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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/cdn\/css\/http\/css_Xg7z6oCTVgud_Q0huYz9x9iiD5H_2YPSJ5z2ZViSWdY.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EThe Robert Wartenberg Lecture is the premier award and address at the American Academy of Neurology\u0027s Annual Meeting. In 2014, the award was given to David M. Holtzman, MD, Washington University School of Medicine, St. Louis, Missouri, USA. Dr. Holtzman lectured on the current state of our understanding of biomarkers for Alzheimer\u0027s disease (AD) and potential immunotherapeutic approaches.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003ECognitive Disorders\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EDementias\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EPrevention \u0026amp; Screening\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group clinical-trial\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003ECognitive Disorders\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ENeurology\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EDementias\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EPrevention \u0026amp; Screening\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EThe Robert Wartenberg Lecture is the premier award and address at the American Academy of Neurology\u0027s annual meeting. This year, the award was given to David M. Holtzman, MD, Washington University School of Medicine, St. Louis, Missouri, USA. Dr. Holtzman lectured on the current state of our understanding of biomarkers for Alzheimer\u0027s disease (AD) and potential immunotherapeutic approaches.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EThere are 2 major types of AD: early-onset familial (\u0026lt;1% of cases) and late-onset (age \u0026gt;60 years; \u0026gt;90% of cases) AD. The strongest risk factors are age and genetics. AD progresses in stages from very mild to severe, on average, over an 8- to 12-year period. Clinical features include gradual onset and progression, memory deficits (particularly recent memory), cognitive dysfunction (eg, executive function, problem solving, attention, language skills), and behavioral dysfunction, such as personality change, depression, delusions, hallucinations, apathy, and sleep disruption. AD is now usually recognized in its early clinical phases on the basis of changes in previous levels of performance as recognized by an informant and validated by additional testing.\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003EThe classic neuropathophysiology of AD was first described in the early 1900s. The process begins with plaque buildup, followed by neurofibrillary tangles (tau) [Holtzman DM et al. \u003Cem\u003ESci Transl Med\u003C\/em\u003E 2011]. These changes are associated with nerve cell and synapse dysfunction, loss of connections, inflammation, brain shrinkage, and cell death. Our understanding of AD pathology has progressed a great deal in the past 25 years. The amyloid plaques are now known to be made up of the amyloid-\u03b2 (A\u03b2) peptide surrounded by dystrophic neurites. The plaques are also surrounded by astrocytes and microglial cells that secrete a variety of cytokines and other molecules, including complement components, interleukin-1, tumor necrosis factor-\u03b1, \u03b1-1 antichymotrypsin, \u03b1-2 macroglobulin, apolipoprotein E, and clusterin. Neurons develop intracellular aggregates of tau in cell bodies and dendrites (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E).\u003C\/p\u003E\u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/6\/4\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Brain Pathology of Alzheimer\u0027s Disease\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-568716040\u0022 data-figure-caption=\u0022Brain Pathology of Alzheimer\u0027s Disease\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/6\/4\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/6\/4\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/6\/4\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/15929\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n            \u003Cp id=\u0022p-5\u0022 class=\u0022first-child\u0022\u003EBrain Pathology of Alzheimer\u0027s Disease\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003EA\u03b2=amyloid-\u03b2; ACT=antichymotrypsin; ApoE=apolipoprotein E; \u03b12M=\u03b1-2 macroglobulin; IL-1=interleukin-1; TNF\u03b1=tumor necrosis factor-\u03b1.\u003C\/q\u003E\u003Cq class=\u0022attrib\u0022 id=\u0022attrib-2\u0022\u003EReproduced from Holtzman DM et al. Alzheimer\u0027s disease: the challenge of the second century. \u003Cem\u003ESci Transl Med.\u003C\/em\u003E 2011;3(77):77sr1. With permission from the American Association for the Advancement of Science.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-6\u0022\u003EA\u03b2 and tau interact to contribute to the pathogenesis of AD. A\u03b2 aggregation leads to local toxicity and inflammation and contributes to the exacerbations of tau accumulation. Once A\u03b2 aggregates into oligomers and fibrils, cell toxicity, inflammation, and increased conversion of soluble tau into aggregated tau occur. The accumulation of tau spreads into other parts of the neocortex and contributes to the cognitive decline. There is evidence that A\u03b2 aggregation is influenced by the A\u03b2-binding molecule apolipoprotein E, a strong genetic risk factor for AD.\u003C\/p\u003E\u003Cp id=\u0022p-7\u0022\u003EThe time course of developing the classic AD-related pathologic changes in relation to developing clinical manifestations is important to understand. Pathologically, there is an initial quick increase of amyloid plaques that peaks early on and a gradual increase in neurofibrillary tangles that spreads into the temporal neocortex and peaks in later clinical stages of disease, accompanied by a linear decline in neuronal integrity. A\u03b2 peptide aggregation begins about 15 years before the onset of memory loss and dementia. Tau elevation, reflecting neurodegeneration, probably begins about 5 years before the onset of symptoms (\u003Ca id=\u0022xref-fig-2-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F2\u0022\u003EFigure 2\u003C\/a\u003E). Thus, it appears critical to develop treatments that are effective before patients become symptomatic and significant damage to the brain has occurred.\u003C\/p\u003E\u003Cdiv id=\u0022F2\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/6\/4\/F2.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022AD Biomarker Changes Relative to Cognitive and Clinical Changes\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-568716040\u0022 data-figure-caption=\u0022AD Biomarker Changes Relative to Cognitive and Clinical Changes\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 2.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/6\/4\/F2.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/6\/4\/F2.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 2.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/6\/4\/F2.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/15930\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 2.\u003C\/span\u003E \n            \u003Cp id=\u0022p-8\u0022 class=\u0022first-child\u0022\u003EAD Biomarker Changes Relative to Cognitive and Clinical Changes\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-3\u0022\u003EA\u03b2=amyloid-\u03b2; AD=Alzheimer\u0027s disease; APOE=apolipoprotein E; CDR=clinical dementia rating; Max=maximum; Min=minimum; Mod.=moderate; Sev.=severe; SNP=single-nucleotide polymorphism.\u003C\/q\u003E\u003Cq class=\u0022attrib\u0022 id=\u0022attrib-4\u0022\u003EReproduced from Holtzman DM et al. Alzheimer\u0027s disease: the challenge of the second century. \u003Cem\u003ESci Transl Med.\u003C\/em\u003E 2011;3(77):77sr1. With permission from the American Association for the Advancement of Science.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-9\u0022\u003EMice expressing the transgenic \u03b2-amyloid precursor protein (APP\u03b2), which increases production of the 42-amino acid form of the peptide (A\u03b2 42), predominantly found in the amyloid plaques of AD, were first used to study AD treatments. Besides A\u03b2 deposits, these mice develop neuritic plaques, gliosis, and cognitive abnormalities similar to AD in humans. However, mice show no strong signs of tauopathy or prominent neuronal cell loss. The first positive results were noted when transgenic mice were immunized with A\u03b2 42. When mice were immunized at young ages (6 to 8 weeks), they developed very little amyloid plaques. In older animals that received active immunization (11 months of age), progression of amyloid-related neuropathologies was reduced [Schenk D et al. \u003Cem\u003ENature\u003C\/em\u003E 1999]. The following year, data indicated that APP-transgenic mice immunized with A\u03b2 42 had improved learning ability (\u003Ca id=\u0022xref-fig-3-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F3\u0022\u003EFigure 3\u003C\/a\u003E) [Janus C et al. \u003Cem\u003ENature\u003C\/em\u003E 2000].\u003C\/p\u003E\u003Cdiv id=\u0022F3\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/6\/4\/F3.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Effect of Amyloid-\u0026#x3B2; Immunization on Learning Ability of APP-Transgenic Mice\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-568716040\u0022 data-figure-caption=\u0022Effect of Amyloid-\u0026#x3B2; Immunization on Learning Ability of APP-Transgenic Mice\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 3.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/6\/4\/F3.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/6\/4\/F3.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 3.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/6\/4\/F3.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/15932\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 3.\u003C\/span\u003E \n            \u003Cp id=\u0022p-10\u0022 class=\u0022first-child\u0022\u003EEffect of Amyloid-\u03b2 Immunization on Learning Ability of APP-Transgenic Mice\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-5\u0022\u003EAPP=amyloid precursor protein.\u003C\/q\u003E\u003Cq class=\u0022attrib\u0022 id=\u0022attrib-6\u0022\u003EReproduced from Janus C et al. A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer\u0027s disease. \u003Cem\u003ENature.\u003C\/em\u003E 2000;408(6815):979\u2013982. With permission from the Nature Publishing Group.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-11\u0022\u003ESubsequent to this, it was reported that peripheral administration of A\u03b2 antibodies reduces amyloid plaques, with the antibodies triggering microglial cells to clear plaques through Fc receptor-mediated phagocytosis and subsequent degradation of peptides [Bard F et al. \u003Cem\u003ENat Med\u003C\/em\u003E 2000]. One of these antibodies, called bapineuzumab, was humanized and went into clinical trials. Another anti-A\u03b2 antibody, m266, when given in a prevention mode to APP-transgenic mice, also decreased A\u03b2 levels in the brain, and it also went into clinical trials, as solanezumab [DeMattos RB et al. \u003Cem\u003EProc Natl Acad Sci USA\u003C\/em\u003E 2001].\u003C\/p\u003E\u003Cp id=\u0022p-12\u0022\u003ESeveral mechanisms for how these antibodies against A\u03b2 work have been proposed. One suggestion is through clearance of amyloid plaques by phagocytosis. Evidence for this mechanism was shown in several studies. One study showed that the direct application of the anti-A\u03b2 antibody 10D5 to the brain surface of APP mice decreased deposited A\u03b2 and increased microglial infiltration [Bacskai BJ et al. \u003Cem\u003ENat Med\u003C\/em\u003E 2001]. Imaging of A\u03b2 deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy [\u003Cem\u003ENat Med\u003C\/em\u003E 2001]. Other suggested mechanisms include a shift in equilibrium from amyloid plaques to A\u03b2 monomers and blockade of soluble A\u03b2 toxicity (analogous to neutralizing the part of A\u03b2 that damages nerve cells) [Brody DL, Holtzman DM. \u003Cem\u003EAnnu Rev Neurosci\u003C\/em\u003E 2008].\u003C\/p\u003E\u003Cp id=\u0022p-13\u0022\u003ETrials in humans with passive immunization targeting A\u03b2 were usually initiated in patients with mild to moderate dementia. At this point, many of these patients have large amounts of amyloid deposition and good amounts of tau deposits throughout the neocortex, suggesting that there may be too much brain damage to reverse the changes substantially [Salloway S et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2014].\u003C\/p\u003E\u003Cp id=\u0022p-14\u0022\u003EIn 2 recently published Phase 3 trials in patients with mild to moderate AD, bapineuzumab and solanezumab failed to improve cognition or functional ability as measured in the primary endpoints [Doody RS et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2014; Salloway S et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2014]; however, there were some significant effects that were positive on the secondary endpoints in patients with mild dementia (Alzheimer\u0027s Disease Assessment Scale-Cognitive score and others) in the solanezumab trial.\u003C\/p\u003E\u003Cp id=\u0022p-15\u0022\u003ETreating patients with moderate dementia with anti-A\u03b2 therapies may be too late. Thus, solanezumab is being tested in patients with mild AD as well as in asymptomatic individuals with gene mutations that cause dominantly inherited AD and in individuals older than 65 years who have amyloid plaques. Newer anti-A\u03b2 therapies that may remove plaques more extensively (eg, crenezumab, gantenerumab) are also in development and being tested in the preclinical and early clinical phases of the disease.\u003C\/p\u003E\u003Cp id=\u0022p-16\u0022\u003EDr. Holtzman suggested that future trials might need to increase the doses used, despite the potential for brain swelling noted with bapineuzumab, or to use combination therapies that decrease A\u03b2 production, enhance A\u03b2 clearance, and neutralize A\u03b2 toxicity. Immunotherapy specifically designed to block transcellular tau aggregate propagation may be also be a productive treatment strategy. Antitau monoclonal antibodies (eg, HJ8.5) infused into tau-transgenic mice diminished cognitive deficits and reduced the accumulation of insoluble tau protein in the cortex [Yanamandra K et al. \u003Cem\u003ENeuron\u003C\/em\u003E 2013].\u003C\/p\u003E\u003Cp id=\u0022p-17\u0022\u003EDr. Holtzman concluded that active and passive immunization against A\u03b2 using antibodies with the best therapeutic properties administered in the preclinical stage of AD has the highest likelihood of success for this approach. Targeting tau with an immunotherapeutic agent, though still in its very early stages, also appears to be a promising approach.\u003C\/p\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2014 MD Conference Express\u00ae\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/14\/6\/4.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nzp9ve\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzp9ve\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}