Annals of Neurology最新文献

{"title":"Co-Opting MBNL-Dependent Alternative Splicing Cassette Exons to Control Gene Therapy in Myotonic Dystrophy.","authors":"Samuel T Carrell, Ellie M Carrell, Ryan Giovenco, Beverly L Davidson","doi":"10.1002/ana.78024","DOIUrl":"https://doi.org/10.1002/ana.78024","url":null,"abstract":"<p><strong>Objective: </strong>Myotonic dystrophy type 1 (DM1) is a highly variable, multisystemic genetic disorder caused by a CTG repeat expansion in the 3' untranslated region of DMPK. Toxicity is exerted by repeat-containing DMPK transcripts that sequester muscleblind-like (MBNL) proteins and lead to deleterious yet predictable changes in alternative splicing. To contend with high phenotypic and molecular variability that complicate application of viral-based therapies, we develop and test a DM1-responsive genetic element to control viral-based therapeutic output.</p><p><strong>Methods: </strong>We used MBNL-dependent cassette exons to generate adeno-associated virus (AAV)-compatible control elements (DMX^on). Minigenes were tested in vitro using a Dox-inducible MBNL1 cell model and induced pluripotent stem cell (iPSC)-derived DM1 myotubes and in vivo using DM1 model mice following intramuscular and systemic AAV injection. DMX^on splicing, correction of endogenous splicing or skeletal muscle myotonia, and prevention of cardiac toxicity associated with therapeutic MBNL1 overexpression were assessed.</p><p><strong>Results: </strong>DMX^on cassettes respond to MBNL1 dose or expression of CUG repeat RNA. DMX^on controlled expression of therapeutic MBNL1 protein can improve skeletal muscle myotonia or prevent cardiac toxicity due to MBNL1 overexpression in mice.</p><p><strong>Interpretation: </strong>DMX^on control elements can increase the therapeutic window of viral-based therapeutics in DM1, and activity is dependent upon delivered cargo and model severity. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beta Power Response After Levodopa Intake in Parkinson's Disease Patients With Chronic Sensing-Enabled Deep Brain Stimulation.","authors":"Martijn G J de Neeling, Bart J Keulen, Mariëlle J Stam, Deborah Hubers, Rob M A de Bie, Bernadette C M van Wijk, P Rick Schuurman, Arthur W G Buijink, Martijn Beudel","doi":"10.1002/ana.78025","DOIUrl":"https://doi.org/10.1002/ana.78025","url":null,"abstract":"<p><strong>Objective: </strong>In Parkinson's disease (PD), the power of beta oscillations (± 13-30 hertz [Hz]) from subthalamic nucleus (STN) local field potentials (LFPs) is associated with motor symptoms. Beta power can be used for adaptive deep brain stimulation (aDBS) algorithms based upon symptom fluctuations. The time course of beta power modulations after levodopa intake at home remains to be described.</p><p><strong>Methods: </strong>Ten-minute averages of beta peak power were recorded in 33 patients with PD treated with STN-DBS for a median duration of 134 days during the titration phase. Median beta power after scheduled medication intakes (n = 24,103) and the effects of peak frequency, stun effect, stimulation amplitude, levodopa dose, and preoperative levodopa response were analyzed using cluster-based permutation testing.</p><p><strong>Results: </strong>Beta power was significantly reduced between 30 and 140 minutes after intake for stimulation amplitudes between 0 and 2.1 mA (p < 0.01). This response was seen in low (12.7-20.5 Hz) but not high (21.5-30.3 Hz) beta frequencies. Significant clusters were found regardless of stun effect and preoperative levodopa response, during low stimulation amplitudes (< 1 mA), and for 100 and 150 mg but not 50 mg doses. A linear mixed-effects model for the area under the curve (AUC) levodopa beta response (30-180 min) revealed a dose-response relationship, a stronger negative response in low-beta compared with high-beta frequencies, and no significant effect of stimulation amplitude.</p><p><strong>Interpretation: </strong>STN beta power responds to levodopa during low to moderate stimulation amperages, depending on the beta peak frequency and dose, which is informative for aDBS implementation. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phenotypic Changes in a Monocyte Cluster with High Interleukin-1 Beta Expression during Long-Term Anti-CD20 Therapy.","authors":"Mie Waede, Christina Kingo, Karina Damsbo, Maiken Uhrbrand Joergensen, Mhaned Oubounyt, Morten Gjerstorff, Mads Thomassen, Jan Baumbach, Jesper B Moeller, Maria L Elkjaer, Zsolt Illes","doi":"10.1002/ana.78004","DOIUrl":"https://doi.org/10.1002/ana.78004","url":null,"abstract":"<p><strong>Objective: </strong>We aimed to investigate disease-related and anti-CD20 therapy-related changes in peripheral blood mononuclear cells (PBMCs) from multiple sclerosis (MS) patients compared to healthy controls (HC) using multi-omics single-cell analysis.</p><p><strong>Methods: </strong>Targeted single-cell sequencing of transcriptomes and epitopes was performed on PBMCs isolated from 64 blood samples collected from MS patients at baseline and at 3 time points following anti-CD20 treatment, alongside HC. Multicolor spectral flow cytometry was performed on 15 of the samples.</p><p><strong>Results: </strong>Cell cluster analysis identified a subpopulation of classical monocytes with significantly high interleukin-1 beta (IL1B) expression and a pro-inflammatory profile compared to other monocyte clusters. This monocyte cluster expressed genes of pro-inflammatory chemokines and cytokines, such as CXCL8, CCL3, CCL4, and TNFα and was a major cell transmitter subset within the intercellular communication network. The IL1B^high monocyte cluster was prevalent in HC (8.1% of PBMCs), but reduced in untreated MS patients (0.8% of PBMCs). High CXCR4 expression and Gene Ontology-term analysis indicated that IL1B^high monocytes from MS patients had central nervous system (CNS)-infiltrating abilities in contrast to HC, likely regulated by LEF1. After anti-CD20 treatment, IL1B^high monocytes showed changes in pro-inflammatory gene expression and MYC-associated regulatory networks, and their abundance increased 6-fold in the blood.</p><p><strong>Interpretation: </strong>Our single-cell analysis identified a unique peripheral IL1B^high monocyte cluster with a suggested CNS-infiltrating cellular phenotype that may explain its lower abundance in the blood of untreated compared to anti-CD20 treated MS patients. Treatment-associated changes in this population may contribute to the non-B cell related effects of anti-CD20 therapy. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Annals of Neurology: Volume 98, Number 3, September 2025","authors":"","doi":"10.1002/ana.26989","DOIUrl":"https://doi.org/10.1002/ana.26989","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"98 3","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.26989","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144910259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reply to From Topography to Therapy: Rethinking Cognitive Monitoring in GBA1-Linked PD.","authors":"Sofie Slingerland, Sygrid van der Zee, Teus van Laar","doi":"10.1002/ana.70009","DOIUrl":"https://doi.org/10.1002/ana.70009","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TARDBP (TDP-43) Knock-in Zebrafish Display a Late-Onset Motor Phenotype and Loss of Large Spinal Cord Motor Neurons.","authors":"Ziyaan A Harji, Christian J Rampal, Esteban C Rodríguez, Virginie Petel Légaré, Alexandra Lissouba, Sabrina Semmler, Meijiang Liao, Jay P Ross, Guy A Rouleau, Christine Vande Velde, Gary A B Armstrong","doi":"10.1002/ana.78012","DOIUrl":"https://doi.org/10.1002/ana.78012","url":null,"abstract":"<p><strong>Objective: </strong>Mutations in TARDBP (encoding TDP-43) are associated with the neurodegenerative disease amyotrophic lateral sclerosis (ALS) and include familial missense mutations where there are a lack of models and mechanisms examining how they are pathogenic.</p><p><strong>Methods: </strong>In this study, we developed 2 tardbp (Tdp-43) knock-in (KI) zebrafish mutant models encoding the analogous A382T and G348C variants and investigated their degenerative phenotypes.</p><p><strong>Results: </strong>We show that both models display reduced survival as well as an age-dependent motor phenotype that manifests at 1.5 years. Both variants in either the heterozygous or homozygous state did not impact protein expression levels of Tdp-43 in the central nervous system. However, homozygous G347C zebrafish displayed reduced expression levels of the tardbp transcript. We observed muscle cell atrophy starting at 1 year of age and loss of large spinal cord motor neurons in both KI models in older fish (2.35-3 years of age). We did not observe Tdp-43 aggregates. However, we did observe increased cytoplasmic Tdp-43 localization in spinal cord motor neurons in A379T zebrafish. At 1 year of age, whole spinal cord RNA-sequencing revealed an upregulation of neuroinflammatory transcripts in both models, as well as the selective downregulation of transcripts involved with synaptic function in G347C zebrafish, including syn2a, syn2b, syt2a, and stxbp1a.</p><p><strong>Interpretation: </strong>These novel models of common TDP-43 disease variants provide a unique opportunity to further our understanding of neurodegeneration in vivo and demonstrate that mutations in the same protein and domain can manifest with different phenotypes. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disease Progression in Multiple System Atrophy: The ASPIRE Multi-Modal Biomarker Study.","authors":"Margherita Fabbri, Natalia Del Campo, Wassilios G Meissner, Vanessa Rousseau, Agnès Sommet, Pierre Payoux, Pierre Gantet, Amel Drif, Hélène Catalá, Claire Thalamas, Christine Tranchant, Franck Durif, Ana Marques, Alexandre Eusebio, Luc Defebvre, Jean-Christophe Corvol, Stéphane Thobois, Anthime Flaus, Anne-Gaelle Corbille, Solène Frismand, Beverley Patterson, Alexandra Foubert-Samier, Anne Pavy-Le Traon, Germain Arribarat, Patrice Péran, Olivier Rascol","doi":"10.1002/ana.70028","DOIUrl":"https://doi.org/10.1002/ana.70028","url":null,"abstract":"<p><strong>Objective: </strong>The objective of this study was to characterize changes in candidate biomarkers in early multiple system atrophy (MSA) and identify baseline predictors of faster progression.</p><p><strong>Methods: </strong>This 1-year, multicenter, prospective study assessed clinical, neuroimaging (3T-magnetic resonance imaging [MRI], dopamine transporter single-photon emission computed tomography [DaT-SPECT]), and neurofilament light chain (NfL) changes in patients with early MSA (< 5 years from symptom onset) and healthy controls (HCs). Clinical and biomarker changes from baseline to 6 months (M6) and 12 months (M12) were analyzed. Survival status was collected at 24 months. Mixed linear regression analyzed repeated measures, whereas univariate regression identified biomarkers linked to progression. Sample size simulations were conducted for future trials.</p><p><strong>Results: </strong>Forty-one patients with MSA and 20 HCs were included in this study. The Unified Multiple System Atrophy Rating Scale (UMSARS)-I + II scores worsened (mean percent change from baseline was 19.8% at M6; 95% confidence interval [CI] = 13.3 to 26.4% and 31.1% 95% CI = 24.9 to 37.2% at M12). Patients with MSA showed increased cerebellar white matter and pons atrophy (M6 = -5.9 to -2.8% and M12 = -9 to -4.9%) and decreased striatal specific binding ratio (SBR; M6 = -15.8 to -7.9% and M12 = -24 to -10.4%). Patients with multiple system atrophy parkinsonian (MSA-P) exhibited greater striatal SBR reduction, whereas patients with multiple system atrophy cerebellar (MSA-C) had greater cerebellar and pons atrophy, evident at M6. Baseline brainstem and pons volume predicted clinical worsening at M6, whereas SBR predicted worsening at M12. Higher plasma NfL levels correlated with early dropout (14% at M12), worse UMSARS scores, lower SBR, and increased mortality risk within 24 months.</p><p><strong>Interpretation: </strong>Neuroimaging changes occur within 6 months in early MSA. High plasma NfL levels are linked to increased mortality and dropout risk. Longitudinal biomarker assessments provide valuable insights into disease progression. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intranasal Wharton's Jelly-Derived Mesenchymal Stem Cell Therapy, Alone or in Conjunction With Therapeutic Hypothermia, Alleviates Neonatal Hypoxic-Ischemic Brain Injury in Mice.","authors":"Caroline G M de Theije, Sara T De Palma, Josine E G Vaes, Katiuscia Dallaglio, Giorgia Volpi, Diego Ardigò, Sabine van Rijt, Frank van Bel, Manon J N L Benders, Cora H A Nijboer","doi":"10.1002/ana.78000","DOIUrl":"https://doi.org/10.1002/ana.78000","url":null,"abstract":"<p><strong>Objective: </strong>Neonatal hypoxic-ischemic brain injury (HIBI) caused by perinatal asphyxia is a primary cause of long-term neurological morbidity. Hypothermia is the sole available clinical intervention despite its limited efficacy. Intranasal mesenchymal stem cells (MSCs) show promise for the treatment of HIBI. This study explores the efficacy, migration, treatment window, and therapeutic mechanisms of intranasally applied Wharton's jelly-derived MSCs (WJ-MSCs) in a neonatal HIBI mouse model, and assesses its therapeutic benefit in conjunction with hypothermia.</p><p><strong>Methods: </strong>Nine-day-old C57BL/6 mice underwent hypoxia-ischemia (HI), with or without hypothermia, and were intranasally dosed with 0.1 to 2.0 × 10⁶ WJ-MSCs, at 3 or 10 days post-HI. WJ-MSCs were traced using different techniques. Neurogenesis was examined 2 days post-treatment. Neuroinflammation, sensorimqotor outcome, and neuronal tissue loss was assessed 28 days post-HI. Additionally, anti-inflammatory and neuroregenerative properties of WJ-MSCs were investigated in non-contact co-cultures with microglia and neural stem cells, and by secretome profiling.</p><p><strong>Results: </strong>Intranasally delivered WJ-MSCs reduced HI-induced lesion size and sensorimotor impairments. WJ-MSCs expressed multiple receptors for upregulated chemokines in the HI-lesion, and migrated from the nasal cavity into the meninges and brain parenchyma. WJ-MSCs secreted a broad spectrum of immunomodulatory and neuroregenerative proteins, and inhibited neuroinflammation and boosted neuroregeneration in vivo and in vitro. WJ-MSC potency was sustained across different donors. Importantly, intranasal WJ-MSCs augmented the therapeutic benefits of hypothermia following neonatal HIBI in mice.</p><p><strong>Interpretation: </strong>This study provides new translational evidence that intranasal WJ-MSCs, either alone or in combination with hypothermia, mitigate the consequences of neonatal HIBI by resolving inflammation and boosting neurorepair through their secretome. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Persisting Transglutaminase 6 Antibodies in Neurological Gluten-Related Disorders.","authors":"Iain D Croall, Marios Hadjivassiliou, David S Sanders, Kevin Teh, Alberto M Biancardi, Nick Trott, Nigel Hoggard","doi":"10.1002/ana.78020","DOIUrl":"https://doi.org/10.1002/ana.78020","url":null,"abstract":"<p><strong>Objective: </strong>Gluten-related autoimmunity can cause neurological disease, although the best way to diagnose and monitor such patients is unclear. Serological testing for antibodies against transglutaminase 6 (TG6) has been proposed; however, this is not widely available in clinical practice. Using longitudinal data from patients attending a specialist neurological center with routine TG6 testing, this observational study explores how antibody history relates to brain atrophy, cognition, and quality of life.</p><p><strong>Methods: </strong>Serological records of patients with gluten-related neurological disease were collected alongside clinical brain magnetic resonance imaging. Patients were recruited to undertake questionnaires that assessed/included chronic symptom severity, the hospital anxiety and depression scale, the SF-12, and the Biagi scale for gluten-free diet adherence. Volunteers were offered the cerebellar cognitive affective syndrome scale for cognitive testing. Primary analyses focused on patients with ≥5 years of serology (n = 462), and related TG6 history to available clinical outcomes (primary analysis range 89-104).</p><p><strong>Results: </strong>Patients with a previous positive immunoglobulin A (IgA) TG6 result reported greater depression, symptom severity, and poorer physical functioning. IgA TG6 antibody exposure was correlated with regional brain atrophy (age-corrected). Greater self-reported gluten-free diet adherence significantly predicted a recent negative IgA TG6 test. Subgroup analyses replicated multiple findings in patients with and without celiac disease.</p><p><strong>Interpretation: </strong>TG6 testing can identify patients at risk of accelerated brain atrophy, poorer physical functioning, and worsened mental health. IgA TG6 should be used as a diagnostic and monitoring test for patients with relevant neurological presentations, while achieving negative serology with a strict gluten-free diet should be the goal. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biallelic Truncating Variants in SCN3B Encoding Nav Channel Subunit β3 Lead to Neurodevelopmental Phenotype with and without Epilepsy and Ataxia.","authors":"Nathan Routledge, Maxime Lammens, Reza Maroofian, Bakht Beland, David Murphy, Asif Mir, Zia Ullah, Javeria Reza Alvi, Tipu Sultan, Stephanie Efthymiou, Frank Bosmans, Henry Houlden","doi":"10.1002/ana.78014","DOIUrl":"https://doi.org/10.1002/ana.78014","url":null,"abstract":"<p><p>SCN3B encodes the β3 auxiliary subunit, essential for voltage-gated Na⁺ (Nav) channel trafficking and gating. Although SCN3B has been associated with cardiac disorders, a link with neurodevelopmental disorders (NDD) has not been established. Using a genotype-first approach, we identified homozygous truncating variants (c.281G>A-β3^W94*, c.584 + 1G>A-β3^S196*) in 2 consanguineous Pakistani families, leading to global developmental delay, intellectual disability and autism, with severe cognitive impairment, ataxia, and seizures in the case of β3^W94*. Electrophysiological analysis revealed subtype-specific gating alterations on multiple brain Nav channel subtypes. This is the first report linking SCN3B mutations to NDD, expanding our understanding of Nav channelopathies. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}