From graphite to diamond to Buckminster fullerenes, nanotubes and graphene, carbon can display in a range of structures.

But the search for a stable three-dimensional form of carbon that is metallic under , including temperature and pressure, has remained an ongoing challenge for scientists in the field.

Researchers from Peking University, Virginia Commonwealth University and Shanghai Institute of Technical Physics employed state-of-the-art theoretical methods to show that it is possible to manipulate carbon to form a three-dimensional metallic phase with interlocking hexagons.

“The interlocking of hexagons provides two unique features – hexagonal arrangement introduces metallic character, and the interlocking form with tetrahedral bonding guarantees stability,” said co-lead investigator Puru Jena, Ph.D., distinguished professor of physics in the VCU College of Humanities and Sciences.

The right combination of these properties could one day be applied to a variety of technologies.

“Unlike high-pressure techniques that require three terapascals of pressure to make carbon metallic, the studied structures are stable at ambient conditions and may be synthesized using benzene or polyacenes molecules,” said co-lead investigator Qian Wang, Ph.D., who holds a professor position at Peking University and an adjunct faculty position at VCU.

“The new metallic  structures may have important applications in lightweight metals for space applications, catalysis and in devices showing negative differential resistance or superconductivity,” Wang said.

According to Jena, the team is still early in its discovery process, but hope that these findings may move the work from theory to the experimental phase.

The study is titled, “Three-dimensional Metallic Carbon: Stable Phases with Interlocking Hexagons.”

Report Finds ‘Culture of Resistance’ on Youth Concussion.

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Young athletes in the United States face a “culture of resistance” to telling a coach or parent they might have a concussion, according to a new report from the Institute of Medicine and National Research Council. 

The 306-page report, “Sports-Related Concussions in Youth: Improving the Science, Changing the Culture,” was released during a briefing today at the National Academy of Sciences in Washington, DC.

“Even though there is an increased willingness to report a concussion, there is still the desire on the part of the athlete not to report it because they feel they are letting their teammates down; on the part of the coaches because it upsets the team they have on the field, or their own belief that, ‘I had these, I’m okay, it’s just part of the sport’; and on the part of the parents who want to see their children excel and be accepted,” said Robert Graham, MD, chair of the committee that wrote the report.

Attitude Adjustment

Efforts are needed to “change the culture,” said Dr. Graham, who is director of the National Program Office for Aligning Forces for Quality at George Washington University in Washington, DC.

Over 9 months, the committee did a comprehensive review of the literature on concussions in youth sports with athletes aged 5 to 21 years. 

“The findings of our report justify the concerns about sports concussions in young people,” said Dr. Graham. “However, there are numerous areas in which we need more and better data.  Until we have that information, we urge parents, schools, athletic departments, and the public to examine carefully what we do know, as with any decision regarding risk, so they can make more informed decisions about young athletes playing sports,” he added.

The reported number of individuals aged 19 and under treated in US emergency departments for concussions and other nonfatal sports- and recreation-related traumatic brain injuries (TBIs) increased from 150,000 in 2001 to 250,000 in 2009.

“This could possibly be due to an increase in awareness or reporting of concussions,” committee member Tracey Covassin, PhD, director of the undergraduate athletic training program at Michigan State University in East Lansing. “However, we do not know the true incidence of concussions as several concussions go unreported, as well as a lack of consistency in terminology with different studies that have reported different definitions of concussions.”

The committee found that the majority of research into concussions is at the high school and collegiate levels, with very few to no data reported below the high school level.

The committee also found a “shift” in the incidence of concussions, with more reported at the high school level than the collegiate level, Dr. Covassin said.

Football, ice hockey, lacrosse, wrestling, and soccer are associated with the highest rates of reported concussions for male athletes at the high school and college levels, while soccer, lacrosse, and basketball are associated with the highest rates of reported concussions for female athletes at these levels of play.

Limited Evidence Helmets Cut Risk

The committee found little evidence that current sports helmet designs cut the risk for concussions. 

“What the literature tells us is that diffuse brain injuries like concussion are caused by a combination of linear and rotational forces,” explained committee member Kristy Arbogast, PhD, engineering core director, Center for Injury Research and Prevention, Children’s Hospital of Philadelphia in Pennsylvania. “What we do know is that helmets reduce that linear portion. There is limited evidence that they can manage the rotational components of the impact. This is in part due to standards.”

The committee stressed, however, that properly fitted helmets, face masks, and mouth guards should still be used because they reduce the risk for other injuries.

The committee also examined the scientific literature on concussion recognition, diagnosis, and management. They found that the signs and symptoms of concussion are usually placed into 4 categories — physical, cognitive, emotional, and sleep — with patients having 1 or more symptoms from 1 or more categories. 

Most youth athletes with concussion will recover within 2 weeks of the injury, but in 10% to 20% of cases concussion symptoms persist for several weeks, months, or even years. 

Return to Play

The committee advises that a concussed athlete return to play only when he or she has recovered demonstrably and is no longer having any symptoms. An individualized treatment plan that includes physical and mental rest may be beneficial for recovery from a concussion, but current research does not suggest a standard or universal level and duration of rest needed, the committee notes.

Athletes who return to play before complete recovery are at increased risk for prolonged recovery or more serious consequences if they sustain a second concussion. “The evidence is pretty clear” on this, said committee member Arthur Maerlender, PhD, director of pediatric neuropsychological services at Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire.

The literature also suggests that single and multiple concussions can lead to impairments in the areas of memory and processing speed.  However, it remains unclear whether repetitive head impacts and multiple concussions sustained in youth lead to long-term neurodegenerative disease, such as chronic traumatic encephalopathy, the committee said.

It notes, however, that surveys of retired professional athletes provide some evidence that a history of multiple concussions increases risk for depression. In a survey of more than 2500 retired professional football players, approximately 11% reported having clinical depression. “Very little” research has evaluated the relationship between concussions and suicidal thoughts and behaviors, the committee notes.

In youth sports, several organizations have called for a “hit count” to limit the amount of head contact a player receives over a given amount of time. Although this concept is “fundamentally sound,” the committee found that implementing a specific threshold for the number of impacts or the magnitude of impacts per week or per season is without scientific basis.

The committee calls for establishing a national surveillance system to accurately determine the number of sports-related concussions, identify changes in the brain following concussions in youth, conduct studies to assess the consequences and effects of concussions over a life span, and evaluate the effectiveness of sports rules and playing practices in reducing concussions. 

Brain-inspired synaptic transistor learns while it computes.

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It doesn’t take a Watson to realize that even the world’s best supercomputers are staggeringly inefficient and energy-intensive machines.

Our brains have upwards of 86 billion neurons, connected by synapses that not only complete myriad logic circuits; they continuously adapt to stimuli, strengthening some connections while weakening others. We call that process learning, and it enables the kind of rapid, highly efficient computational processes that put Siri and Blue Gene to shame.

Materials scientists at the Harvard School of Engineering and Applied Sciences (SEAS) have now created a new type of transistor that mimics the behavior of a synapse. The novel device simultaneously modulates the flow of information in a circuit and physically adapts to changing signals.

Exploiting unusual properties in modern materials, the synaptic transistor could mark the beginning of a new kind of artificial intelligence: one embedded not in smart algorithms but in the very architecture of a computer. The findings appear in Nature Communications.

“There’s extraordinary interest in building energy-efficient electronics these days,” says principal investigator Shriram Ramanathan, associate professor of materials science at Harvard SEAS. “Historically, people have been focused on speed, but with speed comes the penalty of power dissipation. With electronics becoming more and more powerful and ubiquitous, you could have a huge impact by cutting down the amount of energy they consume.”

https://i0.wp.com/cdn.physorg.com/newman/gfx/news/2013/1-synaptictran.jpg
The human mind, for all its phenomenal computing power, runs on roughly 20 Watts of energy (less than a household light bulb), so it offers a natural model for engineers.

“The transistor we’ve demonstrated is really an analog to the synapse in our brains,” says co-lead author Jian Shi, a postdoctoral fellow at SEAS. “Each time a neuron initiates an action and another neuron reacts, the synapse between them increases the strength of its connection. And the faster the neurons spike each time, the stronger the synaptic connection. Essentially, it memorizes the action between the neurons.”

In principle, a system integrating millions of tiny synaptic transistors and neuron terminals could take parallel computing into a new era of ultra-efficient high performance.

While calcium ions and receptors effect a change in a biological synapse, the artificial version achieves the same plasticity with oxygen ions. When a voltage is applied, these ions slip in and out of the crystal lattice of a very thin (80-nanometer) film of samarium nickelate, which acts as the synapse channel between two platinum “axon” and “dendrite” terminals. The varying concentration of ions in the nickelate raises or lowers its conductance—that is, its ability to carry information on an electrical current—and, just as in a natural synapse, the strength of the connection depends on the in the electrical signal.

Structurally, the device consists of the nickelate semiconductor sandwiched between two platinum electrodes and adjacent to a small pocket of ionic liquid. An external circuit multiplexer converts the time delay into a magnitude of voltage which it applies to the ionic liquid, creating an electric field that either drives into the nickelate or removes them. The entire device, just a few hundred microns long, is embedded in a silicon chip.

The synaptic transistor offers several immediate advantages over traditional silicon transistors. For a start, it is not restricted to the binary system of ones and zeros.

“This system changes its conductance in an analog way, continuously, as the composition of the material changes,” explains Shi. “It would be rather challenging to use CMOS, the traditional circuit technology, to imitate a synapse, because real biological synapses have a practically unlimited number of possible states—not just ‘on’ or ‘off.'”

The synaptic transistor offers another advantage: non-volatile memory, which means even when power is interrupted, the device remembers its state.

Additionally, the new transistor is inherently energy efficient. The nickelate belongs to an unusual class of materials, called correlated electron systems, that can undergo an insulator-metal transition. At a certain temperature—or, in this case, when exposed to an external field—the conductance of the material suddenly changes.

“We exploit the extreme sensitivity of this material,” says Ramanathan. “A very small excitation allows you to get a large signal, so the input energy required to drive this switching is potentially very small. That could translate into a large boost for energy efficiency.”

The nickelate system is also well positioned for seamless integration into existing silicon-based systems.

“In this paper, we demonstrate high-temperature operation, but the beauty of this type of a device is that the ‘learning’ behavior is more or less temperature insensitive, and that’s a big advantage,” says Ramanathan. “We can operate this anywhere from about room temperature up to at least 160 degrees Celsius.”

For now, the limitations relate to the challenges of synthesizing a relatively unexplored material system, and to the size of the device, which affects its speed.

“In our proof-of-concept device, the time constant is really set by our experimental geometry,” says Ramanathan. “In other words, to really make a super-fast , all you’d have to do is confine the liquid and position the gate electrode closer to it.”

In fact, Ramanathan and his research team are already planning, with microfluidics experts at SEAS, to investigate the possibilities and limits for this “ultimate fluidic transistor.”

He also has a seed grant from the National Academy of Sciences to explore the integration of synaptic into bioinspired circuits, with L. Mahadevan, Lola England de Valpine Professor of Applied Mathematics, professor of organismic and evolutionary biology, and professor of physics.

“In the SEAS setting it’s very exciting; we’re able to collaborate easily with people from very diverse interests,” Ramanathan says.

For the materials scientist, as much curiosity derives from exploring the capabilities of correlated oxides (like the nickelate used in this study) as from the possible applications.

“You have to build new instrumentation to be able to synthesize these new materials, but once you’re able to do that, you really have a completely new material system whose properties are virtually unexplored,” Ramanathan says. “It’s very exciting to have such to work with, where very little is known about them and you have an opportunity to build knowledge from scratch.”

“This kind of proof-of-concept demonstration carries that work into the ‘applied’ world,” he adds, “where you can really translate these exotic electronic properties into compelling, state-of-the-art devices.”

Cannabis Use Associated with Neuropsychological Decline, Drop in IQ .

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Persistent cannabis use, especially when begun during adolescence, leads to measurable neuropsychological decline by midlife, according to a study in the Proceedings of the National Academy of Sciences.

Researchers followed a birth cohort of some 1000 New Zealanders. The subjects’ cannabis use was periodically measured, starting at age 18 and continuing through age 38. Intelligence testing was done during childhood and again at age 38.

Use of cannabis at least 4 days per week was associated with neuropsychological decline by age 38. The decline was especially notable among adolescents who were cannabis dependent (8-point loss in IQ by adulthood). The overall effect persisted after controlling for education and use of other drugs and tobacco.

Asked to comment, Barbara Geller of Journal Watch Psychiatry said: “The belief that cannabis represents a more benign recreational drug than alcohol is belied by this research and by reports of increased vulnerability to psychosis in adolescent-onset users.”

Source: PNAS