Monthly Archives: June 2013

Helicopter Ambulances Save Lives

Helicopter Ambulances Save Lives
Photo courtesy of Dreamstime.

For over 40 years, helicopters have been used in medical emergencies to transport severely injured patients to the hospital. Compared to ambulances that take trauma patients to the hospital via roads, the service is both faster but also far more expensive. Due to the cost, there is ongoing debate about whether or not emergency helicopters are “worth it” when balanced with how effective they are at saving lives.

New research has suggested that the cost may be justified. Researchers analyzed data about patient transportation to hospitals, and they found that patients who were taken in a helicopter had a higher survival rate than those taken on the road, despite having more serious injuries.

Anonymous data was collected from more than 300 European hospitals, with transport and medical records of 13,000 patients. Approximately one-third of these patients traveled to the hospital in a helicopter. Research analysts found that these patients tended to be more severely injured, often with abdominal and chest injuries that required extensive treatment at the scene. While in the hospital,  these patients were also more likely to suffer complications and typically required more time in the hospital than those transported in an ambulance. However, the air-traveling patients benefited from a higher survival rate than the road-traveling patients.

The data analysis also found that patient diagnosis and quality of care in the hospital seemed to be the same among both groups of patients. This means that the reason for the better survival rate is likely tied to the transportation method, with helicopters offering increased speed to arrive at the hospital and medical staff providing more thorough treatment at the scene and during transport.

These findings support the use of air ambulance services in saving patient lives.

Reference

Andruszkow H, et al. Survival benefit of helicopter emergency medical services compared to ground emergency medical services in traumatized patients. Critical Care 2013; 17: R124. doi:10.1186/cc12796.

Motorcyclists Medical Insurance Claims Spike 36%

Motorcyclists Medical Insurance Claims Spike 36%
Photo by Elvert Barnes via Creative Commons

Severe injury claims by motorcyclists have risen by 36% in Michigan, after the state passed laws that exempt most riders from wearing helmets, according to a new study. The findings are consistent with earlier research showing that looser helmet laws lead to more hospitalizations and fatalities.

Michigan had previously required all riders to wear helmets, but in April 2012, Michigan Governor Rick Synder signed a bill exempting riders over the age of 21 from the requirement if they carried at least $20,000 in medical insurance coverage. Safety groups said the change would result in more fatalities since helmets reduce the risk of motorcycle fatalities by 37%, according to estimates from the National Highway and Traffic Safety Administration.

Now a new analysis from HLDI found that motorcycle injuries have indeed become more severe and costly in the state. Researchers from HLDI compared medical payment losses from the 2010-11 riding season with the 2012 riding season. To see what the expected losses would have been without the change, they also compared Michigan losses to Ohio, Illinois, Indiana, and Wisconsin losses, where helmet requirements did not change.

Overall, medical payment costs were 50% higher than expected. This hike may have partially resulted from an increased crash risk since the frequency of auto-collision claims rose by about 12%. However researchers believe that higher medical payments were mostly the result of increased claim severity, which rose by 36%.

The researchers were also aware that some motorcyclists with lower insurance coverage would increase their insurance policy limits with the new law since it allows riders to go without a helmet only if they have at least $20,000 in coverage. That could affect claim severity since policies with higher limits pay more for severe injuries. After taking policy limit changes into account, they estimated that there was still a 22% increase in claim severity.

“Weakening the helmet law seems to have made it somewhat more likely that riders will sustain injuries, but the big impact has been on the seriousness of the injuries,” said David Zuby,  chief researcher at HLDI and the Insurance Institute for Highway Safety. “Helmets can’t protect against all injuries, but they do help prevent debilitating and often fatal head trauma.”

Even with the looser helmet restrictions in Michigan, the increase in severe motorcycle injuries in the state reflects a national trend. A recent study found that motorcycle injuries have risen across all age groups, and that fatal crashes among older rider rose by 145% between 2000-2006.

Reference

Michigan‘s weakened  helmet use law leads to costlier injury claims. Highway Loss Data Institute. Press Release. May 30, 2013. Accessed June 26, 2013.

The effects of Michigan’s weakened motorcycle helmet use law on insurance losses. Highway Loss Data Institute Bulletin 2013; 30 (9).

Txt Hands-free? U Are Still In Danger

The Chevrolet Mylink is one of the many new interfaces allowing drivers to have hands-free mobile communications. Photo via Creative Commons.
The Chevrolet Mylink is one of the many new interfaces allowing drivers to have hands-free mobile communications in effort to improve auto safety. But new research shows that such interfaces aren’t as safe as previously thought. Photo via Creative Commons.

More and more new cars are coming equipped with elaborate voice-activated systems that allow drivers to text, call, and even check their email with ease. But does hands-free mean risk-free? No, according to a new study that found that hands-free tasks can lead to dangerous distracted driving.

The study from the AAA Foundation and the University of Utah shows that any task that increases mental workload while driving can put drivers at-risk of an accident.

Earlier research from the US Department of Transportation found that 78% of all crashes and near crashes are caused by inattentive driving. The DOT study characterized inattention as any task that created visual, physical, and cogntive distractions.

In this latest AAA study, researchers tracked drivers’ eye and head movement; reaction time to triggers of red and green lights; and mental workload with EEG skull caps that measured brain activity. Drivers performed various hands-free tasks while keeping their hands on the wheel and their eyes on the road. In one task, participants interacted with a voice-command system to answer message and dictate texts. Based on these measures, researchers rated drivers’ attention on a scale of 1-5. A score of 1 meant no distraction, and a score of 5 indicated the mental attention it would take to solve a challenging math or memory problem.

Photo via Creative Commons
Photo via Creative Commons

Drivers were the least distracted while listening to the radio (with a score of 1.21) or when listening to an audio book (1.75). Having a conversation with another person in the car scored a 2.33. Phone calls with a hands-free device were scored at 2.27 and without a hand-held phone at 2.45. By the far the most distracting task was hands-free texting, which received a score of 3.06. The results suggest that hands-free texting and voice-command systems require enough mental workload to make drivers dangerously distracted.

“These findings reinforce previous research that hands-free is not risk-free,” remarked AAA Foundation President and CEO Peter Kissinger in a press release. “Increased mental workload and cognitive distractions can lead to a type of tunnel vision or inattention blindness where motorists don’t see potential hazards right in front of them.” Kissinger said there was a “looming public safety crisis ahead” with the growth in hands-free technologies in new vehicles.

Texting while driving is now the leading cause of death in teen auto collision, according to a recent study. Other research suggest texting behind the wheel may be as dangerous as drunk driving. But this latest AAA study shows that hands-free technologies aren’t the answer this growing safety concern.

The AAA foundation encouraged automakers to limit voice-commands to driving-related activities and to disable social media and texting functions while the car is in motion.

Reference

Why is hands-free texting dangerous? The Economist. June 24, 2013. Accessed June 25, 2013.

Strayer DL, et al. Measuring cognitive distraction in the automobile. June 2013. AAA Foundation. 

TMJ Disorders Cause Teeth Grinding and Headache, Study Finds

TMJ Disorders Cause Teeth Grinding and Headache, Study FindsDamage to the temporomandibular joint is known to cause a long list of problems and medical complications in patients with temporomandibular disorders, or TMD. Former research has linked TMD with fibromyalgia, and studies have also demonstrated that TMD patients are at risk of chronic headache, just to name a few associations.

To further our understanding of pain and complications related to TMD, researchers recently analyzed the association between TMD, sleep bruxism, and primary headaches in patients with injuries in the jaw and pain in this crucial joint. Sleep bruxism, which is excessive grinding of the teeth and clenching the jaw while sleeping, as well as certain types of primary headache, were found to be mutually associated with TMD.

The study included 301 TMD patients aged 18 to 76. Researchers examined each patient, classifying their TMD using the Research Diagnostic Criteria for Temporomandibular Disorders, diagnosing possible bruxism using clinical criteria from the American Academy of Sleep Medicine, and diagnosing headaches according to the International Classification of Headache Disorders-II.

Patients with painful TMD were found to be at risk of migraine and tension-type headaches. The highest association was between TMD and chronic migraine. Participants also were diagnosed with episodic migraine and episodic tension-type headache, associated with pain in the temporomandibular joint.

Researchers also discovered that sleep bruxism was prevalent in patients with both painful TMD and chronic migraine. They found that patients with both painful TMD and sleep bruxism were significantly more likely to suffer chronic migraine, episodic migraine, or episodic tension-type headaches.

Jaw symptoms are common among patients with whiplash injuries. However, jaw pain often does not appear immediately after a crash. The long-term effects may not be immediately realized for victims of auto injuries who are affected not only by jaw pain, but also debilitating headache and tooth-damaging grinding. This is why research that demonstrates the connection between TMD and damage to the cervical spine is so important. Patients who sustain whiplash injuries have the potential for a whole host of health problems down the road, and this should be considered when assessing the damage caused by a collision.

Reference

Fernandes G, Franco AL, et al. Temporomandibular disorders, sleep bruxism, and primary headaches are mutually associated. Journal of Orofacial Pain 2013; 27(1): 14-20. doi: 10.11607/jop.921.

What Gets Patients to Work Sooner After Brain Injury?

What Gets Patients to Work Sooner After Brain Injury?Vocational rehabilitation has proven to be successful in helping patients return to work after brain injury, but is it worth the cost? It’s easy to assume additional appointments with therapists and specialists could cause patients to rack up medical bills, but few studies have actually taken the time to analyze the cost-efficacy of such treatments.

In a new study, researchers from the UK studied 94 patients admitted to Nottingham hospitals within 48 hours post brain injury, and monitored their progress for the next 15 months. Half of the patients received vocational rehabilitative (VR) treatments that included individualized interdisciplinary care provided by a team of nurses, occupational therapists, and neuro-pyschologists. The researchers analyzed patient progress and compared their results to patients under usual care (UC).

  • At three months, 37% more VR patients had returned to work compared to UC patients. Although most usual care patients were working after one year, there were still 10% more VR patients working compared to UC patients.
  • VR patients were less likely to claim welfare benefits after 12 months.
  • There were no differences in return to work in those claiming and not claiming compensation.
  • Usual care patients stayed in the hospital an average of 11 days longer than VR patients.

The vocational rehabilitation patients did see specialists more frequently but not by a significant amount. That meant there were no major differences in treatment costs between the groups.

  • VR patients spent about £75.23  more than the UC patients (about the cost of one occupational therapy session in the UK or $126.91 USD).
  • When considering lost wages due to missed work days, UC patients were at a disadvantage. As a result, when taking into account this broader perspective, VR patients had an average annual savings of £1,862 per person($3141.01 USD).

In addition to preventing lost wages, VR patients were more likely to stay working when they returned to their jobs, instead of dropping out due to lack of support. Those with moderate to severe injuries benefited the most from VR treatments, but even mild TBI patients had better outcomes with VR. That suggests that even those with mild TBI can struggle with reintegrating into the workplace after the injury.

These findings suggest possible treatment options that could aide in the rehabilitation efforts for thousands of soldiers suffering from mild traumatic brain injuries, now called the signature wound of war.

Reference

Radford K, et al. Return to work after traumatic brain injury: cohort comparison and economic evaluation. Brain Injury 2013: 27(5): 507-520.

MRI Confirms Brain Damage From “Heading” Soccer Ball

Photo courtesy of Creative Commons

Athletes using their head to move a soccer ball: It is called “heading,” and it is quite common. During competitive games, each soccer player averages six to 12 headings every game, with the ball moving up to 50 miles an hour. Players often perform the maneuver during practice time as well, with up to 30 rapid-succession headings a typical practice drill.

A recent study suggested that soccer players who head the ball may suffer impaired thinking abilities. That research included teen female soccer players subjected to cognitive tests.

New research published in the journal Radiology goes even further to show that this common maneuver injures a player’s brain, using MRI brain scans and a different demographic group as participants.

Researchers recruited 37 amateur soccer players with the average age of 31 who had played soccer an average of 22 years. They sought data about the long-term damage that may result from the small but repeated impacts to the head that are caused by heading the soccer ball. They sought to identify a threshold above which injury and cognitive problems might be detectable.

Participants were questioned about their headings over the previous year, performed neurocognitive tests, and were given MRI scans of the brain.

The study found that soccer players who repeatedly head the ball had lower performance on neurognitive testing and changes in their brain microstructure. These findings suggested that using the head to move the soccer ball may indeed lead to long-term brain injury.

The MRI scans detected three areas of white matter in the brain with lower fractional anisotropy. “We were able to detect changes to the microscopic structure of what’s essentially the brain’s wiring, the white matter axons,” head researcher Michael Lipton told MedPage Today for an article about the study.

The threshold that researchers found was a range of 885 to 1,550 headings per year; players who headed the ball in or above that range were most likely to suffer the damage visible on the brain scans.

The number of headings also affected the players in the area of memory. The threshold for this impairment was slightly higher; players heading the ball about 1,800 times per year were at risk for memory loss.

While the researchers were able to identify some safety thresholds, they also found that in a subset of the study participants, brain changes were seen even below the identified thresholds. This suggested that some players may be particularly vulnerable to brain injury from heading the ball. Why this is the case was not clear, but the study authors urged further research to identify a possible genetic cause of susceptibility.

Unexpectedly, these findings were not associated with prior concussion. However, the brain damage was consistent with damage seen in patients with traumatic brain injury. Another surprise that was revealed by the research was the site of the injury, which was on the opposite side of the head as the impact with the ball. The researchers wrote, “We interpret this an analogous to the phenomenon of contrecoup injury, which occurs opposite the site of impact in contusional brain injury.” They also noted that it is likely that other areas of the brain were damaged by heading the ball, but the changes were too subtle to be detected by MRI.

More research will be needed to confirm these results and more clearly establish safety thresholds, as this study was limited by its small sample size, lack of data about ball velocity and location of head impact, and the reliance on fractional anisotropy measurements for imaging. Further research may use other types of MRI studies to reveal more about mechanisms and effects.

This future work could be used to recommend safety measures analogous to “pitch counts” for baseball players, determining how many headings an individual soccer player can perform before being required to rest and recover.

References

Lipton M, Kim N, et al. Soccer heading is associated with white matter microstructural and cognitive abnormalities. Radiology (published online before print June 11, 2013). doi: 10.1148/radiol.13130545.

Walsh Nancy. ‘Heading’ soccer ball injures brain. MedPage Today (online June 11, 2013). www.medpagetoday.com/Neurology/HeadTrauma/39725.

Drug Could Prevent PTSD

Drug Could Prevent PTSD A new drug could prevent PTSD symptoms after a traumatic incident, scientists have found, and can mitigate the effects of a newly-discovered gene linked to PTSD.

An estimated 38% of whiplash patients suffer from posttrauamtic stress after an auto collision, and the condition is likely just as common in patients with other auto injuries. PTSD has received increased attention in recent years with an estimated 20% of US troops returning from Iraq and Afghanistan. The condition remains stubbornly hard to treat, and can often exacerbate the physical symptoms of whiplash or other injuries sustained during the traumatic incident. Although cognitive behavioral therapy has proven to be successful for managing PTSD symptoms in whiplash patients in earlier studies, is it possible to prevent the symptoms form happening in the first place?

Researchers sought to answer that question by seeing whether they could develop a drug to prevent PTSD in a group of traumatized lab mice.  By analyzing brain tissue from the mice, they discovered a specific gene, called OPRL1, that made the mice more likely to develop PTSD symptoms. The gene contains instructions for creating a receptor for a brain chemical call nociceptin, and is involved in fear response.

In later human studies, the researchers found that people with this Oprl1 gene had more difficulty differentiating between real and perceived fear. In other words, those with the Oprl1 gene were more likely to suffer posttraumatic stress.

Then the researchers wanted to see if they could target this gene to prevent PTSD symptoms. After subjecting the lab mice to a traumatizing experience, they injected some of the mice with a drug that triggers a brain receptor responsible for fear response. The drug blocked PTSD symptoms whether it was injected directly before or after the traumatic experience.

There are likely many more genes involved in the risk for PTSD after a traumatic event, according to co-author Kerry Ressler, who commented for HHMI. Ressler explained that for any PTSD drug to work, doctors would first have to identify who is at risk for PTSD based on psychological factors or biomarkers. “We would then predict that if we gave those individuals such a drug within a few hours after trauma, it would prevent the development of PTSD pathology.”

 

References

Andero R, et al. Amygdala-dependent fear id regulated by Oprl1 in mice and humans with PTSD. Science Translational Medicine 2013; 5: 188-188ra73. doi: 10.1126/scitranslmed.3005656.

Anderson TE, et al. The relationship between chronic whiplash-associated disorder and post-traumatic stress: attachment-anxiety may be a vulnerability factor. European Journal of Psychotraumatology 2011; 2: 10.3402/ejpt.v2i0.5633.

 HHMI News: Drug prevents post-traumatic stress-like symptoms in mice. Howard Hughes Medical Institute. June 5, 2013. Accessed June 19, 2013.

Zarembo A. PTSD may be prevented, researchers find. Los Angeles Times. June 5, 2013. Accessed June 19, 2013.

Mechanisms That Cause Chronic Whiplash Pain

Mechanisms That Cause Chronic Whiplash PainWhiplash is a multi-faceted type of injury and the subject of a great deal of scientific research and discussion. There are dozens of ways that whiplash can manifest depending on the type and location of the injury, the victim subjected to the injury, and the specific factors and severity of the crash, in addition to other variables.

A recent research review, published in The Journal of Forensic and Legal Medicine, attempted to analyze a wide array of current data to provide some insights about the mechanisms that underlie whiplash injury developing into chronic pain.

The author of the study, Dr. Charles Davis, referred to whiplash-associated disorders (WAD) as “a wide variety of clinical manifestations.” Indeed, because whiplash injury can damage bones as well as soft tissue, victims of whiplash can suffer a great variety of different symptoms.

Researchers have traditionally distinguished acute from chronic whiplash pain by using an interval of time of pain symptoms, usually either three months or six months since the collision. But what happens biologically to whiplash victims that develops into a chronic condition?

Dr. Davis looked at what happens when the whiplash injury activates pain receptors in peripheral nerve endings called nocicpetors. These neurons can send pain signals throughout a person’s body through the spinal cord, and tissue injuries can release chemical reactions that exacerbate the sensitivity to pain stimuli even further.

Other factors identified in the study as possible causes of chronic WAD involved central sensitization. Dr. Davis cited that whiplash has been shown to damage the facet joint and the intervertebral disc, which can result in an overall pain sensitivity in the nervous system and spinal cord.

This sensitization creates an abnormal perception of pain in some whiplash patients. But even this is manifested in different ways. Some experience a spontaneous, continuous pain (described as “burning” or “aching”); some experience spontaneous, intermittent pain (described as “stinging”); others suffer from abnormally evoked pain from touch or movement, meaning either an overreaction to normally painful stimuli or pain produced by normally non-painful stimulation.

Whiplash can also result in inflammation in the soft tissue, which produces its own type of pain. To help the injured area heal and repair, the patient’s sensory nervous system can go into overdrive responsiveness, making pain feel exaggerated or prolonged.

Other types of pain are even more difficult to pinpoint and may be present without any inflammation or structural damage to the nervous system. The study cited cases of neuropathic pain, sensory hypoesthesia, mechanical allodynia, and chronic cervical radiculopathy. Among these, there is evidence that different pain-processing mechanisms are underlying causes.

In addition, muscle fatty infiltrates that develop after a whiplash injury may contribute to the vulnerability of a subsequent injury and the risk of posttraumatic stress disorder in whiplash patients.

In the study’s conclusion, Dr. Davis highlighted the usefulness of animal experiments for additional data about whiplash-injury mechanisms. He also urged that patients with whiplash injuries be assessed with proper imaging and quantitative sensory testing. He wrote that if injury to the discs, facets, or upper cervical ligaments are found, it is unlikely the patient will recover spontaneously and will likely develop chronic symptoms. He also said that patients with a nociceptive type of pain may be difficult to treat, and that neuropathic pain is likely to cause hypersensitivity and a higher rate of pain and disability.

Reference

Davis CG. Mechanisms of chronic pain from whiplash injury. Journal of Forensic and Legal Medicine 2013; 20: 74-85.

Evidence of Whiplash Hyperexcitability to Pain

Evidence of Whiplash Hyperexcitability to PainIt has long been noted that whiplash seems to cause widespread sensitivity to pain in some chronic patients. About half of people who suffer from whiplash-associated disorder (WAD) continue to report pain and disability one year after their injury. Many experts believe that these long-term effects are due to lasting damage to the spine and central nervous system as a result of a whiplash injury. A growing body of research supports these claims, including a recent study confirming a link between whiplash and pain hypersensitivity and another study that demonstrated a possible relationship between whiplash and emotional sensitivity to trauma.

Researchers at the Center of National Research on Disability and Rehabilitation Medicine in Australia conducted a systematic research review to make determinations about sensory hyperexcitability to pain stimuli, lowering the pain threshold and increasing “excitability” of the reflexes in chronic WAD patients.

The study authors selected 13 research articles and conducted a full review and a meta-analysis of all the data. This data reflected results from research on 483 WAD patients and 334 health controls. The tests that study-participants had been subjected to included pain threshold data involving pressure, cold, and heat; Nociceptive Flexor Reflex threshold (which tests spinal cord excitability); Electrocuaneous Stimulation; Brachial Plexus Provocation; and cold and heat detection thresholds.

The results of the review demonstrated significantly lower pain thresholds and reflex thresholds among the whiplash patients compared to healthy controls, present both in the injured area of the body as well as in other body parts far from the injured area. They also found that WAD patients demonstrated less ability to detect heat and cold when subjected to detection testing, compared to controls. Researchers said that these results were indicative of damage to the central nervous system processes. They concluded that their results supported the involvement of central hyperexcitability in chronic WAD.

The study team also found that some of the quantitative sensory testing that had been used may not be reliable, due to the scattered and inconsistent results in this meta-analysis, especially Pressure Pain Threshold, which they suggested may not be an optimal test for future studies to use. They wrote that cold and heat, Nociceptive Flexor Reflex tests, and Electronic muscle stimulation may be stronger measures to determine pain thresholds. However, these tests, in addition to the other tests in the study that may be more reliable options, are limited because they have not be used extensively. Further investigations using these methods will be needed in independent settings to determine the most reliable clinical testing.

Reference

Stone A, Vicenzino B, Lim E, Sterling M. Measures of central hyperexcitability in chronic whiplash associated disorder- a systematic review and meta-analysis. Manual Therapy 2013; 18: 111-117.

 

Hospitals Make Medication Errors With Blood Thinners

Hospitals Make Medication Errors With Blood ThinnersBlood thinners, including anticoagulants, are used to prevent heart attack or stroke. They help keep blood clots from forming in the arteries and veins.

New research has revealed that in hospitals, blood thinners account for about 7% of medication errors that patients are subjected to. The study was conducted by a health-care panel of experts and was endorsed by the Anticoagulation Forum, a group that works to improve anticoagulation care. Its purpose was to provide new recommendations for optimized anticoagulant therapy in hospitals and to outline the structure for effective management of blood thinners, to prevent errors and improve patient safety.

In their report, the group discussed  ways to reduce the frequency of these types of mistakes. They noted that standardized dosing protocols should be made easily accessible for all hospital employees, through an electronic medical record. They also cited the usefulness of tools such as bar code scanning and programmable infusion pumps. In addition, they established that each patient’s physician should enter medication orders themselves, and that all medical personnel should routinely examine each patient’s range of dosage.

When technology isn’t available, it was discovered that having a pharmacist rotate on patient rounds reduced the number of errors by about 78 percent. In addition to pharmacists, researchers also highlighted the usefulness of including clinicians who specialize in quality and safety as part of the hospital health-care team. They said that a team leader should be assigned for communicating the anticoagulation management system to the rest of the team.

This anticoagulation management system should have an effective procedure to track patients receiving blood thinners and should be integrated with other hospital resources for patient care. Standards of practiced should be established, based on research, and implemented and regularly reviewed and updated.

The study also found that one of the most frequent causes of medication prescribing errors is “lack of knowledge of a patient’ medication or condition.” Thus, the authors of the study urged that hospitals develop an anticoagulation management system that includes staff training and ongoing education for all people involved in the drug therapy, including patients.

Dr. Edith Nutescu, head researcher of the study, commented on the effects of patient education. She said, “Many patients have inadequate knowledge regarding their medication therapy. Improved outcomes have been reported when patients take responsibility for, understand, and adhere to an anticoagulation plan of care.”

The study also analyzed the transition period from chronic patients transferring to outpatient care. For a safe transition, patients should receive education about blood thinners, timely follow-up care, and regular communication with their health-care providers.

In their study’s conclusion, the researchers wrote, “Anticoagulants are high-risk medications associated with a significant rate of medication errors among hospitalized patients.”

Reference

Nutescu E, Wittkowsky A, et al. Delivery of optimized inpatient anticoagulation therapy: consensus statement from the anticoagulation forum. The Annals of Pharmacotherapy 2013: 47(5): 714-724. doi: 10.1345/aph.1R634.