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Kobeissy FH, editor. Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects. Boca Raton (FL): CRC Press/Taylor & Francis; 2015.

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Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects.

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Chapter 47The Problem of Neurodegeneration in Cumulative Sports Concussions

Emphasis on Neurofibrillary Tangle Formation

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Traumatic brain injury (TBI) has been a common cause of morbidity and mortality throughout history, but has had interesting twists in the industrial era and in the world of aggressive sports or modern warfare. The American public is especially troubled by the problem of hundreds of thousands of injured veterans returning from the lengthy post-9/11 campaigns and is also fearful that repeat concussions experienced in contact sports played by millions of young athletes may result in progressive neurodegenerative disease and dementia. The problem of traumatic degeneration, termed chronic traumatic encephalopathy (CTE), has been long recognized in the world of boxing, but has recently come to the forefront because of several highly publicized deaths of popular NFL protagonists. Despite extensive publicity, the real risk of CTE among amateur and professional players has not been measured or adequately characterized and notions derived from autopsy studies, although useful for understanding mechanisms, cannot give an accurate picture of the range of outcomes after repeat concussions and are limited because of ascertainment bias. It is imperative that prospective studies are designed and deployed to the problem, but such approaches will take a long time to bear fruits in view of the long incubation time of key pathologies. Meanwhile, emphasis on molecular and cellular mechanisms of deposition of a key protein, the microtubule-associated protein tau, as well as the construction of relevant animal models, may help define cause-and-effect relationships, shed light into mechanisms, and generate ideas about biomarkers and therapeutic targets. Imports from extensive work in other degenerative tauopathies such as frontotemporal degeneration may greatly facilitate innovation in this area.

47.1.1. Clinico-Pathological Considerations The Pathological Signature of CTE: Differentiation from Other Common Types of Traumatic Brain Injury

There are between 2 and 3 million new cases of TBI in the United States every year, most of them from motor vehicle accidents (MVA) and falls. The majority of cases of TBI are concussions that cause brief or no changes in mental status and a constellation of symptoms that usually improve over a few weeks or months. However, a substantial number of TBI events are associated with chronic disability because of permanent damage to the brain or, in some cases, progressive disease. Classical forms of severe TBI include focal contusions often caused by falls (Courville, 1942) and diffuse axonal lesions (diffuse axonal injury, DAI) usually associated with dynamic stretching of axons with rotational acceleration as it occurs in motor vehicle crashes (Adams et al., 1982; Strich, 1961). The association of chronic progressive TBI with boxing (dementia pugilistica) has also been well recognized since the 1930s (Corsellis et al., 1973; Martland, 1928; Millspaugh, 1937). The U.S. military has had a major exposure to TBI risk in the post-9/11 deployments, although exact numbers are difficult to establish and figures vary among estimates (Congressional Research Service,; Defense and Veterans Brain Injury Center, Much of this exposure relates to explosion (blast) from mines or improvised explosive devices in the Iraq and Afghanistan war theaters (Warden, 2006). A 100-year-old problem recognized since World War I (Mott, 1916), blast injury to brain has become the signature health problem of recent wars (Warden, 2006).

A recent trend that has attracted much attention is an increasing number of cases of progressive tauopathy in professional and amateur athletes with careers in collision sports, especially football. These cases have been linked to repeat concussions and are identical to cases of dementia pugilistica, with which they are classified under the rubric of CTEs (McKee et al., 2009; Omalu et al., 2005, 2006). The recent discovery of CTE lesions in younger subjects with histories of subconcussive TBI (Schwarz, 2010) suggests a broader risk in all scenarios where repeat mild TBI takes place, including the military. Repeat mild blast TBI is also very common in the Iraq and Afghanistan war theaters and the Defense and Veterans Brain Injury Center has recently developed return-to-duty guidelines to prevent additional TBI in soldiers with concussive histories. The public concern over repeat concussions is growing not only because of the risk among National Football League (NFL) professionals and active-duty soldiers or veterans, but also because of the exposure of millions of nonprofessional athletes playing contact and collision sports such as football, mixed martial arts, hockey, and rugby. It has been argued that high school or college football is even more aggressive than professional NFL play (Broglio et al., 2009).

Neuropathologies associated with various types of TBI present important differences, but also overlap with each other. For example, MVA- and fall-associated TBI present primarily as static encephalopathies due to diffuse axonal or focal parenchymal lesions, although there is some evidence of limited progression, especially with MVA-associated TBI (Buki and Povlishock, 2006). With contusions, more so than with DAI, there are some generally accepted correlations between neuropathology and neuropsychiatric morbidity, although patterns are far from linear (Lishman et al., 1968).

Axonal injury is a common denominator in many types of TBI including, besides DAI, focal contusions (Mac Donald et al., 2007), blast injuries, and the early stages of CTE (Dr. Juan Troncoso, personal communication) (Figure 47.1). Importantly, the prevalence of DAI is increasingly recognized across various types of TBI, including mild injuries (Mittl et al., 1994).

FIGURE 47.1. A sketch of fiber pathways affected in blast injury (gray) that recapitulate pathways at risk in many forms of DAI.


A sketch of fiber pathways affected in blast injury (gray) that recapitulate pathways at risk in many forms of DAI. Pathways include corticospinal, callosal, visual, somatosensory, and cerebellar circuits. (From Koliatsos et al., J. Neuropathol. Exp. (more...)

In contrast to focal contusions or DAI that are generally viewed as static encephalopathies and the generally benign course of single concussions, CTE is a progressive tauopathy that more closely resembles other neurodegenerative tauopathies such as frontotemporal degeneration (FTD) and Alzheimer disease (AD) or progressive supranuclear palsy (PSP) (McKee et al., 2009). This is perhaps the most characteristic signature of CTE and is the source of some confusion and controversy, but also creates great opportunities for research into mechanisms. The Clinical Signature of CTE: The Predominance of Neuropsychiatric Symptoms

Although it is still too early to have a full picture of the clinical signature of CTE, existing reports from cases that have come to autopsy (McKee et al., 2009, 2012) and a few recent highly publicized cases have emphasized the early presence of psychiatric symptoms. Clinical presentation in CTE is an important matter because, in the absence of biological markers, it may help settle issues of diagnosis and prognosis and facilitate early interventions. Common symptoms attributed to CTE are mood changes (mainly depression), irritability with aggressive/violent outbursts, paranoia, poor insight/judgment, apathy, memory loss and other cognitive deficits, parkinsonism, dysarthria and other speech abnormalities, and gait ataxia. Remarkably, causes of death include suicide and the often-violent result of poor judgment, such as an accidental gunshot while cleaning a gun (J. Grimsley) or falling from the back of a moving truck on which the patient jumped in the course of chasing his fiancé (C. Henry).

The prevalence, in the young adult population, of psychiatric symptoms, especially those related to mood and even personality disorders, is relatively high. If we accept, based on existing clinical information, that a long period in the early stage of the CTE lifecycle is featured almost exclusively by mood and behavioral symptoms. A key question is whether the clinical presentation is merely the corresponding common idiopathic psychiatric illness or the relatively uncommon organic psychiatric illness that will prove, in the end, to be the harbinger of CTE. For example, if a young NFL player or a young/middle-aged NFL veteran presents with depression, how do we know that the problem is a sign of CTE versus common major depression that prevails in a community sample?

In general, clinical neuropsychiatric presentations on the left column of Table 47.1 are consistent with idiopathic psychiatric (i.e., mental) illness, whereas presentations and symptoms on the right column are more typical of neurological illness. Based on the high prevalence of non-manic impulsivity, aggressiveness, and cognitive deficits in several studied or publicized cases of CTE, it appears that many patients have “organic” features that are common with neuropsychiatric illnesses arising from frontal lobe lesions and neurodegenerative dementias (especially some variants of FTD).

TABLE 47.1

TABLE 47.1

Psychiatric Presentations Differentiating Idiopathic (Mental) from Organic (Neurological) Illness CTE as a Distinct Illness: Some Challenges

One of the features that distinguish CTE from other forms of TBI is its very nature as a neurodegenerative disease. A challenging attribute in this regard is the delay between the occurrence of injury and the onset of symptoms. It has been noted that the less-than-decade incubation time of football-related CTE is shorter than that of dementia pugilistica, which is much as 15 years (McKee et al., 2009). The incubation time in the younger athletes may be a separate matter: for example, the brain of the 21-year-old University of Pennsylvania defensive lineman Owen Thomas showed some evidence of tau aggregation (Schwarz, 2010), although the diagnosis of CTE was far from certain in this young man. Whatever the scenario, there are several years intervening between the suspected cause and the degenerative outcome in all these cases.

The delay between concussive or even subconcussive hits and the appearance of symptoms raises classical cause-and-effect questions. Mood changes overlap with extremely common idiopathic psychiatric disorders such as major depression. Cognitive/personality symptoms overlap with other neurodegenerative diseases, especially presenile forms of FTD (Figure 47.2).

FIGURE 47.2. A sketch illustrating the problem of ascribing all or most mood or cognitive changes in patients with histories of multiple concussions to entities other than common mood disorders or neurodegenerative diseases.


A sketch illustrating the problem of ascribing all or most mood or cognitive changes in patients with histories of multiple concussions to entities other than common mood disorders or neurodegenerative diseases. The problem is especially serious with (more...)

The neuropathological profile also raises issues of distinction. Although CTE does not resemble brain contusions or DAI, it overlaps extensively with other neurodegenerative tauopathies such as AD, FTD, and PSP. As we will see later, this overlap also creates enormous opportunities of importing possible mechanisms as well as models of disease from better-studied disorders. Meanwhile, the question that arises is whether trauma is both a necessary and sufficient condition for tauopathy or merely shortens the incubation of other presenile tauopathies whose course has been already initiated by genetic or other, nontrauma related, causes. In the same vein, does CTE also increase the risk for depression? The sketch in Figure 47.2 is meant to illustrate the issue of overlap, but arrows in the blue and purple sets depict the potential role of CTE in altering the prevalence and/or time course of more common disorders.

On a related topic, what is the role of genes? Is it possible that the same genes that cause familial FTD also play a causative role in CTE? And what is the role of severity of exposure measured by frequency of hits or hit (impact) nature and intensity? All these issues must be examined in light of the fact that cause-and-effect models for accumulating exposure to an offending agent or condition can be quite complex (Bandeen-Roche et al., 1999).

There are several well-established epidemiological methods to address cause-and-effect questions in medicine. From the weakest to the strongest level of evidence, these methods include case series, case-control studies, and cohort studies. All these methodologies have shortcomings and practical limitations when applied to the problem of CTE. Case series have well-known selection bias and they can best generate Oxford level-3 evidence. One such study has shown an earlier onset of AD in NFL players, although there was no association between recurrent concussions and incidence of AD (Guskiewicz et al., 2005). Another study from the University of Michigan (Institute for Social Research) based on a phone survey has shown a significant increase in memory complaints and dementia in NFL retirees, especially in the 30–49-year-old range (Weir et al., 2009). Case-control studies also have well-characterized confounding problems (i.e., problems of separation of the chooser from the choice) and cannot prove causation, although they have been traditionally associated with breakthroughs in medicine such as the first evidence that smoking may cause lung cancer. At best, case-control studies can generate level 2 evidence. Cohort (prospective) studies can generate level 1 evidence, but in the case of CTE, they would be hard-pressed to resolve between a relatively uncommon condition such as CTE and common chronic conditions such as idiopathic mood disorders (major depression) and, in the older age spectrum, AD and FTD, or other tauopathies. An earlier prospective NFL study drew severe criticism and was terminated; there are ongoing efforts to restart this work on new foundations.

47.1.2. Neurobiological Approaches to CTE Lessons from Animal Models and Cellular/Molecular Neuropathology

In view of the several challenges of clinical-epidemiological studies, the question should turn to modeling. Can basic research from animal models and cellular and molecular biology provide insights and explanations that may help resolve issues critical to CTE, especially the problem of the link between trauma and degeneration? There are several steps in the sequence leading from trauma to cytoskeletal pathology to neuronal degeneration/cell death and here we will briefly examine each one of them in a logical order. Can Injury Cause Cytoskeletal Abnormalities?

The neuronal cytoskeleton is the backbone that stabilizes and maintains the unusual geometry of neurons, including a complex dendritic tree and axons whose cytoplasm (axoplasm) often has volume exceeding multiple times that of the cell body. As shown by studies on the retrograde axonal transport of trophic peptides (Ehlers et al., 1995), cytoskeletal integrity is not only important for the structure and function of neurons as components of particular networks, but also for neuronal survival. In earlier studies that were first performed starting in the late 1980s, it became clear that various cytoskeletal constituents, especially neurofilaments, undergo alterations after axonal lesions, primarily in the form of aberrant or ectopic phosphorylation (Koliatsos et al., 1989). Tau abnormalities as a result of lesions are less well established, although some evidence for accumulation and phosphorylation exists with both repetitive mild injury (Kanayama et al., 1996) and a single lateral fluid percussion impact (Hoshino et al., 1998). Can Injury Cause Neuronal Cell Death?

This association is very well established with proximal axonal lesions that cause retrograde degeneration of neurons in the peripheral nervous system, a type of degeneration that is reversible by trophic factors (Koliatsos and Price, 1996), but is also seen in the CNS with denervation lesions (Koliatsos et al., 2004). A correlation between injury and neuronal cell death is also established in focal models of traumatic brain injury, although it is less well shown in models of DAI. Is Tau Pathology Toxic to Neurons?

There is some evidence that accumulation of hyperphosphorylated tau within neurons is associated with activation of caspase 3 (Gastard et al., 2003) and various enzymatic downstream events, including cleavage of alpha II spectrin (fodrin) to 120-kDa species (Koliatsos et al., 2006). Recent studies in Tg4510 mice that used cranial windows to image cortical neurons have indicated that the caspase-3 activation step comes first and tau cleavage and aggregation with tangle formation follows (de Calignon et al., 2010). The breakthrough finding here is that tangle formation is “off cycle” with respect to the apoptotic pathway and a “marker” or a consequence, rather than a direct cause, of neuronal degeneration. Can Repeat Mild Closed Injury Cause a Progressive Tauopathy with Brain Atrophy and Neuronal Cell Death?

The answer is unknown. There have been very few attempts to address this issue in its entirety. In one study that used a model of repetitive closed-head injury on transgenic mice expressing the shortest human tau isoform (T44), no differences were found in severity of tauopathy and degeneration between noninjured and injured subjects (Yoshiyama et al., 2005). In more recent studies, there is evidence that repeat injury may accelerate some aspects of tauopathy in genetically predisposed subjects (Ojo et al., 2013), but the role of concussion in initiating tauopathy in genetically normal subjects remains elusive. The Microtubule-Associated Protein Tau: Essential Biochemistry and Role in Neurodegenerative Disease

Tau is a microtubule-associated protein that occurs in six alternatively spliced isoforms differing by number of inserts at the N terminus (one or two) and the microtubule-binding domain (three or four) (Spillantini and Goedert, 1998). Normal tau is soluble and serves to stabilize microtubules (i.e., organelles critical for axonal transport). The physiological role of tau depends on a perpetual cycle between phosphorylated and nonphosphorylated states, a mechanism allowing for the smooth movement of cargo, comprising the motor proteins and associated vesicles, down the axon (Ballatore et al., 2007).

Perhaps as a result of its critical importance in axonal transport, tau pathology has been found in more than 20 neurodegenerative diseases including AD, FTD, parkinsonism-plus diseases such as PSP, and traumatic encephalopathies (Ludolph et al., 2009). In all of these disorders (“tauopathies”), tau protein displays misfolding, hyperphosphorylation, and aggregation, events leading to its critical transformation from the normal soluble state to a fibrillar insoluble state featured by beta conformation. Molecular Mechanisms of Tauopathies: Tau as a Protein Prone to Aggregation

A number of studies in transgenic animals harboring mutations associated with FTD with parkinsonism mapping to chromosome 17 (P301L, V337M, others) and molecular studies summarized in the next section have indicated that tau is a protein with great proneness to aggregation (Wolfe, 2009). Aggregation may be the result of mutation, a particular type of enzymatic processing of tau, or both.

Transgenic tau associated with FTD-17 aggregates much more than normal tau. The microtubule-binding (repeat-domain) region aggregates faster than full-length tau and the pathogenic role of this region is highlighted by the fact that nearly all mutations associated with FTD-17 cluster in this region (Wolfe, 2009). The proneness of the repeat-domain tau to aggregation is increased substantially when the flanking regions are removed (see the following section). Mechanisms of Tau Aggregation Are Being Increasingly Understood

As mentioned previously, repeat-domain tau fragments with FTD-17 mutations are especially predisposed to aggregation and beta structure. Cleavage of whole tau to repeat-domain fragments may be initiated by the action of a thrombin-like endogenous protease and then N- and C-terminal truncation of repeat-domain tau in an orderly fashion uncovered by Mandelkow and colleagues in seminal in vitro experiments (Khlistunova et al., 2006; Wang et al., 2007). These repeat-domain fragments nucleate full-length tau with a speed that is substantially higher in mutant than wild-type tau and this causes a slow aggregation process that is toxic to cells.

Aggregation is modulated by, but may not be dependent on, tau phosphorylation. Importantly, the transition from soluble to aggregated tau is a dynamic process that can be restored to normal with antiaggregation agents, for example N-phenylamine compounds and others (Khlistunova et al., 2006). Aggregated Tau Enters Neurons and May Spread from One to Another in a Prion-Like Fashion

The work of Mandelkow and colleagues showing mechanisms of aggregation and the toxicity of aggregated tau has been nicely complemented by additional in vitro and in vivo work. Frost and Diamond have shown that tau aggregates are taken up from outside of cells and, acting as fibrillogenic nuclei, recruit normal tau onto their mass. Newly aggregated tau can be transferred from one cell to another (Frost and Diamond, 2010; Frost et al., 2009).

Clavaguera and colleagues have used transgenic mice that express FTD-P301S tau and develop fibrillar tau inclusions and neurodegeneration (2009). Mice expressing wild-type human tau have normal brains. These investigators were able to transmit tauopathy by injecting brain extracts from transgenic mice into the brains of wild-type mice. Importantly, they showed that pathology can spread from the injection site to other brain regions, presumably via synaptic contacts. Some of these findings have been confirmed using site-specific expression of tau transgenes (de Calignon et al., 2012; Liu et al., 2012)

47.1.3. Animal Modeling of CTE: Shedding Light Where Other Approaches Stumble Animal Models of CTE Require a Central Hypothesis

Animal models can be extremely powerful tools to explore cause-and-effect relationships between traumatic insults and progressive neurodegeneration and, eventually, to serve as vehicles for therapeutic targeting and experimental therapeutics or for biomarker discovery and validation. To construct these models, we need a basic hypothesis or schema of disease cause and progression.

Based on various lines of clinical, epidemiological, and neurobiological data presented above we propose that CTE may arise from the effects of mild, yet repetitive head injury that occurs during contact sports, but that these outcomes are enabled or facilitated by a genetic predisposition of exposed individuals to form toxic tau aggregates within nerve cells. In other words, we propose a diathesis-stress approach in which diathesis (genetic risk) is configured as the genetic propensity of the subject’s tau to form toxic aggregates in the brain and stress is defined as repeated, mild, noncontusive TBI. The genetic propensity to aggregation may be conferred by the expression of FTD with parkinsonism mapping to chromosome 17–linked mutations such as mutations P301L, P301S, V337M, the deletion mutation ΔK280, or the expression of particular tau isoforms (Caffrey and Wade-Martins, 2012; Wolfe, 2009). The stress contribution may be mediated by the increased likelihood of brain tau to be cleaved into multiple-repeat domain fragments under conditions of repeat concussive injury.

Repetitive concussive injury can cause axonal disruption/damage that is a very common phenomenon across various types of TBI (Figure 47.3). Such injury may allow the “leaking” of tau in the extracellular space (Figure 47.3a, step 1) and, in conjunction with microvascular damage or microhemorrhage or mere disruptions of the blood–brain barrier (see “leaky” capillary in sketch), may expose entire tau molecules to endogenous protease (thrombin) cleavage and truncation to repeat-domain, pro-aggregation tau (Figure 47.3a, step 2), as described by Mandelkow and colleagues (Khlistunova et al., 2006; Wang et al., 2007). In this “vascular” model of tauopathy, tau mutations such as the ones associated with FTD can further facilitate aggregation. These mutations are the best characterized genetic causes of progressive tauopathy and appear to exert their pathogenic effect by cleaving tau to multiple-repeat fragments with high aggregation potential that self-assemble in fibrils and subsequently recruit and corrupt normal tau (Wang et al., 2007). Once tau aggregates form, they can be internalized from the extracellular to intracellular compartment (Figure 47.3a, step 3) or become propagated from one cell to another via prion-like mechanisms long after the injurious insults have ceased. Tau tangles may spread along synaptic circuits or via extrusion from dying neurons: as entire neural systems become involved, individuals develop symptoms (Figure 47.3a, step 4). The lengthy interval associated with the transition from aggregation to toxicity (Wang et al., 2007) or the propagation along circuits (Clavaguera et al., 2009) is consistent with the long incubation time required for clinically manifest CTE (McKee et al., 2009).

FIGURE 47.3. Two possible tau cascades initiated by repeat mild injury involve externalization of intact tau from its microtubular binding sites and digestion by endogenous proteases into multiple-repeat, pro-aggregation fragments (a).


Two possible tau cascades initiated by repeat mild injury involve externalization of intact tau from its microtubular binding sites and digestion by endogenous proteases into multiple-repeat, pro-aggregation fragments (a). Axotomy followed by retrograde (more...)

Another mechanism of tauopathy may be related to traumatic axonal injury (Figure 47.3b). Tau accumulates retrogradely in neuronal cell body. Neuronal injury activates adjacent microglia via fractalkine signaling and, in turn, activated microglia contributes to the phosphorylation of accumulated tau via IL1-p38 mitogen-activated protein K signaling (Bhaskar et al., 2010). Hyperphosphorylation increases the probability of fibrillization and, once this happens, steps 3 and 4 of Figure 47.3a are initiated. Asp 421 cleavage by caspases (Figure 47.3, bottom right) can contribute to either one of these two mechanisms.

In our laboratory, we have modified a well-characterized model of closed head injury (i.e. the impact acceleration model of Marmarou et al., 1994). Besides strictly replicating closed-head injury conditions, this model has been extensively characterized, during the past 15 years, to define mechanisms and treatments for TBI and can be modified to encompass a range of injury severity (Beaumont et al., 1999). Although the impact acceleration model can produce a graded, widespread injury involving neurons, astrocytes, axons, and the microvasculature, it does not cause focal damage regardless of injury severity. The standard impact acceleration model can be altered to generate repetitive mild injury and imitate the conditions of repeat concussion in contact sports.

47.2. Conclusions: Critical Issues in CTE and the Role of Experimental Neurobiology

As outlined in the beginning of the chapter, CTE may have neuropsychiatric symptoms and signs consistent with a frontal-limbic dementia with similarities to FTD, but also has a substantial early overlap with mood disorders. The neuropathological signature of CTE is that of a neurodegenerative tauopathy rather than other classical forms of focal or diffuse TBI (i.e., contusions and traumatic axonal injury). A key problem is that only a subpopulation of exposed individuals appears to develop CTE. The size of the exposed population is uncertain. The character and severity of injury is still being defined. The nature of genetic predisposition to the disorder is unclear. Epidemiological studies could easily stumble into problems of overlap with other diseases such as common forms of major depression and early-onset neurodegenerative disorders.

The CTE risk is a real threat to the community because of the popularity of contact and collision sports and is reminiscent of another era in medicine when scientists debated the nature and cause of transmission of contagious diseases (i.e., “miasma” versus some sort of microorganism). Robert Koch, one of the towering figures in modern medicine, while endorsing and actually doing clinical studies, also encouraged people to use experimental models in his famous third postulate: the suspected cause (microorganism) shall cause disease when introduced into a healthy organism (1884). A more precise clinical and neuropathological characterization can be certainly useful in clarifying the nature of CTE and well-designed cohort studies may sometimes determine the size of risk in the community. However, it is the animal models that will provide proof of principle that trauma, under certain circumstances, can cause degeneration and allow early insights into mechanisms. Such mechanistic insights will then facilitate the establishment of biomarkers and the formulation of appropriate treatments.


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Bookshelf ID: NBK299181PMID: 26269885


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