News & Analysis Medical News & Perspectives .....p2477
Global Health ................................p2481
News From the CDC .....................p2482
Nobel Prize Winners’ Research Relates to Brain Function and Neurodegenerative Diseases
Sierra Leone Patient Data Provide Insight for Curbing Ebola Outbreak
Alcohol Combined With Drug Abuse Leads to More Overdoses and Deaths
The JAMA Forum .........................p2479
Diagnosing and Treating Infections in Young Infants in Developing Countries
Hispanic/Latino Individuals Lack Sufficient HIV Treatment
The Challenges of Reforming Graduate Medical Education Payments
Higher Global Burden of TB Latrines Alone Do Not Improve Health of Children in Rural India
Medical News & Perspectives
Nobel Prize Winners’ Research Relates to Brain Function and Neurodegenerative Diseases Tracy Hampton, PhD
©The Nobel Committee for Physiology or Medicine
W
ork by this year’s Nobel Prize in Physiology or Medicine awardees, a British-American scientist and 2 Norwegian researchers, has had a significant effect on our understanding of human cognition and will likely lead to insights related to processes involved in the development of neurological diseases. The award was given to John O’Keefe, PhD, May-Britt Moser, PhD, and Edvard Moser, PhD, for their discoveries of cells that constitute a positioning system, or “inner GPS” (Global Positioning System), in the brain. “This is major,” said Creighton Phelps, PhD, who is the deputy director of the division of neuroscience at the National Institute on Aging. “The research uncovered a fundamental process in the brain that needs to be studied in depth to see how this inbuilt system is modified by complex signals from multiple sensory inputs and to see if problems there are causing changes to normal function.” The cells O’Keefe discovered are called place cells, while those found by the Mosers are called grid cells. “Overall, their Nobel prize–winning research has suggested how place cells and grid cells make it possible to determine position and to navigate,” said Kazu Nakazawa, MD, PhD, an associate professor in the department of psychiatry and behavioral neurobiology at the University of Alabama at Birmingham. “A simple explanation would be that
Specialized cells in the hippocampus and entorhinal cortex form neural networks that constitute the brain’s spatial navigation system, or inner ‘GPS.’ These discoveries by this year’s awardees of the Nobel Prize in Physiology or Medicine may lead to a better understanding of the spatial losses that occur with certain neurological conditions.
the place cells are used to remember certain locations in an environment, whereas the grid cells help us navigate between those locations.”
Putting Place Cells on the Map While conducting research at University College London in the 1970s, O’Keefe, who was born in 1939 in New York City and holds both US and British citizenships, recorded signals from individual nerve cells in the brains of rats to discover that certain cells in the hippocampus were always activated when a rat was at a certain place in a room, while other nerve cells were activated when the animal was at other places (O’Keefe. Exp Neurol.
jama.com
1976;51[1]:78-109). Such cells were active in a way that had not been seen for any cells in the brain before. O’Keefe concluded that the hippoc a m p u s g e n e ra t e s n u m e r o u s m a p s through the collective activity of such place cells that are activated in different environments. In this way, the memory of an environment can be stored as a specific combination of place cell activities in the hippocampus. The complexity of the system is quite impressive, with the hippocampus containing multiple maps represented by combinations of activity in different place cells that are activated at different times in different environments. JAMA December 17, 2014 Volume 312, Number 23
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of Memphis User on 05/17/2015
2477
News & Analysis
“I’d say that at the beginning, most people were quite skeptical of the idea that you could go deep inside the brain and find things which corresponded to aspects of the environment,” O’Keefe told the Nobel Prize staff. “But now the field has blossomed, and I think the prize actually is as much for the field as it is for myself and the Mosers. We’re just representatives of a large number of people who are working away at the hippocampus and memory and spatial navigation.” Experts note that before the discovery of hippocampal place cells, there were 2 popular theories for hippocampal function. One was a “cognitive map” theory, which proposed that the hippocampus stores a cognitive map of the environment for navigation. The second theory proposed that the hippocampus is involved in the formation of memories of daily events. “The discovery of place cells, which show location-specific firings in an environment, strongly supported the cognitive map theory and in particular has emphasized the navigational role of hippocampus; however, in subsequent experiments, Dr O’Keefe and others showed that place cells may have mnemonic functions as well,” said Nakazawa. For example, when an environment is changed, a different set of place cells is fired, a process referred to as remapping. O’Keefe discovered that once the remapping is established, it can be stable over time, like long-term memory. Because the spatial location of an event that an individual experiences is an important feature of most memories, the hippocampus may have evolved a specialized system to be able to represent and process the spatial aspects of memories, according to Bettina Osborn, PhD, who is chief of the Substrates of Memory and Learning Program at the National Institute of Mental Health. Studies of place cells have also shown that spatial information is stored not in a s i ng l e n e u r o n’s a c t i v i ty, b u t i n t h e ensemble pattern of a number of specialized neurons’ firing. Furthermore, groups of place cells that are activated in a particular sequence in a certain environment or situation display the same sequence of activation later, during sleep. This may be a way to consolidate and store a particular memory (Wilson MA, McNaughton BL. Science. 1994;265[5172]:676-679). 2478
Navigating With Grid Cells In 2005, more than 3 decades after O’Keefe’s discovery of place cells, the wife and husband team of May-Britt and Edvard Moser identified neurons in the entorhinal cortex, a region of the brain mediating communication between the hippocampus and neocortex, that were activated when a rat passed multiple locations arranged in a grid (Hafting T et al. Nature. 2005; 436[7052]:801-806). “We found that each cell fired in many places, and those places formed a hexagonal pattern—a pattern that is perfect for expressing distance and direction in the local environment and perfect for a positioning system,” said Edvard Moser. Therefore, these “grid cells” might function as a type of hexagonal graph paper that the brain uses to represent location. Together, place and grid cells allow animals to determine their position and to navigate through their surroundings much like an inner GPS. The Mosers, who were both born in the early 1960s in Norway and were visiting scientists in O’Keefe’s laboratory in London in the 1990s, made their discoveries while at the Norwegian University of Science and Technology in Trondheim, Norway. “Our research is basic research, and the aim is to determine how the normally functioning brain works. We are convinced that such knowledge will lead to many applications, although, as with all basic research, it is not clear in advance what the applications will be and how far ahead they will be,” said Edvard Moser. More recent research has shown that place and grid cells exist in humans, in addition to other spatial cells such as border or boundary cells and head direction cells, each with characteristic firing patterns that encode spatial parameters relating to an individual’s current position and orientation. Border cells are active in reference to walls that an animal encounters when moving in a closed environment, while head direction cells act like a compass and are active when the head of an animal points in a certain direction (Solstad T et al. Science. 2008;322[5909]: 1865-1868; Muller RU et al. Curr Opin Neurobiol. 1996;6[2]:196-206).
Insights for Health and Disease A better sense of the brain’s positioning system may lead to new insights into
human memory and planning. “I think the research greatly advances our fundamental knowledge and understanding of how spatial information is coded and memorized in the brain,” said Gabriele Janzen, PhD, an associate professor at the Radboud University Nijmegen, in the Netherlands. An improved mechanistic understanding of spatial processing has clear clinical implications as visuospatial performance is a measure used to assess cognitive decline in humans (Vemuri P et al. JAMA Neurol. 2014;71[8]:1017-1024) and visuospatial deficits have been reported as one of the earliest signs of preclinical dementia (Johnson et al. Arch Neurol. 2009;66[1]:1254-1259). “The knowledge relates very well to deficits in Alzheimer patients where hippocampal atrophy and connected spatial navigation and orientation problems occur early in the process of the disease,” Janzen said. Also, Phelps notes that the neurofibrillary tangles that are a hallmark of Alzheimer disease are first seen in the entorhinal cortex. “I find it hard to imagine that it’s not connected somehow,” he said. Osborn anticipates that the research could apply to other conditions as well. “Understanding these spatially and temporally precise computations about relative location in space, and about memory encoding of what happened where, might eventually allow new types of treatments that could improve cognition, which has been among the least tractable of symptoms in brain diseases from autism to Alzheimer’s disease to schizophrenia,” she said. Osborn also suspects that similar types of computations may be relevant for other advanced cognitive functions such as reasoning or number processing. “Along with spatial navigation and memory formation, these functions can impact a person’s ability to maintain employment, live independently, and manage a bank account,” she said. Although several decades of research have revealed considerable insights on the brain processes involved in navigation, there are numerous unknowns. “With knowledge of the various classes of spatial cells, our effort to fully understand the mechanisms for spatial representation and spatial cognition has just begun,” said Nakazawa. “There are so many unanswered questions left: for
JAMA December 17, 2014 Volume 312, Number 23
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of Memphis User on 05/17/2015
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News & Analysis
example, where does the sensory information encoding location in place cells, spatial geometry in grid cells, or head direction in head direction cells come from, and how is it combined?” Researchers are actively investigating how grid cell activity influences place cell activity and vice versa and how these interactions may go wrong in Alzheimer disease and
other brain conditions. In a mouse model of Alzheimer disease, O’Keefe and his colleagues have shown that place cell degradation correlates with deterioration of animals’ spatial memory (Cacucci F et al. Proc Natl Acad Sci U S A. 2008;105[22]:78637868). Edvard Moser is excited to be an active part of the effort to find clinical
applications for the field. “We wish to u n d e r st a n d h ow g r i d c e l l s i n t e ra c t with other cell types to produce a sense of location. This will lead to knowledge that can hopefully be used by others to work out strategies to detect dysfunctions in the positioning system early on and to prevent further progression of disease.”
The JAMA Forum
The Challenges of Reforming Graduate Medical Education Payments Gail Wilensky, PhD
A
recent report by an Institute of Medicine (IOM) committee on the f inancing and governance of graduate medical education (GME) considered an important question for health care in the United States: to what extent does the current GME system, which provides the training of interns and residents after medical school, help produce a physician workforce that can deliver efficient, highquality, patient-centered health care? As the report points out, Medicare has been the most important federal funder of GME programs, and the financial support it contributes (nearly $10 billion in fiscal year 2012) has played a significant role in the helping US teaching hospitals function. But as our committee and other groups have pointed out over the years, the GME system has shortcomings that need to be addressed.
American Medical Association
Key Findings Some of the key findings of the IOM committee, which I cochaired with the immediate former administrator of the Centers for Medicare & Medicaid Services (CMS), Donald Berwick, MD, are that Medicare GME payments are inflexible in their current construction, with minimal funding available for new programs or nonhospital sites; are unfair because of the tie to historical costs; and are opaque with regard to the flow and use of funds and the outcomes produced. The committee struggled over whether to support continued government funding for GME. The US government spends $15 billion (two-thirds coming from Medicare) on
GME, which is received primarily by teaching hospitals. Because of the magnitude of its financial commitment and the focus on teaching hospitals, the federal government’s role in funding GME is substantially different from its role in funding undergraduate medical education, training for other health care professionals, or supporting other professions that potentially face workforce shortages. The committee ultimately decided in favor of supporting continued Medicare funding of GME for the next decade (assuming the types of reforms that it recommended are adopted), after which the question of continued funding should be reassessed. We reasoned that given the considerable changes that the US health care delivery system is experiencing, continued GME funding could serve as potential leverage for training a physician workforce better suited to meet the needs of a reformed delivery system.
5 Recommendations The committee made 5 recommendations: 1. Continue Medicare funding of GME education (adjusted for inflation), but phase out the current payment system and gradually replace it with a performancebased system. 2. Create an adequately financed GME policy infrastructure, including establishing a GME Policy Council in the Office of the Secretary of the US Department of Health and Human Services and a GME center within CMS. 3. Develop a single Medicare GME fund with 2 subsidiary funds. An operational fund
jama.com
Gail Wilensky, PhD
would distribute support for training positions that are currently approved and funded. A transformation fund would be used to pilot alternative payment mechanisms for GME, establish and evaluate relevant performance measures for GME, and finance initiatives to develop and evaluate innovative GME programs. 4. Change the Medicare GME payment system to one that offers a single payment to the organization sponsoring GME (based on a per-resident amount) and features performance-based payments. 5. Continue to give states the discretion to use Medicaid funding for GME, but mandate accountability and transparency requirements comparable with those proposed for Medicare GME. The committee was mindful of the challenging politics surrounding changes to a program like GME, where substantial JAMA December 17, 2014 Volume 312, Number 23
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of Memphis User on 05/17/2015
2479
Global Health ................................p2481
News From the CDC .....................p2482
Nobel Prize Winners’ Research Relates to Brain Function and Neurodegenerative Diseases
Sierra Leone Patient Data Provide Insight for Curbing Ebola Outbreak
Alcohol Combined With Drug Abuse Leads to More Overdoses and Deaths
The JAMA Forum .........................p2479
Diagnosing and Treating Infections in Young Infants in Developing Countries
Hispanic/Latino Individuals Lack Sufficient HIV Treatment
The Challenges of Reforming Graduate Medical Education Payments
Higher Global Burden of TB Latrines Alone Do Not Improve Health of Children in Rural India
Medical News & Perspectives
Nobel Prize Winners’ Research Relates to Brain Function and Neurodegenerative Diseases Tracy Hampton, PhD
©The Nobel Committee for Physiology or Medicine
W
ork by this year’s Nobel Prize in Physiology or Medicine awardees, a British-American scientist and 2 Norwegian researchers, has had a significant effect on our understanding of human cognition and will likely lead to insights related to processes involved in the development of neurological diseases. The award was given to John O’Keefe, PhD, May-Britt Moser, PhD, and Edvard Moser, PhD, for their discoveries of cells that constitute a positioning system, or “inner GPS” (Global Positioning System), in the brain. “This is major,” said Creighton Phelps, PhD, who is the deputy director of the division of neuroscience at the National Institute on Aging. “The research uncovered a fundamental process in the brain that needs to be studied in depth to see how this inbuilt system is modified by complex signals from multiple sensory inputs and to see if problems there are causing changes to normal function.” The cells O’Keefe discovered are called place cells, while those found by the Mosers are called grid cells. “Overall, their Nobel prize–winning research has suggested how place cells and grid cells make it possible to determine position and to navigate,” said Kazu Nakazawa, MD, PhD, an associate professor in the department of psychiatry and behavioral neurobiology at the University of Alabama at Birmingham. “A simple explanation would be that
Specialized cells in the hippocampus and entorhinal cortex form neural networks that constitute the brain’s spatial navigation system, or inner ‘GPS.’ These discoveries by this year’s awardees of the Nobel Prize in Physiology or Medicine may lead to a better understanding of the spatial losses that occur with certain neurological conditions.
the place cells are used to remember certain locations in an environment, whereas the grid cells help us navigate between those locations.”
Putting Place Cells on the Map While conducting research at University College London in the 1970s, O’Keefe, who was born in 1939 in New York City and holds both US and British citizenships, recorded signals from individual nerve cells in the brains of rats to discover that certain cells in the hippocampus were always activated when a rat was at a certain place in a room, while other nerve cells were activated when the animal was at other places (O’Keefe. Exp Neurol.
jama.com
1976;51[1]:78-109). Such cells were active in a way that had not been seen for any cells in the brain before. O’Keefe concluded that the hippoc a m p u s g e n e ra t e s n u m e r o u s m a p s through the collective activity of such place cells that are activated in different environments. In this way, the memory of an environment can be stored as a specific combination of place cell activities in the hippocampus. The complexity of the system is quite impressive, with the hippocampus containing multiple maps represented by combinations of activity in different place cells that are activated at different times in different environments. JAMA December 17, 2014 Volume 312, Number 23
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of Memphis User on 05/17/2015
2477
News & Analysis
“I’d say that at the beginning, most people were quite skeptical of the idea that you could go deep inside the brain and find things which corresponded to aspects of the environment,” O’Keefe told the Nobel Prize staff. “But now the field has blossomed, and I think the prize actually is as much for the field as it is for myself and the Mosers. We’re just representatives of a large number of people who are working away at the hippocampus and memory and spatial navigation.” Experts note that before the discovery of hippocampal place cells, there were 2 popular theories for hippocampal function. One was a “cognitive map” theory, which proposed that the hippocampus stores a cognitive map of the environment for navigation. The second theory proposed that the hippocampus is involved in the formation of memories of daily events. “The discovery of place cells, which show location-specific firings in an environment, strongly supported the cognitive map theory and in particular has emphasized the navigational role of hippocampus; however, in subsequent experiments, Dr O’Keefe and others showed that place cells may have mnemonic functions as well,” said Nakazawa. For example, when an environment is changed, a different set of place cells is fired, a process referred to as remapping. O’Keefe discovered that once the remapping is established, it can be stable over time, like long-term memory. Because the spatial location of an event that an individual experiences is an important feature of most memories, the hippocampus may have evolved a specialized system to be able to represent and process the spatial aspects of memories, according to Bettina Osborn, PhD, who is chief of the Substrates of Memory and Learning Program at the National Institute of Mental Health. Studies of place cells have also shown that spatial information is stored not in a s i ng l e n e u r o n’s a c t i v i ty, b u t i n t h e ensemble pattern of a number of specialized neurons’ firing. Furthermore, groups of place cells that are activated in a particular sequence in a certain environment or situation display the same sequence of activation later, during sleep. This may be a way to consolidate and store a particular memory (Wilson MA, McNaughton BL. Science. 1994;265[5172]:676-679). 2478
Navigating With Grid Cells In 2005, more than 3 decades after O’Keefe’s discovery of place cells, the wife and husband team of May-Britt and Edvard Moser identified neurons in the entorhinal cortex, a region of the brain mediating communication between the hippocampus and neocortex, that were activated when a rat passed multiple locations arranged in a grid (Hafting T et al. Nature. 2005; 436[7052]:801-806). “We found that each cell fired in many places, and those places formed a hexagonal pattern—a pattern that is perfect for expressing distance and direction in the local environment and perfect for a positioning system,” said Edvard Moser. Therefore, these “grid cells” might function as a type of hexagonal graph paper that the brain uses to represent location. Together, place and grid cells allow animals to determine their position and to navigate through their surroundings much like an inner GPS. The Mosers, who were both born in the early 1960s in Norway and were visiting scientists in O’Keefe’s laboratory in London in the 1990s, made their discoveries while at the Norwegian University of Science and Technology in Trondheim, Norway. “Our research is basic research, and the aim is to determine how the normally functioning brain works. We are convinced that such knowledge will lead to many applications, although, as with all basic research, it is not clear in advance what the applications will be and how far ahead they will be,” said Edvard Moser. More recent research has shown that place and grid cells exist in humans, in addition to other spatial cells such as border or boundary cells and head direction cells, each with characteristic firing patterns that encode spatial parameters relating to an individual’s current position and orientation. Border cells are active in reference to walls that an animal encounters when moving in a closed environment, while head direction cells act like a compass and are active when the head of an animal points in a certain direction (Solstad T et al. Science. 2008;322[5909]: 1865-1868; Muller RU et al. Curr Opin Neurobiol. 1996;6[2]:196-206).
Insights for Health and Disease A better sense of the brain’s positioning system may lead to new insights into
human memory and planning. “I think the research greatly advances our fundamental knowledge and understanding of how spatial information is coded and memorized in the brain,” said Gabriele Janzen, PhD, an associate professor at the Radboud University Nijmegen, in the Netherlands. An improved mechanistic understanding of spatial processing has clear clinical implications as visuospatial performance is a measure used to assess cognitive decline in humans (Vemuri P et al. JAMA Neurol. 2014;71[8]:1017-1024) and visuospatial deficits have been reported as one of the earliest signs of preclinical dementia (Johnson et al. Arch Neurol. 2009;66[1]:1254-1259). “The knowledge relates very well to deficits in Alzheimer patients where hippocampal atrophy and connected spatial navigation and orientation problems occur early in the process of the disease,” Janzen said. Also, Phelps notes that the neurofibrillary tangles that are a hallmark of Alzheimer disease are first seen in the entorhinal cortex. “I find it hard to imagine that it’s not connected somehow,” he said. Osborn anticipates that the research could apply to other conditions as well. “Understanding these spatially and temporally precise computations about relative location in space, and about memory encoding of what happened where, might eventually allow new types of treatments that could improve cognition, which has been among the least tractable of symptoms in brain diseases from autism to Alzheimer’s disease to schizophrenia,” she said. Osborn also suspects that similar types of computations may be relevant for other advanced cognitive functions such as reasoning or number processing. “Along with spatial navigation and memory formation, these functions can impact a person’s ability to maintain employment, live independently, and manage a bank account,” she said. Although several decades of research have revealed considerable insights on the brain processes involved in navigation, there are numerous unknowns. “With knowledge of the various classes of spatial cells, our effort to fully understand the mechanisms for spatial representation and spatial cognition has just begun,” said Nakazawa. “There are so many unanswered questions left: for
JAMA December 17, 2014 Volume 312, Number 23
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of Memphis User on 05/17/2015
jama.com
News & Analysis
example, where does the sensory information encoding location in place cells, spatial geometry in grid cells, or head direction in head direction cells come from, and how is it combined?” Researchers are actively investigating how grid cell activity influences place cell activity and vice versa and how these interactions may go wrong in Alzheimer disease and
other brain conditions. In a mouse model of Alzheimer disease, O’Keefe and his colleagues have shown that place cell degradation correlates with deterioration of animals’ spatial memory (Cacucci F et al. Proc Natl Acad Sci U S A. 2008;105[22]:78637868). Edvard Moser is excited to be an active part of the effort to find clinical
applications for the field. “We wish to u n d e r st a n d h ow g r i d c e l l s i n t e ra c t with other cell types to produce a sense of location. This will lead to knowledge that can hopefully be used by others to work out strategies to detect dysfunctions in the positioning system early on and to prevent further progression of disease.”
The JAMA Forum
The Challenges of Reforming Graduate Medical Education Payments Gail Wilensky, PhD
A
recent report by an Institute of Medicine (IOM) committee on the f inancing and governance of graduate medical education (GME) considered an important question for health care in the United States: to what extent does the current GME system, which provides the training of interns and residents after medical school, help produce a physician workforce that can deliver efficient, highquality, patient-centered health care? As the report points out, Medicare has been the most important federal funder of GME programs, and the financial support it contributes (nearly $10 billion in fiscal year 2012) has played a significant role in the helping US teaching hospitals function. But as our committee and other groups have pointed out over the years, the GME system has shortcomings that need to be addressed.
American Medical Association
Key Findings Some of the key findings of the IOM committee, which I cochaired with the immediate former administrator of the Centers for Medicare & Medicaid Services (CMS), Donald Berwick, MD, are that Medicare GME payments are inflexible in their current construction, with minimal funding available for new programs or nonhospital sites; are unfair because of the tie to historical costs; and are opaque with regard to the flow and use of funds and the outcomes produced. The committee struggled over whether to support continued government funding for GME. The US government spends $15 billion (two-thirds coming from Medicare) on
GME, which is received primarily by teaching hospitals. Because of the magnitude of its financial commitment and the focus on teaching hospitals, the federal government’s role in funding GME is substantially different from its role in funding undergraduate medical education, training for other health care professionals, or supporting other professions that potentially face workforce shortages. The committee ultimately decided in favor of supporting continued Medicare funding of GME for the next decade (assuming the types of reforms that it recommended are adopted), after which the question of continued funding should be reassessed. We reasoned that given the considerable changes that the US health care delivery system is experiencing, continued GME funding could serve as potential leverage for training a physician workforce better suited to meet the needs of a reformed delivery system.
5 Recommendations The committee made 5 recommendations: 1. Continue Medicare funding of GME education (adjusted for inflation), but phase out the current payment system and gradually replace it with a performancebased system. 2. Create an adequately financed GME policy infrastructure, including establishing a GME Policy Council in the Office of the Secretary of the US Department of Health and Human Services and a GME center within CMS. 3. Develop a single Medicare GME fund with 2 subsidiary funds. An operational fund
jama.com
Gail Wilensky, PhD
would distribute support for training positions that are currently approved and funded. A transformation fund would be used to pilot alternative payment mechanisms for GME, establish and evaluate relevant performance measures for GME, and finance initiatives to develop and evaluate innovative GME programs. 4. Change the Medicare GME payment system to one that offers a single payment to the organization sponsoring GME (based on a per-resident amount) and features performance-based payments. 5. Continue to give states the discretion to use Medicaid funding for GME, but mandate accountability and transparency requirements comparable with those proposed for Medicare GME. The committee was mindful of the challenging politics surrounding changes to a program like GME, where substantial JAMA December 17, 2014 Volume 312, Number 23
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of Memphis User on 05/17/2015
2479
