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Biodiversity collections are experiencing a renaissance fueled by the intersection of informatics, emerging technologies, and the extended use and interpretation of specimens and archived databases. In this article, we explore the potential for transformative research in ecology integrating biodiversity collections, stable isotope analysis (SIA), and environmental informatics. Like genomic DNA, SIA provides a common currency interpreted in the context of biogeochemical principles. Integration of SIA data across collections allows for evaluation of long-term ecological change at local to continental scales. Challenges including the analysis of sparse samples, a lack of information about baseline isotopic composition, and the effects of preservation remain, but none of these challenges is insurmountable. The proposed research framework interfaces with existing databases and observatories to provide benchmarks for retrospective studies and ecological forecasting. Collections and SIA add historical context to fundamental questions in freshwater ecological research, reference points for ecosystem monitoring, and a means of quantitative assessment for ecosystem restoration.

Background: Stiff person syndrome spectrum disorders (SPSD) are a rare group of disabling neuroimmunological disorders. SPSD often requires immune therapies, especially in the setting of inadequate response to symptomatic treatments. The safety and efficacy of therapeutic plasma exchange (TPE) in SPSD remains uncertain., Objectives: To describe the safety, tolerability, and efficacy of TPE in patients with SPSD., Design: A retrospective observational study., Methods: A retrospective review of SPSD patients seen at Johns Hopkins Hospital (JHH) from 1997 to 2021 was performed. Patient demographics/history, examination/diagnostic findings, treatment response, and TPE-related complications were recorded. Assessment for any associations between clinical characteristics, including age, sex, clinical phenotype, and time on immunotherapy, and response to TPE 3 months after treatment was performed. A subgroup of 18 patients treated with TPE at JHH and 6 patients treated with TPE at outside institutions were evaluated for any change in usage of symptomatic medications 3 months after the TPE treatment. Literature review of SPSD and TPE was also conducted., Results: Thirty-nine SPSD patients were treated with TPE (21 at JHH and 18 at outside institutions); median age 48 years, 77% female, median modified Rankin Scale 3; mean initial anti-GAD65 antibody titer was 23,508 U/mL. Twenty-four patients (62%) had classic SPS, 10 (26%) had SPS-plus, 2 (5%) had progressive encephalomyelitis with rigidity and myoclonus, and 3 (8%) had pure cerebellar ataxia. All patients were on symptomatic treatments, 30 (77%) previously received IVIg, and 3 (8%) previously received rituximab. Four patients (10%) had a TPE-related adverse event. One developed asymptomatic hypotension, another had both line thrombosis and infection, and two had non-life-threatening bleeding events. Twenty-three (59%) patients reported improvement in symptoms after TPE. Of the subgroup of 24 patients evaluated for any change in usage of symptomatic medications 3 months after the TPE treatment, 14 (58%) required fewer GABAergic symptomatic medications. Literature review identified 57 additional patients with SPSD; 43 (75%) reported temporary improvement after TPE., Conclusion: The majority of patients treated with TPE had improvement. Moreover, most patients evaluated for any change in usage of symptomatic medications after the TPE treatment no longer required as much symptomatic medications months after TPE. TPE appears safe and well-tolerated in SPSD. Further studies are needed to assess the long-term efficacy of TPE in SPSD and identify which patients may benefit the most from TPE., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Yujie Wang, MD: Research funding from Genentech. Scott D. Newsome, DO: None relevant to this manuscript. Has received consultant fees for scientific advisory boards from Biogen, Genentech, Bristol Myers Squibb, EMD Serono, Greenwich Biosciences, Novartis, TG Therapeutics, and Horizon Therapeutics; is the study lead PI for a Roche clinical trial; was a clinical adjudication committee member for a medDay Pharmaceuticals clinical trial; and has received research funding (paid directly to institution) from Biogen, Roche, Genentech, The Stiff Person Syndrome Research Foundation, National Multiple Sclerosis Society, Department of Defense, and Patient Centered Outcomes Research Institute., (© The Author(s), 2023.)

Abstract: A 68-year-old woman with positional dizziness and progressive imbalance presented for vestibular evaluation. Examination was notable for spontaneous downbeat nystagmus (DBN), horizontal and vertical gaze-evoked nystagmus (GEN) with centripetal and rebound nystagmus, and positional apogeotropic nystagmus. There was also mild-moderate slowing of saccades horizontally and vertically and poor fast phases with an optokinetic stimulus. Further consultation by a movement disorder specialist uncovered asymmetric decrementing bradykinesia and rigidity, masked facies, and a wide-based stance without camptocormia. Screening serum laboratory results for metabolic, rheumatologic, infectious, heavy metal, endocrine, or vitamin abnormalities was normal. Surveillance imaging for neoplasms was unremarkable, and cerebrospinal fluid (CSF) analysis was negative for 14-3-3 and real-time quaking-induced conversion (RT-QuIC). However, her anti-glutamic acid decarboxylase-65 (GAD65) immunoglobulin G (IgG) level was markedly elevated in serum to 426,202 IU/mL (reference range 0-5 IU/mL) and in CSF to 18.1 nmol/L (reference range <0.03 nmol/L). No other autoantibodies were identified on the expanded paraneoplastic panel. The patient was referred to neuroimmunology, where torso rigidity, spasticity, and significant paravertebral muscle spasms were noted. Overall, the clinical presentation, examination findings, and extensive workup were consistent with a diagnosis of anti-GAD65-associated stiff person syndrome-plus (musculoskeletal plus cerebellar and/or brainstem involvement). She was subsequently treated with intravenous immunoglobulin (IVIg) and has been stable since commencing this therapy. In patients with centripetal nystagmus, especially in association with other cerebellar findings, an autoimmune cerebellar workup should be considered., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by North American Neuro-Ophthalmology Society.)

Differences in the bacterial communities inhabiting mammalian gut microbiomes tend to reflect the phylogenetic relatedness of their hosts, a pattern dubbed phylosymbiosis. Although most research on this pattern has compared the gut microbiomes of host species across biomes, understanding the evolutionary and ecological processes that generate phylosymbiosis requires comparisons across phylogenetic scales and under similar ecological conditions. We analysed the gut microbiomes of 14 sympatric small mammal species in a semi-arid African savanna, hypothesizing that there would be a strong phylosymbiotic pattern associated with differences in their body sizes and diets. Consistent with phylosymbiosis, microbiome dissimilarity increased with phylogenetic distance among hosts, ranging from congeneric sets of mice and hares that did not differ significantly in microbiome composition to species from different taxonomic orders that had almost no gut bacteria in common. While phylosymbiosis was detected among just the 11 species of rodents, it was substantially weaker at this scale than in comparisons involving all 14 species together. In contrast, microbiome diversity and composition were generally more strongly correlated with body size, dietary breadth, and dietary overlap in comparisons restricted to rodents than in those including all lineages. The starkest divides in microbiome composition thus reflected the broad evolutionary divergence of hosts, regardless of body size or diet, while subtler microbiome differences reflected variation in ecologically important traits of closely related hosts. Strong phylosymbiotic patterns arose deep in the phylogeny, and ecological filters that promote functional differentiation of cooccurring host species may disrupt or obscure this pattern near the tips., (© 2023 John Wiley & Sons Ltd.)

Prior case studies suggest that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its vaccines may unmask CNS neuroinflammatory conditions. We present a case of relapsing steroid-responsive encephalomyelitis after SARS-CoV-2 infection and subsequent COVID-19 vaccination. We also characterize the frequency of CNS neuroinflammatory events reported in the literature after both SARS-CoV-2 infection and COVID-19 vaccination., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Assessing environmental changes in Southern Ocean ecosystems is difficult due to its remoteness and data sparsity. Monitoring marine predators that respond rapidly to environmental variation may enable us to track anthropogenic effects on ecosystems. Yet, many long-term datasets of marine predators are incomplete because they are spatially constrained and/or track ecosystems already modified by industrial fishing and whaling in the latter half of the 20th century. Here, we assess the contemporary offshore distribution of a wide-ranging marine predator, the southern right whale (SRW, Eubalaena australis ), that forages on copepods and krill from ~30°S to the Antarctic ice edge (>60°S). We analyzed carbon and nitrogen isotope values of 1,002 skin samples from six genetically distinct SRW populations using a customized assignment approach that accounts for temporal and spatial variation in the Southern Ocean phytoplankton isoscape. Over the past three decades, SRWs increased their use of mid-latitude foraging grounds in the south Atlantic and southwest (SW) Indian oceans in the late austral summer and autumn and slightly increased their use of high-latitude (>60°S) foraging grounds in the SW Pacific, coincident with observed changes in prey distribution and abundance on a circumpolar scale. Comparing foraging assignments with whaling records since the 18th century showed remarkable stability in use of mid-latitude foraging areas. We attribute this consistency across four centuries to the physical stability of ocean fronts and resulting productivity in mid-latitude ecosystems of the Southern Ocean compared with polar regions that may be more influenced by recent climate change.

Rationale: Hydrogen isotope (δ 2 H) analysis of keratinaceous bulk tissues has been used in forensic science to reconstruct an individual's travel history or determine their region-of-origin. Here, we use a compound-specific approach to examine patterns of individual amino acid δ 2 H values in relation to those of local tap water, bulk scalp hair tissues, and region-of-origin., Methods: We measured δ 2 H values of amino acids in anonymously collected scalp hair (n = 67) and tap water from 28 locations in the United States. Samples were hydrolyzed into their constituent amino acids, derivatized alongside in-house reference materials, and analyzed in triplicate using a GC-C-IRMS system., Results: Non-essential amino acid (AA NESS ) δ 2 H values and their corresponding tap water samples varied systematically across continental regions. Hydrogen isotope values of alanine, glutamic acid, and glycine were significantly correlated with tap water and an estimated 42%-51% of the hydrogen atoms in these AA NESS were derived from tap water. We used linear discriminate analysis (LDA) to explore regional patterns in scalp hair bulk tissue and amino acid δ 2 H values. For the model that included AA NESS data, 87% of the variance was explained by the first linear discriminant axis (LD1), and was driven by bulk hair tissue, alanine, and proline. This model had an overall 72% successful reclassification with samples from the south and northwest regions reclassifying correctly 92% and 78% of the time, respectively. For the model that included AA ESS data, LD1 explained 81% of the variation and was driven bulk hair, threonine, valine, phenylalanine, and isoleucine. The overall reclassification rate for the model that included AA ESS was 70%., Conclusions: Our findings suggest that δ 2 H analyses of AA NESS and AA ESS could help improve geolocation models for human and wildlife forensics by simultaneously providing information about both dietary and tap water inputs of hydrogen to tissue synthesis., (© 2022 John Wiley & Sons Ltd.)

Populations usually considered foraging generalists may include specialized individuals that feed on a restricted subset of the prey spectrum consumed by the population. By analyzing the time series of δ 13 C and δ 15 N values in sequential growth layer groups within tooth dentin, we measured population- and individual-level variation in resource use of three populations of Guiana dolphins (Sotalia guianensis)-Caravelas River, Babitonga Bay, and Norte Bay-along a latitudinal gradient in the southwestern Atlantic Ocean. We show that the Guiana dolphin at Caravelas River is a generalist population consisting of individual dietary specialists, likely due to the absence of other resident dolphin populations thus allowing individuals to target prey across a wide range of habitats. The Babitonga Bay population is also composed of individual specialists potentially due to the selective foraging behavior of some individuals on high-quality prey sources within and near the bay. In contrast, the Norte Bay population comprises individual generalists, which likely reflects its distinctive cohesive social organization, coexistence with two other dolphin species, and an opportunistic foraging strategy in response to resource fluctuations inherent to the southern limit of the species distribution. Although the Guiana dolphin is generally considered to be a dietary generalist at the population level, our findings reveal that the total niche width of populations and the degree of individual diet specialization are highly context dependent, suggesting dietary plasticity that may be related to a latitudinal gradient in resource availability and environmental conditions., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Food web ecology has revolutionized our understanding of ecological processes, but the drivers of food web properties like trophic position (TP) and food chain length are notoriously enigmatic. In terrestrial ecosystems, above- and belowground systems were historically compartmentalized into "green" and "brown" food webs, but the coupling of these systems by animal consumers is increasingly recognized, with potential consequences for trophic structure. We used stable isotope analysis (δ 13 C, δ 15 N) of individual amino acids to trace the flow of essential biomolecules and jointly measure multichannel feeding, food web coupling, and TP in a guild of small mammals. We then tested the hypothesis that brown energy fluxes to aboveground consumers increase terrestrial food chain length via cryptic trophic transfers during microbial decomposition. We found that the average small mammal consumer acquired nearly 70% of their essential amino acids (69.0% ± 7.6%) from brown food webs, leading to significant increases in TP across species and functional groups. Fungi were the primary conduit of brown energy to aboveground consumers, providing nearly half the amino acid budget for small mammals on average (44.3% ± 12.0%). These findings illustrate the tightly coupled nature of green and brown food webs and show that microbially mediated energy flow ultimately regulates food web structure in aboveground consumers. Consequently, we propose that the integration of green and brown energy channels is a cryptic driver of food chain length in terrestrial ecosystems., (© 2022 The Ecological Society of America. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Objective: To explore longitudinal changes in brain volumetric measures and retinal layer thicknesses following acute optic neuritis (AON) in people with multiple sclerosis (PwMS), to investigate the process of trans-synaptic degeneration, and determine its clinical relevance., Methods: PwMS were recruited within 40 days of AON onset (n = 49), and underwent baseline retinal optical coherence tomography and brain magnetic resonance imaging followed by longitudinal tracking for up to 5 years. A comparator cohort of PwMS without a recent episode of AON were similarly tracked (n = 73). Mixed-effects linear regression models were used., Results: Accelerated atrophy of the occipital gray matter (GM), calcarine GM, and thalamus was seen in the AON cohort, as compared with the non-AON cohort (-0.76% vs -0.22% per year [p = 0.01] for occipital GM, -1.83% vs -0.32% per year [p = 0.008] for calcarine GM, -1.17% vs -0.67% per year [p = 0.02] for thalamus), whereas rates of whole-brain, cortical GM, non-occipital cortical GM atrophy, and T2 lesion accumulation did not differ significantly between the cohorts. In the AON cohort, greater AON-induced reduction in ganglion cell+inner plexiform layer thickness over the first year was associated with faster rates of whole-brain (r = 0.32, p = 0.04), white matter (r = 0.32, p = 0.04), and thalamic (r = 0.36, p = 0.02) atrophy over the study period. Significant relationships were identified between faster atrophy of the subcortical GM and thalamus, with worse visual function outcomes after AON., Interpretation: These results provide in-vivo evidence for anterograde trans-synaptic degeneration following AON in PwMS, and suggest that trans-synaptic degeneration may be related to clinically-relevant visual outcomes. ANN NEUROL 2023;93:76-87., (© 2022 American Neurological Association.)

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a recently described CNS inflammatory disorder that may manifest with optic neuritis, myelitis, seizures, and/or acute disseminated encephalomyelitis. While MOG-specific antibodies in patients with MOGAD are IgG1, a T-cell-dependent antibody isotype, immunologic mechanisms of this disease are not fully understood. Thymic hyperplasia can be associated with certain autoimmune diseases. In this report we describe a case of MOGAD associated with thymic hyperplasia in a young adult., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: The impact of early versus later high-efficacy disease-modifying therapy (DMT) in patients with multiple sclerosis (MS) is uncertain. This study reported the association of early versus later natalizumab treatment with real-world clinical outcomes in MS patients., Methods: The study included 661 participants diagnosed with MS in 1994 or later from 7 US centers participating in the MS Partners Advancing Technology for Health Solutions (MS PATHS) network. Time to natalizumab treatment between diagnosis and first infusion (TTNT) was determined from the Tysabri Outreach: Unified Commitment to Health (TOUCH) registry. Clinical outcomes were defined using neuroperformance tests included in the Multiple Sclerosis Performance Test. Associations were tested using TTNT as a categorical and continuous variable. Linear mixed models addressed within-subject and within-site clustering., Results: TTNT varied from 0.1 to 19.8 years (median [interquartile range] 4.2 [1.8, 9.0] years). A significant association between later natalizumab use and worse outcomes was demonstrated for walking speed (p < 0.001), processing speed (p < 0.001), manual dexterity (p < 0.001), brain atrophy (p = 0.001), and T2 lesion volume (p = 0.02). Covariate-adjusted modelling of a sensitivity population diagnosed with MS in 2006 or later (n = 424) demonstrated significant associations between longer TTNT and worse walking speed (p < 0.05), processing speed (p < 0.001), and manual dexterity (p < 0.001)., Conclusion: Later initiation of natalizumab was associated with worse clinical and radiologic imaging outcomes. Thus, high-efficacy DMT may have greater benefit when started earlier in MS patients. These results provide a rationale for randomized controlled trials to further assess the impact of early highly-effective DMT use versus later escalation of therapy., Competing Interests: Declaration of Competing Interest DO reports research funding from Biogen, grants from the National Institutes of Health, the National Multiple Sclerosis Society, the Patient-Centered Outcomes Research Institute, and Race to Erase MS and grants and personal fees from Genzyme, Genentech/Roche, and Novartis outside the submitted work. EMM has received research funding from the National Institutes of Health, the National Multiple Sclerosis Society, the Department of Defense, Biogen, Genentech, Genzyme, and the Patient-Centered Outcomes Research Institute; free medication for a clinical trial from Teva; and royalties for editorial duties from UpToDate and has been a site principal investigator for studies sponsored by Biogen and Sun Pharma. SDN has received institutional research support from Biogen, Genentech, the National Multiple Sclerosis Society, the Patient-Centered Outcomes Research Institute, and the US Department of Defense and has been a consultant/advisor for Biogen, Celgene, EMD Serono, the Gerson Lehrman Group, and Syntimmune. RTN has consulted for Banner Life Sciences, BeiGene, Biogen, Bristol Myers Squibb, Genentech, Genzyme, Janssen, GW Therapeutics, Horizon Therapeutics, Lundbeck, NervGen, TG Therapeutics, Third Rock Ventures, Viela Bio. JN has received research support from Biogen and has been a consultant for Alexion, Biogen, Celgene, EMD Serono, Genentech, Genzyme, Greenwich Biosciences, the Multiple Sclerosis Association of America, and Novartis and received research grants from Biogen, Genzyme, and Novartis. EF, CdM, AS, and JRW are employees of and may own stock and/or stock options in Biogen. JB, P-RH and RR are former employees of Biogen and may own stock and/or stock options in Biogen., (Copyright © 2022. Published by Elsevier B.V.)

Background and Objectives: Rituximab is used widely for relapse prevention in neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein (MOG)-IgG-associated disease (MOGAD); however, data regarding the effectiveness and safety of long-term rituximab use in these conditions are limited. In this study, we sought to evaluate long-term clinical outcomes in patients with aquaporin-4 IgG-seropositive (AQP4-IgG+) NMOSD and MOGAD treated with rituximab., Methods: We performed a retrospective chart review of patients with AQP4-IgG+ NMOSD or MOGAD followed at the Johns Hopkins Neuromyelitis Optica Clinic and included patients who had received at least 1 dose of rituximab., Results: We identified 111 patients with NMOSD and 23 patients with MOGAD who fulfilled the inclusion criteria. The median duration of rituximab treatment for the patients with NMOSD was 3.7 years (range: 0.5-13.2 years) and for the patients with MOGAD was 2.1 years (range: 0.5-7.0 years). The annualized relapse rate (ARR) decreased after rituximab initiation in both NMOSD (median ARR: pretreatment 1.1, posttreatment 0; p < 0.001) and MOGAD (median ARR: pretreatment 1.9, posttreatment 0.3; p = 0.002). Relapses on rituximab occurred in 31 patients with NMOSD (28%) and 14 patients with MOGAD (61%). The majority of NMOSD treatment failures (37/48 relapses; 77%) occurred either within the initial 6 months after starting rituximab (n = 13 relapses) or in the setting of delayed/missed rituximab doses and/or peripheral B-cell reconstitution (n = 24 relapses), whereas in MOGAD, these circumstances were present in a smaller proportion of treatment failures (19/35 relapses; 54%). The risk of relapse on rituximab was greater for patients with MOGAD compared with patients with NMOSD (hazard ratio: 2.8, 95% CI: 1.5-5.2, p = 0.001). Infections requiring hospitalization occurred in 13% and immunoglobulin G (IgG) hypogammaglobulinemia in 17% of patients. The median rituximab treatment duration before IgG hypogammaglobulinemia onset was 5.4 years (interquartile range: 3.8-7.7 years)., Discussion: Rituximab treatment is associated with the reduced annualized relapse rate in AQP4-IgG-seropositive NMOSD, especially in the absence of gaps in treatment and/or B-cell reconstitution. In MOGAD, although a reduction in relapses was observed after initiation of rituximab, this association appeared to be less robust than in AQP4-IgG-seropositive NMOSD. Severe infections and hypogammaglobulinemia occurred in a significant proportion of patients, highlighting the need for close monitoring of infectious complications., Classification of Evidence: This study provides Class IV evidence that rituximab decreases the annualized relapse rate in AQP4-IgG-seropositive NMOSD and MOGAD., (© 2022 American Academy of Neurology.)

Understanding how intraspecific variation in the use of prey resources impacts energy metabolism has strong implications for predicting long-term fitness and is critical for predicting population-to-community level responses to environmental change. Here, we examine the energetic consequences of variable prey resource use in a widely distributed marine carnivore, juvenile sand tiger sharks (Carcharias taurus). We used carbon and nitrogen isotope analysis to identify three primary prey resource pools-demersal omnivores, pelagic forage, and benthic detritivores and estimated the proportional assimilation of each resource using Bayesian mixing models. We then quantified how the utilization of these resource pools impacted the concentrations of six plasma lipids and how this varied by ontogeny. Sharks exhibited variable reliance on two of three predominant prey resource pools: demersal omnivores and pelagic forage. Resource use variation was a strong predictor of energetic condition, whereby individuals more reliant upon pelagic forage exhibited higher blood plasma concentrations of very low-density lipoproteins, cholesterol, and triglycerides. These findings underscore how intraspecific variation in resource use may impact the energy metabolism of animals, and more broadly, that natural and anthropogenically driven fluctuations in prey resources could have longer term energetic consequences., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The conservation status of large-bodied mammals is dire. Their decline has serious consequences because they have unique ecological roles not replicated by smaller-bodied animals. Here, we use the fossil record of the megafauna extinction at the terminal Pleistocene to explore the consequences of past biodiversity loss. We characterize the isotopic and body-size niche of a mammal community in Texas before and after the event to assess the influence on the ecology and ecological interactions of surviving species (>1 kg). Preextinction, a variety of C 4 grazers, C 3 browsers, and mixed feeders existed, similar to modern African savannas, with likely specialization among the two sabertooth species for juvenile grazers. Postextinction, body size and isotopic niche space were lost, and the δ 13 C and δ 15 N values of some survivors shifted. We see mesocarnivore release within the Felidae: the jaguar, now an apex carnivore, moved into the specialized isotopic niche previously occupied by extinct cats. Puma, previously absent, became common and lynx shifted toward consuming more C 4 -based resources. Lagomorphs were the only herbivores to shift toward C 4 resources. Body size changes from the Pleistocene to Holocene were species-specific, with some animals (deer, hare) becoming significantly larger and others smaller (bison, rabbits) or exhibiting no change to climate shifts or biodiversity loss. Overall, the Holocene body-size-isotopic niche was drastically reduced and considerable ecological complexity lost. We conclude biodiversity loss led to reorganization of survivors and many "missing pieces" within our community; without intervention, the loss of Earth's remaining ecosystems that support megafauna will likely suffer the same fate.

Stiff person syndrome spectrum disorders (SPSD) are a group of rare neuroimmunological disorders that often include painful spasms and rigidity. However, patients have highly heterogeneous signs and symptoms which may reflect different mechanistic disease processes. Understanding subsets of patients based on clinical phenotype may be important for prognosis and guiding treatment. The goal of this review is to provide updates on SPSD and its expanding clinical spectrum, prognostic markers, and treatment considerations. Further, we describe the current understanding in immunopathogenesis and highlight gaps in our knowledge appropriate for future research directions. Examples of revised diagnostic criteria for SPSD based on phenotype are also presented., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Nitrogen isotope (δ 15 N) analysis of bulk tissues and individual amino acids (AA) can be used to assess how consumers maintain nitrogen balance with broad implications for predicting individual fitness. For elasmobranchs, a ureotelic taxa thought to be constantly nitrogen limited, the isotopic effects associated with nitrogen-demanding events such as prolonged gestation remain unknown. Given the linkages between nitrogen isotope variation and consumer nitrogen balance, we used AA δ 15 N analysis of muscle and liver tissue collected from female bonnethead sharks (Sphyrna tiburo, n = 16) and their embryos (n = 14) to explore how nitrogen balance may vary across gestation. Gestational stage was a strong predictor of bulk tissue and AA δ 15 N values in pregnant shark tissues, decreasing as individuals neared parturition. This trend was observed in trophic (e.g., Glx, Ala, Val), source (e.g., Lys), and physiological (e.g., Gly) AAs. Several potential mechanisms may explain these results including nitrogen conservation, scavenging, and bacterially mediated breakdown of urea to free ammonia that is used to synthesize AAs. We observed contrasting patterns of isotopic discrimination in embryo tissues, which generally became enriched in 15 N throughout development. This was attributed to greater excretion of nitrogenous waste in more developed embryos, and the role of physiologically sensitive AAs (i.e., Gly and Ser) to molecular processes such as nucleotide synthesis. These findings underscore how AA isotopes can quantify shifts in nitrogen balance, providing unequivocal evidence for the role of physiological condition in driving δ 15 N variation in both bulk tissues and individual AAs., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

An emerging body of evidence suggests that changes in cognitive and emotional function are common aspects of stiff person spectrum disorders (SPSD). We sought to examine the pattern of cognitive impairment and psychiatric symptoms in SPSD., Methods: A retrospective review of medical records was conducted for patients seen at the Johns Hopkins Stiff Person Syndrome (SPS) center from 1997 to January 1st, 2020. Individuals who had received formal cognitive testing as part of routine clinical care for patient-reported cognitive changes were included. Demographics, prevalence of cognitive impairment, psychoactive medication use, and clinically significant psychiatric symptoms were described., Results: Out of 205 patients screened, 20 completed cognitive testing (75% female, mean age 47.4 years). The most common domains of impairment were verbal learning and recall memory ( n = 14, 70%), verbal fluency ( n = 10, 50%), processing speed ( n = 8, 40%), and attention ( n = 8, 40%). 9/11 patients assessed for depression reported clinically significant symptoms, and 4/9 patients assessed for anxiety reported clinically significant symptoms., Conclusions: Screening for cognitive impairment in SPSD should utilize testing that assesses verbal learning and recall, phonemic verbal fluency, attention, and processing speed. Moreover, it is important to evaluate for co-existing depression and anxiety symptoms, as these are common in SPSD., Competing Interests: The authors declare 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 © 2022 Chan, Pimentel Maldonado, Wang, Obando, Hughes and Newsome.)

Background: People with autoimmune or inflammatory conditions taking immunomodulatory/suppressive medications may have higher risk of novel coronavirus disease 2019 (COVID-19). Chronic disease care has also changed for many patients, with uncertain downstream consequences., Methods: We included participants with autoimmune or inflammatory conditions followed by specialists at Johns Hopkins. Participants completed periodic surveys querying comorbidities, disease-modifying medications, exposures, COVID-19 testing and outcomes, social behaviors, and disruptions to healthcare. We assessed whether COVID-19 risk is higher among those on immunomodulating or suppressive agents and characterized pandemic-associated changes to care and mental health., Results: In total, 265 (5.6%) developed COVID-19 over 9 months of follow-up (April-December 2020). Patient characteristics (age, race, comorbidity, medications) were associated with differences in social distancing behaviors during the pandemic. Glucocorticoid exposure was associated with higher odds of COVID-19 in models incorporating behavior and other potential confounders (odds ratio [OR]: 1.43; 95% confidence interval [CI]: 1.08, 1.89). Other medication classes were not associated with COVID-19 risk. Diabetes (OR: 1.72; 95% CI: 1.08, 2.73), cardiovascular disease (OR: 1.68; 95% CI: 1.24, 2.28), and kidney disease (OR: 1.76; 95% CI: 1.04, 2.97) were associated with higher odds of COVID-19. Of the 2156 reporting pre-pandemic utilization of infusion, mental health or rehabilitative services, 975 (45.2%) reported disruptions therein, which disproportionately affected individuals experiencing changes to employment or income., Conclusions: Glucocorticoid exposure may increase risk of COVID-19 in people with autoimmune or inflammatory conditions. Disruption to healthcare and related services was common. Those with pandemic-related reduced income may be most vulnerable to care disruptions., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Early intervention with well-tolerated disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS) is recommended in order to delay disease progression, reduce neurologic damage, preserve brain volume, and optimize long-term patient outcomes. Lack of conversion of new/newly enlarging T2 (NET2) or gadolinium-enhancing (Gd+) lesions to chronic hypointensities (black hole conversion) and achievement of no evidence of disease activity (NEDA) early in the course of treatment are considered potential indicators of treatment effect and predictors of longer-term clinical outcomes., Methods: Patients with RRMS who were treated with peginterferon beta-1a in the 2-year ADVANCE phase 3 clinical trial (NCT0090639) and its 2-year open-label extension study, ATTAIN (NCT01332019), were grouped as newly diagnosed (diagnosed ≤1 year prior to enrollment and DMT naive) or non-newly diagnosed. For analyses of the impact of early treatment and disease activity control, the newly diagnosed and non-newly diagnosed subgroups were further divided based on whether they initiated peginterferon beta-1a every 2 weeks (Q2W) starting in study year 1 (continuously treated) or peginterferon beta-1a Q2W or every 4 weeks in study year 2 (delayed treatment). Patient subgroups were evaluated for conversion of NET2 or Gd+ lesions to persistent black holes (PBHs), brain atrophy (percentage change in whole brain volume [WBV]), achievement of NEDA composite outcomes, and the association of these disease activity measures with longer-term clinical outcomes (annualized relapse rate [ARR] and confirmed disability worsening [CDW])., Results: At 2 years, significantly fewer PBHs developed from NET2 lesions or Gd+ lesions in newly diagnosed and non-newly diagnosed patients continuously treated with peginterferon beta-1a than in the corresponding delayed-treatment groups (all p<0.0001). Percentage decrease in WBV from 6 months (rebaselined) to 2 years was significantly lower for newly diagnosed and non-newly diagnosed patients who received continuous peginterferon beta-1a treatment than for patients who received delayed treatment (both p ≤ 0.0442). In study year 1, a higher proportion of newly diagnosed and non-newly diagnosed patients treated with peginterferon beta-1a than those treated with placebo achieved NEDA (newly diagnosed: 28.3% vs 13.5% [p = 0.0010]; non-newly diagnosed: 40.8% vs 15.8% [p<0.0001]). NEDA rates remained stable over study years 2-4 for the newly diagnosed (range: 50.0%-53.9%) and non-newly diagnosed (range: 54.4%-57.0%) subgroups. Patients without PBH conversion had significantly lower ARR at 2 years (newly diagnosed: p = 0.0109; non-newly diagnosed: p = 0.0044) and a lower proportion of patients with 12-week CDW at 2 years (newly diagnosed: p = 0.2787; non-newly diagnosed: p = 0.0045) than the corresponding patient subgroups with PBH conversion. Patients who achieved NEDA in ADVANCE (study years 1-2) had a significantly lower ARR in ATTAIN (study years 3-4) than patients who did not achieve NEDA (newly diagnosed, p = 0.0003; non-newly diagnosed, p = 0.0001). Over 4 years, safety outcomes did not differ for the newly diagnosed and non-newly diagnosed patient subgroups., Conclusions: These results indicate that newly diagnosed and non-newly diagnosed patients treated continuously with peginterferon beta-1a Q2W experienced better disease control over time than those who received delayed treatment. Patients with NEDA or evidence of less radiological disease activity in the first 2 years of treatment had better longer-term clinical outcomes than those with evidence of greater disease activity., (Copyright © 2021. Published by Elsevier B.V.)

The visual system offers unparalleled precision in the assessment of neuroaxonal damage. With the majority of patients with multiple sclerosis (MS) experiencing afferent and efferent visual dysfunction, outcome measures capturing these deficits provide insight into neuroaxonal injury, even in those with minimal disability. Ideal for use in clinical trials, visual measures are generally inexpensive, accessible, and reproducible. Quantification of visual acuity, visual fields, visual quality of life, and electrophysiologic parameters allows assessment of function, whereas optical coherence tomography (OCT) provides reliable measures of the structural integrity of the anterior afferent visual pathway. The technology of oculomotor biometrics continues to advance, and discrete measures of fixation, smooth pursuit, and saccadic eye movement abnormalities are ready for inclusion in future trials of MS progression. Visual outcomes allow tracking of neuroaxonal injury and aid in distinguishing MS from diseases such as neuromyelitis optica spectrum disorder (NMOSD) or myelin oligodendrocyte glycoprotein antibody-associated diseases (MOGAD). OCT has also provided unique insights into pathophysiology, including the identification of foveal pitting in NMOSD, possibly from damage to Müller cells, which carry an abundance of aquaporin-4 channels. For some study designs, the cost-benefit ratio favors visual outcomes over more expensive MRI outcomes. With the next frontier of therapeutics focused on remyelination and neuroprotection, visual outcomes are likely to take center stage. As an international community of collaborative, committed, vision scientists, this review by the International MS Visual System Consortium (IMSVISUAL) outlines the quality standards, informatics, and framework needed to routinely incorporate vision outcomes into MS and NMOSD trials., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Intraspecific variation, including individual diet variation, can structure populations and communities, but the causes and consequences of individual foraging strategies are often unclear. Interactions between competition and resources are thought to dictate foraging strategies (e.g. specialization vs. generalization), but classical paradigms such as optimal foraging and niche theory offer contrasting predictions for individual consumers. Furthermore, both paradigms assume that individual foraging strategies maximize fitness, yet this prediction is rarely tested. We used repeated stable isotope measurements (δ 13 C, δ 15 N; N = 3,509) and 6 years of capture-mark-recapture data to quantify the relationship between environmental variation, individual foraging and consumer fitness among four species of desert rodents. We tested the relative effects of intraspecific competition, interspecific competition, resource abundance and resource diversity on the foraging strategies of 349 individual animals, and then quantified apparent survival as function of individual foraging strategies. Consistent with niche theory, individuals contracted their trophic niches and increased foraging specialization in response to both intraspecific and interspecific competition, but this effect was offset by resource availability and individuals generalized when plant biomass was high. Nevertheless, individual specialists obtained no apparent fitness benefit from trophic niche contractions as the most specialized individuals exhibited a 10% reduction in monthly survival compared to the most generalized individuals. Ultimately, this resulted in annual survival probabilities nearly 4× higher for generalists compared to specialists. These results indicate that competition is the proximate driver of individual foraging strategies, and that diet-mediated fitness variation regulates population and community dynamics in stochastic resource environments. Furthermore, our findings show dietary generalism is a fitness maximizing strategy, suggesting that plastic foraging strategies may play a key role in species' ability to cope with environmental change., (© 2021 British Ecological Society.)

Background: Antiglutamic acid decarboxylase (GAD)-associated neurologic disorders are rare, with varied presentations, including stiff-person syndrome (SPS) and cerebellar ataxia (CA). Vestibular and ocular motor (VOM) dysfunction can be the main presentation in a subset of patients., Methods: Retrospective review of the Johns Hopkins Hospital medical records from 1997 to 2018 identified a total of 22 patients with a diagnosis of anti-GAD-associated SPS or CA who had detailed VOM assessments. Eight had prominent VOM dysfunction at the initial symptom onset and were referred to neurology from ophthalmology or otolaryngology ("early dominant"). Fourteen patients had VOM dysfunction that was not their dominant presentation and were referred later in their disease course from neurology to neuro-ophthalmology ("nondominant"). We reviewed clinical history, immunological profiles, and VOM findings, including available video-oculography., Results: In the 8 patients with early dominant VOM dysfunction, the average age of symptom onset was 53 years, and 5 were men. The most common symptom was dizziness, followed by diplopia. Seven had features of CA, and 4 had additional features of SPS. None had a structural lesion on brain MRI accounting for their symptoms. The most common VOM abnormalities were downbeating and gaze-evoked nystagmus and saccadic pursuit. All received immune therapy and most received symptomatic therapy. Most experienced improvement in clinical outcome measures (modified Rankin scale and/or timed 25-foot walk test) or VOM function. By contrast, in the 14 patients in whom VOM dysfunction was nondominant, most had an SPS phenotype and were women. VOM abnormalities, when present, were more subtle, although mostly still consistent with cerebellar and/or brainstem dysfunction., Conclusions: Individuals with anti-GAD-associated neurologic disorders may present with prominent VOM abnormalities at the initial symptom onset that localize to the cerebellum and/or brainstem. In our cohort, immune and symptomatic therapies improved clinical outcomes and symptomatology., Competing Interests: S. D. Newsome has received consultant fees for scientific advisory boards from Biogen, Genentech, Celgene, and EMD Serono, is an advisor for Gerson Lehrman Group and BioIncept, a clinical adjudication committee member for a MedDay Pharmaceuticals' clinical trial and has received research funding (paid directly to institution) from Biogen, Novartis, Genentech, National Multiple Sclerosis Society, Department of Defense, and Patient-Centered Outcomes Institute. The remaining authors report no conflicts of interest., (Copyright © 2020 by North American Neuro-Ophthalmology Society.)

In magnetic resonance (MR) imaging, a lack of standardization in acquisition often causes pulse sequence-based contrast variations in MR images from site to site, which impedes consistent measurements in automatic analyses. In this paper, we propose an unsupervised MR image harmonization approach, CALAMITI (Contrast Anatomy Learning and Analysis for MR Intensity Translation and Integration), which aims to alleviate contrast variations in multi-site MR imaging. Designed using information bottleneck theory, CALAMITI learns a globally disentangled latent space containing both anatomical and contrast information, which permits harmonization. In contrast to supervised harmonization methods, our approach does not need a sample population to be imaged across sites. Unlike traditional unsupervised harmonization approaches which often suffer from geometry shifts, CALAMITI better preserves anatomy by design. The proposed method is also able to adapt to a new testing site with a straightforward fine-tuning process. Experiments on MR images acquired from ten sites show that CALAMITI achieves superior performance compared with other harmonization approaches., (Copyright © 2021. Published by Elsevier Inc.)

Objective: To report clinical characteristics and fluorodeoxyglucose positron emission tomography (FDG-PET) findings in the brain and muscles of individuals with stiff person syndrome (SPS) spectrum disorders (SPSSDs). Methods: Retrospective cohort study from 1997 to 2018 at Johns Hopkins Hospital identified 170 individuals with SPS or cerebellar ataxia (CA) associated with anti-glutamic acid decarboxylase (anti-GAD)-65 antibodies. Fifty-one underwent FDG-PET, with 50 involving the body and 30 with dedicated brain acquisition. The clinical and immunological profiles were extracted via medical record review. The brain scans were analyzed quantitatively using the NeuroQ software, with comparison with an averaged normal database. The body scans were reviewed qualitatively by a blinded nuclear medicine radiologist. Results: Mean age of symptom onset was 41.5 years (range 12-75 years). Majority were female (68%) and White (64%). Of the patients, 82% had SPS (majority being classic phenotype), and 18% had CA. Three had a paraneoplastic process. Forty-seven had serum anti-GAD, two with anti-amphiphysin, and one with anti-glycine receptor antibodies. Brain metabolic abnormalities were seen in both SPS and CA, with significant differences between the groups noted in the right superior frontal cortex, right sensorimotor cortex, left inferior parietal cortex, bilateral thalami, vermis, and left cerebellum. Of the patients, 62% demonstrated muscle hypermetabolism, most commonly bilateral, involving the upper extremities or axial muscles. Neither brain nor muscle metabolism was correlated with functional outcomes nor treatments. Conclusions: Metabolic changes as seen by FDG-PET are present in the brain and muscle in many individuals with SPSSD. Future studies are needed to assess whether FDG-PET can help aid in the diagnosis and/or monitoring of individuals with SPSSD., Competing Interests: LS reports being a principal investigator and has received salary support from Progenics Azedra trial. SN has received consultant fees for scientific advisory boards from Biogen, Genentech, Celgene, EMD Serrono, and Novartis; is an advisor for Autobahn Therapeutics and BioIncept and a clinical adjudication committee member for a medDay Pharmaceuticals clinical trial; and has received research funding (paid directly to institution) from Biogen, Novartis, Genentech, National Multiple Sclerosis Society, Department of Defense, and Patient-Centered Outcomes Research Institute. The remaining authors declare 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 Wang, Sadaghiani, Tian, Fitzgerald, Solnes and Newsome.)

Understanding physiological traits and ecological conditions that influence a species reliance on metabolic water is critical to creating accurate physiological models that can assess their ability to adapt to environmental perturbations (e.g., drought) that impact water availability. However, relatively few studies have examined variation in the sources of water animals use to maintain water balance, and even fewer have focused on the role of metabolic water. A key reason is methodological limitations. Here, we applied a new method that measures the triple oxygen isotopic composition of a single blood sample to estimate the contribution of metabolic water to the body water pool of three passerine species. This approach relies on Δ' 17 O, defined as the residual from the tight linear correlation that naturally exists between δ 17 O and δ 18 O values. Importantly, Δ'17O is relatively insensitive to key fractionation processes, such as Rayleigh distillation in the water cycle that have hindered previous isotope-based assessments of animal water balance. We evaluated the effects of changes in metabolic rate and water intake on Δ' 17 O values of captive rufous-collared sparrows ( Zonotrichia capensis ) and two invertivorous passerine species in the genus Cinclodes from the field. As predicted, colder acclimation temperatures induced increases in metabolic rate, decreases in water intake, and increases in the contribution of metabolic water to the body water pool of Z. capensis , causing a consistent change in Δ' 17 O. Measurement of Δ' 17 O also provides an estimate of the δ 18 O composition of ingested pre-formed (drinking/food) water. Estimated δ 18 O values of drinking/food water for captive Z. capensis were ~ -11‰, which is consistent with that of tap water in Santiago, Chile. In contrast, δ 18 O values of drinking/food water ingested by wild-caught Cinclodes were similar to that of seawater, which is consistent with their reliance on marine resources. Our results confirm the utility of this method for quantifying the relative contribution of metabolic versus pre-formed drinking/food water to the body water pool in birds., Competing Interests: The authors declare 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 Sabat, Newsome, Pinochet, Nespolo, Sanchez-Hernandez, Maldonado, Gerson, Sharp and Whiteman.)

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.)

The 2015 Magnetic Resonance Imaging in Multiple Sclerosis and 2016 Consortium of Multiple Sclerosis Centres guidelines on the use of MRI in diagnosis and monitoring of multiple sclerosis made an important step towards appropriate use of MRI in routine clinical practice. Since their promulgation, there have been substantial relevant advances in knowledge, including the 2017 revisions of the McDonald diagnostic criteria, renewed safety concerns regarding intravenous gadolinium-based contrast agents, and the value of spinal cord MRI for diagnostic, prognostic, and monitoring purposes. These developments suggest a changing role of MRI for the management of patients with multiple sclerosis. This 2021 revision of the previous guidelines on MRI use for patients with multiple sclerosis merges recommendations from the Magnetic Resonance Imaging in Multiple Sclerosis study group, Consortium of Multiple Sclerosis Centres, and North American Imaging in Multiple Sclerosis Cooperative, and translates research findings into clinical practice to improve the use of MRI for diagnosis, prognosis, and monitoring of individuals with multiple sclerosis. We recommend changes in MRI acquisition protocols, such as emphasising the value of three dimensional-fluid-attenuated inversion recovery as the core brain pulse sequence to improve diagnostic accuracy and ability to identify new lesions to monitor treatment effectiveness, and we provide recommendations for the judicious use of gadolinium-based contrast agents for specific clinical purposes. Additionally, we extend the recommendations to the use of MRI in patients with multiple sclerosis in childhood, during pregnancy, and in the post-partum period. Finally, we discuss promising MRI approaches that might deserve introduction into clinical practice in the near future., Competing Interests: Declaration of interests MPW reports personal fees from Novartis, Sanofi Genzyme, Bayer HealthCare Pharmaceuticals, Roche, Biogen, Biologix, Celgene, Merck Serono, Imcyse, IXICO, and Medison and personal fees and non-financial support from Genilac, outside the submitted work. OC reports personal fees from Roche and Merck Serono, outside the submitted work; and is supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre, London, UK. DSR is supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, part of the US National Institutes of Health, and has also received research support from Vertex Pharmaceuticals. BB reports personal fees from Novartis, UCB Pharmaceuticals, and Roche and non-financial support from Teva Neuroscience, Biogen, and Genentech, outside the submitted work; and is funded by the National MS Society, National Institutes of Health, and Multiple Sclerosis Society of Canada. NdS reports personal fees from Biogen, Genzyme, Merck Serono, Novartis, Roche, Celgene, Teva Pharmaceutical, outside the submitted work; and has received research grant support from the Italian MS Society. CE reports personal fees from Biogen, Bayer HealthCare Pharmaceuticals, Merck Serono, Novartis, Shire, Genzyme, Teva Pharmaceuticals, Sanofi, Celgene, and Roche, outside the submitted work. FF reports personal fees from Biogen, Sanofi Genzyme, Merck Serono, Novartis, Teva Pharmaceuticals, Actelion, MedDay, and Parexel, outside the submitted work. MF reports personal fees from Biogen, Merck Serono, Novartis, and Teva Pharmaceuticals, outside the submitted work; receives research support from Biogen, Merck Serono, Novartis, Teva Pharmaceuticals, Roche, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and Fondazione Italiana di Ricerca per la SLA; and is editor-in-chief of the Journal of Neurology. JF reports personal fees from Biogen, Merck Serono, Santhera Pharmaceuticals, Teva Pharmaceuticals, Sanofi, Almirall, Sanofi Genzyme, and Novartis, outside the submitted work. CG reports personal fees from Biogen, Merck Serono, Teva Pharmaceuticals, Sanofi Genzyme, Almirall, Novartis, Roche, and Bayer, outside the submitted work. YH declares no competing interests. LK reports personal fees from Actelion, Addex, Biotica, Celgene Receptos, Sanofi Genzyme, Eli Lilly, Mitsubishi, Ono Pharmaceutical, Pfizer, Sanofi, Santhera Pharmaceuticals, Siemens, Teva Pharmaceuticals, UCB, and XenoPort; grants and personal fees from Bayer HealthCare Pharmaceuticals, Biogen, Merck Serono, and Novartis; and grants from F Hoffmann-La Roche, EU, Innoswiss, Roche Research Foundation, Swiss Multiple Sclerosis Society, and Swiss National Research Foundation, outside the submitted work. DKBL reports personal fees from Academy of Health Care Learning, Biogen, Consortium of MS Centers, and Sanofi Genzyme, outside the submitted work. KM reports personal fees from Siemens and Novartis, outside the submitted work. XM reports personal fees from Actelion, Biogen, Celgene, Sanofi Genzyme, Merck Serono, Novartis, Teva Pharmaceuticals, ExceMed, MS International Federation, and National MS Society, outside the submitted work. SDN reports personal fees from Biogen, Genentech, Celgene, EMD Serono, Gerson Lehrman Group, BioIncept, and MedDay, outside the submitted work; and has received research funding (paid directly to institution) from Biogen, Novartis, Genentech, National Multiple Sclerosis Society, US Department of Defense, and Patient Centered Outcomes Institute. JO reports grants and personal fees from Biogen, Roche, and EMD Serono; and personal fees from Celgene, Novartis, and Sanofi Genzyme, outside the submitted work. JP reports personal fees from Merck Serono, Roche, UCB, Viela Bio, Euroimmun, and MedDay; grants and personal fees from Biogen, Novartis, Teva Pharmaceuticals, Chugai Pharmaceutical, Bayer HealthCare Pharmaceuticals, Alexion, Sanofi Genzyme, MedImmune, Abide ARGENX; grants from Merck Serono, MS Society, Guthrie Jackson Foundation, National Institute for Health Research, Oxford Health Services Research Committee, European Distance and E-Learning Network, Medical Research Council, Grant for Multiple Sclerosis Innovation, John Fell, and Myaware, outside the submitted work; and is partly funded by highly specialised services to run a national congenital myasthenia service and a neuromyelitis service. MAR reports personal fees from Biogen, Novartis, Sanofi Genzyme, Teva Pharmaceuticals, Merck Serono, and Roche, outside the submitted work; and receives research support from the Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla. JS-G reports grants and personal fees from Sanofi Genzyme; and personal fees from Almirall, Biogen, Celgene, Merck Serono, Novartis, Roche, and Teva Pharmaceuticals, outside the submitted work; and is member of the Editorial Committee of Multiple Sclerosis Journal and director of the Scientific Committee of Revista de Neurologia. MT reports personal fees from Almirall, Biogen, Sanofi Genzyme, Bayer HealthCare Pharmaceuticals, Roche, Biogen, Viela Bio, Merck Serono, and Novartis, outside the submitted work; and is co-editor of Multiple Sclerosis Journal—Experimental, Translational and Clinical. AT reports research grants from Roche and Sanofi Genzyme; and personal fees from Biogen, Consortium of MS Centers, Sanofi Genzyme, Roche, Novartis, and Teva Neuroscience, outside the submitted work. HV reports grants and consulting fees paid directly to their institution from Merck Serono and Novartis, and grants from Teva Pharmaceuticals, outside the submitted work. TY reports personal fees from Biogen, Novartis, Bayer HealthCare Pharmaceuticals, and Hikma, outside the submitted work; and has received research support from Biogen, GlaxoSmithKline, Novartis, and Schering. FB reports personal fees from Bayer, Biogen, Merck Serono, Novartis, Roche, Teva Pharmaceuticals, and IXICO, outside the submitted work; and is supported by the National Institute for Health Research Biomedical Research Centre at University College London Hospitals. AR reports personal fees from Novartis, Sanofi-Genzyme, Bayer, Roche, Biogen, Neurodiem, Bracco, Merck Serono, Teva Pharmaceuticals, and Icometrix; and non-financial support from SyntheticMR, outside the submitted work., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Management of multiple sclerosis and neuroimmunologic disorders has become increasingly complex because of the expanding number of recognized neuroimmune disorders, increased number of therapeutic options, and multidisciplinary care management needs of people with multiple sclerosis and neuroimmunologic disorders. More subspecialists are needed to optimize care of these patients, and many fellowship programs have been created or expanded to increase the subspecialty workforce. Consequently, defining the scope and standardizing fellowship training is essential to ensure that trainees receive high-quality training. A workgroup was created to develop a consensus fellowship curriculum to serve as a resource for all current and future training programs. This curriculum may also serve as a basis for future accreditation efforts., (Copyright © 2021 American Academy of Neurology.)

People with multiple sclerosis (MS) are at risk for infections that can result in amplification of baseline symptoms and possibly trigger clinical relapses. Vaccination can prevent infection through the activation of humoral and cellular immune responses. This is particularly pertinent in the era of emerging novel vaccines against severe acute respiratory syndrome coronavirus 2, the virus that causes coronavirus disease 2019 (COVID-19). MS disease-modifying therapies (DMTs), which affect the immune system, may impact immune responses to COVID-19 vaccines in people with MS. The objective of this article is to provide information on immune system responses to vaccinations and review previous studies of vaccine responses in people with MS to support the safety and importance of receiving currently available and emerging COVID-19 vaccines. Immunological studies have shown that coordinated interactions between T and B lymphocytes of the adaptive immune system are key to successful generation of immunological memory and production of neutralizing antibodies following recognition of vaccine antigens by innate immune cells. CD4 + T cells are essential to facilitate CD8 + T cell and B cell activation, while B cells drive and sustain T cell memory. Data suggest that some classes of DMT, including type 1 interferons and glatiramer acetate, may not significantly impair the response to vaccination. DMTs-such as sphingosine-1-phosphate receptor modulators, which sequester lymphocytes from circulation; alemtuzumab; and anti-CD20 therapies, which rely on depleting populations of immune cells-have been shown to attenuate responses to conventional vaccines. Currently, three COVID-19 vaccines have been granted emergency use authorization in the USA on the basis of promising interim findings of ongoing trials. Because analyses of these vaccines in people with MS are not available, decisions regarding COVID-19 vaccination and DMT choice should be informed by data and expert consensus, and personalized with considerations for disease burden, risk of infection, and other factors., (© 2021. The Author(s).)

Rationale: Ecologists increasingly determine the δ 15 N values of amino acids (AA) in animal tissue; "source" AA typically exhibit minor variation between diet and consumer, while "trophic" AA have increased δ 15 N values in consumers. Thus, trophic-source δ 15 N offsets (i.e., Δ 15 N T-S ) reflect trophic position in a food web. However, even minor variations in δ 15 N source AA values may influence the magnitude of offset that represents a trophic step, known as the trophic discrimination factor (i.e., TDF T-S ). Diet digestibility and protein content can influence the δ 15 N values of bulk animal tissue, but the effects of these factors on AA Δ 15 N T-S and TDF T-S in mammals are unknown., Methods: We fed captive mice (Mus musculus) either (A) a low-fat, high-fiber diet with low, intermediate, or high protein; or (B) a high-fat, low-fiber diet with low or intermediate protein. Mouse muscle and dietary protein were analyzed for bulk tissue δ 15 N using elemental analyzer-isotope ratio mass spectrometry (EA-IRMS), and were also hydrolyzed into free AA that were analyzed for δ 15 N using gas chromatography-combustion-IRMS., Results: As dietary protein increased, Δ 15 N Consumer-Diet slightly declined for bulk muscle tissue in both experiments; increased for AA in the low-fat, high-fiber diet (A); and remained the same or decreased for AA in the high-fat, low-fiber diet (B). The effects of dietary protein on Δ 15 N T-S and on TDF T-S varied by AA but were consistent between variables., Conclusions: Diets were less digestible and included more protein in Experiment A than in Experiment B. As a result, the mice in Experiment A probably oxidized more AA, resulting in greater Δ 15 N Consumer-Diet values. However, the similar responses of Δ 15 N T-S and of TDF T-S to diet variation suggest that if diet samples are available, Δ 15 N T-S accurately tracks trophic position. If diet samples are not available, the patterns presented here provide a basis to interpret Δ 15 N T-S values. The trophic-source offset of Pro-Lys did not vary across diets, and therefore may be more reliable for omnivores than other offsets (e.g., Glu-Phe)., (© 2021 John Wiley & Sons Ltd.)

Capital breeders accumulate nutrients prior to egg development, then use these stores to support offspring development. In contrast, income breeders rely on local nutrients consumed contemporaneously with offspring development. Understanding such nutrient allocations is critical to assessing life-history strategies and habitat use. Despite the contrast between these strategies, it remains challenging to trace nutrients from endogenous stores or exogenous food intake into offspring. Here, we tested a new solution to this problem. Using tissue samples collected opportunistically from wild emperor penguins Aptenodytes forsteri, which exemplify capital breeding, we hypothesized that the stable carbon (δ 13 C) and nitrogen (δ 15 N) isotope values of individual amino acids (AAs) in endogenous stores (e.g. muscle) and in egg yolk and albumen reflect the nutrient sourcing that distinguishes capital versus income breeding. Unlike other methods, this approach does not require untested assumptions or diet sampling. We found that over half of essential AAs had δ 13 C values that did not differ between muscle and yolk or albumen, suggesting that most of these AAs were directly routed from muscle into eggs. In contrast, almost all non-essential AAs differed in δ 13 C values between muscle and yolk or between muscle and albumen, suggesting de novo synthesis. Over half of AAs that have labile nitrogen atoms (i.e. 'trophic' AA) had higher δ 15 N values in yolk and albumen than in muscle, suggesting that they were transaminated during their routing into egg tissue. This effect was smaller for AAs with less labile nitrogen atoms (i.e. 'source' AA). Our results indicate that the δ 15 N offset between trophic-source AAs (Δ 15 N trophic-source ) may provide an index of the extent of capital breeding. The value of emperor penguin Δ 15 N Pro-Phe was higher in yolk and albumen than in muscle, reflecting the mobilization of endogenous stores; in comparison, the value of Δ 15 N Pro-Phe was similar across muscle and egg tissue in previously published data for income-breeding herring gulls Larus argentatus smithsonianus. Our results provide a quantitative basis for using AA δ 13 C and δ 15 N, and isotopic offsets among AAs (e.g. Δ 15 N Pro-Phe ), to explore the allocation of endogenous versus exogenous nutrients across the capital versus income spectrum of avian reproduction., (© 2020 British Ecological Society.)

Importance: Emergence of SARS-CoV-2 causing COVID-19 prompted the need to gather information on clinical outcomes and risk factors associated with morbidity and mortality in patients with multiple sclerosis (MS) and concomitant SARS-CoV-2 infections., Objective: To examine outcomes and risk factors associated with COVID-19 clinical severity in a large, diverse cohort of North American patients with MS., Design, Setting, and Participants: This analysis used deidentified, cross-sectional data on patients with MS and SARS-CoV-2 infection reported by health care professionals in North American academic and community practices between April 1, 2020, and December 12, 2020, in the COVID-19 Infections in MS Registry. Health care professionals were asked to report patients after a minimum of 7 days from initial symptom onset and after sufficient time had passed to observe the COVID-19 disease course through resolution of acute illness or death. Data collection began April 1, 2020, and is ongoing., Exposures: Laboratory-positive SARS-CoV-2 infection or highly suspected COVID-19., Main Outcomes and Measures: Clinical outcome with 4 levels of increasing severity: not hospitalized, hospitalization only, admission to the intensive care unit and/or required ventilator support, and death., Results: Of 1626 patients, most had laboratory-positive SARS-CoV-2 infection (1345 [82.7%]), were female (1202 [74.0%]), and had relapsing-remitting MS (1255 [80.4%]). A total of 996 patients (61.5%) were non-Hispanic White, 337 (20.8%) were Black, and 190 (11.7%) were Hispanic/Latinx. The mean (SD) age was 47.7 (13.2) years, and 797 (49.5%) had 1 or more comorbidity. The overall mortality rate was 3.3% (95% CI, 2.5%-4.3%). Ambulatory disability and older age were each independently associated with increased odds of all clinical severity levels compared with those not hospitalized after adjusting for other risk factors (nonambulatory: hospitalization only, odds ratio [OR], 2.8 [95% CI, 1.6-4.8]; intensive care unit/required ventilator support, OR, 3.5 [95% CI, 1.6-7.8]; death, OR, 25.4 [95% CI, 9.3-69.1]; age [every 10 years]: hospitalization only, OR, 1.3 [95% CI, 1.1-1.6]; intensive care unit/required ventilator support, OR, 1.3 [95% CI, 0.99-1.7]; death, OR, 1.8 [95% CI, 1.2-2.6])., Conclusions and Relevance: In this registry-based cross-sectional study, increased disability was independently associated with worse clinical severity including death from COVID-19. Other risk factors for worse outcomes included older age, Black race, cardiovascular comorbidities, and recent treatment with corticosteroids. Knowledge of these risk factors may improve the treatment of patients with MS and COVID-19 by helping clinicians identify patients requiring more intense monitoring or COVID-19 treatment.

Objective: To evaluate whether a retinal spectral-domain optical coherence tomography (SD-OCT) assessment at baseline is associated with long-term disability worsening in people with multiple sclerosis (PwMS), we performed SD-OCT and Expanded Disability Status Scale (EDSS) assessments among 132 PwMS at baseline and at a median of 10 years later., Methods: In this prospective, longitudinal study, participants underwent SD-OCT, EDSS, and visual acuity (VA) assessments at baseline and at follow-up. Statistical analyses were performed using generalized linear regression models, adjusted for age, sex, race, multiple sclerosis (MS) subtype, and baseline disability. We defined clinically meaningful EDSS worsening as an increase of ≥2.0 if baseline EDSS score was <6.0 or an increase of ≥1.0 if baseline EDSS score was ≥6.0., Results: A total of 132 PwMS (mean age 43 years; 106 patients with relapsing-remitting MS) were included in analyses. Median duration of follow-up was 10.4 years. In multivariable models excluding eyes with prior optic neuritis, relative to patients with an average baseline ganglion cell + inner plexiform layer (GCIPL) thickness ≥70 µm (the mean GCIPL thickness of all eyes at baseline), an average baseline GCIPL thickness <70 µm was associated with a 4-fold increased odds of meaningful EDSS worsening (adjusted odds ratio [OR] 3.97, 95% confidence interval [CI] 1.24-12.70; p = 0.02) and an almost 3-fold increased odds of low-contrast VA worsening (adjusted OR 2.93, 95% CI 1.40-6.13; p = 0.04)., Conclusions: Lower baseline GCIPL thickness on SD-OCT is independently associated with long-term disability worsening in MS. Accordingly, SD-OCT at a single time point may help guide therapeutic decision-making among individual PwMS., Classification of Evidence: This study provides Class I evidence that lower baseline GCIPL thickness on SD-OCT is independently associated with long-term disability worsening in MS., (© 2021 American Academy of Neurology.)

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a distinct CNS inflammatory disease with symptoms and imaging findings that overlap other neuroinflammatory disorders. We highlight the imaging characteristics of MOGAD and contrast them with neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS). Intracranial features that suggest MOGAD include childhood acute disseminated encephalomyelitis pattern with diffuse signal abnormality in the cortical gray matter, subcortical white matter, deep white matter, and deep gray matter on T2-weighted and FLAIR images; few bilateral T2-hyperintense fluffy and poorly demarcated lesions; pontine or thalamic involvement (or both); and cerebellar peduncle lesions in children. Intraorbitally, one sees edematous, enlarged, tortuous optic nerve or nerves; bilateral long-segment T2 hyperintensity of anterior segments of the optic nerve; sparing of the optic chiasm and retrochiasmatic pathways; and perioptic nerve sheath and surrounding orbital fat enhancement. Spinal involvement is seen as longitudinally extensive transverse myelitis with a sagittal T2-hyperintense intramedullary spinal line, the axial "H" spinal cord sign (central cord gray matter T2 hyperintensity), and conus medullaris involvement. Early accurate diagnosis of MOGAD is important because prognosis and treatment differ from those for NMOSD and MS.

Although hydrogen isotopes (δ2H) are commonly used as tracers of animal movement, minimal research has investigated the use of δ2H as a proxy to quantify resource and habitat use. While carbon and nitrogen are ultimately derived from a single source (food), the proportion of hydrogen in consumer tissues originates from two distinct sources: body water and food. Before hydrogen isotopes can be effectively used as a resource and habitat tracer, we need estimates of (net) discrimination factors (Δ2HNet) that account for the physiologically mediated differences in the δ2H values of animal tissues relative to that of the food and water sources they use to synthesize tissues. Here, we estimated Δ2HNet in captive green turtles (Chelonia mydas) by measuring the δ2H values of tissues (epidermis and blood components) and dietary macromolecules collected in two controlled feeding experiments. Tissue δ2H and Δ2HNet values varied systematically among tissues, with epidermis having higher δ2H and Δ2HNet values than blood components, which mirrors patterns between keratinaceous tissues (feathers, hair) and blood in birds and mammals. Serum/plasma of adult female green turtles had significantly lower δ2H values compared with juveniles, likely due to increased lipid mobilization associated with reproduction. This is the first study to quantify Δ2HNet values in a marine ectotherm, and we anticipate that our results will further refine the use of δ2H analysis to better understand animal resource and habitat use in marine ecosystems, especially coastal areas fueled by a combination of marine (e.g. micro/macroalgae and seagrass) and terrestrial (e.g. mangroves) primary production., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

Introduction: Intravenous immunoglobulin (IVIG) has been shown to be effective for the treatment of stiff person syndrome (SPS). However, some patients might not tolerate it. We report the tolerability profile of subcutaneous immunoglobulin (SCIg) in patients with SPS who did not tolerate IVIG. To our knowledge, the use of SCIg in SPS has not been reported before in a case series., Patient Concerns: The five patients included in this case series presented with various combinations of symptoms of spasms, axial and limb stiffness, and exaggerated responses to outside stimuli. These symptoms often lead to gait and functional impairment., Diagnosis: Patients were diagnosed with classic SPS as they met the clinical criteria, which require the presence of spasms, axial rigidity, and hyperexcitability., Interventions: Subcutaneous immunoglobulin infusion., Outcomes: Five patients were identified that were treated with SCIg. Three tested positive for serum anti-glutamic acid decarboxylase 65 antibodies prior to any treatment. The mean age at SCIg initiation was 33 years (range: 22-47). The mean duration of SPS prior to SCIg initiation was 5.9 years (range: 2.5-7). All patients used IVIG for at least two months (up to 18 months) but switched to SCIg due to IVIG side effects. Duration of SCIg use ranged from 4 months to 6 years (mean, 19.2 months). Upon switching to SCIg, the SPS symptoms remained stable. SCIg was well-tolerated in most as only one patient discontinued SCIg due to side effects., Conclusion: This case series highlights that SCIg could be a treatment option for patients with SPS, especially when IVIG is not feasible. Injection site reactions might be a limiting factor in some patients treated with SCIg. Prospective controlled studies are needed to confirm SCIg treatment durability and efficacy., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To identify early clinical and paraclinical factors that may help predict later conversion to multiple sclerosis (MS) in patients presenting with isolated myelitis (ie, 'transverse myelitis' without clinical or radiological evidence of inflammation/demyelination elsewhere in the central nervous system)., Methods: In this retrospective cohort study, we included patients with isolated myelitis who were followed clinically and radiologically at our specialised myelopathy clinic. We excluded patients with MS at the onset, aquaporin-4-IgG seropositivity, myelin oligodendrocyte glycoprotein-IgG seropositivity or other identified aetiology. Logistic regression was used to identify factors predictive of conversion to MS (defined by the 2017 McDonald criteria)., Results: We included 100 patients, followed for a median of 4.3 years. Conversion to MS occurred in 25 of 77 patients (32%) with short-segment myelitis (longest lesion spanning <3 vertebral segments on MRI) as compared with 0 of 23 patients (0%) with longitudinally extensive myelitis (p=0.002). Among patients with short-segment myelitis, factors identified as highly predictive of conversion to MS using multivariate logistic regression included cerebrospinal fluid (CSF)-restricted oligoclonal bands (OCB) (OR (OR) 9.2, 95% CI 2.1 to 41.0, p=0.004), younger age (OR 1.1 for each year younger, 95% CI 1.0 to 1.1, p=0.04) and longer follow-up (OR 1.3 for each year longer, 95% CI 1.0 to 1.6, p=0.04). Conversion to MS occurred at a median of 2.8 years after myelitis onset., Conclusions: Short-segment MRI cord lesion(s), CSF-restricted OCB, younger age and longer follow-up are all factors predictive of conversion to MS in patients presenting with isolated myelitis., Competing Interests: Competing interests: SDN has received consultant fees for scientific advisory boards from Biogen, Genentech, Celgene, EMD Serono, Novartis, is a clinical adjudication committee member for a medDay Pharmaceuticals clinical trial, and has received research funding (paid directly to institution) from Biogen, Novartis, Genentech, National MS Society, Department of Defense and Patient Centered Outcomes Institute., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Skipjack tuna (Katsuwonus pelamis) sustain a large-scale fishery in the southwest Atlantic Ocean (SWA), but information about its foraging ecology in this region is still limited. Here we use carbon (δ 13 C) and nitrogen (δ 15 N) stable isotope analysis of muscle from individuals collected in 2017-2018 (n = 383) to quantify diet composition and characterize movement patterns. We found a relatively small degree of variation in δ 13 C (range: -18.9 to -16.5‰) in comparison to δ 15 N values (6.7-14.7‰). At higher latitudes in the southern area (30-34°S), individuals had higher mean (±SD) δ 15 N values (12.2 ± 1.3‰) in comparison to those collected in the northern area (9.7 ± 1.5‰) between 20-26°S. At the northern area, isotope mixing models with informative priors showed that lanternfish (median: 50%) and krill (31%) were the primary foods. In the southern area, lanternfish (53%), krill (23%) and small pelagic fish (23%) were the primary food sources. Spatial shifts in diet composition were related to warming events that likely resulted in low abundance of sardines in the northern area. The latitudinal pattern in skipjack and krill δ 15 N values mirrored that of regional zooplankton isoscapes, suggesting residency at the timescale of isotopic turnover for muscle (~2-4 months), and that geographical variation in the baseline isotopic composition can be exploited to characterize seasonal movements of skipjack and other top marine consumers in this region., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: We aimed to characterize the spectrum of clinical features and examination findings in pediatric-onset stiff person syndrome., Methods: Medical records were reviewed for all patients treated for stiff person syndrome with symptom onset in childhood at a tertiary medical center between March 2001 and February 2019., Results: Of the 15 individuals who met inclusion criteria, 11 (73%) were female and 13 (87%) were Caucasian. Median age at symptom onset was 14.8 years (range 8.4 to 16.9), and median latency from symptom onset to diagnosis was 6.2 years (range 0.4 to 15.0). Nine individuals (60%) were not diagnosed until adulthood. The most common presenting features were painful spasms (n = 12, 80%), hyper-reflexia (n = 11, 73%), axial rigidity (n = =9, 60%), lower extremity rigidity or spasticity (n = 8, 53%), gait abnormalities (n = 6, 40%), and hyperlordosis (n = 6, 40%). Other noted features included anxiety (n = 5, 33%), dysautonomia (n = 3, 20%), and cranial neuropathies (n = 3, 20%). Personal (n = 9, 60%) and family history (n = 9, 60%) of autoimmune conditions was common. Serum antiglutamate decarboxylase 65 antibodies were found in 13 individuals (87%). Nearly all individuals received immunotherapy (n = 14, 93%), symptomatic medications (n = 15, 100%), and nonpharmacologic therapies (n = 14, 93%). However, most had persistent physical limitations, particularly impaired walking (n = 7, 47%) and inability to carry out previous activities (n = 14, 93%)., Conclusions: There is a wide spectrum of typical and less common features seen in individuals with pediatric-onset stiff person syndrome. Despite symptom onset in childhood, diagnosis is often delayed until adulthood, at which point disability accrual is frequently seen. Early recognition is vital to address symptoms and may potentially limit future disability., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The widespread importance of variable types of primary production, or energy channels, to consumer communities has become increasingly apparent. However, the mechanisms underlying this "multichannel" feeding remain poorly understood, especially for aquatic ecosystems that pose unique logistical constraints given the diversity of potential energy channels. Here, we use bulk tissue isotopic analysis along with carbon isotope (δ 13 C) analysis of individual amino acids to characterize the relative contribution of pelagic and benthic energy sources to a kelp forest consumer community in northern Chile. We measured bulk tissue δ 13 C and δ 15 N for >120 samples; of these we analyzed δ 13 C values of six essential amino acids (EAA) from nine primary producer groups (n = 41) and 11 representative nearshore consumer taxa (n = 56). Using EAA δ 13 C data, we employed linear discriminant analysis (LDA) to assess how distinct EAA δ 13 C values were between local pelagic (phytoplankton/particulate organic matter), and benthic (kelps, red algae, and green algae) endmembers. With this model, we were able to correctly classify nearly 90% of producer samples to their original groupings, a significant improvement on traditional bulk isotopic analysis. With this EAA isotopic library, we then generated probability distributions for the most important sources of production for each individual consumer and species using a bootstrap-resampling LDA approach. We found evidence for multichannel feeding within the community at the species level. Invertebrates tended to focus on either pelagic or benthic energy, deriving 13-67% of their EAA from pelagic sources. In contrast, mobile (fish) taxa at higher trophic levels used more equal proportions of each channel, ranging from 19% to 47% pelagically derived energy. Within a taxon, multichannel feeding was a result of specialization among individuals in energy channel usage, with 37 of 56 individual consumers estimated to derive >80% of their EAA from a single channel. Our study reveals how a cutting-edge isotopic technique can characterize the dynamics of energy flow in coastal food webs, a topic that has historically been difficult to address. More broadly, our work provides a mechanism as to how multichannel feeding may occur in nearshore communities, and we suggest this pattern be investigated in additional ecosystems., (© 2020 by the Ecological Society of America.)

Migratory marine megafauna generally move vast distances between productive foraging grounds and environmentally stable breeding grounds, but characterizing how they use these habitats to maintain homeostasis and reproduce is difficult. We used isotope analysis of blue whale skin strata (n = 621) and potential prey (n = 300) to examine their migratory and foraging strategies in the eastern Pacific Ocean. Our results suggest that most whales in the northeast Pacific use a mixed income and capital breeding strategy, and use the California Current Ecosystem as their primary summer-fall foraging ground. A subset of individuals exhibited migratory plasticity and spend most of the year in the Gulf of California or Costa Rica Dome, two regions believed to be their primary winter-spring breeding grounds. Isotope data also revealed that whales in the southern Eastern Tropical Pacific generally do not forage in the northeast Pacific, which suggests a north-south population structure with a boundary near the equator., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose of Review: This review presents a comprehensive analysis of the current high-efficacy disease-modifying therapies (DMTs) available for treatment of multiple sclerosis (MS). We discuss the existing approved and emerging therapeutics in patients with relapsing and progressive forms of MS using data from clinical trials and observational studies. Treatment considerations in pediatric and pregnant populations are also reviewed. Finally, we discuss the treatment paradigms of the escalation and early aggressive approaches to treatment of MS, with review of ongoing clinical trials to compare these approaches., Recent Findings: Natalizumab has shown promising data on efficacy in not only randomized trials but also observational studies when compared with placebo, the injectable DMTs, and fingolimod. The anti-CD20 B cell depleting therapies (rituximab, ocrelizumab, and ofatumumab) have also demonstrated superiority in randomized clinical trials compared to their comparator group (placebo, interferon, and teriflunomide, respectively) and rituximab has shown in observational studies to be more effective than older injectable therapies and some of the oral therapies. Alemtuzumab has shown good efficacy in randomized controlled trials and observational studies yet has several potentially severe side effects limiting its use. Mitoxantrone has similarly demonstrated significant reduction in new disease activity compared to placebo but is rarely used due to its severe side effects. Cladribine is an oral DMT often grouped in discussion with other higher efficacy DMTs but may be slightly less effective than the other therapies described in this review. Many emerging targets for therapeutic intervention are currently under investigation that may prove to be beneficial in early aggressive MS, including autologous hematopoietic stem cell transplantation., Summary: Traditionally, MS has been treated with an escalation approach, starting patients on a modestly effective DMT and subsequently escalating to a higher efficacy DMT when there is evidence of clinical and/or radiologic breakthrough activity. With the development of higher efficacy therapies and emerging data showing the potential positive long-term impact of these therapies when started earlier in the disease course, many clinicians have shifted to an early aggressive treatment approach in which patients are initially started on a higher efficacy DMT. Two clinical trials, the TRaditional versus Early Aggressive Therapy for MS (TREAT-MS) trial and the Determining the Effectiveness of earLy Intensive Versus Escalation approaches for the treatment of Relapsing-remitting MS (DELIVER-MS) trial, aim to directly compare these treatment strategies and their impact on clinical and radiologic outcomes., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021.)

Human-dominated environments alter the availability and quality of resources for many species, especially for scavengers that have large home ranges and plastic foraging behaviors that enable them to exploit novel resources. Along the western slope of the Andes, the modification of natural landscapes have resulted in significant declines in native prey, the introduction of non-native species, and an increase in the availability of anthropogenic resources. These factors have likely influenced the resources available to Andean condors (Vultur gryphus), however, data are lacking as to how condor's diet vary along their large latitudinal range. We evaluated differences in Andean condor diet along a ~2500 km latitudinal gradient in Chile from the heavily modified Central zone (32-34°S) to the more pristine Austral zone (44-56°S). We assessed diet composition through the identification of prey remains in condor pellets, and carbon and nitrogen isotope analysis of condor feathers and their primary prey identified from pellet analysis. Our results identified medium- and large-bodied domesticated mammals (ungulates) and introduced exotic species (lagomorphs) as common prey across the study area. Condors from the Central zone had the largest isotopic niche width, probably related to consumption of anthropogenic resources with distinctly high carbon isotope values indicative of C 4 -based foods likely acquired from landfills or corn-fed livestock. Isotopic niches for condors from the Southern and Austral zones almost completely overlapped. Andean condor diet is strongly influenced by local conditions determining differential access to prey sources. The high dependence of Andean condors on livestock across a large geographical area, and landfills in more (sub)urban areas, may help stabilize their populations via anthropogenic resources subsidies. Long-term dependence on such resources, however, may have health costs including contaminant exposure and greater mortality risk. These data will help identify potential threats related to resource availability and use, and better inform management and conservation decisions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier B.V.)

Radiologically isolated syndrome refers to an entity in which white matter lesions fulfilling the criteria for multiple sclerosis occur in individuals without a history of a clinical demyelinating attack or alternative etiology. Since its introduction in 2009, the diagnostic criteria of radiologically isolated syndrome and its clinical relevance have been widely debated by neurologists and radiologists. The aim of the present study was to review the following: 1) historical evolution of radiologically isolated syndrome criteria, 2) clinical and imaging findings in adults and children with radiologically isolated syndrome, 3) imaging features of patients with radiologically isolated syndrome at high risk for conversion to MS, and 4) challenges and controversies for work-up, management, and therapeutic interventions of patients with radiologically isolated syndrome., (© 2020 by American Journal of Neuroradiology.)