Search

Amber R Salter,1 Ruth Ann Marrie,2,3 Neetu Agashivala,4 Daniel A Belletti,4 Edward Kim,4 Gary R Cutter,1 Stacey S Cofield,1 Tuula Tyry51Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA; 2Department of Internal Medicine, 3Department of Community Health Sciences, University of Manitoba, Winnipeg, MB, Canada; 4Novartis Pharmaceutical Corporation, East Hanover, NJ, USA; 5Division of Neurology, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, USAIntroduction: The evolving landscape of disease-modifying therapies (DMTs) for multiple sclerosis raises important questions about why patients change DMTs. Physicians and patients could benefit from a better understanding of the reasons for switching therapy. Purpose: To investigate the reasons patients switch DMTs and identify characteristics associated with the decision to switch.Method: The North American Research Committee on Multiple Sclerosis (NARCOMS) Registry conducted a supplemental survey among registry participants responding to the 2011 update survey. The supplemental survey investigated reasons for switching DMT, origin of the discussion of DMT change, and which factors influenced the decision. Chi-square tests, Fisher’s exact tests, and logistic regression were used for the analyses. Results: Of the 691 eligible candidates, 308 responded and met the inclusion criteria (relapsing disease course, switched DMT after September 2010). The responders were 83.4% female, on average 52 years old, with a median (interquartile range) Patient-Determined Disease Steps score of 4 (2–5). The most recent prior therapy included first-line injectables (74.5%), infusions (18.1%), an oral DMT (3.4%), and other DMTs (4.0%). The discussion to switch DMT was initiated almost equally by physicians and participants. The primary reason for choosing the new DMT was based most frequently on physician’s recommendation (24.5%) and patient perception of efficacy (13.7%). Conclusion: Participants frequently initiated the discussion regarding changing DMT, although physician recommendations regarding the specific therapy were still weighed highly. Long-term follow-up of these participants will provide valuable information on their disease trajectory, satisfaction with, and effectiveness of their new medication. Keywords: multiple sclerosis, health communication

Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making. Standardized descriptions published in 1996 based on a

OBJECTIVE: The prevalence of helmet use by alpine skiers and snowboarders was estimated and self-reports on risk taking were assessed to test for potential risk compensation when using helmets in these sports. SETTING: Skiers and snowboarders were observed and interviewed at 34 resorts in the western United States and Canada. SUBJECTS: Respondents were 1779 adult skiers and snowboarders in the 2003 ski season. OUTCOME MEASURES: Observations of helmet use and questions about perceived speed and degree of challenge when not wearing a helmet (helmet wearers) or in previous ski seasons (non-helmet wearers). RESULTS: Helmet wearers reported that they skied/snowboarded at slower speeds (OR = 0.64, p<0.05) and challenged themselves less (OR = 0.76, p<0.05) than non-helmet wearers. Adoption of safety helmets in 2003 (23%) continued to increase over 2002 (OR = 0.46, p<0.05) and 2001 (OR = 0.84, p<0.05). CONCLUSIONS: No evidence of risk compensation among helmet wearers was found. Decisions to wear helmets may be part of a risk reduction orientation. Helmet use continues to trend upwards but adoption may be slowing. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The purpose of this study was to examine diffusion of and predictors of helmet use among skiers and snowboarders in the Western United States and Canada. DESIGN: 6400 skiers and snowboarders at 29 ski resorts in the Western United States and Canada were interviewed on chair lifts and observed for helmet use during two consecutive ski seasons (winters 2001 and 2002). SETTING: Skiers and snowboarders were observed and interviewed at 29 ski resorts in Alaska, California, Colorado, Idaho, Montana, New Mexico, Nevada, Oregon, Utah, and British Columbia as part of a sun protection project. SUBJECTS: Participants completing the survey consisted of 3525 adult skiers and snowboarders in the 2002 season and 2978 adult skiers and snowboarders in the 2001 season. MAIN OUTCOME MEASURE: The outcome measure for all analyses was prevalence of helmet use by skiers and snowboarders. RESULTS: Helmet use by skiers and snowboarders is increasing and is most prevalent among snowboarders, experts, and more frequent skiers/snowboarders. No evidence was found for the hypothesis that helmet use is diffusing more rapidly among earlier adopters of helmets than later adopters. CONCLUSIONS: Although controversy remains, helmets are rapidly diffusing as a safety device at western North American ski resorts. Expert and more frequent skiers and snowboarders are more likely to wear helmets, which may indicate that helmets are recognized as a safety device. [ABSTRACT FROM AUTHOR]

Background: The performance of diagnostic mammography for women with signs or symptoms of breast cancer has not been well studied. We evaluated whether age, breast density, self-reported breast lump, and previous mammography influence the performance of diagnostic mammography.Methods: From January 1996 through March 1998, prospective diagnostic mammography data from women aged 25-89 years with no previous breast cancer were linked to cancer outcomes data in six mammography registries participating in the Breast Cancer Surveillance Consortium. We used the final mammographic assessment at the end of the imaging work-up to determine abnormal mammographic examination rate, positive predictive value (PPV), sensitivity, specificity, and area under the receiver operating characteristic (ROC) curve. We used age, breast density, prior mammogram, and self-reported breast lump jointly as predictors of performance. All statistical tests were two-sided.Results: Of 41 427 diagnostic mammograms, 6279 (15.2%) were judged abnormal. The overall PPV was 21.8%, sensitivity was 85.8%, and specificity was 87.7%. Multivariate analysis showed that sensitivity and specificity generally declined as breast density increased (P =.007 and P<.001, respectively), that previous mammography decreased sensitivity (odds ratio [OR] = 0.52, 95% confidence interval [CI] = 0.36 to 0.74; P<.001) but increased specificity (OR = 1.43, 95% CI = 1.31 to 1.57; P<.001), and that a self-reported breast lump increased sensitivity (OR = 1.64, 95% CI = 1.13 to 2.38; P =.013) but decreased specificity (OR = 0.54, 95% CI = 0.49 to 0.59; P<.001). ROC analysis showed that higher breast density and previous mammography were negatively related to accuracy (P<.001 for both).Conclusions: Diagnostic mammography in women with signs or symptoms of breast cancer shows higher sensitivity and lower specificity than screening mammography does. Higher breast density and previous mammographic examination appear to impair performance. [ABSTRACT FROM AUTHOR]

Background and Objectives: Exposure to natalizumab, an efficacious treatment for relapsing-remitting multiple sclerosis (RRMS), is associated with increased risk of progressive multifocal leukoencephalopathy (PML). Compared with every-4-week (Q4W) dosing, extended-interval dosing of natalizumab is associated with decreased risk of PML. Clinical efficacy was maintained in the majority of patients switched to every-6-week (Q6W) dosing in the phase 3b NOVA clinical trial. In this article, we report pharmacokinetics (PK) and pharmacodynamics (PD) of Q6W vs Q4W dosing in NOVA., Methods: In NOVA study Part 1, participants with RRMS (aged 18-60 years) and Expanded Disability Status Scale score <5.5, who were stable on IV natalizumab Q4W dosing for ≥12 months, were randomized to continue IV Q4W dosing or switched to IV Q6W dosing of natalizumab and followed for 72 weeks. Exploratory outcomes were measurements of trough serum natalizumab concentration, α4-integrin saturation, and soluble vascular cell adhesion molecule-1 (sVCAM-1) concentration. A mixed model of repeated measures was used to estimate mean treatment differences between groups. Patient-level PK and PD data were examined in those with relapse or radiologic disease activity., Results: In NOVA, 486 (Q6W, n = 245; Q4W, n = 241) and 487 (Q6W, n = 246; Q4W, n = 241) participants were included in the PK and PD populations, respectively. Mean trough natalizumab concentrations ranged from 10 to 21 μg/mL (Q6W) and 33-38 μg/mL (Q4W), and mean α4-integrin saturation remained above 65.5% (Q6W) and above 77.9% (Q4W). In the Q6W group, mean sVCAM-1 levels increased 23.6% by week 24 and remained elevated throughout the study, while mean sVCAM-1 levels remained generally stable in the Q4W group. Most participants with T2 lesion activity or relapse activity, in either treatment arm, maintained trough natalizumab levels >10 μg/mL and trough α4-integrin saturation >50%., Discussion: Compared with Q4W dosing, Q6W dosing was associated with a 60%-70% decrease in mean trough natalizumab levels and a 9%-16% decrease in mean α4-integrin saturation. At the patient level, neither natalizumab concentration nor α4-integrin saturation was consistently predictive of lesion or relapse activity, suggesting that trough natalizumab and α4-integrin saturation measurements should be interpreted with caution in clinical practice., Trial Registration Information: ClinicalTrials.gov, NCT03689972; EudraCT, 2018-002145-11. Submitted 2018-09-27. First patient enrolled: 2018-12-26. https://clinicaltrials.gov/study/NCT03689972.

Background and Objectives: Despite their high health care use, it is unclear whether the health care needs of people with MS are being met and what their priorities are. We assessed priorities for access to, and affordability of care, by people living with MS in the United States. We also tested the association between perceived inadequate access to care and health-related quality of life (HRQoL)., Methods: In Fall 2022, we conducted a cross-sectional survey of participants in the North American Research Committee on Multiple Sclerosis Registry about access to care and HRQoL (Health Utilities Index Mark III). We used multivariable polytomous logistic regression to test sociodemographic and clinical factors associated with access to care. We used multivariable linear regression analysis to test the association between access to care and HRQoL., Results: We included 4,914 respondents in the analysis, of whom 3,974 (80.9%) were women, with a mean (SD) age 64.4 (9.9) years. The providers who were most reported as needed but inaccessible were complementary providers (35.5%), followed by allied health providers (24.2%), occupational therapists (22.7%), and mental health providers (20.7%). Over 80% of participants reported that it was important or very important to be able to get an appointment with their primary MS health care provider when needed, to have sufficient time in their appointments to explain their concerns, to see their neurologist if their status changed, and that their health care providers communicated to coordinate their care. Participants who reported needing to see the provider but not having access or seeing the provider but would like to see them more often had lower HRQOL (ranging from -0.059 to -0.176) than participants who saw the provider as much as needed., Discussion: Gaps in access to care persist for people with MS in the United States and substantially affect HRQoL. Improving access to care for people with MS should be a health system priority., Competing Interests: R.A. Marrie receives research funding from CIHR, Research Manitoba, MS Canada, Multiple Sclerosis Scientific Foundation, Crohn's and Colitis Canada, National Multiple Sclerosis Society, CMSC, the Arthritis Society and the US Department of Defense, and is a coinvestigator on studies receiving funding from Biogen Idec and Roche Canada. She holds the Waugh Family Chair in Multiple Sclerosis and serves on the editorial board of Neurology. S. Lancia has nothing to disclose. G.R. Cutter serves on Data and Safety Monitoring Boards for Applied Therapeutics, AI therapeutics, AMO Pharma, Astra-Zeneca, Avexis Pharmaceuticals, Biolinerx, Brainstorm Cell Therapeutics, Bristol Meyers Squibb/Celgene, CSL Behring, Galmed Pharmaceuticals, Green Valley Pharma, Horizon Pharmaceuticals, Immunic, Karuna Therapeutics, Mapi Pharmaceuticals LTD, Merck, Mitsubishi Tanabe Pharma Holdings, Opko Biologics, Prothena Biosciences, Novartis, Regeneron, Sanofi-Aventis, Reata Pharmaceuticals, Teva Pharmaceuticals, NHLBI (Protocol Review Committee), University of Texas Southwestern, University of Pennsylvania, Visioneering Technologies, Inc., Consulting or Advisory Boards for Alexion, Antisense Therapeutics, Biogen, Clinical Trial Solutions LLC, Entelexo Biotherapeutics, Inc., Genzyme, Genentech, GW Pharmaceuticals, Immunic, Immunosis Pty Ltd, Klein-Buendel Incorporated, Merck/Serono, Novartis, Perception Neurosciences, Protalix Biotherapeutics, Regeneron, Roche, SAB Biotherapeutics. He is employed by the University of Alabama at Birmingham and President of Pythagoras, Inc., a private consulting company located in Birmingham AL. R.J. Fox receives personal consulting fees from AB Science, Biogen, Bristol Myers Squibb, EMD Serono, Genentech, Genzyme, Greenwich Biosciences, Immunic, INmune Bio, Janssen, Lily, Novartis, Sanofi, Siemens, and TG Therapeutics; clinical trial contract and research grant funding from Biogen, Novartis, and Sanofi. A. Salter receives research funding from Multiple Sclerosis Society of Canada, National Multiple Sclerosis Society, CMSC and the Department of Defense Congressionally Directed Medical Research Program, and is a member of editorial board for Neurology. She serves as a consultant for Gryphon Bio, LLC. She is a member of the Data and Safety Monitoring Board for Premature Infants Receiving Milking or Delayed Cord Clamping (PREMOD2), Central Vein Sign: A Diagnostic Biomarker in Multiple Sclerosis (CAVS-MS), and Ocrelizumab for Preventing Clinical Multiple Sclerosis in Individuals With Radiologically Isolated Disease (CELLO). She holds the Kenney Marie Dixon‐Pickens Distinguished Professorship in Multiple Sclerosis Research. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp., (© 2024 American Academy of Neurology.)

Introduction: Following NOVA (part 1) and the approval of the subcutaneous (SC) route of administration of natalizumab by the European Medicines Agency, an extension phase of the NOVA phase IIIb study (part 2) was initiated to collect patient preference data for SC versus intravenous (IV) dosing in patients receiving every-6-week (Q6W) dosing of natalizumab. This study was performed to evaluate patient preference for SC versus IV natalizumab administration and explore the efficacy, safety, and pharmacology characteristics of both routes of administration., Methods: In part 2, participants received natalizumab (Tysabri ® ) 300 mg via IV infusion Q6W for 36 weeks and then were randomized to 48 weeks of crossover treatment (24 weeks SC Q6W and 24 weeks IV Q6W, or vice versa). The primary endpoint was the proportion of participants who indicated a preference for natalizumab SC administration on the Patient Preference Questionnaire., Results: A total of 153 participants were randomized in NOVA part 2. Of 123 with patient preference data, 108 (87.8%) preferred the SC route of administration for natalizumab over the IV route; 102 (82.9%) specified "requires less time in the clinic" as the reason for the SC preference., Conclusion: In NOVA (part 2), most participants on Q6W dosing of natalizumab preferred SC administration versus IV administration., Clinicaltrials: GOV: NCT03689972. INFOGRAPHIC., (© 2024. The Author(s).)

Acute ingestion of exogenous ketone supplements in the form of a (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (R-BD R-βHB) ketone monoester (KME) can attenuate declines in oxygen availability during hypoxic exposure and might impact cognitive performance at rest and in response to moderate-intensity exercise. In a single-blind randomized crossover design, 16 males performed assessments of cognitive performance before and during hypoxic exposure with moderate exercise [2 × 20 min weighted ruck (∼22 kg) at 3.2 km/h at 10% incline] in a normobaric altitude chamber (4572 m, 11.8% O 2 ). The R-BD R-βHB KME (573 mg/kg) or a calorie- and taste-matched placebo (∼50 g maltodextrin) were co-ingested with 40 g of dextrose before exposure to hypoxia. The R-βHB concentrations were rapidly elevated and sustained (>3 mM; P < 0.001) by KME. The decline in oxygen saturation during hypoxic exposure was attenuated in KME conditions by 2.4%-4.2% (P < 0.05) compared with placebo. Outcomes of cognitive performance tasks, in the form of the Defense Automated Neurobehavioral Assessment (DANA) code substitution task, the Stroop color and word task, and a shooting simulation, did not differ between trials before and during hypoxic exposure. These data suggest that the acute exogenous ketosis induced by KME ingestion can attenuate declining blood oxygen saturation during acute hypoxic exposure both at rest and during moderate-intensity exercise, but this did not translate into differences in cognitive performance before or after exercise in the conditions investigated., (© 2024 The Author(s). Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Estimating the densities of marine prey observed in animal-borne video loggers when encountered by foraging predators represents an important challenge for understanding predator-prey interactions in the marine environment. We used video images collected during the foraging trip of one chinstrap penguin (Pygoscelis antarcticus) from Cape Shirreff, Livingston Island, Antarctica to develop a novel approach for estimating the density of Antarctic krill (Euphausia superba) encountered during foraging activities. Using the open-source Video and Image Analytics for a Marine Environment (VIAME), we trained a neural network model to identify video frames containing krill. Our image classifier has an overall accuracy of 73%, with a positive predictive value of 83% for prediction of frames containing krill. We then developed a method to estimate the volume of water imaged, thus the density (N·m-3) of krill, in the 2-dimensional images. The method is based on the maximum range from the camera where krill remain visibly resolvable and assumes that mean krill length is known, and that the distribution of orientation angles of krill is uniform. From 1,932 images identified as containing krill, we manually identified a subset of 124 images from across the video record that contained resolvable and unresolvable krill necessary to estimate the resolvable range and imaged volume for the video sensor. Krill swarm density encountered by the penguins ranged from 2 to 307 krill·m-3 and mean density of krill was 48 krill·m-3 (sd = 61 krill·m-3). Mean krill biomass density was 25 g·m-3. Our frame-level image classifier model and krill density estimation method provide a new approach to efficiently process video-logger data and estimate krill density from 2D imagery, providing key information on prey aggregations that may affect predator foraging performance. The approach should be directly applicable to other marine predators feeding on aggregations of prey., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Background: People with progressive multiple sclerosis (PMS) present motor (eg, walking) and cognitive impairments, and report fatigue. Fatigue encompasses fatigability which is objectively measured by the capacity to sustain a motor or cognitive task., Objective: To investigate the prevalence of walking and cognitive fatigability (CF) and the associated clinical characteristics in a large sample of PMS patients., Methods: PMS patients (25-65 years old) were included from 11 sites (Europe and North America), having cognitive impairment (1.28 standard deviation below normative data for the symbol digit modality test [SDMT]). Walking fatigability (WF) was assessed using the distance walk index (DWI) and CF using the SDMT (scores from the last 30 seconds compared to the first 30 seconds). Additional measures were: cognitive assessment-Brief International Cognitive Assessment for multiple sclerosis (MS), cardiorespiratory fitness, 6-minute walk, physical activity, depressive symptoms, perceived fatigue-Modified Fatigue Impact Scale (MFIS), MS impact-MSIS-29, and walking ability., Results: Of 298 participants, 153 (51%) presented WF (DWI = -28.9 ± 22.1%) and 196 (66%) presented CF (-29.7 ± 15%). Clinical characteristics (EDSS, disease duration, and use of assistive device) were worse in patients with versus without WF. They also presented worse scores on MSIS-29 physical, MFIS total and physical and reduced physical capacity. CF patients scored better in the MSIS-29 physical and MFIS psychosocial, compared to non-CF group. Magnitude of CF and WF were not related., Conclusions: Half of the cognitively-impaired PMS population presented WF which was associated with higher disability, physical functions, and fatigue. There was a high prevalence of CF but without strong associations with clinical, cognitive, and physical functions., Trial Registration Number: The "CogEx-study," www.clinicaltrial.gov identifier number: NCT03679468., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Distal ischemia is a rare complication in patients undergoing placement of an arteriovenous (AV) fistula or AV graft. There are limited studies on its frequency, risk factors, clinical consequences, or feasibility of subsequent access., Methods: A prospective vascular access database from a large academic medical center was queried retrospectively to identify 1498 patients (mean age 56±15 years, 48% female patients, 73% Black patients) undergoing placement of at least one vascular access from 2011 to 2020. For patients who developed access-related distal ischemia requiring surgical intervention, we determined the frequency of distal ischemia, clinical risk factors, and subsequent outcomes., Results: Severe access-related distal ischemia occurred in 28 patients (1.9%; 95% confidence interval, 1.3% to 2.7%). The frequency was 0.2% for forearm AV fistulas, 0.9% for upper arm AV fistulas, 2.4% for forearm AV grafts, 2.2% for upper arm AV grafts, and 2.8% for thigh AV grafts. Risk factors independently associated with distal ischemia included female sex (odds ratio [OR], 3.64 [95% confidence interval, 1.52 to 8.72]), peripheral vascular disease (OR, 6.28 [2.84 to 13.87]), and coronary artery disease (OR, 2.37 [1.08 to 5.23]). Surgical interventions included ligation, excision, plication (banding), and other surgical procedures. Five patients developed tissue necrosis. A subsequent AV graft was placed in 13 patients, of whom only one (8%) developed distal ischemia requiring intervention., Conclusions: Access-related distal ischemia requiring intervention was rare in this study and more common in women and patients with peripheral vascular disease or coronary artery disease. In some cases, a subsequent vascular access could be placed with a low likelihood of recurrent distal ischemia., (Copyright © 2023 by the American Society of Nephrology.)

Objective: The aim of this study was to assess potential drug-drug interactions between highly purified cannabidiol (CBD) and anti-seizure medications (ASMs)., Methods: Our group previously reported that in a sample of adults and children receiving CBD in an open-label expanded access program, there were several ASMs noted to increase in serum levels with increasing doses of CBD. We analyzed if an increased number of observations over time resulted in changes in potential interactions and if potential interactions were associated with time since enrollment, demographics, or the overall rating of adverse effects., Results: In 169 participants (80 adults), with increasing weight-based CBD dose, there were associated increases in serum levels of clobazam and N-desmethylclobazam, free valproate, felbamate, and topiramate in the adult and pediatric arms combined, levetiracetam in the pediatric arm only, and permapanel in the adult arm only. There were no associations noted in these level changes with time since enrollment, biological sex, and adverse events profile scores., Significance: This study confirms some previously identified interactions with CBD and identifies other potential pharmacokinetic interactions; however, the clinical significance of these observations is likely minor, and there is no effect of time on these findings., (© 2023 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Importance: Taxonomic profiling of microbial communities is essential to model microbial interactions and inform habitat conservation. This work develops approaches in constructing training/testing data sets from publicly available marine metagenomes and evaluates the performance of machine learning (ML) approaches in read-based taxonomic classification of marine metagenomes. Predictions from two models are used to test accuracy in metagenomic classification and to guide improvements in ML approaches. Our study provides insights on the methods, results, and challenges of deep learning on marine microbial metagenomic data sets. Future machine learning approaches can be improved by rectifying genome coverage and class imbalance in the training data sets, developing alternative models, and increasing the accessibility of computational resources for model training and refinement., Competing Interests: The authors declare no conflict of interest.

Osteosarcoma is a devastating bone cancer that disproportionally afflicts children, adolescents, and young adults. Standard therapy includes surgical tumor resection combined with multiagent chemotherapy, but many patients still suffer from metastatic disease progression. Neoadjuvant systemic oncolytic virus (OV) therapy has the potential to improve clinical outcomes by targeting primary and metastatic tumor sites and inducing durable antitumor immune responses. Here we describe the first evaluation of neoadjuvant systemic therapy with a clinical-stage recombinant oncolytic vesicular stomatitis virus (VSV), VSV-IFNβ-NIS, in naturally occurring cancer, specifically appendicular osteosarcoma in companion dogs. Canine osteosarcoma has a similar natural disease history as its human counterpart. VSV-IFNβ-NIS was administered prior to standard of care surgical resection, permitting microscopic and genomic analysis of tumors. Treatment was well-tolerated and a "tail" of long-term survivors (∼35%) was apparent in the VSV-treated group, a greater proportion than observed in two contemporary control cohorts. An increase in tumor inflammation was observed in VSV-treated tumors and RNA-seq analysis showed that all the long-term responders had increased expression of a T cell anchored immune gene cluster. We conclude that neoadjuvant VSV-IFNβ-NIS is safe and may increase long-term survivorship in dogs with naturally occurring osteosarcoma, particularly those that exhibit pre-existing antitumor immunity., Competing Interests: S.N., S.J.R., and Mayo Clinic have a financial conflict of interest related to this research. S.N. and S.J.R. are inventors on patents related to oncolytic vesicular stomatitis virus that has been licensed by Mayo Clinic to Vyriad. S.N. and S.J.R. have equity interests in Vyriad, and S.J.R. is the CEO of Vyriad. The research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Conflict of Interest policies., (© 2023 The Authors.)

Significance Statement: The optimal choice of vascular access for patients undergoing hemodialysis-arteriovenous fistula (AVF) or arteriovenous graft (AVG)-remains controversial. In a pragmatic observational study of 692 patients, the authors found that among patients who initiated hemodialysis with a central vein catheter (CVC), a strategy that maximized AVF placement resulted in a higher frequency of access procedures and greater access management costs for patients who initially received an AVF than an AVG. A more selective policy that avoided AVF placement if an AVF was predicted to be at high risk of failure resulted in a lower frequency of access procedures and access costs in patients receiving an AVF versus an AVG. These findings suggest that clinicians should be more selective in placing AVFs because this approach improves vascular access outcomes., Background: The optimal choice of initial vascular access-arteriovenous fistula (AVF) or graft (AVG)-remains controversial, particularly in patients initiating hemodialysis with a central venous catheter (CVC)., Methods: In a pragmatic observational study of patients who initiated hemodialysis with a CVC and subsequently received an AVF or AVG, we compared a less selective vascular access strategy of maximizing AVF creation (period 1; 408 patients in 2004 through 2012) with a more selective policy of avoiding AVF creation if failure was likely (period 2; 284 patients in 2013 through 2019). Prespecified end points included frequency of vascular access procedures, access management costs, and duration of catheter dependence. We also compared access outcomes in all patients with an initial AVF or AVG in the two periods., Results: An initial AVG placement was significantly more common in period 2 (41%) versus period 1 (28%). Frequency of all access procedures per 100 patient-years was significantly higher in patients with an initial AVF than an AVG in period 1 and lower in period 2. Median annual access management costs were significantly higher among patients with AVF ($10,642) versus patients with AVG ($6810) in period 1 but significantly lower in period 2 ($5481 versus $8253, respectively). Years of catheter dependence per 100 patient-years was three-fold higher in patients with AVF versus patients with AVG in period 1 (23.3 versus 8.1, respectively), but only 30% higher in period 2 (20.8 versus 16.0, respectively). When all patients were aggregated, the median annual access management cost was significantly lower in period 2 ($6757) than in period 1 ($9781)., Conclusions: A more selective approach to AVF placement reduces frequency of vascular access procedures and cost of access management., (Copyright © 2023 by the American Society of Nephrology.)

Background: Fatigue is associated with reduced quality of life and social participation, and poor employment outcomes. However, most studies examining fatigue are limited by small sample sizes or short follow-up periods., Objective: To characterize the natural history of fatigue., Methods: The North American Research Committee on Multiple Sclerosis Registry participants with ≥7 years of longitudinal data between 2004 and 2019 and a relapsing disease course were included. A subset of participants enrolled within 5 years of diagnosis was identified. The Fatigue Performance Scale assessed fatigue and ≥1-point increase in Fatigue Performance Scale sustained at the next survey defined fatigue worsening., Results: Of 3057 participants with longitudinal data, 944 were within 5 years of multiple sclerosis diagnosis. Most participants (52%) reported fatigue worsening during follow-up. Median time to fatigue worsening ranged from 3.5 to 5 years at lower levels of index fatigue. Fatigue worsening was associated with lower annual income, increasing disability, lower initial fatigue level, taking injectable disease-modifying therapies and increasing depression levels in the relapsing multiple sclerosis participants., Conclusion: Most multiple sclerosis participants early in their disease suffer from fatigue and at least half reported fatigue worsening over time. Understanding factors associated with fatigue may help to identify populations most at risk of fatigue worsening will be informative for the overall management of patients with multiple sclerosis., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Amber Salter reports honoraria for consulting for Gryphon Bio, LLC and research funding from Multiple Sclerosis Society of Canada, National Multiple Sclerosis Society, Consortium of MS Centers and the US Department of Defense. She is a member of the Editorial Board for Neurology. Dr Salter is a member of the Data and Safety Monitoring Board for Premature Infants Receiving Milking or Delayed Cord Clamping (PREMOD2), Central Vein Sign: A Diagnostic Biomarker in Multiple Sclerosis (CAVS-MS), Ocrelizumab for Preventing Clinical Multiple Sclerosis in Individuals With Radiologically Isolated Disease (CELLO), and Video Telehealth Pulmonary Rehabilitation to Reduce Hospital Readmission in Chronic Obstructive Pulmonary Disease (Tele-COPD). Gary Cutter data/safety monitoring committees for AMO, BioLineRx, BrainStorm Cell Therapeutics, Galmed, Horizon, Hisun, Merck, Merck/Pfizer, OPKO Biologics, Neurim, Novartis, Orphazyme, Sanofi, Reata, Receptos/Celgene, Teva, NHLBI (Protocol Review Committee), NICHD (OPRU oversight committee); consulting/advisory boards for Biogen, Click Therapeutics, Genzyme, Genentech, GW, Klein Buendel, MedImmune, MedDay, Novartis, Osmotica, Perception Neuroscience, Recursion, Roche, Somahlution, and TG Therapeutics Robert J Fox has received personal consulting fees from AB Science, Biogen, Celgene, EMD Serono, Genentech, Genzyme, Immunic, Janssen, Novartis, Sanofi, and TG Therapeutics; has served on advisory committees for AB Science, Biogen, Genzyme, Immunic, Janssen, Novartis, Sanofi, and TG Therapeutics; and received a clinical trial contract and research grant funding from Biogen, Novartis, and Sanofi. Ruth Ann Marrie receives research funding from CIHR, Research Manitoba, Multiple Sclerosis Society of Canada, Multiple Sclerosis Scientific Foundation, Crohn's and Colitis Canada, National Multiple Sclerosis Society, CMSC, the Arthritis Society, and US Department of Defense. She is a co-investigator on a study funded in part by Biogen Idec and Roche (no funds to her/her institution). She is supported by the Waugh Family Chair in Multiple Sclerosis. Samantha Lancia has nothing to disclose. Alexander Keenan, Hoa H Le, Kavita Gandhi, and Maria Ait-Tihyaty are employees of Janssen Pharmaceuticals and may own stock in Johnson & Johnson., (© The Author(s), 2023.)

Objective: Research directly examining brain tissue has played an important role in understanding the pathology and pathogenesis of multiple sclerosis (MS) and other diseases of the central nervous system. Such research relies heavily on donations of post-mortem brain tissue yet little is known about the attitudes of people with multiple sclerosis (MS) about brain donation. We aimed to assess the attitudes of people with MS toward brain donation, their preferences related to discussions of brain donation, and factors associated with attitudes toward brain donation including sociodemographic and clinical characteristics, health literacy and religiosity., Methods: In a cross-sectional study, we surveyed participants in the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry regarding their attitudes toward brain donation, reasons for participating or not participating in brain donation, and related communication preferences. We used multivariable logistic regression analyses to test factors associated with attitudes regarding brain donation., Results: Most of the 4,520 participants were women (80.8%), self-identified as white (88.1%), with a post-secondary education, functional health literacy and moderate-severe disability. Sixty-two percent of participants would consider brain donation. Factors associated with considering brain donation included female gender, having a post-secondary education, being physically active, having moderate-severe disability and more comorbidities, and alcohol intake. Seventy-five percent of participants indicated that they preferred to receive information regarding brain donations from physicians., Conclusion: Two-thirds of people with MS would consider brain donation. People with MS desire to hear about brain donation from their health care providers rather than other sources., Competing Interests: RM receives research funding from: CIHR, Research Manitoba, Multiple Sclerosis Society of Canada, Multiple Sclerosis Scientific Foundation, Crohn's and Colitis Canada, National Multiple Sclerosis Society, CMSC, the Arthritis Society and the US Department of Defense, and is a co-investigator on studies receiving funding from Biogen Idec and Roche Canada. LK declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. GC reports that he has served on data/safety monitoring committees for Applied Therapeutics, AI therapeutics, AMO Pharma, Astra-Zeneca, Avexis Pharmaceuticals, Biolinerx, Brainstorm Cell Therapeutics, Bristol Meyers Squibb/Celgene, CSL Behring, Galmed Pharmaceuticals, Green Valley Pharma, Horizon Pharmaceuticals, Immunic, Karuna Therapeutics, Mapi Pharmaceuticals Ltd, Merck, Mitsubishi Tanabe Pharma Holdings, Opko Biologics, Prothena Biosciences, Novartis, Regeneron, SanofiAventis, Reata Pharmaceuticals, NHLBI (Protocol Review Committee), University of Texas Southwestern, University of Pennsylvania, Visioneering Technologies, Inc. and on consulting/advisory boards for Alexion, Antisense Therapeutics, Biogen, Clinical Trial Solutions LLC, Entelexo Biotherapeutics, Inc., Genzyme, Genentech, GW Pharmaceuticals, Immunic, Klein-Buendel Incorporated, Merck/Serono, Novartis, Osmotica Pharmaceuticals, Perception Neurosciences, Protalix Biotherapeutics, Recursion/Cerexis Pharmaceuticals, Regeneron, Roche, SAB Biotherapeutics. RF has received personal consulting fees from AB Science, Biogen, Celgene, EMD Serono, Genentech, Genzyme, Immunic, Janssen, Novartis, Sanofi, and TG Therapeutics; has served on advisory committees for AB Science, Biogen, Genzyme, Immunic, Janssen, Novartis, Sanofi, and TG Therapeutics; and received clinical trial contract and research grant funding from Biogen, Novartis, and Sanofi. Amber Salter reports honoraria for consulting for Gryphon Bio, LLC and research funding from Multiple Sclerosis Society of Canada, National Multiple Sclerosis Society, Consortium of MS Centers and the US Department of Defense. She is a member of the Editorial Board for Neurology. AS was a member of the Data and Safety Monitoring Board for Premature Infants Receiving Milking or Delayed Cord Clamping (PREMOD2), Central Vein Sign: A Diagnostic Biomarker in Multiple Sclerosis (CAVS-MS), Ocrelizumab for Preventing Clinical Multiple Sclerosis in Individuals With Radiologically Isolated Disease (CELLO), and Video Telehealth Pulmonary Rehabilitation to Reduce Hospital Readmission in Chronic Obstructive Pulmonary Disease (Tele-COPD)., (Copyright © 2023 Marrie, Kosowan, Cutter, Fox and Salter.)

Abstract: With advances in HIV treatment, people with HIV (PWH) are living longer but experience aging-related comorbidities, including cognitive deficits, at higher rates than the general population. Previous studies have shown alterations in lysosomal proteins in blood from PWH with severe dementia. However, these markers have not been evaluated in PWH with milder neurocognitive impairment. We sought to determine whether levels of the lysosomal cysteine protease cathepsin B (CatB) and its endogenous inhibitor cystatin B (CysB) were altered in PWH with neurocognitive impairment and whether antiretroviral therapy (ART) further influenced these levels. Peripheral blood mononuclear cells were obtained from the tenofovir arm of a multicenter clinical trial in which ART-naive, HIV+ participants received treatment for 48 weeks (ACTG A5303, NCT01400412). PWH were divided by neurocognitive status (eg, with or without neurocognitive impairment) before ART initiation. Intracellular levels of CatB and CysB were measured in T cells and monocytes by means of flow cytometry. Levels of CysB were significantly decreased in both CD4 + T cells and CD8 + T cells after 48 weeks of ART in HIV+ participants without neurocognitive impairment but not in participants with neurocognitive impairment. Levels of CysB were increased in CD14 + monocytes from the participants with neurocognitive impairment after ART. Levels of CysB and CatB positively correlated regardless of HIV, neurocognitive status, or exposure to ART. These findings suggest that CysB has the potential to provide mechanistic insight into HIV-associated neurocognitive disorders or provide a molecular target for systemic monitoring or treatment of neurocognitive impairment in the context of ART and should be investigated further., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Objectives: Observational studies suggest low levels of 25-hydroxyvitamin D (25[OH]D) may be associated with increased disease activity in people with multiple sclerosis (PwMS). Large-scale genome-wide association studies (GWAS) suggest 25(OH)D levels are partly genetically determined. The resultant polygenic scores (PGSs) could serve as a proxy for 25(OH)D levels, minimizing potential confounding and reverse causation in analyses with outcomes. Herein, we assess the association of genetically determined 25(OH)D and disease outcomes in MS., Methods: We generated 25(OH)D PGS for 1,924 PwMS with available genotyping data pooled from 3 studies: the CombiRx trial (n = 575), Johns Hopkins MS Center (n = 1,152), and Immune-Mediated Inflammatory Diseases study (n = 197). 25(OH)D-PGS were derived using summary statistics (p < 5 × 10 -8 ) from a large GWAS including 485,762 individuals with circulating 25(OH)D levels measured. We included clinical and imaging outcomes: Expanded disability status scale (EDSS), timed 25-foot walk (T25FW), nine-hole peg test (9HPT), radiologic activity, and optical coherence tomography-derived ganglion cell inner plexiform layer (GCIPL) thickness. A subset (n = 935) had measured circulating 25(OH)D levels. We fitted multivariable models based on the outcome of interest and pooled results across studies using random effects meta-analysis. Sensitivity analyses included a modified p value threshold for inclusion in the PGS (5 × 10 -5 ) and applying Mendelian randomization (MR) rather than using PGS., Results: Initial analyses demonstrated a positive association between generated 25(OH)D-PGS and circulating 25(OH)D levels (per 1SD increase in 25[OH]D PGS: 3.08%, 95% CI: 1.77%, 4.42%; p = 4.33e-06; R 2 = 2.24%). In analyses with outcomes, we did not observe an association between 25(OH)D-PGS and relapse rate (per 1SD increase in 25[OH]D-PGS: 0.98; 95% CI: 0.87-1.10), EDSS worsening (per 1SD: 1.05; 95% CI: 0.87-1.28), change in T25FW (per 1SD: 0.07%; 95% CI: -0.34 to 0.49), or change in 9HPT (per 1SD: 0.09%; 95% CI: -0.15 to 0.33). 25(OH)D-PGS was not associated with new lesion accrual, lesion volume or other imaging-based outcomes (whole brain, gray, white matter volume loss or GCIPL thinning). The results were similarly null in analyses using other p value thresholds or those applying MR., Discussion: Genetically determined lower 25(OH)D levels were not associated with worse disease outcomes in PwMS and raises questions about the plausibility of a treatment effect of vitamin D in established MS., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

We conducted an anonymous survey in 9 of our university affiliated outpatient dialysis units to address the concern that many in-center hemodialysis patients may not feel comfortable sharing their experiences. Major goals of this study: Investigating level of patient satisfaction with their care; Evaluating the subjective perception of the level of understanding of patients regarding pertinent issues of their disease and its management; Identifying potential avenues for care improvement. Survey was conducted in English, paper-based, with answer choices to individual questions for patient satisfaction and education graded using a 5-point Likert scale. Regarding potential areas of improvement, patients were asked to choose as many areas as deemed appropriate. To ensure anonymity, the completed surveys were folded and dropped into a box. Overall, 253 out of 516 (49%) screened patients were eligible and completed the survey. Patients expressed favorable responses regarding satisfaction (mean rating > 4 in each of 14 questions) and education (mean rating > 4 in 8 questions, > 3.5 in 2 questions) regarding hemodialysis. About 62% of overall study participants identified at least one area where they felt additional information would result in improvement of care. Our results indicate that patients undergoing outpatient hemodialysis were overall satisfied and had a good perceptive understanding about their health. Based on the patients' input, strategies focused on addressing pain and discomfort, privacy, providing information about palliative care/hospice, mental health resources, and the process of kidney transplantation may promote improvement in overall quality of care., Competing Interests: The authors have no conflicts of interest to disclose. Gary C. Cutter reports grants from the National Institutes of Health; and serves on data and safety monitoring boards of Astra-Zeneca; Avexis Pharmaceuticals; Biolinerx; Brainstorm Cell Therapeutics; Bristol Meyers Squibb/Celgene; CSL Behring; Galmed Pharmaceuticals; Mapi Pharmaceuticals LTD; Merck; Merck/Pfizer; Opko Biologics; Neurim; Novartis; Ophazyme; Sanofi-Aventis; Reata Pharmaceuticals; Teva pharmaceuticals; VielaBio Inc.; National Heart, Lung, and Blood Institute (Protocol Review Committee); National Institute of Child Health and Human Development (OPRU oversight committee); has received compensation for consulting or advisory board service from Antisense Therapeutics; Biodelivery Sciences International; Biogen; Genzyme; Genentech; GW Pharmaceuticals; Immunic; Klein-Buendel Incorporated; Medimmune/Viela Bio; Medday, Merck/Serono; Neurogenesis LTD; Novartis; Osmotica Pharmaceuticals; Perception Neurosciences; Recursion/Cerexis Pharmaceuticals; Regeneron; Reckover Pharmaceuticals; Roche; SAB Biotherapeutics; TG Therapeutics; and is president of Pythagoras Inc. - a private consulting company located in Birmingham, AL. Abolfazl Zarjou reports grants from the National Institutes of Health; and is supported by a Southern Society of Clinical Investigation (SSCI) Research Scholar Award. Arun Rajasekaran, Anand Prakash, Spencer Hatch, and Yan Lu have no conflicts of interest to declare., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Natalizumab is a recombinant humanized monoclonal antibody (mAb) against α4-integrin that is approved for relapsing forms of multiple sclerosis (MS). Natalizumab is associated with an increased risk of developing progressive multifocal leukoencephalopathy (PML), and with disease reactivation after cessation of treatment that is likely mediated by an accumulation of pro-inflammatory lymphocytes in the blood during therapy. Alemtuzumab is a mAb against CD52 that reduces the number of peripheral lymphocytes., Rationale: To determine if treatment with alemtuzumab after natalizumab reduces disease activity in patients with relapsing forms of MS. This review article will outline the rationale and objectives of the sequential natalizumab - alemtuzumab therapy in patients with relapsing forms of multiple sclerosis (SUPPRESS; ClinicalTrials.gov ID: NCT03135249) trial in greater detail than would be feasible in a manuscript that summarizes the study results., Methods: The SUPPRESS trial is single arm, open-label, multicenter, efficacy pilot study that aims to establish a disease-free state over a 24-months period in patients who received the natalizumab- alemtuzumab sequential therapy. Participants will be recruited from four different sites. The primary endpoint is the annualized relapse rate (ARR) from the time of cessation of natalizumab treatment. Key secondary endpoint is freedom of relapse at 12-months, the number of new/enlarging T2 lesions on magnetic resonance imaging (MRI), and the number of gadolinium (Gd)-enhancing lesions on MRI. An exploratory endpoint is the Expanded Disability Status Scale (EDSS), retinal nerve fiber layer (RNFL) thickness assessment by optic coherence tomography (OCT) and assessment of quality of life (QoL) measures by a pre-defined, self-administered testing battery. To evaluate immunological effects, blood leukocytes will be collected and immunophenotyped by multi-parameter flow cytometry., Conclusion: The SUPPRESS trial will provide clinical, imaging, and biological data to determine whether sequential natalizumab to alemtuzumab combination therapy establish a disease-free state in patients with relapsing forms of MS., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Objective: We estimated coronavirus disease 2019 (COVID-19) vaccination rates in the North American Research Committee on Multiple Sclerosis (NARCOMS) population and investigated reasons for vaccine hesitancy., Methods: In Spring 2021, we surveyed the NARCOMS participants about COVID-19 vaccinations. Participants reported whether they had received any COVID-19 vaccination; if not, they reported why not. They also reported whether they had received influenza vaccination. Using multivariable logistic regression, we assessed participant characteristics associated with uptake of COVID-19 and influenza vaccines., Results: Of 4955 eligible respondents, 3998 (80.7%) were females with a mean (SD) age of 64.0 (9.7) years. Overall, 4165 (84.1%) reported that they had received a COVID-19 vaccine, most often Pfizer-BioNTech and Moderna, and 3723 (75.4%) received a seasonal influenza vaccine. Reasons for not getting the COVID-19 vaccine included possible adverse effects (47.73%), possible lack of efficacy (13.7%), and lack of perceived need (17.1%). Factors associated with receiving the COVID-19 vaccine included receipt of influenza vaccine, older age, higher socioeconomic status, any leisure physical activity, and use of disease-modifying therapy., Conclusion: In this older cohort of people with multiple sclerosis, COVID-19 vaccine uptake was high, exceeding uptake of seasonal influenza vaccine. Concerns regarding safety, efficacy, and lack of perceived risk were associated with not obtaining the COVID-19 vaccine., (© The Author(s), 2022.)

Introduction: Clinical trials for sporadic Alzheimer's disease generally use mixed models for repeated measures (MMRM) or, to a lesser degree, constrained longitudinal data analysis models (cLDA) as the analysis model with time since baseline as a categorical variable. Inferences using MMRM/cLDA focus on the between-group contrast at the pre-determined, end-of-study assessments, thus are less efficient (eg, less power)., Methods: The proportional cLDA (PcLDA) and proportional MMRM (pMMRM) with time as a categorical variable are proposed to use all the post-baseline data without the linearity assumption on disease progression., Results: Compared with the traditional cLDA/MMRM models, PcLDA or pMMRM lead to greater gain in power (up to 20% to 30%) while maintaining type I error control., Discussion: The PcLDA framework offers a variety of possibilities to model longitudinal data such as proportional MMRM (pMMRM) and two-part pMMRM which can model heterogeneous cohorts more efficiently and model co-primary endpoints simultaneously., Competing Interests: None, (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Objective: Since the properties of health-related quality of life measures vary across samples, studies directly comparing the properties of different measures can be useful in understanding their relative strengths and limitations. We aimed to compare the psychometric properties of the Health Utilities Index Mark III (HUI3) and the Multiple Sclerosis Impact Scale-29 (MSIS-29). Methods: In Spring 2020, North American Research Committee on Multiple Sclerosis (NARCOMS) Registry participants completed the HUI3, MSIS-29, Patient Determined Disease Steps (PDDS) and SymptoMScreen. For the HUI3 and MSIS-29 we assessed floor and ceiling effects, construct validity, and internal consistency reliability. We used relative efficiency to compare the discriminating ability of the two measures with respect to disability. Results: We included 5,664 participants in the analysis, with mean (SD) age 63 (10.1) years; 4,579 (80.8%) were women. For the HUI3 the mean (SD) score was 0.44 (0.32), for the MSIS-29 physical it was 34.0 (24.2) and for the MSIS-29 psychological it was 25.9 (20.4). Neither of the measures had floor or ceiling effects, and internal consistency reliability was > 0.70 for both. The HUI3 and MSIS-29 physical were strongly correlated (r = -0.78; 95%CI:-0.79,-0.77). The correlation between the HUI3 and MSIS-29 psychological was weaker but remained moderately strong (r = -0.64; 95%CI:-0.66,-0.63). After adjusting for sociodemographic and clinical factors, relative efficiency to discriminate between disability (PDDS) groups was highest for the MSIS-29 physical scale, followed by the HUI3. Conclusion: Both measures had adequate validity and reliability. The MSIS-29 physical discriminated between disability groups better than the HUI3., Competing Interests: RM receives research funding from: CIHR, Research Manitoba, Multiple Sclerosis Society of Canada, Multiple Sclerosis Scientific Foundation, Crohn's and Colitis Canada, National Multiple Sclerosis Society, CMSC and the US Department of Defense, and is a co-investigator on studies receiving funding from Biogen Idec and Roche Canada. GC data/safety monitoring committees for AMO, BioLineRx, BrainStorm Cell Therapeutics, Galmed, Horizon, Hisun, Merck, Merck/Pfizer, OPKO Biologics, Neurim, Novartis, Orphazyme, Sanofi, Reata, Receptos/Celgene, Teva, NHLBI (Protocol Review Committee), NICHD (OPRU oversight committee); consulting/advisory boards for Biogen, Click Therapeutics, Genzyme, Genentech, GW, Klein Buendel, MedImmune, MedDay, Novartis, Osmotica, Perception Neuroscience, Recursion, Roche, Somahlution, and TG Therapeutics. RF has received personal consulting fees from AB Science, Biogen, Celgene, EMD Serono, Genentech, Genzyme, Immunic, Janssen, Novartis, Sanofi, and TG Therapeutics; has served on advisory committees for AB Science, Biogen, Genzyme, Immunic, Janssen, Novartis, Sanofi, and TG Therapeutics; and received clinical trial contract and research grant funding from Biogen, Novartis, and Sanofi. AS is a journal editor/member of editorial advisory board for Circulation: Cardiovascular Imaging. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Marrie, Dolovich, Cutter, Fox and Salter.)

Osteosarcoma has a guarded prognosis. A major hurdle in developing more effective osteosarcoma therapies is the lack of disease-specific biomarkers to predict risk, prognosis, or therapeutic response. Exosomes are secreted extracellular microvesicles emerging as powerful diagnostic tools. However, their clinical application is precluded by challenges in identifying disease-associated cargo from the vastly larger background of normal exosome cargo. We developed a method using canine osteosarcoma in mouse xenografts to distinguish tumor-derived from host-response exosomal messenger RNAs (mRNAs). The model allows for the identification of canine osteosarcoma-specific gene signatures by RNA sequencing and a species-differentiating bioinformatics pipeline. An osteosarcoma-associated signature consisting of five gene transcripts (SKA2, NEU1, PAF1, PSMG2, and NOB1) was validated in dogs with spontaneous osteosarcoma by real-time quantitative reverse transcription PCR (qRT-PCR), while a machine learning model assigned dogs into healthy or disease groups. Serum/plasma exosomes were isolated from 53 dogs in distinct clinical groups ("healthy", "osteosarcoma", "other bone tumor", or "non-neoplastic disease"). Pre-treatment samples from osteosarcoma cases were used as the training set, and a validation set from post-treatment samples was used for testing, classifying as "osteosarcoma detected" or "osteosarcoma-NOT detected". Dogs in a validation set whose post-treatment samples were classified as "osteosarcoma-NOT detected" had longer remissions, up to 15 months after treatment. In conclusion, we identified a gene signature predictive of molecular remissions with potential applications in the early detection and minimal residual disease settings. These results provide proof of concept for our discovery platform and its utilization in future studies to inform cancer risk, diagnosis, prognosis, and therapeutic response., (© 2021. The Author(s), under exclusive licence to United States and Canadian Academy of Pathology.)

Observational studies and registries can play a critical role in elucidating the natural and treated history of multiple sclerosis (MS) and identifying factors associated with outcomes such as disability and health-related quality of life. The North American Research Committee on Multiple Sclerosis (NARCOMS) Registry is one of multiple registries worldwide that focuses on people with MS, but one of the very few patient-driven MS registries. On the 25th anniversary of the first data collection for the NARCOMS Registry, we discuss the importance of disease registries in the MS field, describe key concepts related to registry design and management, and highlight findings from MS registries relevant to clinical care or health policy., Competing Interests: Financial Disclosures: Dr Marrie is a co-investigator on a study funded by Biogen and Roche. Dr Cutter serves on the data/safety monitoring committees for AstraZeneca, Avexis Pharmaceuticals, BioLineRx, BrainStorm Cell Therapeutics, Bristol Myers Squibb/Celgene, CSL Behring, Galmed, Green Valley Pharma, Mapi Pharmaceuticals, Merck, Merck/Pfizer, Mitsubishi Tanabe, OPKO Biologics, Neurim, Novartis, Orphazyme, Sanofi, Reata, Teva, Viela Bio, the National Heart, Lung, and Blood Institute (Protocol Review Committee), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Obstetric-Fetal Pharmacology Research Unit Oversight Committee); serves on consulting/advisory boards for Alexion, Antisense Therapeutics, Biodelivery Sciences International, Biogen, Clinical Trial Solutions LLC, Genzyme, Genentech, GW Pharmaceuticals, Immunic, Klein Buendel, MedImmune/Viela Bio, MedDay, Merck/Serono, Neurogenesis Ltd, Novartis, Osmotica, Perception Neuroscience, Protolix Biotherapeutics, Recursion/Cerexis Pharmaceuticals, Regeneron, Reckover Pharmaceuticals, Roche, SAB Biotherapeutics, and TG Therapeutics; and is president of Pythagoras, Inc, a private consulting company. Dr Fox has received consulting fees from AB Science, Biogen, Celgene, EMD Serono, Genentech, Genzyme, Immunic, Janssen, Novartis, Sanofi, and TG Therapeutics; research funding from Biogen, Novartis, and Sanofi; and royalties from Demos Publishing. Dr Vollmer received compensation for lectures and consultancy from Biogen, Genentech/Roche, Viela Bio, Celgene, EMD Serono, and Novartis and received research support from Rocky Mountain Multiple Sclerosis Center, Celgene, Biogen, Anokion, Genentech, F. Hoffmann-La Roche Ltd, GW Pharmaceuticals, and TG Therapeutics Inc. Dr Salter serves as a statistical editor for Circulation: Cardiovascular Imaging. Dr Tyry declares no conflicts of interest., (© 2021 Consortium of Multiple Sclerosis Centers.)

In this issue of Neurotherapeutics, Li et.al. report a large retrospective study of the beneficial effects of thymectomy on the progression of ocular myasthenia gravis (OMG) to generalized MG (GMG) (Huanhuan et al. in Neurotherapeutics XX, 2021). This paper demonstrates a more than 50% reduction in the risk of GMG when a thymectomy was performed on these patients. The authors conclude with the recommendation that well-designed clinical trials be performed to evaluate the potential that thymectomy in OMG reduces the burden of GMG., (© 2021. The American Society for Experimental NeuroTherapeutics, Inc.)

Background and Objective: To describe the impact of coronavirus disease 2019 (COVID-19) on people with neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD)., Methods: The COVID-19 Infections in Multiple Sclerosis (MS) and Related Diseases (COViMS) Registry collected data on North American patients with MS and related diseases with laboratory-positive or highly suspected SARS-CoV-2 infection. Deidentified data were entered into a web-based registry by health care providers. Data were analyzed using t -tests, Pearson χ 2 tests, or Fisher exact tests for categorical variables. Univariate logistic regression models examined effects of risk factors and COVID-19 clinical severity., Results: As of June 7, 2021, 77 patients with NMOSD and 20 patients with MOGAD were reported in the COViMS Registry. Most patients with NMOSD were laboratory positive for SARS-CoV-2 and taking rituximab at the time of COVID-19 diagnosis. Most patients with NMOSD were not hospitalized (64.9% [95% CI: 53.2%-75.5%]), whereas 15.6% (95% CI: 8.3%-25.6%) were hospitalized only, 9.1% (95% CI: 3.7%-17.8%) were admitted to the ICU and/or ventilated, and 10.4% (95% CI: 4.6%-19.5%) died. In patients with NMOSD, having a comorbidity was the sole factor identified for poorer COVID-19 outcome (OR = 6.0, 95% CI: 1.79-19.98). Most patients with MOGAD were laboratory positive for SARS-CoV-2, and almost half were taking rituximab. Among patients with MOGAD, 75.0% were not hospitalized, and no deaths were recorded; no factors were different between those not hospitalized and those hospitalized, admitted to the ICU, or ventilated., Discussion: Among the reported patients with NMOSD, a high mortality rate was observed, and the presence of comorbid conditions was associated with worse COVID-19 outcome. There were no deaths reported in the patients with MOGAD, although these observations are limited due to small sample size., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: Little is known about how symptom severity in the various neurologic domains commonly affected by multiple sclerosis (MS) varies by age, sex, and race/ethnicity., Methods: This was a retrospective study of patients with MS attending 2 tertiary centers in the New York City metropolitan area, who self-identified as White, African American (AA), or Hispanic American (HA). Disability was rated with Patient-Determined Disability Steps (PDDS) and symptom severity, with SymptoMScreen (SyMS), a validated battery for assessing symptoms in 12 domains. Analyses comparing race, sex, and age groups were performed using analysis of variance models and Tukey honestly significant difference tests to control the overall type I error. A multivariable model was constructed to predict good self-rated health (SRH) that included demographic variables, PDDS, and SyMS domain scores., Results: The sample consisted of 2,622 patients with MS (age 46.4 years; 73.6% female; 66.4% White, 21.7% AA, and 11.9% HA). Men had higher adjusted PDDS than women ( p = 0.012), but similar total SyMS scores. Women reported higher fatigue and anxiety scores, whereas men had higher walking and dexterity scores. AAs and HAs had higher symptom domain scores than Whites in each of the 12 domains and worse SRH. In a multivariable logistic model, only pain, walking, depression, fatigue, and global disability (PDDS), but not sex or race/ethnicity, predicted good SRH., Conclusions: AA and HA race/ethnicity was associated with higher overall disability, higher symptom severity in each of the 12 domains commonly affected by MS, and worse SRH relative to Whites. However, only symptom severity and disability, and not demographic variables, predicted good SRH., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: By surveying a multiple sclerosis (MS) population, we tested the hypothesis that influenza vaccine uptake would not meet public health targets and that vaccine misconceptions would contribute to lower than desired uptake., Methods: In spring 2020, we surveyed participants in the North American Research Committee on Multiple Sclerosis Registry regarding vaccinations. Participants reported whether they had received hepatitis A, hepatitis B, pneumococcal, shingles, varicella, measles/mumps/rubella, tetanus, or influenza vaccines. Participants who had not received influenza vaccine last year reported the reasons. We summarized responses descriptively. Using multivariable logistic regression, we assessed participant characteristics associated with uptake of seasonal influenza vaccine., Results: Of 5,244 eligible respondents, 80.8% were female, with a mean (SD) age of 61.8 (10.1) years. Overall, 43.0% (2,161/5,032) of participants reported that their neurologist had ever asked about their immunization history. The percentage of participants who received the seasonal flu vaccine last year ranged from 59.1% among those aged 18-24 years to 79.9% for persons aged ≥65 years. Among those who did not get the influenza vaccination, the most common reasons were personal preference (29.6%), concerns about possible adverse effects in general (29.3%), and concerns that the vaccine would worsen their MS (23.7%)., Conclusion: Vaccination uptake is lower than desired in the MS population compared with existing recommendations, including for seasonal influenza. Misconceptions about the safety of vaccination in the context of MS and personal preference appear to play important roles in vaccination choices, highlighting the importance of education about these issues., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: To determine the activation status and cytokine profiles of CD4 + T cells, CD8 + T cells, and CD19 + B cells from patients with early-stage Parkinson disease (PD) compared with healthy controls (HCs)., Methods: Peripheral blood samples from 41 patients with early-stage PD and 40 HCs were evaluated. Peripheral blood mononuclear cells were analyzed by flow cytometry for surface markers and intracellular cytokine production. Correlations of immunologic changes and clinical parameters were analyzed., Results: Adaptive immunity plays a role in the pathogenesis of PD, yet the contribution of T cells and B cells, especially cytokine production by these cells, is poorly understood. We demonstrate that naive CD4 + and naive CD8 + T cells are significantly decreased in patients with PD, whereas central memory CD4 + T cells are significantly increased in patients with PD. Furthermore, IL-17-producing CD4 + Th17 cells, IL-4-producing CD4 + Th2 cells, and IFN-γ-producing CD8 + T cells are significantly increased in patients with PD. Regarding B cells, we observed a decrease in naive B cells and an increase in nonswitched memory and double-negative B cells. As well, TNF-α-producing CD19 + B cells were significantly increased in patients with PD. Notably, some of the changes observed in CD4 + T cells and B cells were associated with clinical motor disease severity., Conclusions: These findings suggest that alterations in the adaptive immune system may promote clinical disease in PD by skewing to a more proinflammatory state in the early-stage PD patient cohort. Our study may shed light on potential immunotherapies targeting dysregulated CD4 + T cells, CD8 + T cells, and CD19 + B cells in patients with PD., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Acute kidney injury (AKI) remains a significant clinical problem through its diverse etiologies, the challenges of robust measurements of injury and recovery, and its progression to chronic kidney disease (CKD). Bridging the gap in our knowledge of this disorder requires bringing together not only the technical resources for research but also the investigators currently endeavoring to expand our knowledge and those who might bring novel ideas and expertise to this important challenge. The University of Alabama at Birmingham-University of California-San Diego O'Brien Center for Acute Kidney Injury Research brings together technical expertise and programmatic and educational efforts to advance our knowledge in these diverse issues and the required infrastructure to develop areas of novel exploration. Since its inception in 2008, this O'Brien Center has grown its impact by providing state-of-the-art resources in clinical and preclinical modeling of AKI, a bioanalytical core that facilitates measurement of critical biomarkers, including serum creatinine via LC-MS/MS among others, and a biostatistical resource that assists from design to analysis. Through these core resources and with additional educational efforts, our center has grown its investigator base to include >200 members from 51 institutions. Importantly, this center has translated its pilot and catalyst funding program with a $37 return per dollar invested. Over 500 publications have resulted from the support provided with a relative citation ratio of 2.18 ± 0.12 (iCite). Through its efforts, this disease-centric O'Brien Center is providing the infrastructure and focus to help the development of the next generation of researchers in the basic and clinical science of AKI. This center creates the promise of the application at the bedside of the advances in AKI made by current and future investigators.

Background: Disease-modifying therapies (DMTs) for multiple sclerosis (MS) are approved for their ability to reduce disease activity, namely clinical relapses and signal changes on magnetic resonance imaging (MRI). Disease activity appears age dependent. Thus, the greatest benefit would be expected in younger people with MS (PwMS) whereas benefits in the elderly are uncertain., Methods: Real-world data were obtained from PwMS from the North American Research Committee on Multiple Sclerosis (NARCOMS) registry and the US Department of Veterans Affairs Multiple Sclerosis Surveillance Registry (MSSR)., Results: 6948 PwMS were surveyed from NARCOMS, and the MSSR had 1719 participants. In younger adult PwMS 40-years old or less, 183 (61.4%) in NARCOMS and 179 (70.5%) in the MSSR were prescribed DMTs. Among PwMS over age 60, 1575 (40.1%) in NARCOMS and 239 (36.3%) in the MSSR were prescribed DMTs. More PwMS in the age group of 31-40 ( p  = 0.035) and 41-50 ( p  = 0.001) in the MSSR were using DMTs compared with PwMS of the same age groups in NARCOMS., Conclusion: These findings suggest that DMTs are under-utilized in the younger population and continue to be commonly prescribed in the elderly. Broader access may explain the higher prescription rate of DMTs in US veterans., Competing Interests: Conflict of interest statement: Y Zhang, A Salter, S Jin, W Culpepper, and M Wallin declare no competing interests related to this study. G Cutter has participated on data-monitoring and safety-monitoring boards for Avexis Pharmaceuticals, Biolinerx, Brainstorm Cell Therapeutics, CSL Behring, Galmed Pharmaceuticals, Horizon Pharmaceuticals,Hisun Pharmaceuticals, Mapi Pharmaceuticals, Merck, Merck/Pfizer, Opko Biologics, Neurim, Novartis, Ophazyme, Sanofi-Aventis, Reata Pharmaceuticals, Receptos/Celgene, Teva pharmaceuticals, Vivus, NHLBI (Protocol Review Committee), NICHD (OPRU oversight committee); participated in consulting or advisory boards for Biogen, Click Therapeutics, Genzyme, Genentech, Gilgamesh Pharmaceuticals, GW Pharmaceuticals, Klein-Buendel Incorporated, Medimmune, Medday, Novartis, Osmotica Pharmaceuticals, Perception Neurosciences, Recursion Pharmaceuticals, Roche, Somahlution, TG Therapeutics; is employed by the University of Alabama at Birmingham and President of Pythagoras, Inc. a private consulting company located in Birmingham AL. O Stuve serves on the editorial boards of Therapeutic Advances in Neurological Disorders and on data-monitoring committees for Genentech-Roche, Pfizer, and TG Therapeutics without monetary compensation, advised EMD Serono, Celgene, Genentech, TG Therapeutics, and Genzyme, and receives grant support from Sanofi Genzyme and EMD Serono., (© The Author(s), 2021.)

Objective: To assess treatment effects on Expanded Disability Status Scale (EDSS) score worsening and modified Rankin Scale (mRS) scores in the N-MOmentum trial of inebilizumab, a humanized anti-CD19 monoclonal antibody, in participants with neuromyelitis optica spectrum disorder (NMOSD)., Methods: Adults (N = 230) with aquaporin-4 immunoglobulin G-seropositive NMOSD or -seronegative neuromyelitis optica and an EDSS score ≤8 were randomized (3:1) to receive inebilizumab 300 mg or placebo on days 1 and 15. The randomized controlled period (RCP) was 28 weeks or until adjudicated attack, with an option to enter the inebilizumab open-label period. Three-month EDSS-confirmed disability progression (CDP) was assessed using a Cox proportional hazard model. The effect of baseline subgroups on disability was assessed by interaction tests. mRS scores from the RCP were analyzed by the Wilcoxon-Mann-Whitney odds approach., Results: Compared with placebo, inebilizumab reduced the risk of 3-month CDP (hazard ratio [HR]: 0.375; 95% CI: 0.148-0.952; p = 0.0390). Baseline disability, prestudy attack frequency, and disease duration did not affect the treatment effect observed with inebilizumab (HRs: 0.213-0.503; interaction tests: all p > 0.05, indicating no effect of baseline covariates on outcome). Mean EDSS scores improved with longer-term treatment. Inebilizumab-treated participants were more likely to have a favorable mRS outcome at the end of the RCP (OR: 1.663; 95% CI: 1.195-2.385; p = 0.0023)., Conclusions: Disability outcomes were more favorable with inebilizumab vs placebo in participants with NMOSD., Classification of Evidence: This study provides Class II evidence that for patients with NMOSD, inebilizumab reduces the risk of worsening disability. N-MOmentum is registered at ClinicalTrials.gov: NCT02200770., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Neurofibromatosis type 1 (NF1) plexiform neurofibromas (PNs) are progressive, multicellular neoplasms that cause morbidity and may transform to sarcoma. Treatment of Nf1 fl/fl ;Postn-Cre mice with cabozantinib, an inhibitor of multiple tyrosine kinases, caused a reduction in PN size and number and differential modulation of kinases in cell lineages that drive PN growth. Based on these findings, the Neurofibromatosis Clinical Trials Consortium conducted a phase II, open-label, nonrandomized Simon two-stage study to assess the safety, efficacy and biologic activity of cabozantinib in patients ≥16 years of age with NF1 and progressive or symptomatic, inoperable PN ( NCT02101736 ). The trial met its primary outcome, defined as ≥25% of patients achieving a partial response (PR, defined as ≥20% reduction in target lesion volume as assessed by magnetic resonance imaging (MRI)) after 12 cycles of therapy. Secondary outcomes included adverse events (AEs), patient-reported outcomes (PROs) assessing pain and quality of life (QOL), pharmacokinetics (PK) and the levels of circulating endothelial cells and cytokines. Eight of 19 evaluable (42%) trial participants achieved a PR. The median change in tumor volume was 15.2% (range, +2.2% to -36.9%), and no patients had disease progression while on treatment. Nine patients required dose reduction or discontinuation of therapy due to AEs; common AEs included gastrointestinal toxicity, hypothyroidism, fatigue and palmar plantar erythrodysesthesia. A total of 11 grade 3 AEs occurred in eight patients. Patients with PR had a significant reduction in tumor pain intensity and pain interference in daily life but no change in global QOL scores. These data indicate that cabozantinib is active in NF1-associated PN, resulting in tumor volume reduction and pain improvement.

Background: Sedentary behavior is a major concern in multiple sclerosis, as it may accelerate disease progression and physical disability. This is especially concerning in African Americans, who present with greater neurological disability than Caucasians., Objective: We conducted a feasibility trial on an intervention targeting sedentary behavior in African Americans with multiple sclerosis., Methods: We examined the feasibility of the Sit Less, Move More program, a 12-week behavioral intervention that used text messaging along with theory-driven newsletters and behavioral coaching for managing sedentary behavior. We recruited ambulatory, inactive, African Americans with multiple sclerosis, and assessed feasibility on process, resource, management, and scientific outcomes., Results: Of the 64 people initially contacted, 45 were assessed for eligibility, 31 were sent the informed consent document, and 30 returned a signed document and were included in the study. Study costs were US$7242.38. Personnel time to complete the study was 130 h. There was a small effect on both device-measured ( d =  -0.19) and self-reported ( d =  -0.39) sedentary behavior., Conclusions: The Sit Less, Move More intervention is safe and feasible for African Americans with multiple sclerosis, and yielded a small reduction in sedentary behavior. The intervention was low cost and well received. Our results suggest the Sit Less, Move More program should progress towards a Phase II trial to determine its efficacy., (© The Author(s) 2020.)

Objective: To describe the presence of practice effects in persons with Alzheimer disease (AD) or mild cognitive impairment (MCI) and to evaluate how practice effects affect cognitive progression and the outcome of clinical trials., Methods: Using data from a meta-database consisting of 18 studies including participants from the Alzheimer disease Cooperative Study (ADCS) and the Alzheimer Disease Neuroimaging Initiative (ADNI) with ADAS-Cog11 as the primary outcome, we defined practice effects based on the improvement in the first two ADAS-Cog11 scores and then estimated the presence of practice effects and compared the cognitive progression between participants with and without practice effects. The robustness of practice effects was investigated using CDR SB, an outcome independent the definition itself. Furthermore, we evaluated how practice effects can affect sample size estimation., Results: The overall percent of practice effects for AD participants was 39.0% and 53.3% for MCI participants. For AD studies, the mean change from baseline to 2 years was 12.8 points for the non-practice effects group vs 7.4 for the practice effects group; whereas for MCI studies, it was 4.1 for non-practice effects group vs 0.2 for the practice effects group. AD participants without practice effects progressed 0.9 points faster than those with practice effects over a period of 2 years in CDR-SB; whereas for MCI participants, the difference is 0.7 points. The sample sizes can be different by over 35% when estimated based on participants with/without practice effects., Conclusion: Practice effects were prevalent and robust in persons with AD or MCI and affected the cognitive progression and sample size estimation. Planning of future AD or MCI clinical trials should account for practice effects to avoid underpower or considers target trials or stratification analysis based on practice effects., Competing Interests: The authors have declared that no competing interests exist.

Objective: To determine the prevalence of functional gastrointestinal disorders, the demographic and clinical characteristics associated with the presence of functional gastrointestinal disorders, and the effects of these disorders with health-related quality of life (HRQOL) in a large, diverse population of persons with MS., Methods: In 2014, we surveyed participants in the North American Research Committee on Multiple Sclerosis registry regarding functional gastrointestinal disorders using the Rome III questionnaire. Participants also reported their sociodemographic characteristics, disability status using Patient Determined Disease Steps, the presence of comorbid depression and anxiety, health behaviors, and HRQOL using the RAND-12. We determined the prevalence of each gastrointestinal disorder using the Rome III criteria. Using multivariable logistic regression models, we assessed the factors associated with the presence of each bowel disorder. Using linear regression, we evaluated the association between functional gastrointestinal disorders and HRQOL., Results: Of 6,312 eligible respondents, 76.5% were female, with a mean (SD) age of 58.3 (10.2) years. Forty-two percent of respondents (n = 2,647) had a functional gastrointestinal disorder, most often irritable bowel syndrome (IBS), which affected 28.2% of participants. The prevalence of all functional gastrointestinal disorders increased with greater disability, and the prevalence of IBS increased with longer disease duration. After adjusting for sociodemographic and clinical characteristics, functional gastrointestinal disorders were associated with lower physical and mental HRQOL (both p < 0.0001)., Conclusions: Functional gastrointestinal disorders are common in MS and are associated with reduced HRQOL., (© 2019 American Academy of Neurology.)