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AMHERST, Mass. - India has one of the highest rates of type 2 diabetes in the world, and there is now "growing national and international concern" about the drug regulatory system there, which allows use of a drug treatment that has not been shown effective or safe, say researchers at the University of Massachusetts Amherst and the U.K.'s Newcastle University in a paper published today in the British Medical Journal.

In what they believe is the first study of its kind, lead author Valerie Evans, now a biostatistician at UMass Amherst's School of Public Health and Health Sciences, with legal advisor Peter Roderick and senior author Allyson Pollock, now at Newcastle, used World Health Organization guidelines for approving metformin fixed-dose combinations (FDC) to assess the efficacy and safety of those top-selling diabetes drugs in India.

Evans, who did this work while at the University of Edinburgh with senior author Pollock, says "This work is relevant to an active case in the courts in India. We are in the six-month review window ordered by India's Supreme Court right now."

FDCs combine two or more drugs in a fixed ratio into a single dose form, usually a tablet or capsule, which is appropriate for some conditions. FDCs can make medications more convenient and less costly for patients. However, no national or international treatment guidelines recommend use of FDCs for type 2 diabetes, because individual monitoring and adjustment of blood sugar is so important in the disease, the authors say.

Multinational corporations manufacture all five of India's 500 top-selling FDCs for diabetes, they add, and Pollock, who is director of the Institute of Health and Society at Newcastle University, says, "The lack of good trial evidence for these five top-selling metformin combination medicines for treatment of type 2 diabetes is of deep concern."

Evans points out that India's pharmaceutical companies are drug distributors for the world, "so if there's a problem it can go everywhere," she says. "You hope that the regulatory systems in the consumer countries can filter out problems, but that's not always the case. We feel that people really need to know about this. We want the medicines that doctors prescribe for their patients to be safe and effective and for that to be supported by sound evidence and by properly conducted, transparent clinical trials."

The authors point out that in March 2016, the government of India banned 344 unapproved FDCs that lacked clinical support or that were found to be potentially harmful. The ban included different doses of three of the five top-selling metformin FDCs. But the ban was overturned by the state-level Delhi High Court in December 2016. When the government later appealed this to the Supreme Court, it gave the country's Drugs Technical Advisory Board six months to consider the banned drugs.

In their current paper, Pollock and colleagues state, "Our examination exposes serious deficiencies in the evidence base for metformin FDCs for type 2 diabetes and raises questions about the role of multinational corporations in manufacturing these for sale and use." They urge India's regulatory drug agency, the Central Drugs Standard Control Organization, to make public its evidence for approving the FDCs now in use, to provide "confidence in their efficacy and safety."

Further, Evans and colleagues say if that evidence does not extend beyond the clinical trials they reviewed, "those FDCs should be banned immediately." Pollock urges, "The Government's 2016 ban on FDCs should be reinstated and a review of FDCs mandated by the Indian Parliament."

For this work, the researchers searched the published literature, clinical trial registries and other data on the use of metformin FDCs in adults with type 2 diabetes in India. Evans says this work grew out of a larger project supported by the European Commission's FP7 and led by Pollock that is looking at seven pharmaceuticals, one of which is metformin, and tracing them from production to consumption in India, South Africa and Uganda.

People with undiagnosed neurocognitive deficits are undergoing hip and knee replacements at high rates and are more likely to have poorer short-term outcomes after surgery, according to new research led by orthopedic surgeons at NYU Langone Health.

The study of patients who were screened with cognitive assessments prior to undergoing a total joint arthroplasty, or replacement, showed that those who scored worse on the tests were significantly more likely to fail to progress in rehabilitation and to require admission into the intensive care unit (ICU).

"Our data suggest that neurocognitive impairment is highly prevalent in older individuals who are set to undergo total joint replacements, and we suspect that rates may be underestimated nationwide," says James Slover, MD, an associate professor of orthopedic surgery at NYU School of Medicine, and an attending orthopedic surgeon and clinical site chief at NYU Langone Orthopedic Hospital. "These patients required more hospital resources and progressed more slowly with physical therapy after surgery. Therefore, it is critical that strategies are developed to screen these patients and protocols are put in place to allocate more support to them before and after surgery."

The research was presented Thursday, March 8, 2018, in a poster session at the American Academy of Orthopaedic Surgeons (AAOS) 2018 Annual Meeting in New Orleans, Louisiana. The findings were also published in the February 2018 issue of the Journal of Arthroplasty.

Screening Patients Preoperatively May Yield Targets for Intervention

Total joint replacements are performed on a wide array of individuals, which includes an older population who may have significant medical comorbidities. Previous research suggests that neurocognitive impairment before any major surgery may raise risk for increased complications and worse outcomes, but this phenomenon has not been well-studied in patients undergoing joint replacements. More than 645,000 people undergo a total knee replacement each year, and more than 306,000 undergo a total hip replacement annually, according to the AAOS.

Slover and colleagues prospectively screened more than 100 patients who were set to undergo total joint replacements at NYU Langone Orthopedic Hospital for neurocognitive impairment using three validated cognitive tests: a grooved pegboard test for dexterity and coordination for both a dominant and nondominant hand, and an auditory verbal learning test for memory function.

Ninety-nine completed all screening tests before undergoing joint replacements and were followed for at least one year. Patients with previously diagnosed neurocognitive conditions, including Alzheimer's and other dementias, were excluded from the study.

The researchers found that 53 percent of patients (or 53 out of 99) had neurocognitive deficits identified on at least one of the three tests: There was a significant prevalence of neurocognitive impairment in patients between the ages of 50 and 59 (20 out of 34), though the highest proportion was reported in patients 70 years of age or older (62 percent, or 13 out of 21 patients screened). Depression was linked to higher likelihood of worse neurocognitive scores, with 77 percent (13 of 17) patients with depression testing positive for neurocognitive impairment on any test, versus 48 percent (38 of 79) of non-depressed patients.

Among patients with neurocognitive impairment, statistically significant differences were noted: 48 percent required ICU admission and medical response team consults, and 64 percent had failures to progress in physical therapy, compared with 14 percent and 17 percent of controls, respectively. These patients also trended toward needing longer length of stays and were more likely to be readmitted to the hospital within 30 days or one year of the procedure, but the findings were not statistically significant.

Future research will focus on developing pre- and postsurgical evaluations and interventions to improve the outcomes of these patients, and larger studies are planned.

"If we identify patients with neurocognitive impairment prior to a joint replacement, our surgical care team can plan better and concentrate post-operative resources accordingly to make sure we are doing all we can to ensure the best outcomes," says Slover.

A team of international researchers led by a Canadian biologist has found that infection with parasites makes it harder for seafish living in coral reefs to think.

The study, conducted at the Lizard Island Research Station in Australia and led by Assistant Professor Sandra Binning of Université de Montréal's Department of Biological Sciences, was published today in Proceedings of the Royal Society B: Biological Sciences.

It highlights the important role of both parasites and cleaning organisms in the decision-making abilities of reef fish.

Binning and her team found that sick seafish can get well again by seeking out other animals like the blue-streaked "cleaner wrasse," a common aquarium fish that eats harmful parasites off their "clients", helping keep them healthy.

"We collected wild damselfish with or without access to cleaner wrasse and tested their ability to solve a feeding test in the lab." Binning recalled. "We then compared their performance to fish that we infected with parasites experimentally."

"We found that infection with parasites, especially in high numbers, really affects the ability of fish to learn."

These results may not be surprising to anyone who's been sick and tried to do activities requiring thinking and concentration. "When we're sick, our body diverts resources away from our brain towards fighting off the infection," Binning noted. "This makes it harder for us to think and learn."

Humans may also benefit from staying parasite-free. "Studies have found that schoolchildren with stomach worms perform worse on standardized tests that their parasite-free peers," said Binning. "Treating these kids with anti-parasite medication improves their performance."

Although fish can't take medication when they're feeling under the weather, they can enlist the help of cleaners to help rid them of their parasites. This access to cleaning services can dramatically improve a fish's performance in a learning test.

According to Dr. Binning, "cleaner wrasse act like the vets of the sea. Clients visit cleaners to get their parasites removed, and this helps boost their ability to think and solve the test."

Interactions with cleaner wrasse are also known to reduce client stress levels and increase local recruitment of coral reef fishes.

However, this vital role in maintaining healthy reef communities may be under threat: cleaner wrasse are among the top marine fishes caught for the aquarium industry, due to their colourful patterns and charismatic behaviour.

"It's important that we understand the impacts of reduced access to cleaners on client fishes," said Binning. "Cleaners may not be the largest or most abundant fish on the reef, but they affect the well-being of thousands of their clients. This needs to be taken into consideration when setting collection limits and managing marine parks."

A novel risk assessment tool helps identify which patients undergoing total hip replacement may be at higher risk for an implant dislocation after surgery, according to a new study from researchers at NYU Langone Health and described in the Best Poster in the Adult Reconstruction Hip at the American Academy of Orthopaedic Surgeons (AAOS) 2018 Annual Meeting in New Orleans.

More than 310,000 hip replacements are performed in the United States each year, and an estimated 2.5 million Americans are currently living with hip replacements. In a hip replacement, an artificial joint comprising a ball and socket is implanted to replace the natural ball and socket in the pelvis, enabling movement that is typical of the hip joint. While dislocations only occur in about 1 percent of patients after hip replacement, certain individuals may be at a higher risk.

NYU Langone research presented at last year's AAOS Annual Meeting showed that spinal deformity was a significant risk factor for dislocation and subsequent revision surgery. The researchers reported at the time how the lumbar spine, or lower back, moves during posture changes like transitioning from sitting to standing, creating alterations in so-called spinopelvic relationship," which changes position of the hip socket and may cause an implant to dislocate in a person with spinal deformity.

This led researchers to further develop a risk prediction tool to better identify which patients undergoing a hip replacement may be at higher risk for dislocation, and then implement a treatment algorithm to help reduce that risk.

"Dislocation is a common reason for a total hip replacement to fail, and when it happens, sufferers can experience significant pain and require another surgery to fix the problem," explains lead study author Jonathan Vigdorchik, MD, an assistant professor of orthopedic surgery at NYU School of Medicine and associate fellowship director of the Division of Adult Reconstructive Surgery at NYU Langone Orthopedic Hospital. "Orthopedic surgeons need to be more aware of this problem and think about the risk of dislocation prior to performing a hip replacement instead of just dealing with the complications after the surgery. We need to be proactive in our approach."

What the Study Found

Some newer hip implants are designed with dual mobility cups that allow for increased range of motion, which helps reduce dislocation risk. However, no guidelines currently exist to aid clinicians in deciding when to use these more flexible implants, which are often more expensive than conventional implants, may not be medically necessary, and may carry added risks if implanted unnecessarily.

For the study, researchers reviewed data on 1,082 total hip replacements performed using computer navigation between January 2014 and December 2015, during which period no dual-mobility implants were used. The overall implant dislocation rate among this cohort was found to be 1.8 percent. Of this group, 320 patients had spinal disease and deformity as evidenced by imaging scans, and of them, 10 experienced dislocations, suggesting a dislocation rate of 3.1 percent for high-risk patients, or about three times higher than normal.

Beginning in 2016, surgeons used the standardized risk prediction model and treatment algorithm developed at NYU Langone, which factored in data collected from preoperative imaging taken while the patient was sitting and standing, and other measures that might affect risk for dislocation, including presence of a previous lumbar fusion. Using the risk assessment tool, the researchers identified 192 of 1,009 patients as high risk for a dislocation after surgery. All 192 patients underwent a total hip replacement through the high-risk algorithm, with dual mobility implants being used in 143 of the cases. The researchers reported only one dislocation in this high-risk group (or 0.5 percent of high-risk patients), compared with 3.1 percent in the previous group not assessed with the risk assessment and treatment algorithm. These findings represent a six-fold decrease in the rate of dislocation in the high-risk group.

"There were significantly fewer dislocations in the high-risk group once all of our patients were analyzed through our new treatment algorithm," explains study co-author Aaron J. Buckland, MD, an assistant professor of orthopedic surgery in the Division of Spine Surgery and director of spine research at NYU Langone. "We were able to stop these implant dislocations from occurring in the first place, sparing our patients follow-up care and the need for revision surgery."

All patients who undergo hip replacement at NYU Langone Orthopedic Hospital now go through the risk assessment screening and treatment algorithm prior to surgery. Other technologies including laser-guidance, computer navigation, and robotic surgical devices are used for the especially high-risk and complex cases identified through the algorithm in order to ensure the best possible outcome free of complications.

Researchers from the University of Pennsylvania have developed a gene therapy that successfully treats a form of macular degeneration in a canine model. The work sets the stage for translating the findings into a human therapy for an inherited disease that results in a progressive loss of central vision and which is currently untreatable.

The study, published today in Proceedings of the National Academy of Sciences, was led by Karina E. Guziewicz, a research assistant professor in Penn's School of Veterinary Medicine, and Artur V. Cideciyan, a research professor of ophthalmology in Penn's Perelman School of Medicine. The research is part of a long-standing partnership between Penn Vet and Penn Medicine scientists to push forward gene and other novel therapies for blinding disorders.

"In the eye, you have these two integral retinal cell layers that puzzle into one another and, like a zipper, they interweave your vision cells and the support cells," Cideciyan says. "What this disease is doing is basically unzipping those layers, and what we've done is rezip them, bringing them together tightly."

"With this research," Guziewicz says, "we have demonstrated that there is a therapy that is working in a large animal model. Following safety studies, a human clinical trial could be less than two years away."

Guziewicz and Cideciyan's colleagues who collaborated on the work included vision scientists from Penn Vet's Division of Experimental Retinal Therapies, Gustavo D. Aguirre, professor of medical genetics and ophthalmology, and William Beltran, professor of ophthalmology; and from Penn Medicine Samuel G. Jacobson, professor of ophthalmology.

Best disease, or vitelliform macular degeneration, is an inherited blinding disorder caused by mutations in the BEST1 gene. It often manifests in children and young adults, gradually robbing them of their central vision.

Through a variety of studies during the last several years, the Penn team has shown that dogs, too, develop a strikingly similar disease. A 2014 study led by Beltran revealed that dogs, like humans, have a tiny region at the center of their retina that is densely packed with cone photoreceptor cells--those responsible for reading, driving, and perceiving fine details--called a fovea. BEST1 mutations in both humans and dogs compromise the fovea, leading to vision loss.

Based on success treating other blinding diseases, the group has been developing a gene therapy to treat this condition. And working with the canine model, Guziewicz and colleagues reported last year the discovery of the underlying defect responsible for disease, the failure of a supporting structure known as the retinal pigment epithelium, or RPE, to tightly connect to the light-sensing photoreceptor cells. That finding gave the researchers the outcome measures they needed to determine with confidence whether a gene therapy would work.

In the newly published study, the researchers further probed the canine Best disease while also examining human patients with BEST1 mutations to see if analogous defects could be seen.

While Best disease and related conditions were known to affect central vision, it had long been known that the disorders involved dysfunctions all across the retina. Examining the retinas of dogs with disease mutations, the researchers found a retina-wide abnormality; the internal surface of the RPE, critical for communication with the light-sensing photoreceptor cells, failed to develop normally, preventing the photoreceptors from coming into close contact. This could be detected very early, when the affected dogs were only 6 weeks old.

"This was unexpected," says Aguirre, "and helps explain this puzzling finding in the disease that, while patients have lesions that are very local, when you do electrophysiological measurements you see that there is a retina-wide defect. Now that we can see this separation happening very early between the RPE and photoreceptors, we know that the disease involves a structural abnormality across the retina that precedes the loss of photoreceptor cells."

An additional finding that arose when the dogs were examined under light was that light exposure dramatically increased the severity of the RPE-photoreceptor separation. When dogs were returned to darkness, the separation decreased.

It's unknown whether this association with light is present in human patients. But the researchers did take steps to show that a similar separation between RPE and photoreceptors is affecting vision. By measuring the time it took for patients to adjust to darkness, or acquire "night vision," the researchers obtained a proxy for the time it takes for nutrients to diffuse between these two layers of cells, a process that enables dark adaptation. They showed that a longer distance was associated with much slower rates of nutrient transport.

"This flow of nutrients normally occurs over a very small distance," Cideciyan says. "So if you have a separation between these two layers, the recovery rate to get night vision slows down. The implication is that, if we could correct the apposition of these two tissues, we would correct the visual defect as well."

That is what the researchers set out to do in testing the gene therapy construct. Using a harmless viral vector, they injected a healthy copy of the BEST1 gene, using either the canine or human version of the gene, into the dogs with the canine version of Best disease, at early- and middle-disease stages.

Remarkably, they were able to correct both mild and more severe lesions. Close examination of the eyes of treated dogs revealed that the gene therapy restored the "zipper" structure between RPE and photoreceptor cells. To ensure their therapy was functioning to correct this RPE-photoreceptor interface, they exposed to light the eyes of dogs that had been previously injected with gene therapy and saw that the triggered RPE-photoreceptor cell separation did not occur in the area of the retinas that had been treated.

"Since we understand the mechanism of disease better than before," says Guziewicz, "it also allows us to understand the mechanism of rescue. We can visualize these projections extending from the RPE that never existed before; it's incredible. That restored the proper apposition between those two cell layers."

The therapy appears to be lasting, as the treated dogs' eyes remained disease-free for as long as five years.

Work remains to be done before embarking on human clinical trials, including identifying which patients might benefit, assessing how far advanced a disease could be and still be effectively treated, and ensuring safety so as not to compromise vision that the patients still have. But, given the closeness with which dogs recapitulate the human disease, the researchers are hopeful that the findings will translate.

"On a human level, there are a lot of families who know that previous generations have had this disease, and the young people can live in fear of whether it is going to affect them," Jacobson says. "This is the unveiling of a mechanism and a treatment for a previously untreatable form of juvenile or inherited macular degeneration, and that's a major step forward."

Scientists have used lab experiments to retrace the chemical steps leading to the creation of complex hydrocarbons in space, showing pathways to forming 2-D carbon-based nanostructures in a mix of heated gases.

The latest study, which featured experiments at the Department of Energy's Lawrence Berkeley National Laboratory (Berkeley Lab), could help explain the presence of pyrene, which is a chemical compound known as a polycyclic aromatic hydrocarbon, and similar compounds in some meteorites.

A team of scientists, including researchers from Berkeley Lab and UC Berkeley, participated in the study, published March 5 in the Nature Astronomy journal. The study was led by scientists at the University of Hawaii at Manoa and also involved theoretical chemists at Florida International University.

"This is how we believe some of the first carbon-based structures evolved in the universe," said Musahid Ahmed, a scientist in Berkeley Lab's Chemical Sciences Division who joined other team members to perform experiments at Berkeley Lab's Advanced Light Source (ALS).

"Starting off from simple gases, you can generate one-dimensional and two-dimensional structures, and pyrene could lead you to 2-D graphene," Ahmed said. "From there you can get to graphite, and the evolution of more complex chemistry begins."

Pyrene has a molecular structure composed of 16 carbon atoms and 10 hydrogen atoms. Researchers found that the same heated chemical processes that give rise to the formation of pyrene are also relevant to combustion processes in vehicle engines, for example, and the formation of soot particles.

The latest study builds on earlier work that analyzed hydrocarbons with smaller molecular rings that have also been observed in space, including in Saturn's moon Titan - namely benzene and naphthalene.

Ralf I. Kaiser, one of the study's lead authors and a chemistry professor at the University of Hawaii at Manoa, said, "When these hydrocarbons were first seen in space, people got very excited. There was the question of how they formed." Were they purely formed through reactions in a mix of gases, or did they form on a watery surface, for example?

Ahmed said there is an interplay between astronomers and chemists in this detective work that seeks to retell the story of how life's chemical precursors formed in the universe.

"We talk to astronomers a lot because we want their help in figuring out what's out there," Ahmed said, "and it informs us to think about how it got there."

Kaiser noted that physical chemists, on the other hand, can help shine a light on reaction mechanisms that can lead to the synthesis of specific molecules in space.

Pyrene belongs to a family known as polycyclic aromatic hydrocarbons, or PAHs, that are estimated to account for about 20 percent of all carbon in our galaxy. PAHs are organic molecules that are composed of a sequence of fused molecular rings. To explore how these rings develop in space, scientists work to synthesize these molecules and other surrounding molecules known to exist in space.

Alexander M. Mebel, a chemistry professor at Florida International University who participated in the study, said, "You build them up one ring at a time, and we've been making these rings bigger and bigger. This is a very reductionist way of looking at the origins of life: one building block at a time."

For this study, researchers explored the chemical reactions stemming from a combination of a complex hydrocarbon known as the 4-phenanthrenyl radical, which has a molecular structure that includes a sequence of three rings and contains a total of 14 carbon atoms and nine hydrogen atoms, with acetylene (two carbon atoms and two hydrogen atoms).

Chemical compounds needed for the study were not commercially available, said Felix Fischer, an assistant professor of chemistry at UC Berkeley who also contributed to the study, so his lab prepared the samples. "These chemicals are very tedious to synthesize in the laboratory," he said.

At the ALS, researchers injected the gas mixture into a microreactor that heated the sample to a high temperature to simulate the proximity of a star. The ALS generates beams of light, from infrared to X-ray wavelengths, to support a range of science experiments by visiting and in-house researchers.

The mixture of gases was jetted out of the microreactor through a tiny nozzle at supersonic speeds, arresting the active chemistry within the heated cell. The research team then focused a beam of vacuum ultraviolet light from the synchrotron on the heated gas mixture that knocked away electrons (an effect known as ionization).

They then analyzed the chemistry taking place using a charged-particle detector that measured the varied arrival times of particles that formed after ionization. These arrival times carried the telltale signatures of the parent molecules. These experimental measurements, coupled with Mebel's theoretical calculations, helped researchers to see the intermediate steps of the chemistry at play and to confirm the production of pyrene in the reactions.

Mebel's work showed how pyrene (a four-ringed molecular structure) could develop from a compound known as phenanthrene (a three-ringed structure). These theoretical calculations can be useful for studying a variety of phenomena, "from combustion flames on Earth to outflows of carbon stars and the interstellar medium," Mebel said.

Kaiser added, "Future studies could study how to create even larger chains of ringed molecules using the same technique, and to explore how to form graphene from pyrene chemistry."

Other experiments conducted by team members at the University of Hawaii will explore what happens when researchers mix hydrocarbon gases in icy conditions and simulate cosmic radiation to see whether that may spark the creation of life-bearing molecules.

"Is this enough of a trigger?" Ahmed said. "There has to be some self-organization and self-assembly involved" to create life forms. "The big question is whether this is something that, inherently, the laws of physics do allow."

A new Canadian guideline for managing opioid use disorders lays out the optimal strategies for the treatment of opioid addiction, including recommending opioid agonist treatment with buprenorphine-naloxone as the preferred first-line treatment. The guideline, published in CMAJ (Canadian Medical Association Journal), was created for a wide range of health care providers to address an urgent need for evidence-based treatment of opioid use causing overdoses and death.

"Opioid use disorder is a public health emergency nationwide and this guideline provides a blueprint for health practitioners to step up and provide evidence-based care," says Dr. Julie Bruneau lead author of the pan-Canadian guideline group and a physician at the Centre hospitalier de l'Université de Montréal.

In 2016, the rate of opioid-related deaths in Canada was 7.9 per 100 000 (a total of 2861 deaths), and the number of deaths continues to increase. The opioid epidemic affecting both Canada and the United States is fuelled by a combination of overprescribing as well as the influx of highly potent illegal synthetic opioids, such as illicitly manufactured fentanyl.

"Traditionally, resources for the treatment of opioid addiction have been scarce, and guidelines outlining best practices and practices to avoid have been lacking," says Dr. Evan Wood, senior author and director of the BC Centre on Substance Use at St. Paul's Hospital and the University of British Columbia.

To address the traditional gaps in knowledge in this area, the guideline aims to provide Canadian health care professionals and health authorities with national clinical practice recommendations for treating opioid use disorder. The review panel included 43 health care practitioners with broad experience who are part of the Canadian Institutes of Health Research's Canadian Research Initiative in Substance Misuse (CRISM). The guideline group also involved people with opioid use disorder experience, and considered patient values and preferences in developing its recommendations.

Key recommendations:

Start opioid agonist treatment with buprenorphine-naloxone whenever possible to reduce risk of toxicity, illness and death

In people who respond poorly to buprenorphine-naloxone, consider transitioning to methadone treatment

Start opioid agonist treatment with methadone when buprenorphine-naloxone is not the preferred option

In people who respond well to methadone and who want simpler treatment, consider transitioning to buprenorphine-naloxone

In patients who do not respond to the above therapies, consider slow-release oral morphine, prescribed as daily witnessed doses

Avoid withdrawal management alone without transition to long-term treatment to reduce risk of relapse and death.

Opioid agonist treatment with buprenorphine-naloxone is recommended as first-line treatment because of its better safety record, including lower risk of overdose and lower risk of breathing suppression; ease of use, especially in rural and remote areas where daily witnessed ingestion is not practical; dosing flexibility; and milder withdrawal symptoms if stopping treatment, making it a better option for people with milder opioid dependence.

Beyond recommending best practices, like the use of buprenorphine-naloxone as first-line treatment whenever possible, the guideline also identifies how certain common practices in the Canadian health care system should be avoided -- specifically, how offering withdrawal management as an isolated strategy for the treatment of opioid use disorder actually increases rates of overdose.

"With these recommendations laid out, there is an urgent need for health systems to look at the historical gaps in care and invest in providing timely and evidence-based treatment, says Dr. Bruneau, who is also a professor in the Faculty of Medicine at Université de Montréal. "By encouraging physicians to work alongside their patients to identify the safest, most effective approach first, these new guidelines ensure the best science and evidence are integrated into care."

Opioid use disorder is often a chronic, relapsing condition associated with increased morbidity and risk of death. However, with appropriate treatment and follow-up, individuals can reach sustained long-term remission.

For the full list of recommendations, see Table 1 in the guideline.

In a related commentary http://www.cmaj.ca/lookup/doi/10.1503/cmaj.180209, Drs. Joseph Donroe and Jeanette Tetrault from the Yale University School of Medicine, New Haven, Connecticut, write "this national guideline describing the pharmacologic management of opioid use disorder is timely and needed to address the expanding epidemic of opioid use disorder and overdose. Importantly, the guideline is geared toward front-line providers, who are vitally important to decrease the existing treatment gap."

Next steps include increasing education of health care providers about recognizing and managing opioid use disorders and chronic pain, reducing stigma associated with substance use disorders, expanding prescribing access to opioid agonists and expanding access to harm reduction services.

The guideline was funded through the Canadian Research Initiative in Substance Misuse (CRISM), a network funded by the Canadian Institutes of Health Research (CIHR).

"Management of opioid use disorders: a national clinical practice guideline" is published March 5, 2018.

Cold Spring Harbor, NY - Because liver cancer is particularly diverse, genetically, and prone to relapse, identifying biomarkers that can predict disease progression is a critical goal in the fight against it.

Researchers at Cold Spring Harbor Laboratory (CSHL), led by CSHL Professor Adrian Krainer, now report in Genome Research that they have developed a method for identifying splicing-based biomarkers for the most common form of liver cancer, hepatocellular carcinoma (HCC). They believe the method will be useful in other cancer types as well.

"This study underscores the potential for learning how RNA splicing variants can contribute to cancer and points to these variants as potential biomarkers for cancer progression," Krainer says.

Splicing refers to a process in which an RNA message copied from information encoded in a gene is edited before it is able to serve as a blueprint for the manufacture of a specific protein. A gene can give rise to multiple RNA messages, each resulting in a different protein variant, or "isoform." Many diseases have been associated with errors or variations in the way that RNA is spliced. Errors or variations in splicing can lead to non-functional proteins or proteins with distinct or aberrant functions.

Recent studies have identified splicing irregularities in liver cancer cells. Led by CSHL postdoctoral researcher Kuan-Ting Lin, Krainer's team developed a method that comprehensively analyzes all RNA messages made from a given gene. The team tested their splicing-variant detection method in HCC, by analyzing RNA messages in HCC cells sampled from hundreds of patients.

They found that particular splicing isoforms of the gene AFMID correlated with very poor patient survival. These variants lead cells to manufacture truncated versions of the AFMID protein. These unusual versions of the protein are associated in adult liver cancer cells with mutations in tumor-suppressor genes called TP53 and ARID1A.

These mutations, the researchers hypothesize, are associated with low levels of a molecule called NAD+ that is involved in repairing damaged DNA. Restoring missing portions, called exons, to AFMID's normal RNA message, they propose, might raise NAD+ to normal levels, avoiding mutations in TP53 and ARID1A. The team hopes to use small molecules called ASOs (antisense oligonucleotides) that can bind to RNA, to change the way AFMID's RNA messages are spliced. Krainer's team previously used this technique to correct errors in the splicing of the gene SMN2 as a way to treat spinal muscular atrophy (SMA).

Fixing AFMID splicing could lead to enhanced production of NAD+ and an increase in DNA repair. "If we can do this, AFMID splicing can become a therapeutic target and the source of a new drug for liver cancer," Lin says. Preliminary experiments suggest the team is on the right track. They demonstrated that coaxing cells to over-express AFMID spliced in the normal manner led to higher NAD+ levels and slower growth of liver cancer cells.

Washington, DC - March 2, 2018 - A team of investigators has found that the mcr-1 drug resistance gene, which encodes resistance to a drug that is used as a last resort, has been found for the first time in Shigella flexneri. Shigella are one of the leading causes of diarrhea worldwide. The research is published March 2nd in Applied and Environmental Microbiology, a journal of the American Society for Microbiology.

In the study, the investigators screened more than 2,000 Shigella isolates for the mcr-1 gene. (Isolates are bacteria from samples which in this case were taken from animal feces on a farm, from patients, and from the environment). Just one isolate tested positive.

That may sound scarce; however, "...as only a small number of strains (Shigella bacteria

"Isolation of plasmid-mediated colistin resistance in S. flexneri from animal feces on a farm suggests that it is circulating via the fecal-oral route at least amongst animals on that farm, and possibly further afield via the food distribution network," according to the report. "In addition, it suggests that farm environments may be an unrecognized reservoir of S. flexneri."

Through a technique called "filter mating," the investigators found that the plasmid was capable of jumping from S. flexneri to a strain of Escherichia coli. (It can likely also jump to other Shigella species, and to other genera of bacteria.)

The original host strain was also multidrug resistant, and that multidrug resistance was also transferable, according to the report. "This is concerning, as S. flexneri is the main cause of Shigella infections in low and middle income countries," said coauthor Adam P. Roberts, PhD. Dr. Roberts is a Senior Lecturer, Antimicrobial Chemotherapy and Resistance, the Liverpool School of Tropical Medicine, UK.

In order to try and control antimicrobial resistance, we need to understand the epidemiology of the resistance genes and how they move around," said Dr. Roberts, "This work is part of that overall effort. Now that we know mcr-1 is functional and can transfer in Shigella we can monitor this situation to see if Shigella is responsible for transfer of this gene to other species."

Citing intensive use of colistin in Chinese agriculture to boost growth of farm animals, the investigators wrote that "the selective pressures are high enough to suggest that a large proportion of drug resistance emerged from the agriculture sector. This use has allowed for the selection, transfer, and maintenance of plasmid mediated colistin resistance into clinical strains of E. coli, [Klebsiella] pneumoniae, and Salmonella spp. and rarely into other Enterobacteriaceae."

The researchers also noted that in their filter mating experiments, a host of additional mobile elements, containing multidrug resistance among much else, also transferred among microbes, suggesting, they wrote, that "other plasmids conferring multi-drug resistance phenotypes can be acquired from the S. flexneri strain." On this basis, they concluded that "...surveillance of mcr-1 in both environmental and clinical isolates would be advised."

HOUSTON - A powerful resistance mutation that appeared to emerge in melanoma after a patient received a targeted therapy combination, instead was lurking in the tumor all along, primed to thwart treatment before it began, researchers at The University of Texas MD Anderson Cancer Center report online at Cancer Discovery.

Researchers analyzed a series of biopsies taken before and during treatment to ferret out the pre-existing mutation and then developed a potential way to target its troublesome abilities.

The team, led by Lawrence Kwong, Ph.D., assistant professor of Translational Molecular Pathology, set out to find resistance mechanisms that arise against a combination of MEK and CDK4 inhibitors to treat melanoma that has a mutation in the NRAS gene.

The mutation, to a gene called PIK3CA, appeared initially to be an acquired resistance variation that arose after treatment. By re-analyzing the pretreatment biopsy, Kwong and colleagues were able to establish that it was rare but present from the start, hiding on one side of the tumor.

PIK3CA variant started rare, expanded rapidly

"Our study is the first to measure multiple regions in pre-treatment tumor biopsies at high resolution and then track the resistant mutation over years of treatment through six biopsies," Kwong said. "We are able to say that this mutation started out rare and then rapidly expanded as the MEK/CDK4 inhibitors killed off a large number of non-resistant cells."

This finding helps establish that such pre-existing mutations can lurk in a patient's tumor at 10 times the rarity than previously appreciated and still cause rapid drug resistance, raising the possibility that even more rare mutations exist in other patients, below the detection rate of current technology.

"Right now, when we detect a resistance mutation after treatment, we often don't know whether it came out of nowhere as a new mutation or was pre-existing but undetected in the original tumor," Kwong said.

Understanding the difference could guide treatment to make it more effective, earlier, Kwong notes, and identifying rare mutations that are geographically isolated on a tumor will require improving our approach to analyzing biopsies.

NRAS mutations occur in 15-20 percent of melanomas, and the MEK/CDK4 combination is often effective initially against these tumors, but resistance arises.

Initial response, then swift progression

A 59-year-old woman with stage III malignant melanoma was found to have an NRAS mutation in her tumor. She was enrolled in a clinical trial combining a MEK and a CDK4 inhibitor. After an initial partial response of a 39 percent reduction in tumor burden, resistance to the treatment arose swiftly and the disease progressed and spread.

Whole exome sequencing of the resistant tumor after treatment revealed a mutation to PIK3CA known to promote tumor growth. Since the mutation was detected only 16 days after treatment began, Kwong and colleagues decided to re-examine the pretreatment biopsy, which sampled a single region of the tumor and had not found a PI3KCA mutation.

By examining seven regions of the biopsy sample using an amplification method developed by co-author David Zhang, Ph.D., assistant professor of Bioengineering at Rice University, the team found PIK3CA mutations in three regions. The pre-existing mutation was both rare and geographically dispersed in the tumor, making it hard to detect by sampling a single region.

Their findings suggest multi-region sampling would expose pre-existing resistant cells, an approach that would not be cost-effective at present, Kwong said, but is likely to become more practical as technology develops.

The PIK3CA mutation could also be detected by isolating circulating cell-free DNA in the blood after resistance developed, making it a potential target for liquid biopsies that are under development.

S6 provides a common target

Simply adding a PIK3CA inhibitor to the MEK/CDK4 combination would likely be too toxic, so the team analyzed 300 proteins to find targets that might be present in more than one of the three pathways.

They found a protein called S6 to be the only spot where all three of these cancer-promoting pathways meet. Treating mice with an S6 inhibitor re-sensitized them to treatment with the MEK/CDK4 combination, restoring the drugs' ability to shrink the PIK3CA mutation-bearing melanomas.

Kwong said an optimized human version of the S6 inhibitor in mice has not yet been developed, but their findings point to a possible target for human drug development.

"One of the main questions in cancer drug resistance is how often it comes from a pre-existing or a completely new mutation" said Gabriele Romano, Ph.D., a postdoctoral fellow in Translational Molecular Pathology and the study's first author. "Our study helps define some of the parameters and tools that will be needed to answer this tricky question."

Boston, MA – People with worrisome levels of obesity and poor control of their type 2 diabetes face two dramatically different options to substantially improve their health: bariatric (weight loss) surgery or intensive lifestyle management. In a randomized controlled clinical trial, scientists from Joslin Diabetes Center and Brigham and Women’s Hospital found that patients treated with a form of bariatric surgery known as Roux-en-Y gastric bypass did significantly better, after three years, than patients provided with an intensive diabetes and weight management program.

“Our study demonstrates that in patients with mild-moderate obesity and type 2 diabetes, gastric bypass surgery leads to a sustained reduction in weight, improvement in glycemic control, and decrease in cardiovascular risk compared to a medical diabetes and weight management program,” said lead author Donald C. Simonson, M.D., M.P.H., Sc.D., of the BWH Division of Endocrinology, Diabetes and Hypertension. “Gastric bypass surgery and the medical/lifestyle intervention program are not investigational – both are routinely available to patients at our institutions, and comparable programs exist at many other hospitals and health care facilities.”

Given rapid advances in recent years in delivering both of these alternative treatments, “this kind of information is very important to clinicians and patients to help inform decision making,” says Allison Goldfine, MD, head of clinical research at Joslin during the trial and senior author on a paper published this month in Diabetes Care.

The paper provided the latest results from the SLIMM-T2D (Surgery or Lifestyle with Intensive Medical Management in the Treatment of Type 2 Diabetes) study, which randomly allocated 38 obese patients with type 2 diabetes to treatment either by surgery at BWH or through an intensive lifestyle management program at Joslin. These participants had an average weight of 230 pounds and body mass index (BMI) of 36.3.

After three years, patients given surgery saw dramatically greater weight loss, averaging 55 pounds compared to 11 pounds for those in the lifestyle management intervention. The surgical cohort also lowered their hemoglobin A1c levels (a measure of blood sugar over several months) by an average of 1.79% compared to 0.39% for the lifestyle management cohort. Additionally, those given surgery showed significantly lower risk of coronary heart disease and stroke.

Although patients given the lifestyle intervention program made encouraging initial progress in both weight loss and diabetes control, those improvements dropped noticeably over time. “Patients who had the gastric bypass procedure had superior ability to sustain changes both in weight and blood sugar, and they did so requiring less medication for their diabetes, their blood pressure and their lipids,” says Goldfine.

The two groups of trial participants generally self-reported similar improvements in quality of life overall and less distress in living with diabetes—important positive outcomes. Those given surgery did see a significantly higher impact of weight loss on their quality of life, and greater improvement in the domains of physical functioning, self-esteem, and work performance.

“As a result of these findings, we expect that more physicians will consider gastric bypass surgery as a viable option for patients with type 2 diabetes and mild to moderate obesity when previous attempts to lose weight and improve glycemic control have not been successful,” said Simonson.

Goldfine emphasized, however, that treatment must be personalized for all patients who are struggling with obesity and diabetes, and that gastric bypass surgery is not always the best option.

The Roux-en-Y gastric bypass procedure is done laparoscopically, through small cuts in the abdomen. Surgeons make a small pouch at the top of the stomach and connect the pouch to the middle of small intestine.

Joslin’s 12-week intensive lifestyle management program included a change in diabetes medications to enhance weight reduction, structured dietary intervention with lower carbohydrates and higher protein and meal replacement, an exercise program with emphasis on strength training, and weekly educational and support sessions.

Both surgical procedures and intensive lifestyle management techniques now take advantage of major medical advances achieved in the past decade or two, Goldfine says.

“Older surgical procedures were much more invasive, with much higher surgical risk and complication rates, and older types of procedures had higher failure rates over time,” she says. “Laparoscopic rather than open surgery made the biggest impact on the surgical experience and recovery, but we have improved surgical techniques all the way from preoperative evaluations to better post-operative care.”

Medical options also have improved substantially, with the availability in recent years of new classes of diabetes drugs such as GLP-1 (glucagon-like peptide-1) receptor agonists and SGLT2 (sodium-glucose co-transporter-2) inhibitors. These drugs lower blood sugars, reduce weight and have lower rates of hypoglycemia, she points out.

Another arm of the SLIMM-T2D trial examines the use of an alternate approach to bariatric surgery, the adjustable band procedure, which inserts a band around the upper stomach whose tightness can be modified. (Earlier research has indicated that Roux-en-Y surgery produces greater weight loss and better diabetes control than adjustable-band surgery, but also changes hormones differently and presents a different set of complications.) In previously released SLIMM-T2D research, participants given gastric band surgery or intensive lifestyle management achieved similar lowering of blood sugar levels after one year. Participants given the band saw greater average weight loss (30 pounds compared to 19 pounds).

The research team at Joslin and BWH is now joining in a larger study known as ARMMS-T2D (Alliance of Randomized Trials of Medicine versus Metabolic Surgery in Type 2 Diabetes). ARMMS-T2D will follow about 240 patients from four smaller-scale randomized controlled trials (including SLIMM-T2D) that compared bariatric surgical procedures with lifestyle interventions. The Joslin/Brigham site for the ARMMS-T2D study is led by Joslin principal investigator Mary-Elizabeth Patti, MD.

Kathleen Foster of Joslin also contributed to the research, as did Florencia Halperin, MD, medical director of the Program for Weight Management at BWH/Faulkner, and Ashley Vernon, MD, a member of the BWH Center for Metabolic and Bariatric Surgery. Lead funding came from the National Institute for Diabetes and Digestive and Kidney Diseases. Covidien and Ethicon provided funds to pay for surgery for less-obese participants for whom the surgery was research and not established care. Novo Nordisk contributed medications and Nestle provided nutritional supplements.

Singapore - A joint 7-year cohort study of 2039 patients in both Singapore's restructured hospitals and New Zealand's hospitals, revealed answers to key questions about the epidemiology of heart failure. The study recently published in the European Heart Journal, set out how two distinct forms of heart failure previously considered similar in prevalence and risk of death, are in fact very different.

The heart failure patients were recruited from 6 major national specialty centres and hospitals in Singapore which include the National University Health System, the National Heart Centre Singapore and 4 centres in New Zealand which are Christchurch Heart Institute, University of Otago, Middlemore Hospital and Waikato Hospital.

Professor Rob Doughty, NZ Heart Foundation Chair of Heart Health at the University of Auckland's Faculty of Medical and Health Sciences, led New Zealand's participation in the seven-year collaborative study, explained that, "Heart failure is a common and serious condition affecting around 80,000 New Zealanders. In many people with heart failure the heart muscle is stretched and weakened and does not pump properly. However, in other cases of heart failure, the heart may have near normal pumping function but the muscle is stiff and often thicker than usual and the heart cannot fill properly between beats. These two types of heart failure were thought to be equal in occurrence and risk of death.

"However, our new findings reveal that the stiff heart muscle is less common than originally thought, affecting about three out of every 10 heart failure patients, and there is less risk of dying from this type compared with heart failure where the heart is not pumping properly," says Professor Doughty.

Two percent of New Zealand's population live with heart failure, and the study's findings provide greater accuracy about their risk of dying. In Singapore, 16 people die from cardiovascular disease (heart disease and stroke) every day. Cardiovascular disease accounted for 29.6% of all deaths in 2015. This means that nearly 1 out of 3 deaths in Singapore, is due to heart disease or stroke. (Source: University of Auckland; Singapore's Ministry of Health)

For over a decade, there has been uncertainty and controversy surrounding the clinical outcomes for patients with the two heart failure classes, which are heart failure with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF).

This new research showed that heart failure patients with preserved ejection fraction (HFpEF) are more likely to survive, have better outcomes, contrary to what the decade-old studies revealed.

Professor Mark Richards, Director of Singapore's Cardiovascular Research Institute of the National University Health System of Singapore, provided overall international leadership and coordination of the work between the two countries.

"Our findings are pivotal to the understanding of occurrence, death rates and risk prediction within different classes of heart failure,'' says Professor Richards who is also Christchurch Heart Institute Director and Heart Foundation Chair of Cardiovascular Studies in New Zealand.

Professor Richards won research funding and supervised execution of the study in Singapore. A total of 16 distinguished heart doctors and researchers have been involved, including Professor Carolyn Lam of the National Heart Centre in Singapore and Professor Richard Troughton of the Christchurch Heart Institute.

"We are particularly proud to have proven these findings, with identical procedures executed simultaneously in two countries, 5000 miles apart," Professor Richards says.

"In addition, we demonstrated that the world's most successful-ever cardiac biomarker, NT-proBNP, (discovered and validated in the Christchurch Heart Institute) is similarly prognostically powerful in both types of heart failure in both Singapore and New Zealand. Overall, this will exert major influence on clinical thinking and planning."

Can Rationing through Inconvenience Be Ethical? Nir Eyal, Paul L. Romain, and Christopher Robertson

"Rationing through inconvenience" refers to burdensome arrangements such as application forms, waiting periods, and other red tape that are intended to steer clinicians and patients to limit the use of health care resources. This strategy has been "roundly but uncritically condemned," the authors write. But they argue that under some conditions it may be ethical, and even preferable to direct rationing, such as drug formularies or copayments. Nir Eyal is an associate professor at the Harvard T. H. Chan School of Public Health; Paul L. Romain is a faculty member at Harvard Medical School; and Christopher Robertson is a professor at Harvard Law School.

Another Voice

James E. Sabin, who directs the ethics program at Harvard Pilgrim Health Care and is co-author of Setting Limits Fairly, a book about rationing policies, agrees that rationing through inconvenience can be justified, but he identifies a significant downside to the practice: that it reduces the capacity of health systems to learn from experience.

At Law: Tackling Obesity and Disease: The Culprit Is Sugar; the Response Is RegulationLawrence O. Gostin

Sugar is a deeply consequential pathway to obesity, and the single greatest dietary source is sugar-sweetened beverages. The copious amount of sugar in the American diet is no accident. Industry practices and regulatory failures have fueled this explosion. Yet there are sensible, effective interventions that would create the conditions for healthier behaviors. Gostin, of Georgetown University Law Center, writes that he is "kick-starting scholarly and policy conversation by systematically laying out the major legal tools." He thinks that tobacco control offers a powerful model, suggesting that success requires a suite of interventions working in concert: labeling, warnings, taxation, portion sizes, product formulation, marketing restrictions, and bans in high-risk settings such as schools and hospitals.

Policy and Politics: Raising the Stakes for Nondiscrimination Protections in the ACA
Kristen Underhill

In the struggle over the durability of the Affordable Care Act, defenders of the ACA stand guard at many fronts. A major contribution of the ACA to nondiscrimination law, however, appears increasingly vulnerable. The ACA established significant new nondiscrimination protections for patients. Several of these regulations--including protections on the basis of gender identity and pregnancy termination--are now under reconsideration at the Department of Health and Human Services. Nondiscrimination laws matter, of course, because they promote equal access to health care. But focusing on discriminatory behavior alone is a narrow view of the purpose and potential of nondiscrimination rules--and underestimates the stakes of softening them. Nondiscrimination laws may affect not only discriminatory behavior in health activities but also the attitudes, beliefs, and decisions of people who are legally protected.

Also in this issue:

"Community Engagement and Field Trials of Genetically Modified Insects and Animals"
Special Report: Governance of Emerging Technologies: Aligning Policy Analysis with the Public's Values

PHILADELPHIA -- Patients who sustain severe head injuries tend to have better outcomes if they are taken to a designated trauma center, but 44 percent of them are first taken to hospitals without these specialized care capabilities, according to new research from the Perelman School of Medicine at the University of Pennsylvania. In the largest study of its kind, researchers found that patients under 65 were significantly more likely to fare well -- going home from the hospital without the need for nursing care or inpatient rehabilitation -- if taken to a trauma center first, rather than a non-trauma center. Patients over 65 were significantly less likely to die from their head injury when they went first to a trauma center.

The results, published today in the Journal of the American College of Surgeons, highlight a serious care disparity for these severely injured patients, and point to the need for systematic changes to improve care.

"These findings highlight a big opportunity to improve outcomes for head injury patients," said the study's senior author, M. Kit Delgado, MD MS, an assistant professor of Emergency Medicine and Epidemiology. "Regional trauma centers were set up to serve patients like these, but clearly many of them are still ending up in hospitals that may not have protocols, resources, and experience to appropriately treat these severe injuries."

Head injuries are a factor in about 50,000 deaths in the United States every year, and the incidence of these injuries appears to be rising. Between 2000 and 2010, emergency room visits and hospitalizations for head injuries increased from 521 to 824 per 100,000 people annually. Head injuries are also a major cause of hospitalization for the elderly, and also account for the majority of severe injuries undertriaged to non-trauma centers. Prior research has demonstrated that patients under 55 have significantly improved outcomes if treated in trauma centers, but these studies did not determine if older adults or patients with isolated head injuries had the same benefits. Since time to treatment may be critical and many non-trauma centers have neurosurgeons on staff capable of treating isolated head injuries, bypassing these hospitals to travel to further away trauma centers could theoretically lead to unintended consequences.

Delgado and colleagues, including lead author Elinore J. Kaufman, MD, MSHP, a resident in General Surgery at New York-Presbyterian Weill Cornell Medicine, who was a Penn Master of Science in Health Policy Research (MSHP) degree candidate at the time of the study, examined databases on emergency room visits for six states (NJ, NC, AZ, NY, FL, UT) during 2011-12. They identified 62,198 patients with severe, isolated head injuries who had been taken either to a trauma center (56 percent) or to a non-trauma center capable of performing neurosurgery (44 percent).

The ideal comparison of trauma center vs. non-trauma center outcomes would be a clinical trial in which patients are randomly assigned to one type of hospital or another. But, the authors say that for many logistical and ethical reasons that isn't feasible. However, the researchers had enough data to partly simulate a clinical trial setup by matching trauma-center and non-trauma center patients according to their sociodemographics, geography, cause, type, and severity of injury, and other variables. They then used the patient's relative distance from their home to the closest trauma center and non-trauma center with neurosurgery as a variable that effectively randomized where patients were treated.

In the resulting matched set of 21,823 cases, patients taken to trauma centers fared significantly better than those taken to non-trauma centers. Patients under 65 years old saw no mortality benefit, but had a 6.9 percent higher rate of a favorable discharge. Patients 65-and-older had a 3.4 percent lower risk of mortality with equal rates of being favorably discharged.

"These estimates of the benefits of sending patients to a trauma center are probably conservative, since we didn't include patients sent to non-trauma centers without neurosurgical capabilities," Kaufman said, adding that the complementary results for the two age groups are consistent with an overall improvement in outcomes. "If some of the older patients survived at trauma centers when they wouldn't have survived at non-trauma centers, that would have reduced mortality for that group but left many of those survivors in need of ongoing care and rehabilitation."

"It's good to now have evidence that demonstrates the benefit of traveling farther to a trauma center for these patients," Delgado said. "Hopefully, this will motivate EMS and trauma systems to double their efforts to triage patients with severe head injuries directly to trauma centers. There is major opportunity to improve outcomes as nearly half of these patients are being taken to non-trauma centers where their outcomes are worse."

The researchers suggest increasing compliance with current ambulance triage guidelines and future research to inform whether these guidelines should be revised to be more sensitive for picking up severe head injuries that may be less obvious at the time of presentation. Improvements in care at non-trauma centers would also reduce the differences in outcomes, Delgado said.

Only about 2 percent of the physicians and other health care providers in New York State are equipped to provide timely and quality care to veterans in the community, according to a new RAND Corporation study.

Scoring the civilian medical workforce across seven measures of readiness to treat veterans, the study found that most providers fell short on items such as being familiar with the military culture or routinely screening for conditions common among veterans.

The study is the first to gather information about the readiness of community-based providers across a wide array of professional types to address the health needs facing veterans. The issue is important because federal officials are considering whether to encourage more veterans to use their benefits to receive care in the community rather than from the Veterans Affairs health system.

"These findings reveal significant gaps and variations in the readiness of community-based health care providers to provide high-quality care to veterans," said Terri Tanielian, the study's lead author and a senior behavioral scientist at RAND, a nonprofit research organization. "It appears that more work needs to be done to prepare the civilian health care workforce to care for the unique needs of veterans."

New York State is home to more than 800,000 veterans, half of whom are younger than 65 years of age. The VA spends about $6.3 billion annually on benefits and services for veterans in the state, with nearly one-half spent on medical services.

The New York State Health Foundation asked RAND to assess the readiness and capacity of the state's civilian health workforce to deliver high-quality care to veterans.

"We know from earlier RAND research that about half of New York's veterans prefer to get care in their own communities, rather than at the VA," said David Sandman, president and CEO of the New York State Health Foundation. "Given this demand for community-based care, we wanted to better understand whether providers are prepared to meet veterans' needs. This report offers both a snapshot of where we are today and a roadmap for improvement."

The study is based on a survey of 746 health care providers from across the state, who were asked about their practice habits and familiarity with the VA health system. Those questioned included physicians, nurse practitioners, psychologists and other types of licensed health professionals.

Health providers were asked about seven measures of readiness: whether they were accepting new patients, whether they were prepared to treat conditions common among veterans, whether they used clinical practice guidelines in providing care, whether they screen for conditions common among veterans, whether they accommodate patients with disabilities, whether they were familiar with military culture, and whether they screen patients for military and veteran affiliation.

Researchers developed the measures of preparedness by consulting the medical literature about issues important for offering high-quality and timely care to veterans.

While more than 90 percent of the health providers said they could accommodate new patients, the proportion of providers prepared to care for veterans falls sharply as researchers applied the other measures across the health workforce.

Apart from whether providers are ready to provide high-quality care for veterans, researchers found that it may be difficult for veterans in New York to find health providers prepared to accept VA coverage.

Fewer than 5 percent of the health care providers surveyed reported being part of VA Community Care, the network of providers who accept VA benefits. Mental health providers were the least likely to be enrolled in the program.

Researchers suggest that training programs are needed to increase health providers' military cultural competence and knowledge of the VA. In addition, efforts are needed to encourage providers to appropriately screen veteran patients for common service-connected conditions.