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Background We undertook a phase-III, randomized controlled trial (RCT) that examined the effectiveness of a behavioral intervention based on social cognitive theory (SCT) and delivered through the Internet using e-learning approaches for immediate and sustained increases in physical activity among persons with multiple sclerosis (MS). Method The study followed a parallel group RCT design. Persons with MS ( N = 318) were randomized into either behavioral intervention ( n = 159) or attention/social contact control ( n = 159) conditions. The conditions were administered over a 6-month period by persons who were uninvolved in screening, recruitment, random assignment, and outcome assessment. There was a 6-month follow-up period without access of conditions. We collected outcome data every 6 months over the 12-month period. The primary outcome was device-measured minutes/day of moderate-to-vigorous physical activity (MVPA). The data analysis involved a modified intent-to-treat approach (i.e. those who received the allocated conditions) using a linear mixed model. Results There was a significant group by time interaction on the primary outcome of device-measured minutes/day of MVPA ( p Conclusion This study provides evidence for the effectiveness of a widely scalable approach for increasing MVPA in persons with MS.

Aggregation structures of Antarctic krill (Euphausia superba) and predator interactions were investigated using active acoustic data collected for approximately one month by WBAT and Signature100 echosounders deployed on moorings in two hydrographically different sites in Bransfield Strait. Near Nelson Island, water flows from the northwest to southeast while Deception Island is influenced by the Bransfield Front with stronger net current velocities from the southwest to northeast. Krill aggregations were identified and then classified in three clusters using a swarm-identification algorithm and hierarchical clustering using aggregation morphological characteristics: acoustic density, mean depth, center of mass, inertia, equivalent area, aggregation index, and proportion occupied. A total of 693 and 736 aggregations were detected at the mooring sites close to Nelson and Deception Islands. The three aggregation categories ranged from high to low densities, evenness and dispersion and were distributed throughout the water column. Krill aggregation densities and mean thickness are influenced by current velocities, direction, mean depth, and predator foraging. The majority of observed predator dive profiles occurred over the aggregation type with highest krill densities at both Nelson and Deception Islands, and within the first 25 m of the water column. The heterogeneity of krill aggregations potentially impacts predator foraging strategies and predator-krill interactions in the hydrodynamically active Bransfield Strait.

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.

ImportanceRacial, ethnic, and geographic differences in multiple sclerosis (MS) are important factors to assess when determining the disease burden and allocating health care resources.ObjectiveTo calculate the US prevalence of MS in Hispanic, non-Hispanic Black (hereafter referred to as Black), and non-Hispanic White individuals (hereafter referred to as White) stratified by age, sex, and region.Design, Setting, and ParticipantsA validated algorithm was applied to private, military, and public (Medicaid and Medicare) administrative health claims data sets to identify adult cases of MS between 2008 and 2010. Data analysis took place between 2019 and 2022. The 3-year cumulative prevalence overall was determined in each data set and stratified by age, sex, race, ethnicity, and geography. The insurance pools included 96 million persons from 2008 to 2010. Insurance and stratum-specific estimates were applied to the 2010 US Census data and the findings combined to calculate the 2010 prevalence of MS cumulated over 10 years. No exclusions were made if a person met the algorithm criteria.Main Outcomes and MeasurementsPrevalence of MS per 100 000 US adults stratified by demographic group and geography. The 95% CIs were approximated using a binomial distribution.ResultsA total of 744 781 persons 18 years and older were identified with MS with 564 426 cases (76%) in females and 180 355 (24%) in males. The median age group was 45 to 54 years, which included 229 216 individuals (31%), with 101 271 aged 18 to 24 years (14%), 158 997 aged 35 to 44 years (21%), 186 758 aged 55 to 64 years (25%), and 68 539 individuals (9%) who were 65 years or older. White individuals were the largest group, comprising 577 725 cases (77%), with 80 276 Black individuals (10%), 53 456 Hispanic individuals (7%), and 33 324 individuals (4%) in the non-Hispanic other category. The estimated 2010 prevalence of MS per 100 000 US adults cumulated over 10 years was 161.2 (95% CI, 159.8-162.5) for Hispanic individuals (regardless of race), 298.4 (95% CI, 296.4-300.5) for Black individuals, 374.8 (95% CI, 373.8-375.8) for White individuals, and 197.7 (95% CI, 195.6-199.9) for individuals from non-Hispanic other racial and ethnic groups. During the same time period, the female to male ratio was 2.9 overall. Age stratification in each of the racial and ethnic groups revealed the highest prevalence of MS in the 45- to 64-year-old age group, regardless of racial and ethnic classification. With each degree of latitude, MS prevalence increased by 16.3 cases per 100 000 (95% CI, 12.7-19.8; P P Conclusions and RelevanceThis study found that White individuals had the highest MS prevalence followed by Black individuals, individuals from other non-Hispanic racial and ethnic groups, and Hispanic individuals. Inconsistent racial and ethnic classifications created heterogeneity within groups. In the United States, MS affects diverse racial and ethnic groups. Prevalence of MS increases significantly and nonuniformly with latitude in the United States, even when adjusted for race, ethnicity, age, and sex. These findings are important for clinicians, researchers, and policy makers.

SummaryDespite their importance, how linker histone H1s interact in chromatin and especially how the highly positively charged and intrinsically disordered H1 C-terminal domain (CTD) binds and stabilizes nucleosomes and higher-order chromatin structures remains unclear. Using single-molecule FRET we found that about half of the H1 CTDs in H1-nucleosome complexes exhibit well-defined FRET values indicative of distinct, static conformations, while the remainder of the population exhibits dynamically changing values, similar to that observed for H1 in the absence of nucleosomes. We also find that the first 30 residues of the CTD participate in relatively localized interactions with the first ∼20 bp of linker DNA, and that two separate regions in the CTD contribute to H1-dependent organization of linker DNA, consistent with some non-random CTD-linker DNA interactions. Finally, our data show that acetylation mimetics within the histone H3 tail induce decondensation and enhanced dynamics of the nucleosome-bound H1 CTD. (148 words)

Background and Objectives:Cognitive impairment is a common and impactful symptom of relapsing-remitting multiple sclerosis (RRMS). Cognitive outcome measures are often used in cross-sectional studies, but their performance as longitudinal outcome measures in clinical trials is not widely researched. In this study, we used data from a large clinical trial to describe change on the Symbol Digit Modalities Test (SDMT) and the Paced Auditory Serial Addition Test (PASAT) over up to 144 weeks of follow-up.Methods:We used the dataset from DECIDE (clinicaltrials.gov identifierNCT01064401), a large randomized controlled RRMS trial to describe change on the SDMT and PASAT over 144 weeks of follow-up. We compared change on these cognitive outcomes with change on the timed 25-foot walk (T25FW), a well-established physical outcome measure. We investigated several definitions for clinically meaningful change: any change, 4-point change, 8-point change, and 20% change for the SDMT, any change, 4-point change and 20% change for the PASAT, and 20% change for the T25FW.Results:DECIDE included 1,814 trial participants. SDMT and PASAT scores steadily improved throughout follow-up: the SDMT from a mean 48.2 (standard deviation, SD, 16.1) points at baseline to 52.6 (SD 15.2) at 144 weeks, and the PASAT from 47.0 (SD 11.3) at baseline to 50.0 (SD 10.8) at 144 weeks. This improvement in scores is most likely due to a practice effect. Throughout the trial, participants were more likely to experience improvement than worsening of their SDMT and PASAT performance, while the number of worsening events on the T25FW steadily increased. Changing the definition of clinically meaningful change for the SDMT and PASAT, or using a 6-month confirmation changed the overall number of worsening or improvement events, but did not affect the overall behaviour of these measures.Discussion:Our findings suggests that the SDMT and PASAT scores do not accurately reflect the steady cognitive decline that people with RRMS experience. Both outcomes show post baseline increases in scores, which complicates the interpretation of these outcome measures in clinical trials. More research into the size of these changes is needed before recommending a general threshold for clinically meaningful longitudinal change.

VSV-IFNβ-NIS is a recombinant oncolytic vesicular stomatitis virus (VSV) that is being evaluated clinically for the treatment of advanced malignancies. As with other cancer immunotherapies, identifying biomarkers of response will be critical to the clinical advancement of this treatment approach. Here we describe the first evaluation of neoadjuvant intravenous oncolytic VSV therapy in naturally occurring cancer, specifically appendicular osteosarcoma in companion dogs, a disease with similar natural history as its human counterpart. VSV-IFNβ-NIS was administered prior to standard of care surgical resection, permitting microscopic and genomic analysis of tumors pre and post-treatment. Alterations in the tumor microenvironment (micronecrosis, fibrosis, and inflammation) were more pronounced in VSV-treated dogs than in placebo-treated dogs. A “tail” of seven long-term survivors (35%) was apparent in the VSV-treated group. RNAseq analysis showed that virtually all the long-term responders had increased expression of a CD8 T-cell anchored immune gene cluster. We conclude that neoadjuvant VSV-IFNβ-NIS has an excellent safety profile and may provide a survival benefit for dogs with osteosarcoma whose tumors are permissive for immune infiltration. These data support ongoing translation of neoadjuvant VSV-IFNβ-NIS to human cancer patients. Strategies to further enhance clinical benefit include dose escalation or combination with other immunomodulatory agents.

BACKGROUND: The benefits and safety of the treatment of mild chronic hypertension (blood pressure

CE Information Activity Available Online: To access the article, post-test, and evaluation online, go to https://www.highmarksce.com/mscare. Target Audience: The target audience for this activity is physicians, physician assistants, nursing professionals, and other health care providers involved in the management of patients with multiple sclerosis (MS). Learning Objectives: 1) Describe what constitutes a registry. 2) Discuss the difference(s) between clinician-driven and patient-driven registries, including potential advantages of patient-driven registries. Accreditation Statement: In support of improving patient care, this activity has been planned and implemented by the Consortium of Multiple Sclerosis Centers (CMSC) and Delaware Media Group. The CMSC is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. Physician Credit: The CMSC designates this journal-based activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Nurse Credit: The CMSC designates this enduring material for 1.0 contact hour of nursing continuing professional development (NCPD) (none in the area of pharmacology). Disclosures: Francois Bethoux, MD, Editor in Chief of the International Journal of MS Care (IJMSC), has served as Physician Planner for this activity. He has disclosed relationships with Springer Publishing (royalty); Qr8 (receipt of intellectual property rights/patent holder); Biogen (receipt of intellectual property rights/patent holder, speakers’ bureau); MedRhythms (consulting fee, contracted research); GW Pharmaceuticals, Genentech, Helius Medical Technologies, Osmotica, Ipsen (consulting fee); and Adamas Pharmaceuticals (contracted research). Ruth Ann Marrie, MD, PhD, has disclosed being a co-investigator on a study funded by Biogen and Roche. Gary R. Cutter, PhD, has disclosed serving 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); serving 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 being president of Pythagoras, Inc, a private consulting company. Robert J. Fox, MD, MSc, has disclosed receiving 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. Timothy Vollmer, MD, has disclosed receiving compensation for lectures and consultancy from Biogen, Genentech/Roche, Viela Bio, Celgene, EMD Serono, and Novartis; and research support from Rocky Mountain Multiple Sclerosis Center, Celgene, Biogen, Anokion, Genentech, F. Hoffmann-La Roche Ltd, GW Pharmaceuticals, and TG Therapeutics Inc. Tuula Tyry, PhD, has disclosed no relevant financial relationships. Amber Salter, PhD, has disclosed serving as a statistical editor for Circulation: Cardiovascular Imaging. The staff at IJMSC, CMSC, and Delaware Media Group who are in a position to influence content have disclosed no relevant financial relationships. Laurie Scudder, DNP, NP, Continuing Education Director CMSC, has served as Reviewer for this activity. She has disclosed no relevant financial relationships. One peer reviewer for IJMSC has disclosed relationships with Alexion (consulting fee, speakers’ bureau); Biogen, Bristol Myers Squibb, EMD Serono, Genentech (consulting fee, speakers’ bureau, contracted research); Celgene, Novartis, Sanofi Genzyme (consulting fee, contracted research); Viela Bio (consulting fee); National MS Society, PCORI, Atara Biotherapeutics, Roche (contracted research); and Taro Pharmaceuticals, AstraZeneca, Pfizer, Johnson & Johnson, Inovio, GlaxoSmithKline, Viatris, Gilead, Altimmune Inc, CytoDyn Inc (ownership interest [common stocks]). The other peer reviewer has disclosed relationships with Celgene (speakers’ bureau, contracted research); and Merck, EMD Serono, Roche, AbbVie (contracted research). Note: Financial relationships may have changed in the interval between listing these disclosures and publication of the article. Method of Participation: Release Date: December 1, 2021 Valid for Credit Through: December 1, 2022 In order to receive CME/NCPD/CPE credit, participants must: 1) Review the continuing education information, including learning objectives and author disclosures.2) Study the educational content.3) Complete the post-test and evaluation, which are available at https://www.highmarksce.com/mscare. Statements of Credit are awarded upon successful completion of the evaluation and the post-test with a passing score of >70%. The post-test may be retaken if necessary. There is no fee to participate in this activity. Disclosure of Unlabeled Use: This educational activity may contain discussion of published and/or investigational uses of agents that are not approved by the FDA. The CMSC and Delaware Media Group do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the CMSC or Delaware Media Group. Disclaimer: Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any medications, diagnostic procedures, or treatments discussed in this publication should not be used by clinicians or other health care professionals without first evaluating their patients’ conditions, considering possible contraindications or risks, reviewing any applicable manufacturer’s product information, and comparing any therapeutic approach with the recommendations of other authorities.

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.

We undertook a randomized controlled trial (RCT) that investigated the effectiveness of a theory-based, Internet-delivered, behavioral intervention focusing on physical activity promotion for immediate and sustained improvements in secondary, patient-reported outcomes (PROs) of function, symptoms, and quality of life (QOL) in multiple sclerosis (MS).Persons with MS (N = 318) were recruited from throughout the United States and randomized into behavioral intervention (n = 159) or attention/social contact control (n = 159) conditions. The conditions were administered over a 6-month period by persons who were uninvolved in screening, recruitment, random assignment, and outcome assessment. There was a 6-month follow-up period without intervention access/content. We collected PROs data every 6 months over the 12-month period. The PROs included validated measures of walking and cognitive function, symptoms of fatigue, depression, anxiety, pain, and sleep quality, and QOL. The data analysis involved a modified intent-to-treat approach using a linear mixed model in JMP Pro 16.0.There was a significant group by time interaction on Fatigue Severity Scale scores (p .01) and physical subscale scores of the Modified Fatigue Impact Scale (p .05). Scores on both measures decreased immediately after the 6-month period in the behavioral intervention compared with no change in the control condition, and this differential pattern of change was sustained over the 6-month follow-up. There were no group by time interactions on the other PROs.This study provides evidence for the effectiveness of a novel, widely scalable approach for physical activity promotion and fatigue management in persons with MS, yet this must be contextualized with the absence of improvements in the other PROs.

Developing an effective automatic classifier to separate genuine sources from artifacts is essential for transient follow-ups in wide-field optical surveys. The identification of transient detections from the subtraction artifacts after the image differencing process is a key step in such classifiers, known as real-bogus classification problem. We apply a self-supervised machine learning model, the deep-embedded self-organizing map (DESOM) to this ‘real-bogus’ classification problem. DESOM combines an autoencoder and a self-organizing map to perform clustering in order to distinguish between real and bogus detections, based on their dimensionality-reduced representations. We use 32 × 32 normalized detection thumbnails as the input of DESOM. We demonstrate different model training approaches, and find that our best DESOM classifier shows a missed detection rate of $6.6{{\ \rm per\,cent}}$ with a false-positive rate of $1.5{{\ \rm per\,cent}}$. DESOM offers a more nuanced way to fine-tune the decision boundary identifying likely real detections when used in combination with other types of classifiers, e.g. built on neural networks or decision trees. We also discuss other potential usages of DESOM and its limitations.

Background and ObjectivesObservational 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.MethodsWe 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 modifiedpvalue threshold for inclusion in the PGS (5 × 10−5) and applying Mendelian randomization (MR) rather than using PGS.ResultsInitial 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; R2= 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 otherpvalue thresholds or those applying MR.DiscussionGenetically 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.

BACKGROUND AND OBJECTIVES: Thalamic atrophy (TA) represents a biomarker of neurodegeneration and associated dysfunction/decline in physical and cognitive functioning among persons with multiple sclerosis (MS). Aerobic fitness, as an end point of exercise training, represents a promising target for restoring function in MS, but it is unknown if such effects differ by TA. This cross-sectional study examined whether aerobic fitness was differentially associated with cognitive processing speed and walking endurance in persons with MS who present with and without TA. METHODS: 44 fully ambulatory persons with MS completed a graded exercise test for measuring aerobic fitness (VO(2peak)) and underwent 3T MRI for measuring TA, the Symbol Digit Modalities Test (SDMT), and the 6-min walk (6MW). We performed Spearman correlations (r(s)) among VO(2peak), SDMT, and 6MW scores overall, and in persons with and without TA. We applied Fisher’s z-test for comparing correlations based on TA status. RESULTS: When controlling for age, EDSS score, and global MRI measures of atrophy, VO(2peak) was strongly associated with SDMT scores (pr(s) = 0.74, p < 0.01) and 6MW performance (pr(s) = 0.77, p < 0.01) in persons with TA, whereas VO(2peak) was not associated with SDMT scores (pr(s) = − 0.01, p = 0.99) or 6MW performance (pr(s) = 0.25, p = 0.38) in those without TA. The correlations between VO(2peak) and SDMT (z = 2.86, p < 0.01) and VO(2peak) and 6MW (z = 2.33, p = 0.02) were significantly stronger in the TA group. DISCUSSION: This study provides initial evidence of strong, selective associations among aerobic fitness, cognitive processing speed, and walking endurance in persons with TA as a biomarker for MS-related neurodegeneration. Such data support TA as a moderator of the association among aerobic fitness, cognitive processing speed, and walking endurance in persons with MS. Future research should carefully consider the role of TA when designing trials of aerobic exercise, cognition, and mobility in MS.

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.

Large-scale sky surveys have played a transformative role in our understanding of astrophysical transients, only made possible by increasingly powerful machine learning-based filtering to accurately sift through the vast quantities of incoming data generated. In this paper, we present a new real-bogus classifier based on a Bayesian convolutional neural network that provides nuanced, uncertainty-aware classification of transient candidates in difference imaging, and demonstrate its application to the datastream from the GOTO wide-field optical survey. Not only are candidates assigned a well-calibrated probability of being real, but also an associated confidence that can be used to prioritise human vetting efforts and inform future model optimisation via active learning. To fully realise the potential of this architecture, we present a fully-automated training set generation method which requires no human labelling, incorporating a novel data-driven augmentation method to significantly improve the recovery of faint and nuclear transient sources. We achieve competitive classification accuracy (FPR and FNR both below 1%) compared against classifiers trained with fully human-labelled datasets, whilst being significantly quicker and less labour-intensive to build. This data-driven approach is uniquely scalable to the upcoming challenges and data needs of next-generation transient surveys. We make our data generation and model training codes available to the community., 17 pages, 12 figures, resubmitted to MNRAS following reviewer comments

BACKGROUND: Emerging evidence supports the superiority of balanced crystalloids such as Lactated Ringer’s (LR) compared to normal saline but concerns for the development of hyperkalemia have limited its use. Although LR inherently contains potassium, there exists a paucity of evidence to suggest that LR could potentiate hyperkalemia. To address this, we evaluated the effect of LR on serum potassium in patients with reduced kidney function who are at risk of developing hyperkalemia. METHODS: We conducted a single-center, retrospective cohort-based observational clinical study that included 293 clinical encounters who were hospitalized with an estimated glomerular filtration rate (eGFR) of < 30 ml/min/1.73m(2), at the time of hospital admission. Subjects must have received a minimum of 500 ml of LR continuously during the admission. Only those with a minimum of one lab report within 24 hours prior to-, and post-LR administration that reported serum measurements of potassium, glucose, and bicarbonate levels were included. Other potential risk factors for developing hyperkalemia including medication, tube feeds, potassium supplements, and red blood cell transfusion during or within 24 hours after LR administration were recorded. RESULTS: Serum potassium prior to LR use was highly correlated and predictive of the serum potassium after LR use [P < 0.0001; Odds Ratio 6.77 (3.73 – 12.28)]. Sixteen encounters (5%) developed de-novo hyperkalemia following LR use. No significant positive correlation between the amount of LR administered and the development of hyperkalemia was found. CONCLUSIONS: LR use was not independently associated with the development of hyperkalemia in patients with reduced kidney function.

Background: Accurate longitudinal modelling of cognitive decline is a major goal of Alzheimer’s disease and related dementia (ADRD) research. However, the impact of subject-specific effects is not well characterized and may have implications for data generation and prediction. Objective: This study seeks to address the impact of subject-specific effects, which are a less well-characterized aspect of ADRD cognitive decline, as measured by the Alzheimer’s Disease Assessment Scale’s Cognitive Subscale (ADAS-Cog). Methods: Prediction errors and biases for the ADAS-Cog subscale were evaluated when using only population-level effects, robust imputation of subject-specific effects using model covariances, and directly known individual-level effects fit during modelling as a natural control. Evaluated models included pre-specified parameterizations for clinical trial simulation, analogous mixed-effects regression models parameterized directly, and random forest ensemble models. Assessment used a meta-database of Alzheimer’s disease studies with validation in simulated synthetic cohorts. Results: All models observed increases in variance under imputation leading to increased prediction error. Bias decreased with imputation except under the pre-specified parameterization, which increased in the meta-database, but was attenuated under simulation. Known fitted subject effects gave the best prediction results. Conclusion: Subject-specific effects were found to have a profound impact on predicting ADAS-Cog. Reductions in bias suggest imputing random effects assists in calculating results on average, as when simulating clinical trials. However, reduction in error emphasizes population-level effects when attempting to predict outcomes for individuals. Forecasting future observations greatly benefits from using known subject-specific effects.

International audience; Background: Ofatumumab, a subcutaneous anti-CD20 monoclonal antibody, selectively depletes B cells. Teriflunomide, an oral inhibitor of pyrimidine synthesis, reduces T-cell and B-cell activation. The relative effects of these two drugs in patients with multiple sclerosis are not known.Methods: In two double-blind, double-dummy, phase 3 trials, we randomly assigned patients with relapsing multiple sclerosis to receive subcutaneous ofatumumab (20 mg every 4 weeks after 20-mg loading doses at days 1, 7, and 14) or oral teriflunomide (14 mg daily) for up to 30 months. The primary end point was the annualized relapse rate. Secondary end points included disability worsening confirmed at 3 months or 6 months, disability improvement confirmed at 6 months, the number of gadolinium-enhancing lesions per T1-weighted magnetic resonance imaging (MRI) scan, the annualized rate of new or enlarging lesions on T2-weighted MRI, serum neurofilament light chain levels at month 3, and change in brain volume.Results: Overall, 946 patients were assigned to receive ofatumumab and 936 to receive teriflunomide; the median follow-up was 1.6 years. The annualized relapse rates in the ofatumumab and teriflunomide groups were 0.11 and 0.22, respectively, in trial 1 (difference, -0.11; 95% confidence interval [CI], -0.16 to -0.06; P

ObjectiveTo determine whether comorbidity is associated with clinical (relapses, disability worsening) and MRI outcomes in multiple sclerosis (MS) by conducting a secondary analysis of the CombiRx clinical trial.MethodsCombiRx compared interferon beta-1a, glatiramer acetate, and the combination of these agents. For participants eligible for evaluation of 6-month confirmed disability worsening, we used medical history, concomitant medications, and adverse events to ascertain comorbidity status. Comorbid conditions evaluated included hypertension, dyslipidemia, diabetes mellitus, depression, anxiety disorders, and migraine. Clinical outcomes included disease activity consisting of protocol-defined relapses, disability worsening, and MRI activity. We summarized the prevalence of these comorbid conditions and their association with disease activity and its components using multivariable Cox regression.ResultsOf the 1,008 participants randomized, 959 (95.1%) were eligible for assessment of 6-month disability worsening; for this subgroup, the median length of follow-up was 3.4 years (range 0.5–6.9 years). Overall, 55.1% of participants had ≥1 comorbidity at enrollment. After adjustment, anxiety (hazard ratio [HR] 1.25, 95% confidence interval [CI] 1.01–1.55) and dyslipidemia (HR 1.32, 95% CI 1.01–1.72) were associated with an increased hazard of any disease activity, while migraine (HR 0.80, 95% CI 0.67–0.97) was associated with a decreased hazard.ConclusionsIn this large trial population with rigorously obtained outcomes, comorbid conditions were common among participants and influenced disease outcomes, including relapses. The comorbidity burden of clinical trial participants with MS may be an important factor in the outcome of clinical trials. Additional investigations of the impact of comorbidity on clinical trial outcomes and response to disease-modifying therapies are warranted.

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.

This abstract is being presented as a short talk in the scientific program. A full abstract is available in the Short Talks from Proffered Abstracts section (PR008) of the Conference Proceedings. Citation Format: Jaime F. Modiano, Ashley J. Schulte, Taylor A. DaPauw, Ali Khammanivong, Jong H. Kim, Aaron L. Sarver, Gary R. Cutter, Eric Lindquist, Kelly M. Makielski. Identification and characterization of the cancer permissive environment in companion dogs [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr A004.

Domestic dogs are the only species besides humans where we recognize spontaneous, non-transmissible cancers as a significant cause of mortality(1-3). Recently, there has been a recognition that an important aspect of the natural history of cancer is that both species “live longer than nature intended” thanks to social, medical, and technological advances. We and others have proposed that this extended longevity is partly responsible for a decline in cancer protective mechanisms, and possibly for the arisal of cancer permissive (aged) environments(1). We have developed platforms to study the development of these environments. One such platform is the Shine On Suspicion (SOS) test, which uses flow cytometry and machine learning to identify patterns of mesenchymal and progenitor cells in blood that are associated with the presence of cancer or with the increased risk of developing cancer. Our hypothesis is that the cells responsible for these patterns contribute to the formation and/or to the remodeling of the cancer niche. The training set for the Shine On project included a group of healthy dogs that were past puberty but had not reached the age boundary where cancer risk is apparent (2-4 years old), and three independent groups of dogs with pathologically confirmed (1) hemangiosarcomas, (2) other malignant cancers, or (3) benign splenic hematomas. The validation set included 209 dogs over 6 years of age that had no evidence of cancer or other chronic diseases. Our data show that using the SOS test, we could assign dogs to a “low-risk” category, where the probability of developing cancer over the next 400 days (approximately 1/10th of a modern domestic dog’s lifespan) was less than 4%, or to a “high-risk” category, where the probability of developing cancer over the same time period was almost 25%, and it increased to more than 50% by 1,450 days. Intriguingly, as we followed dogs assigned to the low-risk category beyond 400 days, many converted to a high-risk category, with the relative risk of cancer in this group increasing in a fashion that was comparable to that seen in dogs originally assigned to the high-risk category. Ongoing experiments using the SOS test and other platforms seek to define the identity and the functional properties of the putative-niche forming cells, their relationship to biological aging, and the development of safe and effective interventions that can delay or prevent cancer in companion dogs – and eventually in humans. References: 1. A. L. Sarver, K. M. Makielski, T. A. DePauw, A. J. Schulte, J. F. Modiano, Increased risk of cancer in dogs and humans: a consequence of recent extension of lifespan beyond evolutionarily-determined limitations? Aging Cancer 3, 3-19 (2022). 2. L. Nunney, The real war on cancer: the evolutionary dynamics of cancer suppression. Evol Appl 6, 11-19 (2013). 3.S. M. Schwartz et al., Lifetime prevalence of malignant and benign tumours in companion dogs: Cross-sectional analysis of Dog Aging Project baseline survey. Vet Comp Oncol, (2022). Citation Format: Jaime F. Modiano, Ashley J. Schulte, Taylor A. DaPauw, Ali Khammanivong, Jong H. Kim, Aaron L. Sarver, Gary R. Cutter, Eric Lindquist, Kelly M. Makielski. Identification and characterization of the cancer permissive environment in companion dogs [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr PR008.

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).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.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.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.