Nora E Fritz, Deb A Kegelmeyer, Ashwini K Rao, Lori Quinn, Anne D Kloos
{"title":"Clinical Decision Trees to Guide Physical Therapy Management of Persons with Huntington's Disease.","authors":"Nora E Fritz, Deb A Kegelmeyer, Ashwini K Rao, Lori Quinn, Anne D Kloos","doi":"10.3233/JHD-220549","DOIUrl":"https://doi.org/10.3233/JHD-220549","url":null,"abstract":"<p><strong>Background: </strong>In 2020, our group published physical therapy clinical practice guidelines (CPG) for people with Huntington's disease (HD). The guideline recommendations were categorized according to six primary movement impairment classifications.</p><p><strong>Objective: </strong>To facilitate implementation of this CPG, we have developed guideline-based algorithms for physical therapy assessments and interventions and recommendations for therapists to overcome barriers to CPG implementation for people with HD.</p><p><strong>Methods: </strong>We conducted a literature review of papers that evaluated physical therapy interventions in individuals with HD (n = 26) to identify assessments for each of the primary movement impairment classifications, and then searched for papers (n = 28) that reported their clinometric/psychometric properties in HD. Assessments were evaluated using modified Movement Disorder Society Committee on Rating Scales criteria and other relevant criteria.</p><p><strong>Results: </strong>We identified a \"core set\" of physical therapy assessments for persons with HD, including the Six Minute Walk Test, Timed Up and Go Test, Berg Balance Scale, and the Medical Outcomes Study Short Form 36 (SF-36). We then developed guideline-based decision trees to assist in decision making and implementation of the CPG into practice for persons with HD across the continuum of care. Finally, we developed strategies for overcoming barriers to implementation, such as seeking specialized training in HD, engaging caretakers or family members to help the person with HD to exercise, and establishing clinical pathways that support early physical therapy referrals.</p><p><strong>Conclusion: </strong>Knowledge translation documents such as this are essential to promoting implementation of the physical therapy CPGs into clinical practice.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":"11 4","pages":"435-453"},"PeriodicalIF":3.1,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/dc/70/jhd-11-jhd220549.PMC9837690.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10690344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Erin E Reasoner, Ellen van der Plas, Douglas R Langbehn, Amy L Conrad, Timothy R Koscik, Eric A Epping, Vincent A Magnotta, Peggy C Nopoulos
{"title":"Cortical Features in Child and Adolescent Carriers of Mutant Huntingtin (mHTT).","authors":"Erin E Reasoner, Ellen van der Plas, Douglas R Langbehn, Amy L Conrad, Timothy R Koscik, Eric A Epping, Vincent A Magnotta, Peggy C Nopoulos","doi":"10.3233/JHD-210512","DOIUrl":"https://doi.org/10.3233/JHD-210512","url":null,"abstract":"<p><strong>Background: </strong>Molecular studies provide evidence that mutant huntingtin (mHTT) affects early cortical development; however, cortical development has not been evaluated in child and adolescent carriers of mHTT.</p><p><strong>Objective: </strong>To evaluate the impact of mHTT on the developmental trajectories of cortical thickness and surface area.</p><p><strong>Methods: </strong>Children and adolescents (6-18 years) participated in the KidsHD study. mHTT carrier status was determined for research purposes only to classify participants as gene expanded (GE) and gene non-expanded (GNE). Cortical features were extracted from 3T neuroimaging using FreeSurfer. Nonlinear mixed effects models were conducted to determine if age, group, and CAG repeat were associated with cortical morphometry.</p><p><strong>Results: </strong>Age-related changes in cortical morphometry were similar across groups. Expanded CAG repeat was not significantly associated with cortical features.</p><p><strong>Conclusion: </strong>While striatal development is markedly different in GE and GNE, developmental change of the cortex appears grossly normal among child and adolescent carrier of mHTT.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":"11 2","pages":"173-178"},"PeriodicalIF":3.1,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9177765/pdf/nihms-1793431.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9928566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xiao-Yan Li, Yu-Feng Bao, Juan-Juan Xie, Shu-Xia Qian, Bin Gao, Miao Xu, Yi Dong, Jean-Marc Burgunder, Zhi-Ying Wu
{"title":"The Chinese Version of UHDRS in Huntington's Disease: Reliability and Validity Assessment.","authors":"Xiao-Yan Li, Yu-Feng Bao, Juan-Juan Xie, Shu-Xia Qian, Bin Gao, Miao Xu, Yi Dong, Jean-Marc Burgunder, Zhi-Ying Wu","doi":"10.3233/JHD-220542","DOIUrl":"https://doi.org/10.3233/JHD-220542","url":null,"abstract":"<p><strong>Background: </strong>The Unified Huntington's Disease Rating Scale (UHDRS) is a universal scale assessing disease severity of Huntington's disease (HD). However, the English version cannot be widely used in China, and the reliability and validity of the Chinese UHDRS have not yet been confirmed.</p><p><strong>Objective: </strong>To test the reliability and validity of Chinse UHDRS in patients with HD.</p><p><strong>Methods: </strong>Between August 2013 and August 2021, 159 HD patients, 40 premanifest HD, and 64 healthy controls were consecutively recruited from two medical centers in China and assessed by Chinese UHDRS. Internal consistency and interrater reliability of the scale were examined. Intercorrelation was performed to analyze the convergent and divergent validity of the scale. A receiver operating characteristic analysis was conducted to explore the optimal cutoff point of each cognitive test.</p><p><strong>Results: </strong>High internal consistency was found in Chinese UHDRS, and its Cronbach's alpha values of the motor, cognitive, behavioral and functional subscales were 0.954, 0.826, 0.804, and 0.954, respectively. The interrater reliability of the total motor score was 0.960. The convergent and divergent validity revealed that motor, cognitive and functional subscales strongly related to each other except for Problem Behavior Assessment. Furthermore, we not only provided the normal level of each cognitive test in controls, but also gave the optimal cutoff points of cognitive tests between controls and HD patients.</p><p><strong>Conclusion: </strong>We demonstrate for the first time that the translated version of UHDRS is reliable for assessing HD patients in China. This can promote the universal use of UHDRS in clinical practice.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":"11 4","pages":"407-413"},"PeriodicalIF":3.1,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10451251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"XJB-5-131 Is a Mild Uncoupler of Oxidative Phosphorylation.","authors":"Zhiyin Xun, Peter Wipf, Cynthia T McMurray","doi":"10.3233/JHD-220539","DOIUrl":"https://doi.org/10.3233/JHD-220539","url":null,"abstract":"<p><strong>Background: </strong>Mitochondria (MT) are energy \"powerhouses\" of the cell and the decline in their function from oxidative damage is strongly correlated in many diseases. To suppress oxygen damage, we have developed and applied XJB-5-131 as a targeted platform for neutralizing reactive oxygen species (ROS) directly in MT. Although the beneficial activity of XJB-5-131 is well documented, the mechanism of its protective effects is not yet fully understood.</p><p><strong>Objective: </strong>Here, we elucidate the mechanism of protection for XJB-5-131, a mitochondrial targeted antioxidant and electron scavenger.</p><p><strong>Methods: </strong>The Seahorse Flux Analyzer was used to probe the respiratory states of isolated mouse brain mitochondria treated with XJB-5-131 compared to controls.</p><p><strong>Results: </strong>Surprisingly, there is no direct impact of XJB-5-131 radical scavenger on the electron flow through the electron transport chain. Rather, XJB-5-131 is a mild uncoupler of oxidative phosphorylation. The nitroxide moiety in XJB-5-131 acts as a superoxide dismutase mimic, which both extracts or donates electrons during redox reactions. The electron scavenging activity of XJB-5-131 prevents the leakage of electrons and reduces formation of superoxide anion, thereby reducing ROS.</p><p><strong>Conclusion: </strong>We show here that XJB-5-131 is a mild uncoupler of oxidative phosphorylation in MT. The mild uncoupling property of XJB-5-131 arises from its redox properties, which exert a protective effect by reducing ROS-induced damage without sacrificing energy production. Because mitochondrial decline is a common and central feature of toxicity, the favorable properties of XJB-5-131 are likely to be useful in treating Huntington's disease and a wide spectrum of neurodegenerative diseases for which oxidative damage is a key component. The mild uncoupling properties of XJB-5-131 suggest a valuable mechanism of action for the design of clinically effective antioxidants.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":"11 2","pages":"141-151"},"PeriodicalIF":3.1,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9798833/pdf/nihms-1856716.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10510889","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nicole M Wakida, Alice L Lau, Jessica Nguyen, Gladys Mae S Cruz, Gianna M Fote, Joan S Steffan, Leslie M Thompson, Michael W Berns
{"title":"Diminished LC3-Associated Phagocytosis by Huntington's Disease Striatal Astrocytes.","authors":"Nicole M Wakida, Alice L Lau, Jessica Nguyen, Gladys Mae S Cruz, Gianna M Fote, Joan S Steffan, Leslie M Thompson, Michael W Berns","doi":"10.3233/JHD-210502","DOIUrl":"10.3233/JHD-210502","url":null,"abstract":"<p><strong>Background: </strong>In recent years the functions of astrocytes have shifted from conventional supportive roles to also include active roles in altering synapses and engulfment of cellular debris. Recent studies have implicated astrocytes in both protective and pathogenic roles impacting Huntington's disease (HD) progression.</p><p><strong>Objective: </strong>The goal of this study is to determine if phagocytosis of cellular debris is compromised in HD striatal astrocytes.</p><p><strong>Methods: </strong>Primary adult astrocytes were derived from two HD mouse models; the fast-progressing R6/2 and slower progressing Q175. With the use of laser nanosurgery, a single astrocyte was lysed within an astrocyte network. The phagocytic response of astrocytes was observed with phase contrast and by fluorescence microscopy for GFP-LC3 transiently transfected cells.</p><p><strong>Results: </strong>Astrocyte phagocytosis was significantly diminished in primary astrocytes, consistent with the progression of HD in R6/2 and Q175 mouse models. This was defined by the number of astrocytes responding via phagocytosis and by the average number of vesicles formed per cell. GFP-LC3 was found to increasingly localize to phagocytic vesicles over a 20-min imaging period, but not in HD mice, suggesting the involvement of LC3 in astrocyte phagocytosis.</p><p><strong>Conclusion: </strong>We demonstrate a progressive decrease in LC3-associated phagocytosis in HD mouse striatal astrocytes.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":"11 1","pages":"25-33"},"PeriodicalIF":2.1,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9028675/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48573233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Carlos Estevez-Fraga, Sarah J Tabrizi, Edward J Wild
{"title":"Huntington's Disease Clinical Trials Corner: November 2022.","authors":"Carlos Estevez-Fraga, Sarah J Tabrizi, Edward J Wild","doi":"10.3233/JHD-229006","DOIUrl":"https://doi.org/10.3233/JHD-229006","url":null,"abstract":"<p><p>In this edition of the Huntington's Disease Clinical Trials Corner, we expand on the PIVOT HD (PTC518), and SIGNAL (pepinemab) trials, and list all currently registered and ongoing clinical trials in Huntington's disease.We also introduce a 'breaking news' section highlighting recent updates about the SELECT HD, uniQure AMT-130, and VIBRANT HD clinical trials.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":"11 4","pages":"351-367"},"PeriodicalIF":3.1,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10450559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Striving for a Realistic and Unapologetic View of Huntington's Disease.","authors":"Kenneth P Serbin","doi":"10.3233/JHD-220551","DOIUrl":"https://doi.org/10.3233/JHD-220551","url":null,"abstract":"<p><p>This article describes how the author, a Huntington's disease (HD) gene expansion carrier and long-time advocate, has helped give voice to the HD community through his blog, At Risk for Huntington's Disease. Since 2005, the 321 articles have helped document the new and harrowing experience of living in the gray zone between a genetic test result and disease onset. At Risk for HD has explored major challenges for the HD community, has become a key reference for HD families, and has chronicled the quest to defeat the disease. This article analyzes the blog's thematic impact.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":"11 4","pages":"369-371"},"PeriodicalIF":3.1,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e9/43/jhd-11-jhd220551.PMC9837684.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10637161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rebecca K Hendel, Marie N N Hellem, Lena E Hjermind, Jørgen E Nielsen, Asmus Vogel
{"title":"An Exploratory Study Investigating Autonomy in Huntington's Disease Gene Expansion Carriers.","authors":"Rebecca K Hendel, Marie N N Hellem, Lena E Hjermind, Jørgen E Nielsen, Asmus Vogel","doi":"10.3233/JHD-220540","DOIUrl":"https://doi.org/10.3233/JHD-220540","url":null,"abstract":"<p><strong>Background: </strong>Autonomy describes a psychological state of self-regulation of motivation and action, which is a central characteristic of healthy functioning. In neurodegenerative diseases measures of self-perception have been found to be affected by the disease. However, it has never been investigated whether measures of self-perception, like autonomy, is affected in Huntington's disease.</p><p><strong>Objective: </strong>We investigated whether autonomy is affected in Huntington's disease and if the degree of autonomy is associated with motor function, neuropsychiatric symptoms, cognitive impairments, and apathy.</p><p><strong>Methods: </strong>We included 44 premanifest and motor-manifest Huntington's disease gene expansion carriers and 19 controls. Autonomy was examined using two self-report questionnaires, the Autonomy-Connectedness Scale-30 and the Index of Autonomous Functioning. All participants were examined according to motor function, cognitive impairments, and neuropsychiatric symptoms, including apathy.</p><p><strong>Results: </strong>Statistically significant differences were found between motor-manifest Huntington's disease gene expansion carriers and premanifest Huntington's disease gene expansion carriers or controls on two measures of autonomy. Between 25-38% of motor-manifest Huntington's disease gene expansion carriers scored significantly below the normal level on subscales of autonomy as compared to controls. One autonomy subscale was associated with apathy (r = -0.65), but not with other symptoms of Huntington's disease.</p><p><strong>Conclusion: </strong>This study provides evidence for impaired autonomy in individuals with Huntington's disease and an association between autonomy and apathy. The results underline the importance of maintaining patient autonomy and involvement in care throughout the disease.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":"11 4","pages":"373-381"},"PeriodicalIF":3.1,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10798012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
F. B. Rodrigues, G. Owen, S. Sathe, Elena Pak, D. Kaur, A. Ehrhardt, S. Lifer, J. Townhill, Katarzyna Schubert, B. Leavitt, M. Guttman, J. Bang, J. Lewerenz, Jamie Levey, C. Sampaio, E. Wild
{"title":"Safety and feasibility of research lumbar puncture in Huntington's disease: the HDClarity cohort and bioresource","authors":"F. B. Rodrigues, G. Owen, S. Sathe, Elena Pak, D. Kaur, A. Ehrhardt, S. Lifer, J. Townhill, Katarzyna Schubert, B. Leavitt, M. Guttman, J. Bang, J. Lewerenz, Jamie Levey, C. Sampaio, E. Wild","doi":"10.1101/2021.07.30.21261340","DOIUrl":"https://doi.org/10.1101/2021.07.30.21261340","url":null,"abstract":"Background: Biomarkers are needed to monitor disease progression, target engagement and efficacy in Huntington's disease (HD). Cerebrospinal fluid (CSF) is an ideal medium to research such biomarkers due to its proximity to the brain. Objectives: To investigate the safety and feasibility of research lumbar punctures (LP) in HD. Methods: HDClarity (NCT02855476) is an ongoing international biofluid collection initiative built on the Enroll-HD platform, where clinical assessments are recorded. It aims to recruit 1,200 participants. Biosamples are collected following an overnight fast: blood via venipuncture and CSF via LP. Participants are healthy controls and HD gene expansion carriers across the disease spectrum. We report on monitored data from February 2016 to September 2019. Results: Of 448 participants screened, 398 underwent at least 1 sampling visit, of which 98.24% were successful (i.e. CSF was collected), amounting to 10,610mL of CSF and 8,200mL of plasma. In the total 572 sampling visits, adverse events were reported in 24.13%, and headaches of any kind and post-LP headaches in 14.86% and 12.24%, respectively. Frequencies were less in manifest HD; gender, age, body mass index and disease burden score were not associated with the occurrence of the events in gene expansion carriers. Headaches and back pain were the most frequent adverse events. Conclusions: HDClarity is the largest CSF collection initiative to support scientific research into HD and is now established as a leading resource for HD research. Our data confirm that research LP in HD are feasible and acceptable to the community, and have a manageable safety profile.","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":"11 1 1","pages":"59-69"},"PeriodicalIF":3.1,"publicationDate":"2021-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45923724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Modifiers of CAG/CTG Repeat Instability: Insights from Mammalian Models.","authors":"Vanessa C Wheeler, Vincent Dion","doi":"10.3233/JHD-200426","DOIUrl":"https://doi.org/10.3233/JHD-200426","url":null,"abstract":"<p><p>At fifteen different genomic locations, the expansion of a CAG/CTG repeat causes a neurodegenerative or neuromuscular disease, the most common being Huntington's disease and myotonic dystrophy type 1. These disorders are characterized by germline and somatic instability of the causative CAG/CTG repeat mutations. Repeat lengthening, or expansion, in the germline leads to an earlier age of onset or more severe symptoms in the next generation. In somatic cells, repeat expansion is thought to precipitate the rate of disease. The mechanisms underlying repeat instability are not well understood. Here we review the mammalian model systems that have been used to study CAG/CTG repeat instability, and the modifiers identified in these systems. Mouse models have demonstrated prominent roles for proteins in the mismatch repair pathway as critical drivers of CAG/CTG instability, which is also suggested by recent genome-wide association studies in humans. We draw attention to a network of connections between modifiers identified across several systems that might indicate pathway crosstalk in the context of repeat instability, and which could provide hypotheses for further validation or discovery. Overall, the data indicate that repeat dynamics might be modulated by altering the levels of DNA metabolic proteins, their regulation, their interaction with chromatin, or by direct perturbation of the repeat tract. Applying novel methodologies and technologies to this exciting area of research will be needed to gain deeper mechanistic insight that can be harnessed for therapies aimed at preventing repeat expansion or promoting repeat contraction.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":"10 1","pages":"123-148"},"PeriodicalIF":3.1,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.3233/JHD-200426","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10680148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}