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Introduction: Intracranial artery calcification (ICAC) is a common finding on computed tomography (CT) in patients presenting with large vessel occlusion acute ischemic stroke (LVO-AIS) and could serve as a useful biomarker of intracranial atherosclerosis and altered intracranial vessel pliability in patients undergoing endovascular thrombectomy (EVT)., Methods: This was a retrospective cohort study analyzing consecutive patients undergoing CT head prior to EVT between 2016 and 2020. Extent of ICAC proximal to the target vessel was scored using a validated grading scale examining thickness and circumferential extent of calcifications. The relationship between 3 levels of ICAC burden and procedural, clinical, and safety outcomes was analyzed., Results: Among 86 patients meeting inclusion criteria, ICAC of any degree was present in 72.1 %. Median ICAC score was 3 [IQR 0-4]. There was a U-shaped association between ICAC score and successful reperfusion: 90.9 %, 65.7 %, and 94.4 % in the low, intermediate, and high ICAC score groups, respectively (p = 0.008). Use of rescue intervention, most often angioplasty and stenting, was greatest in the high ICAC score group: 3.0 % vs. 5.7 % vs. 22.2 % (p = 0.05). Functional independence at 90 days did not differ significantly among groups (41.7 % vs. 31.0 % vs. 15.4 %, p = 0.26), nor did rates of symptomatic intracranial hemorrhage (15.2 % vs. 14.3 % vs. 16.7 %, p = 0.97)., Conclusions: ICAC is seen on CT in nearly three-quarters of patients with LVO-AIS. Extent of ICAC has a U-shaped association with successful reperfusion, in part due to more frequent use of rescue interventions in patients with extensive ICAC., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: David S. Liebeskind reports a relationship with Cerenovus that includes: consulting or advisory. David S. Liebeskind reports a relationship with Genentech that includes: consulting or advisory. David S. Liebeskind reports a relationship with Medtronic that includes: consulting or advisory. David S. Liebeskind reports a relationship with Stryker that includes: consulting or advisory. David S. Liebeskind reports a relationship with Rapid Medical that includes: consulting or advisory. Geoffrey P. Colby reports a relationship with Stryker Neurovascular that includes: consulting or advisory. Geoffrey P. Colby reports a relationship with Medtronic that includes: consulting or advisory. Geoffrey P. Colby reports a relationship with MicroVention Inc that includes: consulting or advisory. Geoffrey P. Colby reports a relationship with Cerenovus that includes: consulting or advisory. Geoffrey P. Colby reports a relationship with Rapid Medical that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The gastrointestinal (GI) tract is innervated by intrinsic neurons of the enteric nervous system (ENS) and extrinsic neurons of the central nervous system and peripheral ganglia. The GI tract also harbors a diverse microbiome, but interactions between the ENS and the microbiome remain poorly understood. Here, we activate choline acetyltransferase (ChAT)-expressing or tyrosine hydroxylase (TH)-expressing gut-associated neurons in mice to determine effects on intestinal microbial communities and their metabolites as well as on host physiology. The resulting multi-omics datasets support broad roles for discrete peripheral neuronal subtypes in shaping microbiome structure, including modulating bile acid profiles and fungal colonization. Physiologically, activation of either ChAT + or TH + neurons increases fecal output, while only ChAT + activation results in increased colonic contractility and diarrhea-like fluid secretion. These findings suggest that specific subsets of peripherally activated neurons differentially regulate the gut microbiome and GI physiology in mice without involvement of signals from the brain., Competing Interests: Declaration of interests B.B.Y. declares financial interests in Nuanced Health, which is not related to the present study. S.K.M. declares financial interests in Axial Therapeutics and Nuanced Health, which is not related to the present study. P.C.D. is an advisor and holds equity in Cybele and Sirenas and is a scientific co-founder and advisor and holds equity to Ometa, Enveda, and Arome with prior approval by University of California, San Diego. He also consulted for DSM animal health in 2023. R.K. is a scientific advisory board member and consultant for BiomeSense, Inc.; has equity, and receives income. He is a scientific advisory board member of and has equity in GenCirq. He is a consultant and scientific advisory board member for DayTwo and receives income. He has equity in and acts as a consultant for Cybele. He is a co-founder of Biota, Inc. and has equity. He is a cofounder of Micronoma, has equity, and is a scientific advisory board member. The terms of these arrangements have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Narrowing of the lumbar spinal canal, or lumbar stenosis (LS), may cause debilitating radicular pain or muscle weakness. It is the most frequent indication for spinal surgery in the elderly population. Modern diagnosis relies on magnetic resonance imaging and its inherently subjective interpretation. Diagnostic rigor, accuracy, and speed may be improved by automation. In this work, we aimed to determine whether a deep-U-Net ensemble trained to segment spinal canals on a heterogeneous mix of clinical data is comparable to radiologists' segmentation of these canals in patients with LS., Methods: The deep U-nets were trained on spinal canals segmented by physicians on 100 axial T2 lumbar magnetic resonance imaging selected randomly from our institutional database. Test data included a total of 279 elderly patients with LS that were separate from the training set., Results: Machine-generated segmentations (MA) were qualitatively similar to expert-generated segmentations (M E1 , M E2 ). Machine- and expert-generated segmentations were quantitatively similar, as evidenced by Dice scores (MA vs. M E1 : 0.88 ± 0.04, MA vs. M E2 : 0.89 ± 0.04), the Hausdorff distance (MA vs. M E1 : 11.7 mm ± 13.8, MA vs. M E2 : 13.1 mm ± 16.3), and average surface distance (MAvs. M E1 : 0.18 mm ± 0.13, MA vs. M E2 0.18 mm ± 0.16) metrics. These metrics are comparable to inter-rater variation (M E1 vs. M E2 Dice scores: 0.94 ± 0.02, the Hausdorff distances: 9.3 mm ± 15.6, average surface distances: 0.08 mm ± 0.09)., Conclusion: We conclude that machine learning algorithms can segment lumbar spinal canals in LS patients, and automatic delineations are both qualitatively and quantitatively comparable to expert-generated segmentations., (Published by Elsevier Inc.)

Background and Purpose: Treatment of acute ischemic stroke is heavily contingent upon time, as there is a strong relationship between time clock and tissue progression. Work has established imaging biomarker assessments as surrogates for time since stroke (TSS), namely, by comparing signal mismatch between diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) imaging. Our goal was to develop an automatic technique for determining TSS from imaging that does not require subspecialist radiology expertise., Methods: Using 772 patients (66 ± 9 years, 319 women), we developed and externally evaluated a deep learning network for classifying TSS from MR images and compared algorithm predictions to neuroradiologist assessments of DWI-FLAIR mismatch. Models were trained to classify TSS within 4.5 hours and performance metrics with confidence intervals were reported on both internal and external evaluation sets., Results: Three board-certified neuroradiologists' DWI-FLAIR mismatch assessments, based on majority vote, yielded a sensitivity of .62, a specificity of .86, and a Fleiss' kappa of .46 when used to classify TSS. The deep learning method performed similarly to radiologists and outperformed previously reported methods, with the best model achieving an average evaluation accuracy, sensitivity, and specificity of .726, .712, and .741, respectively, on an internal cohort and .724, .757, and .679, respectively, on an external cohort., Conclusion: Our model achieved higher generalization performance on external evaluation datasets than the current state-of-the-art for TSS classification. These results demonstrate the potential of automatic assessment of onset time from imaging without the need for expertly trained radiologists., (© 2022 American Society of Neuroimaging.)

Collateral status has prognostic and treatment implications in acute ischemic stroke (AIS) patients. Unlike CTA, grading collaterals on MRA is not well studied. We aimed to evaluate the accuracy of assessing collaterals on pretreatment MRA in AIS patients against DSA. AIS patients with anterior circulation proximal arterial occlusion with baseline MRA and subsequent endovascular treatment were included. MRA collaterals were evaluated by two neuroradiologists independently using the Tan and Maas scoring systems. DSA collaterals were evaluated by using the American Society of Interventional and Therapeutic Neuroradiology grading system and were used as the reference for comparative analysis against MRA. A total of 104 patients met the inclusion criteria (59 female, age (mean ± SD): 70.8 ± 18.1). The inter-rater agreement ( k ) for collateral scoring was 0.49, 95% CI 0.37-0.61 for the Tan score and 0.44, 95% CI 0.26-0.62 for the Maas score. Total number (%) of sufficient vs. insufficient collaterals based on DSA was 49 (47%) and 55 (53%) respectively. Using the Tan score, 45% of patients with sufficient collaterals and 64% with insufficient collaterals were correctly identified in comparison to DSA, resulting in a poor agreement (0.09, 95% CI 0.1-0.28). Using the Maas score, only 4% of patients with sufficient collaterals and 93% with insufficient collaterals were correctly identified against DSA, resulting in poor agreement (0.03, 95% CI 0.06-0.13). Pretreatment MRA in AIS patients has limited concordance with DSA when grading collaterals using the Tan and Maas scoring systems.

Background: Since IDH-mutant (mIDH) low-grade gliomas (LGGs) progress slowly and have a relatively long survival, there is a significant need for earlier measurements of clinical benefit. Guidance using the LGG RANO criteria recommends serial bidirectional (2D) measurements on a single slice; however, questions remain as to whether volumetric (3D) measurements are better, since they would allow for more accurate measurements in irregular shaped lesions and allow readers to better assess areas of subtle change., Methods: Twenty-one (out of 24) non-enhancing, recurrent mIDH1 LGGs were enrolled in a phase I, multicenter, open-label study of oral ivosidenib (NCT02073994), and with imaging pre- and post-treatment as part of this exploratory ad hoc analysis. 2D and 3D measurements on T2-weighted FLAIR images were centrally evaluated at an imaging contract research organization using a paired read and forced adjudication paradigm. The effects of 2D vs 3D measurements on progression-free survival (PFS), growth rate measurement variability, and reader concordance and adjudication rates were quantified., Results: 3D volumetric measurements showed significantly longer estimated PFS (P = .0181), more stable (P = .0063) and considerably slower measures of tumor growth rate (P = .0037), the highest inter-reader agreement (weighted kappa = 0.7057), and significantly lower reader discordance rates (P = .0002) with 2D LGG RANO., Conclusion: 3D volumetric measurements are better for determining response assessment in LGGs due to more stable measures of tumor growth rates (ie, less "yo-yo-ing" of measurements over time), highest inter-reader agreement, and lowest reader discordance rates. Continued evaluation in future studies is warranted to determine whether these measurements reflect clinical benefit., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

State-of-the-art diagnosis of radiculopathy relies on "highly subjective" radiologist interpretation of magnetic resonance imaging of the lower back. Currently, the treatment of lumbar radiculopathy and associated lower back pain lacks coherence due to an absence of reliable, objective diagnostic biomarkers. Using emerging machine learning techniques, the subjectivity of interpretation may be replaced by the objectivity of automated analysis. However, training computer vision methods requires a curated database of imaging data containing anatomical delineations vetted by a team of human experts. In this chapter, we outline our efforts to develop such a database of curated imaging data alongside the required delineations. We detail the processes involved in data acquisition and subsequent annotation. Then we explain how the resulting database can be utilized to develop a machine learning-based objective imaging biomarker. Finally, we present an explanation of how we validate our machine learning-based anatomy delineation algorithms. Ultimately, we hope to allow validated machine learning models to be used to generate objective biomarkers from imaging data-for clinical use to diagnose lumbar radiculopathy and guide associated treatment plans., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature.)

Treating acute ischemic stroke (AIS) patients is a time-sensitive endeavor, as therapies target areas experiencing ischemia to prevent irreversible damage to brain tissue. Depending on how an AIS is progressing, thrombolytics such as tissue-plasminogen activator (tPA) may be administered within a short therapeutic window. The underlying conditions for optimal treatment are varied. While previous clinical guidelines only permitted tPA to be administered to patients with a known onset within 4.5 hours, clinical trials demonstrated that patients with signal intensity differences between diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) sequences in an MRI study can benefit from thrombolytic therapy. This intensity difference, known as DWI-FLAIR mismatch, is prone to high inter-reader variability. Thus, a paradigm exists where onset time serves as a weak proxy for DWI-FLAIR mismatch. In this study, we sought to detect DWI-FLAIR mismatch in an automated fashion, and we compared this to assessments done by three expert neuroradiologists. Our approach involved training a deep learning model on MRI to classify tissue clock and leveraging time clock as a weak proxy label to supplement training in a semi-supervised learning (SSL) framework. We evaluate our deep learning model by testing it on an unseen dataset from an external institution. In total, our proposed framework was able to improve detection of DWI-FLAIR mismatch, achieving a top ROC-AUC of 74.30%. Our study illustrated that incorporating clinical proxy information into SSL can improve model optimization by increasing the fidelity of unlabeled samples included in the training process.

Mechanical thrombectomy (MTB) is one of the two standard treatment options for Acute Ischemic Stroke (AIS) patients. Current clinical guidelines instruct the use of pretreatment imaging to characterize a patient's cerebrovascular flow, as there are many factors that may underlie a patient's successful response to treatment. There is a critical need to leverage pretreatment imaging, taken at admission, to guide potential treatment avenues in an automated fashion. The aim of this study is to develop and validate a fully automated machine learning algorithm to predict the final modified thrombolysis in cerebral infarction (mTICI) score following MTB. A total 321 radiomics features were computed from segmented pretreatment MRI scans for 141 patients. Successful recanalization was defined as mTICI score >= 2c. Different feature selection methods and classification models were examined in this study. Our best performance model achieved 74.42±2.52% AUC, 75.56±4.44% sensitivity, and 76.75±4.55% specificity, showing a good prediction of reperfusion quality using pretreatment MRI. Results suggest that MR images can be informative to predicting patient response to MTB, and further validation with a larger cohort can determine the clinical utility.

Background and Purpose: Clot fragmentation and distal embolization during endovascular thrombectomy for acute ischemic stroke may produce emboli downstream of the target occlusion or in previously uninvolved territories. Susceptibility-weighted magnetic resonance imaging can identify both emboli to distal territories (EDT) and new territories (ENT) as new susceptibility vessel signs (SVS). Diffusion-weighted imaging (DWI) can identify infarcts in new territories (INT)., Methods: We studied consecutive acute ischemic stroke patients undergoing magnetic resonance imaging before and after thrombectomy. Frequency, predictors, and outcomes of EDT and ENT detected on gradient-recalled echo imaging (EDT-SVS and ENT-SVS) and INT detected on DWI (INT-DWI) were analyzed., Results: Among 50 thrombectomy-treated acute ischemic stroke patients meeting study criteria, mean age was 70 (±16) years, 44% were women, and presenting National Institutes of Health Stroke Scale score 15 (interquartile range, 8–19). Overall, 21 of 50 (42%) patients showed periprocedural embolic events, including 10 of 50 (20%) with new EDT-SVS, 10 of 50 (20%) with INT-DWI, and 1 of 50 (2%) with both. No patient showed ENT-SVS. On multivariate analysis, model-selected predictors of EDT-SVS were lower initial diastolic blood pressure (odds ratio, 1.09 [95% CI, 1.02–1.16]), alteplase pretreatment (odds ratio, 5.54 [95% CI, 0.94–32.49]), and atrial fibrillation (odds ratio, 7.38 [95% CI, 1.02–53.32]). Classification tree analysis identified pretreatment target occlusion SVS as an additional predictor. On univariate analysis, INT-DWI was less common with internal carotid artery (5%), intermediate with middle cerebral artery (25%), and highest with vertebrobasilar (57%) target occlusions (P=0.02). EDT-SVS was not associated with imaging/functional outcomes, but INT-DWI was associated with reduced radiological hemorrhagic transformation (0% versus 54%; P<0.01)., Conclusions: Among acute ischemic stroke patients treated with thrombectomy, imaging evidence of distal emboli, including EDT-SVS beyond the target occlusion and INT-DWI in novel territories, occur in about 2 in every 5 cases. Predictors of EDT-SVS are pretreatment intravenous fibrinolysis, potentially disrupting thrombus structural integrity; atrial fibrillation, possibly reflecting larger target thrombus burden; lower diastolic blood pressure, suggestive of impaired embolic washout; and pretreatment target occlusion SVS sign, indicating erythrocyte-rich, friable target thrombus.

Background: The referral process for consultation with a spine surgeon remains inefficient, given a substantial proportion of referrals to spine surgeons are nonoperative., Objective: To develop a machine-learning-based algorithm which accurately identifies patients as candidates for consultation with a spine surgeon, using only magnetic resonance imaging (MRI)., Methods: We trained a deep U-Net machine learning model to delineate spinal canals on axial slices of 100 normal lumbar MRI scans which were previously delineated by expert radiologists and neurosurgeons. We then tested the model against lumbar MRI scans for 140 patients who had undergone lumbar spine MRI at our institution (60 of whom ultimately underwent surgery, and 80 of whom did not). The model generated automated segmentations of the lumbar spinal canals and calculated a maximum degree of spinal stenosis for each patient, which served as our biomarker for surgical pathology warranting expert consultation., Results: The machine learning model correctly predicted surgical candidacy (ie, whether patients ultimately underwent lumbar spinal decompression) with high accuracy (area under the curve = 0.88), using only imaging data from lumbar MRI scans., Conclusion: Automated interpretation of lumbar MRI scans was sufficient to correctly determine surgical candidacy in nearly 90% of cases. Given that a significant proportion of referrals placed for spine surgery evaluation fail to meet criteria for surgical intervention, our model could serve as a valuable tool for patient triage and thereby address some of the inefficiencies within the outpatient surgical referral process., (© Congress of Neurological Surgeons 2021.)

Treatment of acute ischemic strokes (AIS) is largely contingent upon the time since stroke onset (TSS). However, TSS may not be readily available in up to 25% of patients with unwitnessed AIS. Current clinical guidelines for patients with unknown TSS recommend the use of MRI to determine eligibility for thrombolysis, but radiology assessments have high inter-reader variability. In this work, we present deep learning models that leverage MRI diffusion series to classify TSS based on clinically validated thresholds. We propose an intra-domain task-adaptive transfer learning method, which involves training a model on an easier clinical task (stroke detection) and then refining the model with different binary thresholds of TSS. We apply this approach to both 2D and 3D CNN architectures with our top model achieving an ROC-AUC value of 0.74, with a sensitivity of 0.70 and a specificity of 0.81 for classifying TSS < 4.5 h. Our pretrained models achieve better classification metrics than the models trained from scratch, and these metrics exceed those of previously published models applied to our dataset. Furthermore, our pipeline accommodates a more inclusive patient cohort than previous work, as we did not exclude imaging studies based on clinical, demographic, or image processing criteria. When applied to this broad spectrum of patients, our deep learning model achieves an overall accuracy of 75.78% when classifying TSS < 4.5 h, carrying potential therapeutic implications for patients with unknown TSS., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Multimodal MR imaging provides valuable information in the management of patients with acute ischemic stroke (AIS), with diagnostic, therapeutic, and prognostic implications. MR imaging plays a critical role in treatment decision making for (1) thrombolytic treatment of AIS patients with unknown symptom-onset and (2) endovascular treatment of patients with large vessel occlusion presenting beyond 6 hours from the symptom onset. MR imaging provides the most accurate information for detection of ischemic brain and is invaluable for differentiating AIS from stroke mimics., Competing Interests: Disclosure None., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Manual delineation of anatomy on existing images is the basis of developing deep learning algorithms for medical image segmentation. However, manual segmentation is tedious. It is also expensive because clinician effort is necessary to ensure correctness of delineation. Consequently most algorithm development is based on a tiny fraction of the vast amount of imaging data collected at a medical center. Thus, selection of a subset of images from hospital databases for manual delineation - so that algorithms trained on such data are accurate and tolerant to variation, becomes an important challenge. We address this challenge using a novel algorithm. The proposed algorithm named 'Eigenrank by Committee' (EBC) first computes the degree of disagreement between segmentations generated by each DL model in a committee. Then, it iteratively adds to the committee, a DL model trained on cases where the disagreement is maximal. The disagreement between segmentations is quantified by the maximum eigenvalue of a Dice coefficient disagreement matrix a measure closely related to the Von Neumann entropy. We use EBC for selecting data subsets for manual labeling from a larger database of spinal canal segmentations as well as intervertebral disk segmentations. U-Nets trained on these subsets are used to generate segmentations on the remaining data. Similar sized data subsets are also randomly sampled from the respective databases, and U-Nets are trained on these random subsets as well. We found that U-Nets trained using data subsets selected by EBC, generate segmentations with higher average Dice coefficients on the rest of the database than U-Nets trained using random sampling (p < 0.05 using t-tests comparing averages). Furthermore, U-Nets trained using data subsets selected by EBC generate segmentations with a distribution of Dice coefficients that demonstrate significantly (p < 0.05 using Bartlett's test) lower variance in comparison to U-Nets trained using random sampling for all datasets. We believe that this lower variance indicates that U-Nets trained with EBC are more robust than U-Nets trained with random sampling., Competing Interests: Declaration of Competing Interest Bilwaj Gaonkar and Luke Macyszyn declare stock ownership in Theseus AI, a start up entity spun out of UCLA., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: MRI and CT modalities are both current standard-of-care options for initial imaging in patients with acute ischemic stroke due to large vessel occlusion (AIS-LVO). MR provides greater lesion conspicuity and spatial resolution, but few series have demonstrated multimodal MR may be performed efficiently., Methods: In a prospective comprehensive stroke center registry, we analyzed all anterior circulation LVO thrombectomy patients between 2012-2017 who: (1) arrived directly by EMS from the field, and (2) had initial NIHSS ≥6. Center imaging policy was multimodal MRI (including DWI/GRE/MRA w/wo PWI) as the initial evaluation in all patients without contraindications, and multimodal CT (including CT with CTA, w/wo CTP) in the remainder., Results: Among 106 EMS-arriving endovascular thrombectomy patients, initial imaging was MRI 62.3%, CT in 37.7%. MRI and CT patients were similar in age (72.5 vs 71.3), severity (NIHSS 16.4 v 18.2), and medical history, though MRI patients had longer onset-to-door times. Overall, door-to-needle (DTN) and door-to-puncture (DTP) times did not differ among MR and CT patients, and were faster for both modalities in 2015-2017 versus 2012-2014. In the 2015-2017 period, for MR-imaged patients, the median DTN 42m (IQR 34-55) surpassed standard (60m) and advanced (45m) national targets and the median DTP 86m (IQR 71-106) surpassed the standard national target (90m)., Conclusions: AIS-LVO patients can be evaluated by multimodal MR imaging with care speeds faster than national recommendations for door-to-needle and door-to-puncture times. With its more sensitive lesion identification and spatial resolution, MRI remains a highly viable primary imaging strategy in acute ischemic stroke patients, though further workflow efficiency improvements are desirable., (Published by Elsevier Inc.)

Purpose: Although magnetic resonance imaging (MRI) and 18 F-2-fluorodeoxyglucose-positron emission tomography (FDG-PET) are used for pre-surgical assessment of focal cortical dysplasia (FCD), they often disagree. This study aimed to identify factors that contribute to discrepancies in FCD imaging between MRI and FDG-PET., Methods: Sixty-two patients (mean age, 18.9 years) with a FCD type I or II were retrospectively selected. These patients were visually categorized into two groups: 1) extent of PET abnormality larger than MRI abnormality and 2) vice versa or equivalent. Predictive factors of these two groups were analyzed by multivariate logistic regression. The extent of hypometabolic transient zone surrounding FCDs and their mean standardized uptake values were measured and compared by the Mann-Whitney U-test., Results: FCDs were detected on MRI and PET in 46 and 55 patients, respectively, whereas no abnormality was detected in 4 patients. The PET hypometabolic areas were larger than the MRI abnormal areas in 26 patients (88 % in the temporal lobe), whereas the PET hypometabolic areas were equivalent or smaller than the MRI abnormal areas in 32 patients (69 % in the frontal lobe). The temporal lobe location was an independent predictor for differentiating the two groups (OR = 35.2, 95 % CI = 6.81-168.0, P < .001). The temporal lobe lesions had significantly wider transient zones and lower standardized uptake values than those in the other lobes (P < .001, both)., Conclusion: The discrepancies between MRI and FDG-PET findings of FCD were associated with temporal lobe location., (Copyright © 2020 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Background and Purpose: We aimed to delineate the determinants of the initial speed of infarct progression and the association of speed of infarct progression (SIP) with procedural and functional outcomes., Methods: From a prospectively maintained stroke center registry, consecutive anterior circulation ischemic stroke patients with large artery occlusion, National Institutes of Health Stroke Scale score ≥4, and multimodal vessel, ischemic core, and tissue-at-risk imaging within 24 hours of onset were included. Initial SIP was calculated as ischemic core volume at first imaging divided by the time from stroke onset to imaging., Results: Among the 88 patients, SIP was median 2.2 cc/h (interquartile range, 0-8.7), ranging most widely within the first 6 hours after onset. Faster SIP was positively independently associated with a low collateral score (odds ratio [OR], 3.30 [95% CI, 1.25-10.49]) and arrival by emergency medical services (OR, 3.34 [95% CI, 1.06-10.49]) and negatively associated with prior ischemic stroke (OR, 0.12 [95% CI, 0.03-0.50]) and coronary artery disease (OR, 0.32 [95% CI, 0.10-1.00]). Among the 67 patients who underwent endovascular thrombectomy, slower SIP was associated with a shift to reduced levels of disability at discharge (OR, 3.26 [95% CI, 1.02-10.45]), increased substantial reperfusion by thrombectomy (OR, 8.30 [95% CI, 0.97-70.87]), and reduced radiological hemorrhagic transformation (OR, 0.34 [95% CI, 0.12-0.94])., Conclusions: Slower SIP is associated with a high collateral score, prior ischemic stroke, and coronary artery disease, supporting roles for both collateral robustness and ischemic preconditioning in fostering tissue resilience to ischemia. Among patients undergoing endovascular thrombectomy, the speed of infarct progression is a major determinant of clinical outcome.

Background: MRI exams for patients with MR-conditional active implantable medical devices (AIMDs) are contraindicated unless specific conditions are met. This limits the maximum specific absorption rate (SAR, W/kg). Currently, there is no general framework to guide meeting a lower SAR limit., Purpose: To design and evaluate a workflow for modifying MRI protocols to whole-body SAR (WB-SAR ≤0.1 W/kg) and local-head SAR (LH-SAR ≤0.3 W/kg) limits while mitigating the impact on image quality and exam time., Study Type: Prospective., Population: Twenty healthy volunteers on head (n = 5), C-spine (n = 5), T-spine (n = 5), and L-spine (n = 5) with IRB consent., Assessment: Vendor-provided head, C-spine, T-spine, and L-spine protocols (SAR RT ) were modified to meet both low SAR targets (SAR LOW ) using the proposed workflow. in vitro SNR and CNR were evaluated with a T 1 -T 2 phantom. in vivo image quality and clinical acceptability were scored using a 5-point Likert scale for two blinded readers., Field Strength/sequences: 1.5T/spin-echoes, gradient-echoes., Statistical Analysis: In vitro SNR and CNR values were evaluated with a repeated measures general linear model. in vivo image quality and clinical acceptability were evaluated using a generalized estimating equation analysis (GEE). The two reader's level of agreement was analyzed using Cohen's kappa statistical analysis., Results: Using the workflow, SAR limits were met., Lh-Sar: 0.12 ± 0.02 W/kg, median (SD) values for LH-SAR were 0.12 (0.02) W/kg and WB-SAR: 0.09 (0.01) W/kg. Examination time did not increase ≤2x the initial time. SAR RT SNR values were higher and significantly different than SAR LOW (P < 0.05). However, no significant difference was observed between the CNR values (value = 0.21). Median (IQR) CNR values were 14.2 (25.0) vs. 15.1 (9.2) for head, 12.1 (16.9) vs. 25.3 (14.2) for C-spine, 81.6 (70.1) vs. 71.0 (26.6) for T-spine, and 51.4 (52.6) vs. 37.7 (27.3) for L-spine. Image quality scores were not significantly different between SAR RT and SAR LOW (median [SD] scores were 4.0 [0.01] vs. 4.3 [0.2], P > 0.05)., Data Conclusion: The proposed workflow provides guidance for modifying routine MRI exams to achieve low SAR limits. This can benefit patients referred for an MRI exam with low SAR MR-conditional AIMDs., Level of Evidence: 1 Technical Efficacy Stage: 5 J. Magn. Reson. Imaging 2020;52:91-102., (© 2020 International Society for Magnetic Resonance in Medicine.)

Parkinson's disease is a synucleinopathy that is characterized by motor dysfunction, death of midbrain dopaminergic neurons and accumulation of α-synuclein (α-Syn) aggregates. Evidence suggests that α-Syn aggregation can originate in peripheral tissues and progress to the brain via autonomic fibers. We tested this by inoculating the duodenal wall of mice with α-Syn preformed fibrils. Following inoculation, we observed gastrointestinal deficits and physiological changes to the enteric nervous system. Using the AAV-PHP.S capsid to target the lysosomal enzyme glucocerebrosidase for peripheral gene transfer, we found that α-Syn pathology is reduced due to the increased expression of this protein. Lastly, inoculation of α-Syn fibrils in aged mice, but not younger mice, resulted in progression of α-Syn histopathology to the midbrain and subsequent motor defects. Our results characterize peripheral synucleinopathy in prodromal Parkinson's disease and explore cellular mechanisms for the gut-to-brain progression of α-Syn pathology.

Background and Purpose: Endovascular therapy (ET) has become the standard of care for selected patients with acute ischemic stroke (AIS) due to large vessel occlusion (LVO). However, many LVO or medium vessel occlusion (MVO) patients are ineligible for ET, including some who harbor salvageable tissues. To develop complementary therapies for these patients, it is important to delineate their prevalence, clinical features, and outcomes., Methods: In a prospectively maintained database, we reviewed consecutive AIS patients between December 2015 and September 2016. Based on the first multimodal computed tomography or magnetic resonance imaging, patients were categorized as having substantial penumbra if perfusion lesion volume (Tmax >6 seconds) exceeded ischemic core volume (relative cerebral blood flow <30% on CT perfusion or apparent diffusion coefficient <620 on diffusion weighted image) by ≥20%., Results: Among 174 consecutive AIS patients presenting within 24 hours of last known well time, 29 (17%) had LVO or MVO and substantial penumbra, but were deemed ET ineligible. Among these patients, mean age was 81 (±13), 45% were female, and median National Institute of Health Stroke Scale score was 11 (interquartile range [IQR]: 5-19). The most common reasons for not pursuing ET were: distal occlusion (28%), mild neurologic deficit (16%), and temporally advanced core injury (16%). Ischemic core volume was 20 mL (±31), penumbral volume was 54 mL (±63), and mismatch ratio median was 5.6 (IQR: 2-infinite). Severe disability or death at discharge (modified Rankin scale: 4-6) occurred in 72% of the patients., Conclusion: Even in the modern stent retriever era, 1 in 6 AIS patients presents with substantial penumbra judged not appropriate for ET. This population may benefit from the development of alternative therapies, including collateral enhancement, neuroprotection, and thrombectomy devices deployable in distal arteries., (© 2018 by the American Society of Neuroimaging.)

The decline of tissue regenerative potential with age correlates with impaired stem cell function. However, limited strategies are available for therapeutic modulation of stem cell function during aging. Using skeletal muscle stem cells (MuSCs) as a model system, we identify cell death by mitotic catastrophe as a cause of impaired stem cell proliferative expansion in aged animals. The mitotic cell death is caused by a deficiency in Notch activators in the microenvironment. We discover that ligand-dependent stimulation of Notch activates p53 in MuSCs via inhibition of Mdm2 expression through Hey transcription factors during normal muscle regeneration and that this pathway is impaired in aged animals. Pharmacologic activation of p53 promotes the expansion of aged MuSCs in vivo. Altogether, these findings illuminate a Notch-p53 signaling axis that plays an important role in MuSC survival during activation and is dysregulated during aging, contributing to the age-related decline in muscle regenerative potential., (Published by Elsevier Inc.)

Skeletal muscle is ideal for passive vaccine administration as it is easily accessible by intramuscular injection. Recombinant adeno-associated virus (rAAV) vectors are in consideration for passive vaccination clinical trials for HIV and influenza. However, greater human skeletal muscle transduction is needed for therapeutic efficacy than is possible with existing serotypes. To bioengineer capsids with therapeutic levels of transduction, we utilized a directed evolution approach to screen libraries of shuffled AAV capsids in pools of surgically resected human skeletal muscle cells from five patients. Six rounds of evolution were performed in various muscle cell types, and evolved variants were validated against existing muscle-tropic serotypes rAAV1, 6, and 8. We found that evolved variants NP22 and NP66 had significantly increased primary human and rhesus skeletal muscle fiber transduction from surgical explants ex vivo and in various primary and immortalized myogenic lines in vitro . Importantly, we demonstrated reduced seroreactivity compared to existing serotypes against normal human serum from 50 adult donors. These capsids represent powerful tools for human skeletal muscle expression and secretion of antibodies from passive vaccines.

We have reviewed the English literature published in the last 70 years on Diseases of the Vertebral Basilar Circulation, or Posterior Circulation Disease (PCD). We have found that errors have been made in the conduct and interpretation of these studies that have led to incorrect approaches to the management of PCD. Because of the difficulty in evaluating the PC, the management of PCD has been incorrectly applied from anterior circulation disease (ACD) experience to PCD. PCD is a common form of stroke affecting 20-40% patients with stroke. Yet, the evidence is strong that the Anterior Circulation (AC) and Posterior Circulations (PC) differ in their pathology, in their clinical presentations, in the rapidity of development of symptoms, in optimal imaging methods, and in available treatments. There appears to be two categories of patients who present with PCD. The first, acute basilar artery occlusion has a more rapid onset. The diagnosis must be made quickly and if imaging proves a diagnosis of Basilar Artery Occlusion (BAO), the treatment of choice is Interventional removal of the basilar artery thrombosis or embolus. The second category of PCD and the most commonly seen PCD disease process presents with non-specific symptoms and early warnings of PCD that now can be related to ischemic events in the entire PC vessels. These warning symptoms and signs occur much earlier than those in the AC. IA angiography is still the gold standard of diagnosis and is superior in definition to MR and CT angiography which are commonly used as a convenient screening imaging tool to evaluate PCD but are both inferior to IA angiography in definition for lesions below 3-4 mm. In at least two reported studies 7T MR angiography appears superior to other imaging modalities and will become the gold standard of imaging of PCD in the future. Medical treatments applied to the ACD have not been proven of value in specific forms of PCD. Interventional therapy was promising but of unproven value in Randomized Controlled Trials (RCT) except for the treatment of Basilar Artery Occlusion (BAO). Surgical revascularization has been proved to be highly successful in patients, who are refractory to medical therapy. These studies have been ignored by the scientific community basically because of an incorrect interpretation of the flawed EC-IC Bypass Trial in 1985 as applying to all stroke patients. Moreover, the EC-IC Bypass Study did not include PCD patients in their study population, but the study results were extrapolated to patients with PCD without any scientific basis. This experience led clinicians to an incorrect bias that surgical treatments are of no value in PCD. Thus, incorrectly, surgical treatments of PCD have not been considered among the therapeutic possibilities for PCD. QMRA is a new quantitative MR technique that measures specific blood flow in extra and intracranial vessels. QMRA has been used to select those patients who may benefit from medical, or interventional, or surgical treatment for PCD based on flow determinations with a high success rate. QMRA accurately predicts the flows in many large and small vessels in the PC and AC and clearly indicates that both circulations are intimately related. From medical and surgical studies, the longer one waits for surgical treatment the higher the risk of a poor outcome results. This observation becomes obvious when the rapidity of development of PCD is compared with ACD. Recent advances in endovascular therapy in the treatment of acute basilar thrombosis is a clear sign that early diagnosis and treatment of PCD will reduce the morbidity and mortality of these diseases. In this review it is evident that there are multiple medical and surgical treatments for PCD depending upon the location of the lesion(s) and the collateral circulation demonstrated. It is clear that the AC and PC have significant differences. With the exception of the large population studies from Oxford England, the reported studies on the management of PCD in the literature represent small selected subsets of the universe of PC diseases, the information from which is not generalizable to the universe of PCD patients. At this point in the history of PCD, there are not large enough databases of similar patients to provide a basis for valid randomized studies, with the exception of the surgical studies. Thus, a high index of suspicion of the early warning symptoms of PCD should lead to a rapid individual clinical assessment of patients selecting those with PCD. Medical, interventional, and/or surgical treatments should be chosen based on knowledge presented in this review. Recording the results in a national Registry on a continuing basis will provide the data that may help advance the management of PCD based on larger data bases of well documented patient information to guide the selection of future therapies for PCD treatments. It is also clear that the management of patients within the complex of diseases that comprise PCD should be performed in centers with expertise in the imaging, medical, interventional and surgical approaches to diseases of the PCD., Competing Interests: There are no conflicts of interest.

The purpose of this study was to develop and evaluate a scoring system for assessing reperfusion status based on arterial spin labeled (ASL) perfusion MRI in acute ischemic stroke (AIS) patients receiving thrombolysis and/or endovascular treatment. Pseudo-continuous ASL with background suppressed 3D GRASE was acquired along with DWI in 90 patients within 24 h post-treatment. An automatic reperfusion scoring system (auto-RPS) was devised based on the Alberta Stroke Program Early CT Score (ASPECTS) template, and compared with manual RPS and DWI-ASPECTS. TICI (thrombolysis in cerebral infarction) scores were graded in 48 patients who received endovascular treatment. Favorable outcomes were defined by a modified Rankin Scale score of 0-2 at three months. Auto-RPS was positively correlated with DWI-ASPECTS (ρ = 0.6, P < 0.001) and was on average 1 point lower than DWI-ASPECTS ( P < 0.001). The area under the receiver operating characteristic curve for discriminating poor functional outcome (n = 90) was 0.75 (95% CI, 0.64-0.86) for manual RPS, 0.85 (95% CI, 0.76-0.94) for auto-RPS, and 0.81 (95% CI, 0.71-0.90) for DWI-ASPECTS. Multiple logistic regression analysis in the TICI-graded patients (n = 48) showed that auto-RPS is highly associated with functional outcome (OR = 25.2, 95% CI 4.02-496, P < 0.01). Post treatment auto-RPS within 24 h provides a useful tool to predict functional outcome in AIS patients.

The gut microbiota regulates T cell functions throughout the body. We hypothesized that intestinal bacteria impact the pathogenesis of multiple sclerosis (MS), an autoimmune disorder of the CNS and thus analyzed the microbiomes of 71 MS patients not undergoing treatment and 71 healthy controls. Although no major shifts in microbial community structure were found, we identified specific bacterial taxa that were significantly associated with MS. Akkermansia muciniphila and Acinetobacter calcoaceticus , both increased in MS patients, induced proinflammatory responses in human peripheral blood mononuclear cells and in monocolonized mice. In contrast, Parabacteroides distasonis , which was reduced in MS patients, stimulated antiinflammatory IL-10-expressing human CD4 + CD25 + T cells and IL-10 + FoxP3 + Tregs in mice. Finally, microbiota transplants from MS patients into germ-free mice resulted in more severe symptoms of experimental autoimmune encephalomyelitis and reduced proportions of IL-10 + Tregs compared with mice "humanized" with microbiota from healthy controls. This study identifies specific human gut bacteria that regulate adaptive autoimmune responses, suggesting therapeutic targeting of the microbiota as a treatment for MS., Competing Interests: The authors declare no conflict of interest.

Cortical microinfarcts (CMIs) are microscopically identified wedge-shaped ischemic lesions that occur at or near the cortical surface and result from occlusion of penetrating arterioles. These microscopic lesions can be observed with high-resolution magnetic resonance imaging in aging brains and in patients with cerebrovascular disease. Recent studies have suggested that strategically located microinfarcts strongly correlate with cognitive deficits, which can contribute to Alzheimer's disease as well as other forms of dementia. We have recently shown that the molecular organization of axons into functional microdomains is altered in areas adjacent to white matter lacunar and microinfarcts, creating a peri-infarct penumbral injury in surviving axons. Whether similar changes in nodal, adjacent paranodal, and proximal axon initial segment molecular organization occur in the cortex adjacent to human CMIs is not known. Paraffin-embedded sections of autopsy brain tissue from five patients with CMIs were immunofluorescently labeled for nodal and paranodal markers including beta-IV spectrin, ankyrin-G, and contactin-associated protein. High magnification images from the peri-infarct cortical tissue were generated using confocal microscopy. In surviving cortical tissue adjacent to microinfarcts, we observed a dramatic loss of axon initial segments, suggesting that neuronal firing capacity in adjacent cortical tissue is likely compromised. The number of identifiable nodal/paranodal complexes in surviving cortical tissue is reduced adjacent to microinfarcts, while the average paranodal length is increased indicating a breakdown of axoglial contact. This axonal microdomain disorganization occurs in the relative absence of changes in the structural integrity of myelinated axons as measured by myelin basic protein and neurofilament staining. These findings indicate that the molecular organization of surviving axons adjacent to human CMIs is abnormal, reflecting lost axoglial contact and the functional elements necessary for neural transmission. This study provides support for the concept of a microinfarct penumbral injury that may account for the cumulative cognitive effect of these tiny strokes.

Adeno-associated viruses (AAVs) are commonly used for in vivo gene transfer. Nevertheless, AAVs that provide efficient transduction across specific organs or cell populations are needed. Here, we describe AAV-PHP.eB and AAV-PHP.S, capsids that efficiently transduce the central and peripheral nervous systems, respectively. In the adult mouse, intravenous administration of 1 × 10 11 vector genomes (vg) of AAV-PHP.eB transduced 69% of cortical and 55% of striatal neurons, while 1 × 10 12 vg of AAV-PHP.S transduced 82% of dorsal root ganglion neurons, as well as cardiac and enteric neurons. The efficiency of these vectors facilitates robust cotransduction and stochastic, multicolor labeling for individual cell morphology studies. To support such efforts, we provide methods for labeling a tunable fraction of cells without compromising color diversity. Furthermore, when used with cell-type-specific promoters and enhancers, these AAVs enable efficient and targetable genetic modification of cells throughout the nervous system of transgenic and non-transgenic animals.

Interactions between the nervous and immune systems enable the gut to respond to the variety of dietary products that it absorbs, the broad spectrum of pathogens that it encounters, and the diverse microbiome that it harbors. The enteric nervous system (ENS) senses and reacts to the dynamic ecosystem of the gastrointestinal (GI) tract by translating chemical cues from the environment into neuronal impulses that propagate throughout the gut and into other organs in the body, including the central nervous system (CNS). This review will describe the current understanding of the anatomy and physiology of the GI tract by focusing on the ENS and the mucosal immune system. We highlight emerging literature that the ENS is essential for important aspects of microbe-induced immune responses in the gut. Although most basic and applied research in neuroscience has focused on the brain, the proximity of the ENS to the immune system and its interface with the external environment suggest that novel paradigms for nervous system function await discovery., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background and Purpose: Multi-delay arterial spin-labeling (ASL) perfusion imaging has been used as a promising modality to evaluate cerebral perfusion. Our aim was to assess the association of leptomeningeal collateral perfusion scores based on ASL parameters with outcome of endovascular treatment in patients with acute ischemic stroke (AIS) in the middle cerebral artery (MCA) territory., Materials and Methods: ASL data at 4 post-labeling delay (PLD) times (PLD = 1.5, 2, 2.5, 3 s) were acquired during routine clinical magnetic resonance examination on AIS patients prior to endovascular treatment. A 3-point scale of leptomeningeal collateral perfusion grade on 10 anatomic regions was determined based on arterial transit times (ATT), cerebral blood flow (CBF), and arterial cerebral blood volume (CBV), estimated by the multi-delay ASL protocol. Based on a 90-day modified Rankin Scale (mRS), the patients were dichotomized to moderate/good (mRS 0-3) and poor outcome (mRS 4-6) and the regional collateral flow scores were compared., Results: Fifty-five AIS patients with unilateral MCA stroke (mean 73.95±14.82 years) including 23 males were enrolled. Compared with poor outcome patients, patients with moderate to good outcomes had a significantly higher leptomeningeal collateral perfusion scores on CBV (3.01±2.11 vs. 1.82±1.51, p=0.024) but no differences on scores on CBF (2.31±1.61 vs. 1.66±1.32, p=0.231) and ATT (2.67±2.33 vs. 3.42±3.37, p=0.593)., Conclusions: Higher leptomeningeal collateral perfusion scores on CBV images by ASL may be a specific marker of clinical outcome after endovascular treatment in patients with acute MCA ischemic stroke. Further study with larger sample size is warranted.

Adult skeletal muscle stem cells, or satellite cells (SCs), regenerate functional muscle following transplantation into injured or diseased tissue. To gain insight into human SC (huSC) biology, we analyzed transcriptome dynamics by RNA sequencing of prospectively isolated quiescent and activated huSCs. This analysis indicated that huSCs differentiate and lose proliferative potential when maintained in high-mitogen conditions ex vivo. Further analysis of gene expression revealed that p38 MAPK acts in a transcriptional network underlying huSC self-renewal. Activation of p38 signaling correlated with huSC differentiation, while inhibition of p38 reversibly prevented differentiation, enabling expansion of huSCs. When transplanted, expanded huSCs differentiated to generate chimeric muscle and engrafted as SCs in the sublaminar niche with a greater frequency than freshly isolated cells or cells cultured without p38 inhibition. These studies indicate characteristics of the huSC transcriptome that promote expansion ex vivo to allow enhanced functional engraftment of a defined population of self-renewing huSCs., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The ideal population of patients for endovascular therapy (ET) in acute ischemic stroke remains undefined. Recent ET trials have moved towards selecting patients with proximal middle cerebral artery (MCA) or internal carotid artery occlusions, which will likely leave a gap in our understanding of the treatment outcomes of M2 occlusions., Objective and Methods: To examine the presentation, treatment, and outcomes of M2 compared with M1 MCA occlusions in patients undergoing ET by assessing comprehensive MRI, angiography, and clinical data., Results: We found that M2 occlusions can lead to massive strokes defined by hypoperfused and infarcted volumes as well as death or moderate to severe disability in nearly 50% of patients at discharge. Compared with M1 occlusions, M2 occlusions achieved similar Thrombolysis in Cerebral Infarction (TICI) 2b/3 recanalization rates, with significantly less hemorrhage. M2 occlusions presented with smaller infarct and hypoperfused volumes and had smaller final infarct volumes regardless of recanalization. TICI 2b/3 recanalization of M2 occlusions was associated with smaller infarct volumes compared with TICI 0-2a recanalization, as well as less infarct expansion, in patients who received IV tissue plasminogen activator as well as those that did not. Successful reperfusion of M2 occlusions was associated with improved discharge modified Rankin scale., Conclusions: If suitable as targets of ET, M2 occlusions should be given the same consideration as M1 occlusions., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

The purpose of this study was to investigate the relationship between hyperperfusion and hemorrhagic transformation (HT) in acute ischemic stroke (AIS). Pseudo-continuous arterial spin labeling (ASL) with background suppressed 3D GRASE was performed during routine clinical magnetic resonance imaging (MRI) on AIS patients at various time points. Arterial spin labeling cerebral blood flow (CBF) maps were visually inspected for the presence of hyperperfusion. Hemorrhagic transformation was followed during hospitalization and was graded on gradient recalled echo (GRE) scans into hemorrhagic infarction (HI) and parenchymal hematoma (PH). A total of 361 ASL scans were collected from 221 consecutive patients with middle cerebral artery stroke from May 2010 to September 2013. Hyperperfusion was more frequently detected posttreatment (odds ratio (OR) = 4.8, 95% confidence interval (CI) 2.5 to 8.9, P < 0.001) and with high National Institutes of Health Stroke Scale (NIHSS) scores at admission (P<0.001). There was a significant association between having hyperperfusion at any time point and HT (OR = 3.5, 95% CI 2.0 to 6.3, P < 0.001). There was a positive relationship between the grade of HT and time-hyperperfusion with the Spearman's rank correlation of 0.44 (P = 0.003). Arterial spin labeling hyperperfusion may provide an imaging marker of HT, which may guide the management of AIS patients post tissue-type plasminogen activator (tPA) and/or endovascular treatments. Late hyperperfusion should be given more attention to prevent high-grade HT.

Background: Lesion patterns may predict prognosis after acute ischemic stroke within the middle cerebral artery (MCA) territory; yet it remains unclear whether such imaging prognostic factors are related to patient outcome after intravenous thrombolysis., Aims: The aim of this study is to investigate the clinical outcome after intravenous thrombolysis in acute MCA ischemic strokes with respect to diffusion-weighted imaging (DWI) lesion patterns., Methods: Consecutive acute ischemic stroke cases of the MCA territory treated over a 7-year period were retrospectively analyzed. All acute MCA stroke patients underwent a MRI scan before intravenous thrombolytic therapy was included. DWI lesions were divided into 6 patterns (territorial, other cortical, small superficial, internal border zone, small deep, and other deep infarcts). Lesion volumes were measured by dedicated imaging processing software. Favorable outcome was defined as modified Rankin scale (mRS) of 0-2 at 90 days., Results: Among the 172 patients included in our study, 75 (43.6%) were observed to have territorial infarct patterns or other deep infarct patterns. These patients also had higher baseline NIHSS score (p < 0.001), a higher proportion of large cerebral artery occlusions (p < 0.001) and larger infarct volume (p < 0.001). Favorable outcome (mRS 0-2) was achieved in 89 patients (51.7%). After multivariable analysis, groups with specific lesion patterns, including territorial infarct and other deep infarct pattern, were independently associated with favorable outcome (OR 0.40; 95% CI 0.16-0.99; p = 0.047)., Conclusions: Specific lesion patterns predict differential outcome after intravenous thrombolysis therapy in acute MCA stroke patients., (© 2015 S. Karger AG, Basel.)

Among the key properties that distinguish adult mammalian stem cells from their more differentiated progeny is the ability of stem cells to remain in a quiescent state for prolonged periods of time. However, the molecular pathways for the maintenance of stem-cell quiescence remain elusive. Here we use adult mouse muscle stem cells (satellite cells) as a model system and show that the microRNA (miRNA) pathway is essential for the maintenance of the quiescent state. Satellite cells that lack a functional miRNA pathway spontaneously exit quiescence and enter the cell cycle. We identified quiescence-specific miRNAs in the satellite-cell lineage by microarray analysis. Among these, miRNA-489 (miR-489) is highly expressed in quiescent satellite cells and is quickly downregulated during satellite-cell activation. Further analysis revealed that miR-489 functions as a regulator of satellite-cell quiescence, as it post-transcriptionally suppresses the oncogene Dek, the protein product of which localizes to the more differentiated daughter cell during asymmetric division of satellite cells and promotes the transient proliferative expansion of myogenic progenitors. Our results provide evidence of the miRNA pathway in general, and of a specific miRNA, miR-489, in actively maintaining the quiescent state of an adult stem-cell population.

Background: The Hospital Acquired Condition Strategy (HACS) denies payment for venous thromboembolism (VTE) after total knee arthroplasty (TKA). The intention is to reduce complications and associated costs, while improving the quality of care by mandating VTE prophylaxis. We applied a system dynamics model to estimate the impact of HACS on VTE rates, and potential unintended consequences such as increased rates of bleeding and infection and decreased access for patients who might benefit from TKA., Methods and Findings: The system dynamics model uses a series of patient stocks including the number needing TKA, deemed ineligible, receiving TKA, and harmed due to surgical complication. The flow of patients between stocks is determined by a series of causal elements such as rates of exclusion, surgery and complications. The number of patients harmed due to VTE, bleeding or exclusion were modeled by year by comparing patient stocks that results in scenarios with and without HACS. The percentage of TKA patients experiencing VTE decreased approximately 3-fold with HACS. This decrease in VTE was offset by an increased rate of bleeding and infection. Moreover, results from the model suggest HACS could exclude 1.5% or half a million patients who might benefit from knee replacement through 2020., Conclusion: System dynamics modeling indicates HACS will have the intended consequence of reducing VTE rates. However, an unintended consequence of the policy might be increased potential harm resulting from over administration of prophylaxis, as well as exclusion of a large population of patients who might benefit from TKA.

Background Context: Harnessing the potential of stem cells is an important strategy for regenerative medicine. This study explores the use of bilaminar coculture pellets (BCPs) of mesenchymal stem cells (MSCs) and nucleus pulposus cells (NPCs) as a cell-based therapy for intervertebral disc regeneration. Prior in vitro experiments have shown that BCP can help differentiate MSCs and substantially improve new matrix deposition., Purpose: To evaluate the clinical relevance of BCPs by testing the system in vivo., Study Design/setting: We have designed a novel spherical BCP where MSCs are enclosed in a shell of NPCs. The pellets were tested in vivo in a rat tail model of disc degeneration., Methods: Rat caudal intervertebral discs were denucleated and treated with BCP in a fibrin sealant (FS) carrier (controls were MSCs suspended in FS; NPCs suspended in FS; MSCs and NPCs suspended in FS; FS only; and surgery only). At 14 and 35 days after implantation, the animals were euthanized and discs were evaluated for proteoglycan content, enzyme-linked immunosorbent assay for inflammatory cytokines, cell retention using polymerase chain reaction, disc height, histology, and disc grade based on a blinded scoring system., Results: The proteoglycan and cytokine levels were not significantly different among groups. The BCP group had higher cell retention than controls. Disc height and disc grade increased over time only in the BCP group. Bilaminar coculture pellets were the only treatment to show proteoglycan staining in the nucleus space at 35 days., Conclusions: This study shows that BCPs may prevent postnucleotomy disc degeneration in vivo. Larger animals and longer time points will be necessary to further judge potential clinical impact. As opposed to strategies that require growth factor supplements, predifferentiation, or genetic manipulations, BCPs are a self-sustaining and targeted method for tissue regeneration in situ., (Copyright © 2010 Elsevier Inc. All rights reserved.)