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Adrian L Rabinowicz,1 Edward Faught,2 David F Cook,1 Enrique Carrazana1,3 1Clinical Development & Medical Affairs, Neurelis, Inc., San Diego, CA, USA; 2Emory Epilepsy Program, Emory University School of Medicine, Atlanta, GA, USA; 3John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USACorrespondence: Edward Faught, Department of Neurology, Emory University School of Medicine, 12 Executive Park Drive, NE, Atlanta, GA, 30329, USA, Tel +1 404 778-3444, Email rfaught@emory.eduPurpose: People with epilepsy may experience seizure clusters despite a stable regimen of antiseizure medications. Such clusters have the potential to last ≥ 24 hours, typically occur in the community setting, and may progress to medical emergencies, such as status epilepticus, if untreated. Thus, long-acting rescue therapy for seizure clusters is needed that can be administered by nonmedical individuals outside a hospital. Benzodiazepines are the foundation of rescue therapy for seizure clusters. The approved outpatient treatments (ie, diazepam, midazolam) have differing profiles that may affect multiple aspects of health-care utilization. The current labeling of these medications allows for a second dose if needed to control the cluster. Although no head-to-head studies directly comparing rescue treatments have been conducted, differences between studies with generally similar designs may provide context for the potential importance of second doses of rescue therapy on health-care utilization.Methods: For this analysis, large, long-term, open-label studies of approved seizure-cluster treatments designed for use by nonmedical caregivers were reviewed, and the percentage of seizure clusters for which a second dose was used or that were not controlled at 6, 12, and 24 hours was examined. Available data on hospitalizations were also collected.Results: The 3 identified studies meeting the inclusion criteria were for use of diazepam rectal gel, intranasal midazolam, and diazepam nasal spray. Across these studies, the use of a second dose ranged from < 40% at 6 hours to < 13% at 24 hours. Hospitalizations and serious treatment-emergent adverse events were reported variably across these studies.Conclusion: These results demonstrate the importance of second doses of rescue therapy for seizure clusters for optimizing health-care utilization. Need for second doses should be included as one component. In turn, when second doses are needed, they have the potential to curtail emergency department use and hospitalization and to prevent further seizure clusters.Keywords: diazepam, midazolam, nasal, rectal, acute repetitive seizures, twenty-four hours

The proopiomelanocortin (Pomc)-derived peptides, including adrenocorticotropic hormone and α-melanocyte stimulating hormone (α-Msh), play both a central and a peripheral role in modulating the stress response. The central role is predominantly associated with nutrient homeostasis, while peripherally they play an important role in the synthesis of glucocorticoids (GCs) in response to stress. Pomc mutations are a major risk factor in the development of early-onset childhood obesity in humans. This is attributed primarily to their central effects on melanocortin receptor dysfunction leading to hyperphagia and reduced energy expenditure, while the peripheral mechanism contributing to obesity has largely been unexplored. Here, we tested the hypothesis that Pomc mutation-mediated adrenal insufficiency and the associated changes in GC signaling contribute to postnatal adiposity using zebrafish as a model. We generated a ubiquitous Pomc knockout zebrafish that mimicked the mammalian mutant phenotype of adrenal insufficiency and enhanced adiposity. The loss of Pomc inhibited stress-induced cortisol production and reprogrammed GC signaling by reducing glucocorticoid receptor responsiveness, whereas the mineralocorticoid receptor (Mr) signaling was enhanced. Larval feeding led to enhanced growth and adipogenesis in the Pomc mutants, and this was inhibited by eplerenone, an Mr antagonist. Altogether, our results underscore a key role for Mr signaling in early developmental adipogenesis and a possible target for therapeutic intervention for early-onset childhood obesity due to Pomc dysfunction., (© 2024 The Author(s). Journal of Cellular Physiology published by Wiley Periodicals LLC.)

This analysis assessed the effectiveness and tolerability of brivaracetam (BRV) in older (≥65 years of age) and younger (≥16 to <65 years of age) adults with epilepsy. This was a subgroup analysis from EXPERIENCE/EPD332, a pooled analysis of individual patient records from multiple independent, non-interventional studies of patients with epilepsy starting BRV in Australia, Europe, and the United States. Included patients had ≥6 months of follow-up data. Outcomes included responders (≥50 % reduction from baseline in seizure frequency), seizure freedom (no seizures within 3 months before the time point), and continuous seizure freedom (no seizures from baseline) at 12 months; BRV discontinuation during the whole study follow-up; and treatment-emergent adverse events (TEAEs) at 3, 6, and 12 months. Patients with missing data after BRV discontinuation were deemed non-responders/not seizure-free. Analysis populations included the Full Analysis Set (FAS; patients who received ≥1 BRV dose and had seizure type and age documented at baseline) and the modified FAS (FAS patients who had ≥1 seizure recorded during baseline). The FAS was used for all outcomes except seizure reduction. The FAS included 147 (8.9 %) patients aged ≥65 years and 1497 (91.1 %) aged ≥16 to <65 years. Compared with the younger subgroup, patients aged ≥65 years had a longer median epilepsy duration (33.0 years [n = 144] vs 17.0 years [n = 1460]) and lower median seizure frequency at index (2.0 seizures/28 days [n = 129] vs 4.0 seizures/28 days [n = 1256]), and less commonly had >1 prior antiseizure medication (106/141 [75.2 %] vs 1265/1479 [85.5 %]). At 12 months, a numerically higher percentage of patients aged ≥65 years versus the younger subgroup achieved ≥50 % seizure reduction (46.5 % [n = 71] vs 36.0 % [n = 751]), seizure freedom (26.0 % [n = 100] vs 13.9 % [n = 1011]), and continuous seizure freedom (22.0 % [n = 100] vs 10.7 % [n = 1011]). During the whole study follow-up, 43/147 (29.3 %) patients aged ≥65 years and 508/1492 (34.0 %) aged ≥16 to <65 years discontinued BRV. The incidence of TEAEs since the prior visit was similar in both subgroups at 3 months (≥65 years vs ≥16 to <65 years: 38/138 [27.5 %] vs 356/1404 [25.4 %]), 6 months (19/119 [16.0 %] vs 176/1257 [14.0 %]), and 12 months (8/104 [7.7 %] vs 107/1128 [9.5 %]). This real-world analysis suggests BRV was effective in patients aged ≥65 years and ≥16 to <65 years, with numerically higher effectiveness in the older subgroup. BRV was well tolerated in both subgroups., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: E. Faught has received research funding from Xenon and UCB Pharma, and consulting fees from Aucta, Azurity, Biogen, the Centers for Disease Control and Prevention, LivaNova, Neurelis the State of Georgia, SK Life Science and Trevena, is on the editorial board of the Annals of Neurology and the executive board of The Epilepsy Consortium H. Besson, D. Bourikas, T. Daniels, F. Floricel, and C. Laloyaux are employees of UCB Pharma. W. D’Souza’s salary is part-funded by The University of Melbourne; he has received travel, investigator-initiated, scientific advisory board, and speaker’s honoraria from UCB Pharma Australia & Global; investigator-initiated, scientific advisory board, travel, and speaker’s honoraria from Eisai Australia & Global; advisory board honoraria from LivaNova and Tilray; educational grants from Novartis, Pfizer, and Sanofi-Synthélabo; educational, travel, and fellowship grants from GSK Neurology Australia; and honoraria from SciGen Pharmaceuticals; he has an equity interest in the device company EpiMinder. P. Klein has served as a consultant for Abbott, Arvelle Therapeutics, Neurelis, and SK Life Science; as a consultant, advisory board member, and speaker for Aquestive, Eisai, Sunovion, and UCB Pharma; is a member of the medical advisory board of Stratus and the scientific advisory board of OB Pharma; is the CEO of PrevEp; and has received research support from CURE and Department of Defense/Lundbeck. M. Reuber receives payment from Elsevier as editor-in-chief of Seizure; and has received research grants and speaker’s fees from Eisai, LivaNova, and UCB Pharma. F. Rosenow reports personal fees from Angelini Pharma, Arvelle Therapeutics, Eisai GmbH, and GW Pharmaceuticals; personal fees and other from Novartis; personal fees and grants from UCB Pharma; and grants from the Detlev-Wrobel-Fonds for Epilepsy Research Frankfurt, Deutsche Forschungsgemeinschaft, the European Union, and the State of Hessen outside the submitted work. J. Salas-Puig has received grants from Bial and UCB Pharma; and reports personal fees from Bial, Eisai, Esteve, Sanofi, and UCB Pharma outside the submitted work. V. Soto Insuga has received speaker honoraria from Bial, Eisai, and UCB Pharma. B.J. Steinhoff has received speaker’s honoraria from Al-Jazeera, Desitin, Eisai, GW Pharmaceuticals, Hikma, Novartis, Sandoz, and UCB Pharma; and has served as a consultant for Arvelle Therapeutics, B. Braun, Bial, Desitin, Eisai, GW Pharmaceuticals, and UCB Pharma. A. Strzelczyk reports personal fees and grants from Angelini Pharma, Biocodex, Desitin Arzneimittel, Eisai, GW/Jazz Pharmaceuticals, Marinus Pharma, Precisis, Takeda, UCB Pharma, UNEEG medical, and Zogenix. He is editor-in-chief of Clinical Epileptology and section editor of Neurological Research and Practice. J.P. Szaflarski has received research funding from Biogen, the Department of Defense, Eisai, GW Pharmaceuticals companies, National Institutes of Health, National Science Foundation, NeuroPace, Serina Therapeutics, Shor Foundation for Epilepsy Research, State of Alabama General Funds, and UCB Pharma; has served as a consultant or advisory board member for Elite Medical Experts, GW Pharmaceuticals, LivaNova, Lundbeck, Medical Association of the State of Alabama, NeuroPace, Serina Therapeutics, SK Life Science, and UCB Pharma; has served as an investigator on GW Research Ltd trials; and is an editorial board member for Epilepsy & Behavior, Epilepsy & Behavior Reports (associate editor), Epilepsy Currents (contributing editor), Folia Medica Copernicana, Journal of Epileptology (associate editor), and Journal of Medical Science. D. Friesen is an independent contractor for UCB Pharma. V. Villanueva has served as a consultant or on an advisory board for Arvelle Therapeutics, Bial, Eisai, Esteve, GW Pharmaceuticals, Novartis, and UCB Pharma; has received research grants from Bial, Eisai, and UCB Pharma; and has received speaker’s honoraria from Bial, Eisai, Esteve, GW Pharmaceuticals, Novartis, and UCB Pharma., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The diagnosis of epilepsy is associated with loss of predictability, which invariably results in the fear of when and if future seizures will occur. For a subset of patients with epilepsy (PWE), there may be a pathological persistent fear of seizure occurrence, resulting in limitations to daily activities through avoidant behaviors. Paradoxically, the research of anticipatory anxiety of seizures (AAS; also referred to as seizure phobia) has been practically nonexistent and, not surprisingly, this condition remains underrecognized by clinicians. The available data are derived from three small case series of patients followed in tertiary epilepsy centers. In this study, we review the available data on the reported clinical manifestations of AAS in PWE, and of the potential role of variables associated with it, such as personal and family psychosocial and psychiatric history and epilepsy-related variables. In addition, we review the need for the creation of screening tools to identify patients at risk of AAS and discuss potential treatment strategies, which could be considered as part of the comprehensive management for PWE., (© 2024 The Authors. Epileptic Disorders published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: To assess the effectiveness and tolerability of brivaracetam (BRV) in adults with epilepsy by specific comorbidities and epilepsy etiologies., Methods: EXPERIENCE/EPD332 was a pooled analysis of individual patient records from several non-interventional studies of patients with epilepsy initiating BRV in clinical practice. Outcomes included ≥ 50% reduction from baseline in seizure frequency, seizure freedom (no seizures within prior 3 months), continuous seizure freedom (no seizures since baseline), BRV discontinuation, and treatment-emergent adverse events (TEAEs) at 3, 6, and 12 months. Analyses were performed for all adult patients (≥ 16 years of age) and stratified by comorbidity and by etiology at baseline (patients with cognitive/learning disability [CLD], psychiatric comorbidity, post-stroke epilepsy, brain tumor-related epilepsy [BTRE], and traumatic brain injury-related epilepsy [TBIE])., Results: At 12 months, ≥ 50% seizure reduction was achieved in 35.6% (n = 264), 38.7% (n = 310), 41.7% (n = 24), 34.1% (n = 41), and 50.0% (n = 28) of patients with CLD, psychiatric comorbidity, post-stroke epilepsy, BTRE, and TBIE, respectively; and continuous seizure freedom was achieved in 5.7% (n = 318), 13.7% (n = 424), 29.4% (n = 34), 11.4% (n = 44), and 13.8% (n = 29), respectively. During the study follow-up, in patients with CLD, psychiatric comorbidity, post-stroke epilepsy, BTRE, and TBIE, 37.1% (n = 403), 30.7% (n = 605), 33.3% (n = 51), 39.7% (n = 68), and 27.1% (n = 49) of patients discontinued BRV, respectively; and TEAEs since prior visit at 12 months were reported in 11.3% (n = 283), 10.0% (n = 410), 16.7% (n = 36), 12.5% (n = 48), and 3.0% (n = 33), respectively., Conclusions: BRV as prescribed in the real world is effective and well tolerated among patients with CLD, psychiatric comorbidity, post-stroke epilepsy, BTRE, and TBIE., (© 2024. The Author(s).)

In contemporary biomedical research, the zebrafish (Danio rerio) is increasingly considered a model system, as zebrafish embryos and larvae can (potentially) fill the gap between cultured cells and mammalian animal models, because they can be obtained in large numbers, are small and can easily be manipulated genetically. Given that capillary electrophoresis-mass spectrometry (CE-MS) is a useful analytical separation technique for the analysis of polar ionogenic metabolites in biomass-limited samples, the aim of this study was to develop and assess a CE-MS-based analytical workflow for the profiling of (endogenous) metabolites in extracts from individual zebrafish larvae and pools of small numbers of larvae. The developed CE-MS workflow was used to profile metabolites in extracts from pools of 1, 2, 4, 8, 12, 16, 20, and 40 zebrafish larvae. For six selected endogenous metabolites, a linear response (R 2  > 0.98) for peak areas was obtained in extracts from these pools. The repeatability was satisfactory, with inter-day relative standard deviation values for peak area of 9.4%-17.7% for biological replicates (n = 3 over 3 days). Furthermore, the method allowed the analysis of over 70 endogenous metabolites in a pool of 12 zebrafish larvae, and 29 endogenous metabolites in an extract from only 1 zebrafish larva. Finally, we applied the optimized CE-MS workflow to identify potential novel targets of the mineralocorticoid receptor in mediating the effects of cortisol., (© 2023 The Authors. ELECTROPHORESIS published by Wiley-VCH GmbH.)

Stressors in the environment of aquatic organisms can profoundly affect their immune system. The stress response in fish involves the activation of the hypothalamus-pituitary-interrenal (HPI) axis, leading to the release of several stress hormones, among them glucocorticoids, such as cortisol, which bind and activate corticosteroid receptors, namely the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR). These receptors are highly expressed on immune cells, thereby allowing stress to have a potent effect that is classically considered to suppress immune function. In this review, we highlight the conserved structure and function of GR and MR among vertebrates and describe their role in modulating inflammation by regulating the expression of pro-inflammatory and anti-inflammatory genes. In particular, the involvement of MR during inflammation is reviewed, which in many studies has been shown to be immune-enhancing. In recent years, the use of zebrafish as a model organism has opened up new possibilities to study the effects of stress on inflammation, making it possible to investigate knockout lines for MR and/or GR, in combination with transgenic models with fluorescently labeled leukocyte subpopulations that enable the visualization and manipulation of these immune cells. The potential roles of other hormones of the HPI axis, such as corticotrophin-releasing hormone (Crh) and adrenocorticotropic hormone (Acth), in immune modulation are also discussed. Overall, this review highlights the need for further research to elucidate the specific roles of GR, MR and other stress hormones in regulating immune function in fish. Understanding these mechanisms will contribute to improving fish health and advancing our knowledge of stress signalling., 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 © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The formation of dominance hierarchies in pairs of juvenile rainbow trout (Oncorhynchus mykiss) results in subordinate individuals exhibiting chronically elevated plasma cortisol concentrations. Cortisol levels reflect a balance between cortisol production, which is coordinated by the hypothalamic-pituitary-interrenal (HPI) axis in teleost fish, and negative feedback regulation and hormone clearance, which act to lower cortisol levels. However, the mechanisms contributing to the longer-term elevation of cortisol levels during chronic stress are not well established in fishes. The current study aimed to determine how subordinate fish maintain elevated cortisol levels, by testing the prediction that negative feedback and clearance mechanisms are impaired by chronic social stress. Plasma cortisol clearance was unchanged by social stress based on a cortisol challenge trial, hepatic abundance of the cortisol-inactivating enzyme 11-beta hydroxysteroid dehydrogenase type 2 (11βHSD2), and tissue fate of labelled cortisol. The capacity for negative feedback regulation in terms of transcript and protein abundances of corticosteroid receptors in the preoptic area (POA) and pituitary appeared stable. However, changes in 11βHSD2 and mineralocorticoid receptor (MR) expression suggest subtle regulatory changes in the pituitary that may alter negative feedback. The chronic cortisol elevation observed during social subordination likely is driven by HPI axis activation and compounded by dysregulated negative feedback., 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 © 2023 Elsevier Inc. All rights reserved.)

Background and Objective: Real-world evidence studies of brivaracetam (BRV) have been restricted in scope, location, and patient numbers. The objective of this pooled analysis was to assess effectiveness and tolerability of brivaracetam (BRV) in routine practice in a large international population., Methods: EXPERIENCE/EPD332 was a pooled analysis of individual patient records from multiple independent non-interventional studies of patients with epilepsy initiating BRV in Australia, Europe, and the United States. Eligible study cohorts were identified via a literature review and engagement with country lead investigators, clinical experts, and local UCB Pharma scientific/medical teams. Included patients initiated BRV no earlier than January 2016 and no later than December 2019, and had ≥ 6 months of follow-up data. The databases for each cohort were reformatted and standardised to ensure information collected was consistent. Outcomes included ≥ 50% reduction from baseline in seizure frequency, seizure freedom (no seizures within 3 months before timepoint), continuous seizure freedom (no seizures from baseline), BRV discontinuation, and treatment-emergent adverse events (TEAEs) at 3, 6, and 12 months. Patients with missing data after BRV discontinuation were considered non-responders/not seizure free. Analyses were performed for all adult patients (≥ 16 years), and for subgroups by seizure type recorded at baseline; by number of prior antiseizure medications (ASMs) at index; by use of BRV as monotherapy versus polytherapy at index; for patients who switched from levetiracetam to BRV versus patients who switched from other ASMs to BRV; and for patients with focal-onset seizures and a BRV dose of ≤ 200 mg/day used as add-on at index. Analysis populations included the full analysis set (FAS; all patients who received at least one BRV dose and had seizure type and age documented at baseline) and the modified FAS (all FAS patients who had at least one seizure recorded during baseline). The FAS was used for all outcomes other than ≥ 50% seizure reduction. All outcomes were summarised using descriptive statistics., Results: Analyses included 1644 adults. At baseline, 72.0% were 16-49 years of age and 92.2% had focal-onset seizures. Patients had a median (Q1, Q3) of 5.0 (2.0, 8.0) prior antiseizure medications at index. At 3, 6, and 12 months, respectively, ≥ 50% seizure reduction was achieved by 32.1% (n = 619), 36.7% (n = 867), and 36.9% (n = 822) of patients; seizure freedom rates were 22.4% (n = 923), 17.9% (n = 1165), and 14.9% (n = 1111); and continuous seizure freedom rates were 22.4% (n = 923), 15.7% (n = 1165), and 11.7% (n = 1111). During the whole study follow-up, 551/1639 (33.6%) patients discontinued BRV. TEAEs since prior visit were reported in 25.6% (n = 1542), 14.2% (n = 1376), and 9.3% (n = 1232) of patients at 3, 6, and 12 months, respectively., Conclusions: This pooled analysis using data from a variety of real-world settings suggests BRV is effective and well tolerated in routine clinical practice in a highly drug-resistant patient population., (© 2023. The Author(s).)

Stress and the attendant rise in glucocorticoids (GCs) results in a potent suppression of the immune system. To date, the anti-inflammatory role of GCs, via activation of the glucocorticoid receptor, has been well-characterized. However, cortisol, the primary GC in both fish and humans, also signals through the high-affinity mineralocorticoid receptor (MR), of which the immunomodulatory role is poorly understood. Here, we tested the hypothesis that MR is a key modulator of leukocyte function during inflammation. Using transgenic MR knockout zebrafish with fluorescently labelled leukocytes, we show that a loss of MR results in a global reduction in macrophage number during key development stages. This reduction was associated with impaired macrophage proliferation and responsivity to developmental distribution signals, as well as increased susceptibility to cell death. Using a tail fin amputation in zebrafish larvae as a model for localized inflammation, we further showed that MR knockout larvae display a reduced ability to produce more macrophages under periods of inflammation (emergency myelopoiesis). Finally, we treated wild-type larvae with an MR antagonist (eplerenone) during definitive hematopoiesis, when the macrophages had differentiated normally throughout the larvae. This pharmacological blockade of MR reduced the migration of macrophages toward a wound, which was associated with reduced macrophage Ccr2 signalling. Eplerenone treatment also abolished the cortisol-induced inhibition of macrophage migration, suggesting a role for MR in cortisol-mediated anti-inflammatory action. Taken together, our work reveals that MR is a key modulator of the innate immune response to inflammation under both basal and stressed conditions., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Health care providers have reported low knowledge, skill, and confidence for discussing movement behaviours (i.e., physical activity, sedentary behaviour, and sleep), which may be improved with the use of tools to guide movement behaviour discussions in their practice. Past reviews have examined the psychometric properties, scoring, and behavioural outcomes of physical activity discussion tools. However, the features, perceptions, and effectiveness of discussion tools for physical activity, sedentary behaviour, and/or sleep have not yet been synthesized. The aim of this review was to report and appraise tools for movement behaviour discussions between health care providers and adults 18 + years in a primary care context within Canada or analogous countries., Methods: An integrated knowledge translation approach guided this review, whereby a working group of experts in medicine, knowledge translation, communications, kinesiology, and health promotion was engaged from research question formation to interpretation of findings. Three search approaches were used (i.e., peer-reviewed, grey literature, and forward searches) to identify studies reporting on perceptions and/or effectiveness of tools for physical activity, sedentary behaviour, and/or sleep. The quality of included studies was assessed using the Mixed Methods Appraisal Tool., Results: In total, 135 studies reporting on 61 tools (i.e., 51 on physical activity, one on sleep, and nine combining two movement behaviours) met inclusion criteria. Included tools served the purposes of assessment (n = 57), counselling (n = 50), prescription (n = 18), and/or referral (n = 12) of one or more movement behaviour. Most tools were used or intended for use by physicians, followed by nurses/nurse practitioners (n = 11), and adults accessing care (n = 10). Most tools were also used or intended to be used with adults without chronic conditions aged 18-64 years (n = 34), followed by adults with chronic conditions (n = 18). The quality of the 116 studies that evaluated tool effectiveness varied., Conclusions: Many tools were positively perceived and were deemed effective at enhancing knowledge of, confidence for, ability in, and frequency of movement behaviour discussions. Future tools should guide discussions of all movement behaviours in an integrated manner in line with the 24-Hour Movement Guidelines. Practically, this review offers seven evidence-based recommendations that may guide future tool development and implementation., (© 2023. The Author(s).)

Background: Canada's 24-Hour Movement Guidelines for Adults have shifted the focus from considering movement behaviours (i.e., physical activity, sedentary behaviour, and sleep) separately to a 24-h paradigm, which considers how they are integrated. Accordingly, primary care providers (PCPs) have the opportunity to improve their practice to promote all movement behaviours cohesively. However, PCPs have faced barriers to discussing physical activity alone (e.g., time, competing priorities, inadequate training), leading to low frequency of physical activity discussions. Consequently, discussing three movement behaviours may seem challenging. Tools to facilitate primary care discussions about physical activity have been developed and used; however, few have undergone usability testing and none have integrated all movement behaviours. Following a synthesis of physical activity, sedentary behaviour, and sleep tools for PCPs, we developed the Whole Day Matters Tool and User Guide that incorporate all movement behaviours. The present study aimed to explore PCPs' perceptions on the usability, acceptability, and future implementation of the Whole Day Matters Tool and User Guide to improve their relevancy among PCPs., Methods: Twenty-six PCPs were observed and audio-video recorded while using the Tool and User Guide in a think-aloud procedure, then in a near-live encounter with a mock service-user. A debriefing interview using a guide informed by Normalization Process Theory followed. Recordings were transcribed verbatim and analysed using content analysis and a critical friend to enhance rigour., Results: PCPs valued aspects of the Tool and User Guide including their structure, user-friendliness, visual appeal, and multi-behaviour focus and suggested modifications to improve usability and acceptability. Findings are further discussed in the context of Normalization Process Theory and previous literature., Conclusions: The Tool and User Guide were revised, including adding plain language, reordering and renaming sections, reducing text, and clarifying instructions. Results also informed the addition of a Preamble and a Handout for adults accessing care (i.e., patients/clients/service-users) to explain the evidence underpinning the 24-Hour Movement Guidelines for Adults and support a person-centered approach. These four resources (i.e., Tool, User Guide, Preamble, Handout) have since undergone a consensus building process to arrive at their final versions before being disseminated into primary care practice., (© 2023. The Author(s).)

Background and Objectives: Mood, anxiety disorders, and suicidality are more frequent in people with epilepsy than in the general population. Yet, their prevalence and the types of mood and anxiety disorders associated with suicidality at the time of the epilepsy diagnosis are not established. We sought to answer these questions in patients with newly diagnosed focal epilepsy and to assess their association with suicidal ideation and attempts., Methods: The data were derived from the Human Epilepsy Project study. A total of 347 consecutive adults aged 18-60 years with newly diagnosed focal epilepsy were enrolled within 4 months of starting treatment. The types of mood and anxiety disorders were identified with the Mini International Neuropsychiatric Interview, whereas suicidal ideation (lifetime, current, active, and passive) and suicidal attempts (lifetime and current) were established with the Columbia Suicidality Severity Rating Scale (CSSRS). Statistical analyses included the t test, χ 2 statistics, and logistic regression analyses., Results: A total of 151 (43.5%) patients had a psychiatric diagnosis; 134 (38.6%) met the criteria for a mood and/or anxiety disorder, and 75 (21.6%) reported suicidal ideation with or without attempts. Mood (23.6%) and anxiety (27.4%) disorders had comparable prevalence rates, whereas both disorders occurred together in 43 patients (12.4%). Major depressive disorders (MDDs) had a slightly higher prevalence than bipolar disorders (BPDs) (9.5% vs 6.9%, respectively). Explanatory variables of suicidality included MDD, BPD, panic disorders, and agoraphobia, with BPD and panic disorders being the strongest variables, particularly for active suicidal ideation and suicidal attempts., Discussion: In patients with newly diagnosed focal epilepsy, the prevalence of mood, anxiety disorders, and suicidality is higher than in the general population and comparable to those of patients with established epilepsy. Their recognition at the time of the initial epilepsy evaluation is of the essence., (© 2022 American Academy of Neurology.)

In an aging world, it is important to know the burden of epilepsy affecting populations of older persons. We performed a selective review of epidemiological studies that we considered to be most informative, trying to include data from all parts of the world. We emphasized primary reports rather than review articles. We reviewed studies reporting the incidence and prevalence of epilepsy that focused on an older population as well as studies that included a wider age range if older persons were tabulated as a subgroup. There is strong evidence that persons older than approximately 60 years incur an increasing risk of both acute symptomatic seizures and epilepsy. In wealthier countries, the incidence of epilepsy increases sharply after age 60 or 65 years. This phenomenon was not always observed among reports from populations with lower socioeconomic status. This discrepancy may reflect differences in etiologies, methods of ascertainment, or distribution of ages; this is an area for more research. We identified other areas for which there are inadequate data. Incidence data are scarcer than prevalence data and are missing for large areas of the world. Prevalence is lower than would be expected from cumulative incidence, possibly because of remissions, excess mortality, or misdiagnosis of acute symptomatic seizures as epilepsy. Segmentation by age, frailty, and comorbidities is desirable, because "epilepsy in the elderly" is otherwise too broad a concept. Data are needed on rates of status epilepticus and drug-resistant epilepsy using the newer definitions. Many more data are needed from low-income populations and from developing countries. Greater awareness of the high rates of seizures among older adults should lead to more focused diagnostic efforts for individuals. Accurate data on epilepsy among older adults should drive proper allocation of treatments for individuals and resources for societies., (© 2022 International League Against Epilepsy.)

Older adults represent a highly heterogeneous population, with multiple diverse subgroups. Therefore, an individualized approach to treatment is essential to meet the needs of each unique subgroup. Most comparative studies focusing on treatment of epilepsy in older adults have found that levetiracetam has the best chance of long-term seizure freedom. However, there is a lack of studies investigating other newer generation antiseizure medications (ASMs). Although a number of randomized clinical trials have been performed on older adults with epilepsy, the number of participants studied was generally small, and they only investigated short-term efficacy and tolerability. Quality of life as an outcome is often missing but is necessary to understand the effectiveness and possible side effects of treatment. Prognosis needs to move beyond the focus on seizure control to long-term patient-centered outcomes. Dosing studies with newer generation ASMs are needed to understand which treatments are the best in the older adults with different comorbidities. In particular, more high-level evidence is required for older adults with Alzheimer's disease with epilepsy and status epilepticus. Future treatment studies should use greater homogeneity in the inclusion criteria to allow for clearer findings that can be comparable with other studies to build the existing treatment evidence base., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Introduction: People with recurrent epileptic seizures are typically treated with anti-seizure medications (ASMs). Around a third of epilepsy patients fail to achieve an adequate response to ASMs and may be eligible to receive vagus nerve stimulation (VNS) therapy for their drug-resistant epilepsy (DRE) if they are unsuited to surgery. VNS received approval from the United States (US) Food and Drug Administration agency. However, there has to date been no comprehensive cost effectiveness evaluation of VNS within the US setting. This study was designed, using a US Medicare perspective, to estimate costs and quality-adjusted life years (QALYs) associated with VNS as an adjunct to ongoing ASM therapy, compared to ASMs alone., Methods: We developed a cohort state transition model in Microsoft Excel, with four health states defined by different percentage reductions in seizure frequency, with a 3-month cycle and transition probabilities derived from published clinical trials and registry data. Sensitivity analyses were conducted to understand the impact of parameter uncertainty. Costs included the VNS device, placement, programming, battery changes, and removal; ASM therapy; adverse events associated with VNS (dyspnea, hoarseness, and cough); and costs associated with seizure burden (i.e. hospitalizations, emergency department visits, neurologist visits)., Results: Under base case assumptions, treatment with VNS was associated with a 0.385 QALY gain and a $109,678 saving per patient, when compared with ASM therapy alone. The incremental net monetary benefit (iNMB) was $128,903 at a threshold of $50,000 per QALY, with the positive iNMB indicating that VNS is a highly cost effective treatment. This result is explained by the modeled reduction in relative seizure frequency and associated reduction in healthcare resource use that the VNS group experienced. Sensitivity analyses supported this conclusion., Conclusions: VNS was evaluated as a cost effective addition to the current standard of care in the treatment of DRE in the US Medicare context.

Glucocorticoids (GCs) are essential for maintaining energy homeostasis as part of the adaptive stress response. Most work to date has characterized the metabolic role of GCs via the activation of the glucocorticoid receptor (nr3c1; GR), which is activated under high GC conditions. However, GCs also bind to the mineralocorticoid receptor (nr3c2; MR), a high-affinity corticosteroid receptor active under basal GC conditions. Despite the expression of MR in skeletal muscles, almost nothing is known about its physiological role. Here we tested the hypothesis that the MR promotes anabolic processes during resting cortisol levels and curtails the catabolic actions of the GR during high (stressed) levels of cortisol. To determine the effect of MR, a zebrafish line with a ubiquitous MR knockout (MRca402/ca402) was utilized. The GR was activated in the same group by chronically treating fish with exogenous cortisol. In the muscle, MR primarily promoted nutrient storage, and restricted energy substrate mobilization under resting conditions, whereas GR activation resulted in increased nutrient utilization. Interestingly, MR loss improved GR-driven metabolic flexibility, suggesting that the activation state of these receptors is a key determinant of skeletal muscle ability to switch fuel sources. To determine if the anabolism-promoting nature of MR was due to an interaction with insulin, fish were co-injected with insulin and the fluorescent glucose analogue 2-NBDG. A loss of MR abolished insulin-stimulated glucose uptake in the skeletal muscle. Taken together, we postulate that MR acts as a key modulator of glucose metabolism in the musculature during basal and stress conditions., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Chronic cortisol exposure suppresses food intake in fish, but the central mechanism(s) involved in appetite regulation are unclear. Stress and the associated increase in cortisol levels increase hepatic gluconeogenesis, leading to hyperglycemia. As hyperglycemia causes a reduction in food intake, we tested the hypothesis that cortisol-induced hyperglycemia suppresses feeding in zebrafish (Danio rerio). We first established that stress-independent hyperglycemia suppressed food intake, and this corresponded with a reduction in the phosphorylation of the nutrient sensor, AMP-activated protein kinase (AMPK) in the brain. Chronic cortisol exposure also led to hyperglycemia and reduced food intake, but the mechanisms were distinct. In cortisol-exposed fish, there were no changes in brain glucose uptake or AMPK phosphorylation. Also, the phosphorylation of Akt and mTOR was reduced along with an increase in redd1, suggesting an enhanced capacity for proteolysis. Loss of the glucocorticoid receptor did not rescue cortisol-mediated feeding suppression but did increase glucose uptake and abolished the changes seen in mTOR phosphorylation and redd1 transcript abundance. Taken together, our results indicate that GR activation enhances brain proteolysis, and the associated amino acids levels, and not hyperglycemia, maybe a key mediator of the feeding suppression in response to chronic cortisol stimulation in zebrafish., (© 2022. The Author(s).)

Background: The impact of seizure clusters and the use of intermittent rescue therapy for clusters on the quality of life (QoL) of patients with epilepsy has not been widely studied. The present analysis assessed QoL as a secondary endpoint among adult patients with seizure clusters enrolled in a long-term, phase 3, open-label safety study (NCT02721069) of diazepam nasal spray (Valtoco®). The QoL aspect of patients in this study has not been previously published., Methods: The 12-month safety study of diazepam nasal spray enrolled patients aged 6-65 years with seizure clusters. Adults aged ≥18 years completed the Quality of Life in Epilepsy (QOLIE)-31-P at baseline (day 0) and days 30, 150, 270, and 365. This instrument includes questions about patient health and daily activities with numeric values (1-100) assigned to responses; higher scores indicate better QoL. The QOLIE-31-P includes 7 subscales: Seizure Worry, Overall QoL, Emotional Well-Being, Energy/Fatigue, Cognitive Functioning, Medication Effects, and Social Functioning; an Overall Score is calculated as a weighted composite of the 7 subscales. Comparisons were made between subgroups of patients who had frequent (≥2) and infrequent (<2) monthly dosing of diazepam nasal spray and those whose doses were administered by the patient or a care partner. This safety study was not powered to assess efficacy endpoints; descriptive statistics were calculated across time points. In addition, safety measures, including treatment-emergent adverse events, are reported., Results: Seventy-two adults who responded to the QOLIE-31-P were included in the analyses. Mean QOLIE-31-P scores were stable or increased across time points. The mean total scores increased from day 0 to day 365 by 5.2 among patients providing data for ≥1 time point (follow-up group) and 2.2 among patients providing data at all time points (QOLIE all-assessments subgroup). Subscale means for Seizure Worry and Social Functioning showed the greatest numeric increase from baseline. Mean QOLIE-31-P scores were similar in all subgroups. The safety profile in the follow-up group was similar to that seen in all study adults., Conclusions: Adults with refractory epilepsy who were treated with diazepam nasal spray for seizure clusters maintained or improved QOLIE subscale scores across the 12-month study period. Seizure Worry and Social Functioning subscale scores increased over time, suggesting improvement in these domains for this population with intractable epilepsy. Changes among subscale results suggest differences in sensitivity to the use of an intermittent treatment. The potential to improve patient function with treatment for seizure clusters warrants further study., (Copyright © 2022 Elsevier Inc. All rights reserved.)

One in five Canadians have a disability and there are well-documented gaps in care for this equity-deserving group that have roots in medical education. In this paper, we highlight the unintended consequences of ableist messaging for persons living with disabilities, particularly in the context of promoting healthy movement behaviours. With its broad reach and public trust, the medical community has a responsibility to acknowledge the reality of ableism and take meaningful action. We propose five strategies to counter ableist messaging in medical education: (1) increase knowledge and confidence among physicians and trainees to optimize movement behaviours in persons living with disabilities, (2) perform personal and institutional language audits to ensure terminology related to disability is inclusive and avoids causing unintended harm, (3) challenge ableist messages effectively, (4) address the unmet healthcare needs of persons living with disabilities, and (5) engage in efforts to reform medical curricula so that persons living with disabilities are represented and treated equitably. Physicians and trainees are well-positioned to deliver competent and inclusive care, making medical education an opportune setting to address health inequities related to disability., Competing Interests: The authors have no conflict(s) of interest, (© 2022 Faught, Morgan, Tomasone; licensee Synergies Partners.)

Seizure clusters may initiate a chain of events that have economic as well as clinical consequences. The potential economic consequences of seizure clusters must be weighed against the cost of medication to attenuate them. This is true both for individual patients and for society. Data needed for economic analyses include the chance that a cluster will progress to an adverse outcome, such as a need for emergency care, the costs of such an outcome, the cost of a rescue medication (RM), and the effectiveness of the RM. Indirect costs, such as lost employment for patients and caregivers, must also be considered. Several types of economic analyses can be used to determine costs and benefits of a medical intervention. There are studies comparing different RMs from an economic perspective, but there is little direct information on the costs of using an RM versus allowing clusters to run their course. However, the high expense of consequences of seizure clusters makes it likely that effective RMs will make economic as well as medical sense for many patients., (© 2022 International League Against Epilepsy.)

Introduction: The stress response mediated by the hypothalamus-pituitary-adrenal (HPA) axis activation is highly conserved in vertebrates. Hyperactivity is one such established acute stress response, and corticotropin-releasing hormone (CRH), the primary step in HPA activation, signalling has been implicated in this stressor-mediated behaviour. However, whether CRH mediates the acute behavioural effects either alone or in conjunction with glucocorticoids (GCs) are far from clear. We hypothesized that the CRH receptor 1 (CRHR1)-mediated rise in GCs post-stress is necessary for the initiation and maintenance of the acute stress-related behaviour., Methods: We first generated zebrafish (Danio rerio) with a mutation in the CRHR1 gene (CRHR1-KO) to assess the function of CRH. The behavioural readout utilized for this study was the locomotor activity of larval zebrafish in response to an acute light exposure, a protocol that freezes the larvae in response to the light stimulus. To test whether cortisol signalling is involved in the stress-mediated hyperactivity, we treated wildtype fish with metyrapone (MET), an inhibitor of 11β-hydroxylase, to suppress cortisol production. The temporal role for cortisol signalling in the stress-related hyperactivity was tested using the glucocorticoid receptor knockout (GRKO) and mineralocorticoid receptor knockout (MRKO) zebrafish mutants., Results: CRHR1-KO larvae did not increase cortisol, the principal GC in teleosts, post-stress, confirming a functional knockout. An acute stress resulted in the hyperactivity of the larvae in light at 15, 60, and 240 min post-stress, and this was absent in CRHR1-KO larvae. Addition of MET effectively blocked the attendant rise in cortisol post-stress; however, the stress-mediated hyperactivity was inhibited only at 60 and 240 min but not at 15 min post-stress. Addition of human CRH peptide caused hyperactivity at 15 min, and this response was also abolished in the CRHR1-KO mutants. The stress-induced hyperactivity was absent in the MRKO fish, while GRKO mutants showed transient effects., Conclusions: The results suggest that the stress-induced hyperactivity is induced by the CRH/CRHR1 system, while the temporal activation of cortisol production and the associated GR/MR signalling is essential for prolonging the stressor-induced hyperactivity. This study underscores the importance of systems-level analysis to assess stress responsivity., (© 2021 S. Karger AG, Basel.)

Objective: To evaluate declarative memory outcomes in medically refractory epilepsy patients who underwent either a highly selective laser ablation of the amygdalohippocampal complex or a conventional open temporal lobe resection. Methods: Post-operative change scores were examined for verbal memory outcome in epilepsy patients who underwent stereotactic laser amygdalohippocampotomy (SLAH: n = 40) or open resection procedures ( n = 40) using both reliable change index (RCI) scores and a 1-SD change metric. Results: Using RCI scores, patients undergoing open resection (12/40, 30.0%) were more likely to decline on verbal memory than those undergoing SLAH (2/40 [5.0%], p = 0.0064, Fisher's exact test). Patients with language dominant procedures were much more likely to experience a significant verbal memory decline following open resection (9/19 [47.4%]) compared to laser ablation (2/19 [10.5%], p = 0.0293, Fisher's exact test). 1 SD verbal memory decline frequently occurred in the open resection sample of language dominant temporal lobe patients with mesial temporal sclerosis (8/10 [80.0%]), although it rarely occurred in such patients after SLAH (2/14, 14.3%) ( p = 0.0027, Fisher's exact test). Memory improvement occurred significantly more frequently following SLAH than after open resection. Interpretation: These findings suggest that while verbal memory function can decline after laser ablation of the amygdalohippocampal complex, it is better preserved when compared to open temporal lobe resection. Our findings also highlight that the dominant hippocampus is not uniquely responsible for verbal memory. While this is at odds with our simple and common heuristic of the hippocampus in memory, it supports the findings of non-human primate studies showing that memory depends on broader medial and lateral TL regions., Competing Interests: Medtronic, Inc., contributed research funding to Emory University, and develops products related to the research described in the paper. However, Medtronic, Inc., was not involved in the study design, data collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. RG and JW serve as consultants to Medtronic, Inc., and receive compensation for these services. The terms of this arrangement have been reviewed and approved by Emory University and Washington University in Saint Louis in accordance with their respective conflict of interest policies. 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 Drane, Willie, Pedersen, Qiu, Voets, Millis, Soares, Saindane, Hu, Kim, Hewitt, Hakimian, Grabowski, Ojemann, Loring, Meador, Faught, Miller and Gross.)

Objectives: (1) To evaluate risk of hospitalization following initiation of perampanel (pre- and post-analysis) and (2) to compare hospitalization rates following initiation of perampanel vs lacosamide., Methods: Patients were identified from Symphony Health's Patient Integrated Database if they had a prescription for perampanel (July 1, 2014-June 30, 2016). Patients 4-11 years of age with any partial-onset seizure (POS) or ≥12 years of age with any POS or primary generalized tonic-clonic seizure (GTCS) (pre-post); or ≥12 years of age (perampanel vs lacosamide). The first fill of perampanel ("index date") marked the start of the analysis period. Patients had ≥1 additional fill for perampanel and ≥2 diagnoses for epilepsy or nonfebrile convulsion diagnosis during pre-index (based on ICD-9/ICD-10 codes). Patients were matched using a 1:1 propensity scoring method for the perampanel vs lacosamide analysis. Primary outcome was hospitalization during the one year following medication initiation., Results: Pre- and post-perampanel: N = 1771 (mean age 34 years, 55% female). One-year all-cause hospitalization risk ratio was 0.76 (P < .05) and 36.2% with hospitalization during the pre-period vs 29.5% in the follow-up. One-year epilepsy-related inpatient hospitalization risk ratio was 0.72 (P < .05) and 30.8% with hospitalization during the pre-period vs 23.9% during follow-up. In the perampanel and lacosamide cohorts, N = 1717 per cohort after matching, most baseline demographics were balanced. A higher percentage of subjects were prescribed ≥3 anti-seizure medications for perampanel vs lacosamide (60.5% vs 57.7%, P < .001). The perampanel cohort had a 9.6% reduction in all-cause hospitalizations vs 5.8% for the lacosamide cohort (P < .05). Epilepsy-related hospitalizations decreased from the pre-index rate by 9.9% for perampanel and 8.3% for lacosamide (P < .05). Among those with baseline hospitalizations, perampanel was associated with a 59.9% reduction in all-cause hospitalizations vs 48.6% for lacosamide (P < .05), and for epilepsy-related hospitalizations, a reduction of 65.0% vs 58.9%, respectively (P < .05)., Significance: Perampanel was associated with a significant reduction in one-year hospitalization risk., (© 2021 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background and Objectives: To explore efficacy/safety of natalizumab, a humanized monoclonal anti-α4-integrin antibody, as adjunctive therapy in adults with drug-resistant focal epilepsy., Methods: Participants with ≥6 seizures during the 6-week baseline period were randomized 1:1 to receive natalizumab 300 mg IV or placebo every 4 weeks for 24 weeks. Primary efficacy outcome was change from baseline in log-transformed seizure frequency, with a predefined threshold for therapeutic success of 31% relative reduction in seizure frequency over the placebo group. Countable seizure types were focal aware with motor signs, focal impaired awareness, and focal to bilateral tonic-clonic. Secondary efficacy endpoints/safety were also assessed., Results: Of 32 and 34 participants dosed in the natalizumab 300 mg and placebo groups, 30 (94%) and 31 (91%) completed the placebo-controlled treatment period, respectively (one participant was randomized to receive natalizumab but not dosed due to IV complications). Estimated relative change in seizure frequency of natalizumab over placebo was -14.4% (95% confidence interval [CI] -46.1%-36.1%; p = 0.51). The proportion of participants with ≥50% reduction from baseline in seizure frequency was 31.3% for natalizumab and 17.6% for placebo (odds ratio 2.09, 95% CI 0.64-6.85; p = 0.22). Adverse events were reported in 24 (75%) and 22 (65%) participants receiving natalizumab vs placebo., Discussion: Although the threshold to demonstrate efficacy was not met, there were no unexpected safety findings and further exploration of possible anti-inflammatory therapies for drug-resistant epilepsy is warranted., Trial Registration Information: The ClinicalTrials.gov registration number is NCT03283371., Classification of Evidence: This study provides Class I evidence that IV natalizumab every 4 weeks, compared to placebo, did not significantly change seizure frequency in adults with drug-resistant epilepsy. The study lacked the precision to exclude an important effect of natalizumab., (© 2021 American Academy of Neurology.)

Wild fish living downstream of wastewater treatment plants (WWTPs) often have increased body condition factors or body mass indices compared to upstream fish. This observation has been largely attributed to increased nutrient loading and food availability around wastewater effluent outflows. While a higher condition factor in fish is generally considered a predictor of healthy ecosystems, the metabolic status and capacity of the animals downstream of WWTPs may be a better predictor of fitness and potential population level effects. To address this, we sampled wild longnose dace (Rhinichthys cataractae), a native species in North American waterways, from sites upstream and downstream of WWTPs. Downstream fish had higher body mass indices, which corresponded with higher nutrient (lipid, protein, and glycogen) storage in somatic tissues compared to upstream fish. Liver transcriptome analysis revealed metabolic reprogramming favoring lipid synthesis, including higher hepatic triglyceride levels and transcript abundance of targeted lipogenic genes. This suggests that effluent exposure-mediated obesity in dace is a result of changes at the transcriptional level. To determine potential ecological consequences, we subjected these fish to an acute stressor in situ to determine their stress performance. Downstream fish failed to mobilize metabolites post-stress, and showed a reduction in liver aerobic and anaerobic metabolic capacity. Taken together, fish living downstream of WWTPs exhibit a greater lipid accumulation that results in metabolic disruption and may compromise the ability of these fish to cope with subsequent environmental and/or anthropogenic stressors., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: Combination regimens of antiepileptic drugs (AEDs) with various mechanisms of action (MOA) are commonly used in patients with refractory epilepsy. However, outcomes related to combination AEDs with novel MOA, such as perampanel (PER), are not well described. This study compared healthcare resource utilization (HRU) among recipients of PER-based combinations versus recipients of other non-PER-based combinations., Methods: This retrospective study used claims data from the Symphony Health's IDV® (Integrated Dataverse) database (August 2012 to July 2018). Patients were aged ≥12 years with epilepsy or non-febrile convulsions, were treated with AED combinations, and had ≥12 and ≥6 months pre- and post-index date, respectively (date of initiation of the second AED in the combination). AEDs were categorized based on MOA: selective non-competitive antagonist of AMPA receptors (i.e., PER), sodium channel blocker (SC), synaptic vesicle protein 2A binding (SV2), and gamma-aminobutyric acid analog (G). Patients were then classified into MOA-based cohorts: PER + SC, PER + SV2, PER + G, SC + SC, SC + SV2, SC + G, SV2 + G, and G + G. HRU outcomes were evaluated during follow-up and compared between PER-based cohorts and non-PER-based cohorts., Results: On average, patients in the PER + SC (N = 3,592), PER + SV2 (N = 2,200), and PER + G (N = 1,313) cohorts were younger and had a lower Quan-Charlson comorbidity index than those in non-PER-based cohorts. PER + SC and PER + SV2 users had significantly fewer all-cause hospitalizations than non-PER-based users (adjusted RR range: 0.66-0.89, all P < 0.05), while PER + G recipients had fewer all-cause hospitalizations than recipients of SV2 + G and G + G (adjusted RR range: 0.92-0.94). Similar trends were observed for epilepsy-related hospitalizations. Across all comparisons, PER-based combinations were associated with significantly lower rates of all-cause clinic/office/outpatient visits relative to non-PER-based combinations (adjusted RR range: 0.69-0.86, all P < 0.05)., Significance: Results showed that patients treated with PER-based combinations had fewer all-cause and epilepsy-related hospitalizations, and fewer all-cause clinic/office/outpatient visits compared with patients treated with most other non-PER-based combinations., Competing Interests: Declaration of Competing Interest FL, MSD, GG, and DL are employees of Analysis Group, Inc., a company that provided paid consulting services to Eisai Co., Ltd. for the conduct of this study. MM, FF, and CP are employees of Eisai Co., Ltd. EF is employed by Emory University School of Medicine and has received research funding from Eisai Co., Ltd. VB is employed by VEB HealthCare LLC and has received research funding from Eisai Co., Ltd., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Glucocorticoids (GCs) play a role in stress coping by activating the glucocorticoid receptor (GR), a ligand-bound transcription factor. GCs also exert rapid effects that are nongenomic by modulating second messenger signaling, including Ca 2+ . However, the mechanism of action of GCs in modulating cytoplasmic free calcium level ([Ca 2+ ]i) is unclear. We hypothesized that cortisol increases ([Ca 2+ ]i) in zebrafish (Danio rerio) muscle, and this is independent of GR activation. Indeed, cortisol rapidly stimulated ([Ca 2+ ]i) rise in the developing trunk muscle (DTM), and this response was not abolished in the GR knockout zebrafish. The rapid cortisol-induced ([Ca 2+ ]i) rise was reduced with EGTA, and completely abolished by the pharmacological inhibition of the calcium release-activated calcium channel (CRACC). Also, cortisol stimulation rapidly increased the expression of Orai1, the pore forming protein subunit of CRACC, in the DTM. Altogether, rapid nongenomic action of cortisol on muscle function may involve Ca 2+ signaling by CRACC gating in zebrafish., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Reproductive decline in mid-adult females is an established phenotype of the ageing process. Stress and the rise in glucocorticoids (GCs) accelerate reproductive ageing, but little is known about the mechanisms involved. During stress, GCs activate the glucocorticoid receptor (GR), a ubiquitously expressed, ligand-bound transcription factor, to elicit physiological changes for restoring homeostasis. Here, we tested the hypothesis that GC-GR signalling is essential for accelerating reproductive ageing. To test this, we used a ubiquitous GR knockout (GRKO) zebrafish, which is inherently hypercortisolemic, to delineate the role of high cortisol and GR signalling on reproductive ageing. The loss of GR led to premature ovarian ageing, including high frequency of typical and atypical follicular atresia in vitellogenic oocytes, yolk liquefaction and large inflammatory infiltrates. The reduction in oocyte quality was also associated with a decline in ovarian tert expression in the adult GRKO fish compared to the early adult GRKO and adult wild-type zebrafish. Accelerated ovarian ageing also impacted the progeny, including lower breeding success, fecundity, egg fertilization rate and delayed somitogenesis and embryo survival in the adult GRKO fish. We adduce that GR signalling is essential for prolonging the reproductive lifespan and improving the egg quality and embryo viability in zebrafish.

Robotic systems have fundamentally altered the landscape of functional neurosurgery. These allow automated stereotaxy with high accuracy and reliability, and are rapidly becoming a mainstay in stereotactic surgeries such as deep brain stimulation (DBS), stereoelectroencephalography (SEEG), and stereotactic laser ablation/MRI guided laser interstitial thermal therapy (MRgLITT). Robotic systems have been effectively applied to create a minimally invasive approach for diagnostics and therapeutics in the treatment of epilepsy, utilizing robots for expeditious and accurate stereotaxy for SEEG and MRgLITT. MRgLITT has been shown to approach open surgical techniques in efficacy of seizure control while minimizing collateral injury. We describe the use of robot assisted MRgLITT for a minimally invasive laser anterior temporal lobotomy, describing the approach and potential pitfalls. Goals of MRgLITT are complete ablation of the epileptogenic zone and avoiding injury to uninvolved structures. In the middle fossa these include structures such as cranial nerves in the skull base and cavernous sinus and the thalamus. These can be mitigated with careful trajectory planning and control of laser ablation intensity., Competing Interests: JW: Medtronic-consulting, research contract (SLATE trial), honoraria for teaching, Neuropace-consulting, research contract, honoraria for teaching, Clearpoint Neuro/MRI Interventions-consulting, AiM Medical-consulting. EF has received research support from UCB Pharma, Xenon, Eisai, and the NINDS, and consulting fees from Biogen, Supernus, SKLife Science, and the CDC. RH is involved with the Medtronic SLATE trial but receives no financial support. 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 © 2020 Gupta, Dickey, Hu, Faught and Willie.)

Establishing a step-by-step process that provides practitioners with a blueprint for translating movement guidelines into action stands to optimize the investment in guideline development, improve guideline promotion and uptake, and ultimately enhance population health. The purpose of this paper is to describe how the Knowledge-to-Action framework and integrated knowledge translation were operationalized to systematically inform our knowledge translation (KT) efforts for the Canadian 24-Hour Movement Guidelines for Adults aged 18-64 years and Adults aged 65 years or older. In October 2018, the need for a KT Process, operating in tandem with the Guideline Development Process, led to the establishment of a KT team with a specific structure and terms of reference. The KT team collaboratively agreed on decision-making principles prior to selecting target audiences to focus their efforts. We undertook formative research to assess the local context and determinants of guideline dissemination and implementation efforts among target audiences. Plans for the subsequent steps and research are outlined. We highlight recommendations and lessons learned for applying the process in other settings. Novelty We outline a collaborative and systematic process and research program for the knowledge translation of movement guidelines. This paper provides an innovative and replicable blueprint to optimize future movement guideline knowledge translation efforts.

The Canadian 24-Hour Movement Guidelines for Adults aged 18-64 years and Adults aged 65 years and older ("Guidelines") integrate recommendations for physical activity, sedentary, and sleep behaviours. Given the novelty of these integrated Guidelines, it was important to consider messaging strategies that would be most effective in reaching Canadian adults. The purpose of this study was to examine optimal messaging of the Guidelines as it pertains to communication channels and messages. Representative samples of Guideline end-users ( N = 1017) and stakeholders ( N = 877) each completed a cross-sectional survey. Descriptive statistics were calculated along with tests of statistical significance. Inductive content analysis was used to code stakeholders' comments (i.e., suggestions, concerns) on a draft version of the Guidelines. Most end-users had recently referred to online medical resources; family, friends, and co-workers; and physicians as communication channels for information regarding the movement behaviours. End-users and stakeholders felt that generic messages would foster self-efficacy to meet the Guidelines. Stakeholders highlighted a variety of considerations to ensure the Guidelines are inclusive towards diverse groups within the Canadian population. Findings will inform Guideline messaging. Novelty Most end-users referred to online medical resources; family, friends, and co-workers; and physicians as communication channels. End-users and stakeholders indicated that generic messages would foster self-efficacy to meet the Guidelines. Stakeholders expressed concerns about the inclusivity of the Guidelines for diverse socioeconomic groups.

Purpose: Established tonic-clonic status epilepticus (SE) does not stop in one-third of patients when treated with an intravenous (IV) benzodiazepine bolus followed by a loading dose of a second antiseizure medication (ASM). These patients have refractory status epilepticus (RSE) and a high risk of morbidity and death. For patients with convulsive refractory status epilepticus (CRSE), we sought to determine the strength of evidence for 8 parenteral ASMs used as third-line treatment in stopping clinical CRSE., Methods: A structured literature search (MEDLINE, Embase, CENTRAL, CINAHL) was performed to identify original studies on the treatment of CRSE in children and adults using IV brivaracetam, ketamine, lacosamide, levetiracetam (LEV), midazolam (MDZ), pentobarbital (PTB; and thiopental), propofol (PRO), and valproic acid (VPA). Adrenocorticotropic hormone (ACTH), corticosteroids, intravenous immunoglobulin (IVIg), magnesium sulfate, and pyridoxine were added to determine the effectiveness in treating hard-to-control seizures in special circumstances. Studies were evaluated by predefined criteria and were classified by strength of evidence in stopping clinical CRSE (either as the last ASM added or compared to another ASM) according to the 2017 American Academy of Neurology process., Results: No studies exist on the use of ACTH, corticosteroids, or IVIg for the treatment of CRSE. Small series and case reports exist on the use of these agents in the treatment of RSE of suspected immune etiology, severe epileptic encephalopathies, and rare epilepsy syndromes. For adults with CRSE, insufficient evidence exists on the effectiveness of brivaracetam (level U; 4 class IV studies). For children and adults with CRSE, insufficient evidence exists on the effectiveness of ketamine (level U; 25 class IV studies). For children and adults with CRSE, it is possible that lacosamide is effective at stopping RSE (level C; 2 class III, 14 class IV studies). For children with CRSE, insufficient evidence exists that LEV and VPA are equally effective (level U, 1 class III study). For adults with CRSE, insufficient evidence exists to support the effectiveness of LEV (level U; 2 class IV studies). Magnesium sulfate may be effective in the treatment of eclampsia, but there are only case reports of its use for CRSE. For children with CRSE, insufficient evidence exists to support either that MDZ and diazepam infusions are equally effective (level U; 1 class III study) or that MDZ infusion and PTB are equally effective (level U; 1 class III study). For adults with CRSE, insufficient evidence exists to support either that MDZ infusion and PRO are equally effective (level U; 1 class III study) or that low-dose and high-dose MDZ infusions are equally effective (level U; 1 class III study). For children and adults with CRSE, insufficient evidence exists to support that MDZ is effective as the last drug added (level U; 29 class IV studies). For adults with CRSE, insufficient evidence exists to support that PTB and PRO are equally effective (level U; 1 class III study). For adults and children with CRSE, insufficient evidence exists to support that PTB is effective as the last ASM added (level U; 42 class IV studies). For CRSE, insufficient evidence exists to support that PRO is effective as the last ASM used (level U; 26 class IV studies). No pediatric-only studies exist on the use of PRO for CRSE, and many guidelines do not recommend its use in children aged <16 years. Pyridoxine-dependent and pyridoxine-responsive epilepsies should be considered in children presenting between birth and age 3 years with refractory seizures and no imaging lesion or other acquired cause of seizures. For children with CRSE, insufficient evidence exists that VPA and diazepam infusion are equally effective (level U, 1 class III study). No class I to III studies have been reported in adults treated with VPA for CRSE. In comparison, for children and adults with established convulsive SE (ie, not RSE), after an initial benzodiazepine, it is likely that loading doses of LEV 60 mg/kg, VPA 40 mg/kg, and fosphenytoin 20 mg PE/kg are equally effective at stopping SE (level B, 1 class I study)., Conclusions: Mostly insufficient evidence exists on the efficacy of stopping clinical CRSE using brivaracetam, lacosamide, LEV, valproate, ketamine, MDZ, PTB, and PRO either as the last ASM or compared to others of these drugs. Adrenocorticotropic hormone, IVIg, corticosteroids, magnesium sulfate, and pyridoxine have been used in special situations but have not been studied for CRSE. For the treatment of established convulsive SE (ie, not RSE), LEV, VPA, and fosphenytoin are likely equally effective, but whether this is also true for CRSE is unknown. Triple-masked, randomized controlled trials are needed to compare the effectiveness of parenteral anesthetizing and nonanesthetizing ASMs in the treatment of CRSE.

Early life stages are sensitive to environmental insults and changes during critical developmental periods; this can often result in altered adult behaviour and physiology. Examining the development of the hypothalamus-pituitary-interrenal (HPI) axis and its responsiveness, or lack thereof, during development are important for understanding the short- and long-term impacts of stressors on embryonic and larval fish. We examined the ontogeny of the HPI axis in embryonic (21, 38, 63, 83 and 103 days post-fertilisation (dpf)) and larval (1, 2, 3 and 4 weeks post-hatch (wph)) lake whitefish (Coregonus clupeaformis) by quantifying changes in mRNA levels of several genes associated with HPI axis functioning and whole animal cortisol levels throughout development and in response to a severe or mild hypoxic stress. Cortisol, and crh, crhbp1, pomc and star transcripts were detected from the earliest embryonic age studied. Cortisol levels in control embryos decreased between 21 and 63 dpf, suggesting the utilisation of maternal cortisol deposits. However, by 83 dpf (70% developed) endogenous de novo synthesis had generated a 4.5-fold increase in whole embryo cortisol. Importantly, we provide novel data showing that the HPI axis can be activated even earlier. Whole body cortisol increased in eyed lake whitefish embryos (38 dpf; ~32% developed) in response to hypoxia stress. Coincident with this hypoxia-induced increase in cortisol in 38 dpf embryos were corresponding increases in crh, crhbp1, pomc and star transcript levels. Beyond 38 dpf, the HPI axis in lake whitefish embryos was hyporesponsive to hypoxia stress at all embryonic ages examined (63, 83 and 103 dpf; 54, 72 and 85% developed, respectively). Post-hatch, larvae responded to hypoxia with an increase in cortisol levels and HPI axis genes at 1 wph, but this response was lost and larvae appeared hyporesponsive at subsequent ages (2, 3 and 4 wph). Collectively our work demonstrates that during fish embryogenesis and the larval stage there are windows where the HPI axis is responsive and windows where it is truly hyporesponsive; both could be beneficial in ensuring undisrupted development particularly in the face of increasing environmental changes., 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 Elsevier Inc. All rights reserved.)

Objective: To determine the incidence, causes, predictors, and costs of 30-day readmissions in patients admitted with status epilepticus (SE) from a large representative United States (US) population., Methods: Adults (age ≥18 years) hospitalized with a primary diagnosis of SE (International Classification of Diseases-Ninth Revision-CM codes 345.2 or 345.3) between January 2013 and September 2015 were identified using the Nationwide Readmissions Database. A multivariable logistic regression model was used to identify predictors of 30-day readmissions., Results: Of 42,232 patients with index SE, 6372 (15.0%) were readmitted within 30 days. In the multivariable analysis, intracranial hemorrhage (odds ratio, 1.56; 95% confidence interval, 1.12-2.18), psychosis (1.26 95%, 1.05-1.50), diabetes mellitus (1.12, 95%, 1.00-1.25), chronic kidney disease (1.50, 95%, 1.31-1.72), chronic liver disease (1.51; 95%, 1.24-1.84), >3 Elixhauser comorbidities (1.18; 95%, 1.06-1.31), length of stay >4 days during index hospitalization (1.41; 95%, 1.28-1.56) and discharge to skilled nursing facility (SNF) (1.14; 95%, 1.01-1.28) were independent predictors of 30-day readmission. The most common reason for readmission was seizures (45.1%). Median length of stay and costs of readmission were 4 days (interquartile range [IQR], 2-7 days) and $7882 (IQR, $4649-$15,012), respectively., Conclusion: Thirty-day readmissions after SE occurs in 15% of patients, the majority of which were due to seizures. Readmitted patients are more likely to have multiple comorbidities, a longer length of stay, and discharge to SNF. Awareness of these predictors can help identify and target high-risk patients for interventions to reduce readmissions and costs., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The melanocortin-2 receptor (MC2R) and the melanocortin-5 receptor (MC5R) are found on the same chromosome in most vertebrate genomes, and for the species analyzed in this study, MC2R and MC5R are co-expressed in glucocorticoid-producing cells that also express the accessory protein MRAP1. Since MRAP1 affects the ligand sensitivity of MC2R orthologs, this study tested the hypothesis that co-expression of MC5R with MRAP1 would also affect the ligand sensitivity of MC5R. The hypothesis was confirmed for stingray, rainbow trout, and chicken, MC5R orthologs. However, elephant shark MC5R was not affected in the same way by co-expression of MRAP1. It appears that, for some MC5R orthologs (i.e., stingray, rainbow trout, and chicken), a docking site for the R/KKRRP motif of ACTH(1-24) may become exposed on the receptor following co-expression with MRAP1. However, for elephant shark MC5R co-expression with MRAP1 may not affect engagement ACTH(1-24). Hence during the radiation of the chordates, the interaction between MRAP1 and MC5R has diverged., 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 Elsevier Inc. All rights reserved.)

During early development, stress or exogenous glucocorticoid (GC) administration reduces body mass in vertebrates, and this is associated with the glucocorticoid receptor (GR) activation. Although GCs also activate the mineralocorticoid receptor (MR), the physiological significance of MR activation on early developmental growth is unknown. We tested the hypothesis that activation of both GR and MR are required for postnatal growth suppression by GCs. Differential regulation of GR and MR activation was achieved by using ubiquitous GR- (GRKO) and MR- (MRKO) knockout zebrafish (Danio rerio) in combination with exogenous cortisol treatment. MR activation increased protein deposition in zebrafish larvae and also upregulated lepa and downregulated lepr transcript abundance. Cortisol treatment reduced body mass and protein content in the WT, and this corresponded with the upregulation of muscle proteolytic markers, including murf1 and redd1 by GR activation. The combined activation of MR and GR by cortisol also upregulated the gh and igf1 transcript abundance, and insulin expression compared to the WT. However, cortisol-mediated reduction in body mass and protein content required the activation of both MR and GR, as activation by GR alone (MRKO + cortisol) did not reduce the larval protein content. Collectively, our results indicate that MR activation favors protein deposition and GR activation stimulates proteolysis, while their combined activation is involved in cortisol-mediated growth suppression. Overall, this work provides insight into the physiological significance of MR activation in regulating protein deposition during early development at a systems level.

Purpose: Describe treatment patterns in patients from the United States with new-onset epilepsy, comparing those with and without lesional epilepsy., Methods: In this observational study we used Truven Health MarketScan databases derived from commercial health insurance, Medicare and Medicaid claims covering at least 5 years, commencing in 2008. We identified incident epilepsy cases based on International Classification of Diseases, Ninth Revision, Clinical Modification codes indicating epilepsy or recurrent seizures, taking into account antiepileptic drug (AED) claims, consistent with International League Against Epilepsy Commission on Epidemiology recommendations. We identified patients with lesional epilepsy when associated diagnoses indicated central nervous system infection, neoplasm, traumatic brain injury, stroke, senile dementia and static encephalopathy. Lesional and nonlesional cohorts were matched 1:1 on baseline characteristics of age, sex and insurance type for group comparisons., Results: In unmatched cohorts lesional epilepsy patients (N = 15,302) were more commonly older (mean age 48.7 years) compared with nonlesional epilepsy patients (N = 15,970; mean age 18.5 years). Among lesional patients <20 years of age, the leading putative etiology was static encephalopathy, while among ages ≥20 years and older, the leading putative etiology was stroke or cerebrovascular disease. In matched cohorts (7063 patients each), those with lesional epilepsy were significantly less likely to be untreated at 1 year versus those with nonlesional epilepsy (37.2% vs 56.1%). In children and adults among matched cohorts, levetiracetam was the most common AED prescribed for initial AED therapy for the lesional (39.5%) and nonlesional (32.1%) groups. Lesional epilepsy patients on monotherapy were only slightly less likely than nonlesional epilepsy patients to be on the same AED 1 year after treatment initiation (55.6% vs 59.7%)., Significance: Compared with patients with lesional epilepsy, a higher proportion of patients with nonlesional epilepsy remain untreated 1 year after diagnosis. There were differences in AED selection by epilepsy etiology; levetiracetam is the most commonly prescribed drug for both cohorts., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Key Points: Glucocorticoids (GCs) either enhance or reduce obesity in mammals, but limited information exists on the role of corticosteroid receptors in mediating the effect of GCs on lipid metabolism during postnatal development. Mineralocorticoid receptor (MR) activation leads to triglyceride (TG) accumulation post-feeding, whereas glucocorticoid receptor (GR) activation reduces TG levels. The TG profile was inversely related to the lipoprotein lipase (lpl) transcript abundance, and this gene was downregulated by MR activation. Cortisol plays an important role in adipogenesis during postnatal development in zebrafish, and this includes gene/pathway-specific signalling by GR, MR and GR/MR interactions. Ubiquitous MR and GR knockout in zebrafish provides an excellent model to study the mode of action of GCs in regulating lipid metabolism., Abstract: Glucocorticoids (GCs) act through two receptors, the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR), which differ in both their affinity to bind GCs and their function. As MR has 10-fold higher affinity for GCs compared to GR, it has been postulated that MR activation occurs at basal levels, while stress levels of these steroid hormones activate GR signalling. There is a growing body of evidence that both these receptors are involved in GC-mediated lipid metabolism. However, the role of GCs in lipogenesis and lipolysis is controversial, as these steroids appear to both enhance and reduce obesity. As lipid synthesis is a critical part of early development, we hypothesized that both MR and GR contribute to lipid regulation by GCs during postnatal growth. Using MR and GR knockout zebrafish, we demonstrate that MR activation, but not GR activation, is involved in triglyceride (TG) accumulation during the larval development post feeding. Lack of MRs did not affect the gene expression of fatty acid synthase (fas), or acyl-CoA:diacylglycerol acyltransferase 2 (dgat2), but increased lipoprotein lipase (lpl) transcript abundance. Activation of GR with exogenous cortisol decreased TG levels and increased lpl mRNA levels, but these responses require the presence of MR. Larval transcriptome revealed that MR was the primary regulator of genes involved in lipid synthesis, while GR activation favoured lipid catabolism. Our results underscore a key role for MR activation in mediating postnatal lipid accumulation, as well as cooperatively regulating GR-mediated lipolysis during postnatal stress., (© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.)

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Adequate amounts of physical activity, sleep, and screen time along with a healthy diet have been demonstrated to have positive associations with academic achievement. No longitudinal study has investigated the simultaneous relationship between all of these behaviours and academic achievement. Data from 11,016 adolescent participants of the COMPASS study in Alberta and Ontario were analysed. Students self-reported their adherence to Canadian recommendations for health behaviours and academic achievement in Math and English on school-based surveys administered in the 2015/16 and 2016/17 waves of COMPASS. Multinomial generalized estimating equations were used to evaluate the association between longitudinal changes in adherence to recommendations and academic achievement at follow-up. Models were adjusted for self-reported sociodemographic information, body weight status, and baseline academic achievement. Students who adhered to a greater number of recommendations performed better than students who adhered to fewer recommendations. Meeting recommendations for Meat and Alternatives (protein-rich foods) and screen time were consistently associated with higher academic achievement compared to students who did not meet these recommendations. A change from not meeting recommendations for Vegetables and Fruit to meeting the recommendation in the following year was associated with higher achievement in both subjects. There was no association between sleep behaviours or physical activity and academic achievement. Results indicate that adherence to recommendations for protein-rich foods, screen time, and vegetables and fruit show promise as behavioural targets for higher academic achievement among youth. Further study using objectives measurements of behaviours and further consideration of socioeconomic variables is merited., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To examine health care costs in diverse older Medicare beneficiaries with epilepsy., Methods: Using 2008-2010 claims data, we conducted a longitudinal cohort study of a random sample of Medicare beneficiaries augmented for minority representation. Epilepsy cases (n = 36 912) had ≥1 International Classification of Diseases, Ninth Edition (ICD-9) 345.x or ≥2 ICD-9 780.3x claims, and ≥1 antiepileptic drug (AED) in 2009; new cases (n = 3706) had no seizure/epilepsy claims nor AEDs in the previous 365 days. Costs were measured by reimbursements for all care received. High cost was defined as follow-up 1-year cost ≥ 75th percentile. Logistic regressions examined association of high cost with race/ethnicity, adjusting for demographic, clinical, economic, and treatment quality factors. In cases with continuous 2-year data, we obtained costs in two 6-month periods before and two after the index event., Results: Cohort was ~62% African Americans (AAs), 11% Hispanics, 5% Asians, and 2% American Indian/Alaska Natives. Mean costs in the follow-up were ~$30 000 (median = $11 547; new cases, mean = $44 642; median = $25 008). About 19% white compared to 27% AA cases had high cost. AA had higher odds of high cost in adjusted analyses (odds ratio [OR] = 1.20, 95% confidence interval [CI] = 1.11-1.29), although this was only marginally significant when adjusting for AED adherence (OR = 1.09, 95% CI = 1.01-1.18, P = 0.03). Factors associated with high cost included ≥1 comorbidity, neurological care, and low AED adherence. Costs were highest at ~$17 000 in the 6 months immediately before and after the index event (>$29 000 for new cases)., Significance: The financial sequelae of epilepsy among older Americans disproportionally affect minorities. Studies should examine contributors to high costs., (Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.)

Importance: Limited population-based data are available on antiepileptic drug (AED) treatment patterns in women of childbearing age with epilepsy; the current population risk is not clear., Objectives: To examine the AED treatment patterns and identify differences in use of valproate sodium and topiramate by comorbidities among women of childbearing age with epilepsy., Design, Setting, and Participants: A retrospective cohort study used a nationwide commercial database and supplemental Medicare as well as Medicaid insurance claims data to identify 46 767 women with epilepsy aged 15 to 44 years. The eligible study cohort was enrolled between January 1, 2009, and December 31, 2013. Data analysis was conducted from January 1, 2017, to February 22, 2018., Exposures: Cases required an International Classification of Diseases, Ninth Revision, Clinical Modification-coded epilepsy diagnosis with continuous medical and pharmacy enrollment. Incident cases required a baseline of 2 or more years without an epilepsy diagnosis or AED prescription before the index date. For both incident and prevalent cases, focal and generalized epilepsy cohorts were matched by age, payer type, and enrollment period and then compared., Main Outcomes and Measures: Antiepileptic drug treatment pattern according to seizure type and comorbidities., Results: Of the 46 767 patients identified, there were 8003 incident cases (mean [SD] age, 27.3 [9.4] years) and 38 764 prevalent cases (mean [SD] age, 29.7 [9.0] years). Among 3219 women in the incident epilepsy group who received AEDs for 90 days or more, 3173 (98.6%) received monotherapy as first-line treatment; among 28 239 treated prevalent cases, 18 987 (67.2%) received monotherapy. In 3544 (44.3%) incident cases and 9480 (24.5%) prevalent cases, AED treatment was not documented during 180 days or more of follow-up after diagnosis. Valproate (incident: 35 [5.81%]; prevalent: 514 [13.1%]) and phenytoin (incident: 33 [5.48%]; prevalent: 178 [4.53%]) were more commonly used for generalized epilepsy and oxcarbazepine (incident: 53 [8.03%]; prevalent: 386 [9.89%]) was more often used for focal epilepsy. Levetiracetam (incident: focal, 267 [40.5%]; generalized, 271 [45.0%]; prevalent: focal, 794 [20.3%]; generalized, 871 [22.2%]), lamotrigine (incident: focal, 123 [18.6%]; generalized, 106 [17.6%]; prevalent: focal, 968 [24.8%]; generalized, 871 [22.2%]), and topiramate (incident: focal, 102 [15.5%]; generalized, 64 [10.6%]; prevalent: focal, 499 [12.8%]; generalized, 470 [12.0%]) were leading AEDs prescribed for both focal and generalized epilepsy. Valproate was more commonly prescribed for women with comorbid headache or migraine (incident: 53 of 1251 [4.2%]; prevalent: 839 of 8046 [10.4%]), mood disorder (incident: 63 of 860 [7.3%]; prevalent: 1110 of 6995 [15.9%]), and anxiety and dissociative disorders (incident: 57 of 881 [6.5%]; prevalent: 798 of 5912 [13.5%]). Topiramate was more likely prescribed for those with comorbid headache or migraine (incident: 335 of 1251 [26.8%]; prevalent: 2322 of 8046 [28.9%])., Conclusions and Relevance: Many women appear to be treated with valproate and topiramate despite known teratogenicity risks. Comorbidities may affect selecting certain AEDs despite their teratogenicity risks.

Chronic stress and the associated elevation in corticosteroid levels increase muscle protein catabolism. We hypothesized that the glucocorticoid receptor (GR)-regulated restriction of muscle glucose availability may play a role in the increased protein catabolism during chronic stress. To test this, we generated a ubiquitous GR knockout (GRKO) zebrafish to determine the physiological consequence of glucocorticoid stimulation on muscle metabolism and growth. Adult GRKO zebrafish had higher body mass, and this corresponded to an increased protein and lipid, but not carbohydrate, content. GRKO fish were hypercortisolemic, but they elicited a higher cortisol response to an acute stressor. However, the stressor-induced increase in plasma glucose level observed in the wild type was completely abolished in the GRKO fish. Also, the muscle, but not liver, capacity for glucose uptake was enhanced in the GRKO fish, and this corresponded with a higher hexokinase activity in the mutants. Zebrafish lacking GR also showed a higher capacity for protein synthesis, including increased phosphorylation of eukaryotic initiation factor 4B, higher expression of heat shock protein cognate 70, and total protein content. A chronic fasting stressor reduced body mass and muscle protein content in adult zebrafish, but this decrease was attenuated in the GRKO compared with the wild-type fish. Metabolomics analysis revealed that the free pool of amino acid substrates used for oxidation and gluconeogenesis were lower in the fasted GRKO fish muscle compared with the wild type. Altogether, chronic stressor-mediated GR signaling limits muscle glucose uptake, and this may play a role in protein catabolism, leading to the growth suppression in fish.

Objective: To estimate the treatment gap between a new epilepsy diagnosis and antiepileptic drug (AED) initiation in the United States., Methods: Retrospective claims-based cohort study using Truven Health MarketScan databases (commercial and supplemental Medicare, calendar years 2010-2015; Medicaid, 2010-2014) and a validation study using PharMetrics Plus Database linked to LRx claims database (2009-2014). Persons met epilepsy diagnostic criteria, had an index date (first epilepsy diagnosis) with a preceding 2-year baseline (1 year for persons aged 1 to <2 years; none for persons <1 year), and continuous medical and pharmacy enrollment without epilepsy/seizure diagnosis or AED prescription during baseline. Outcomes included percentage of untreated persons (no AED prescription) up to 3 years' follow-up and comparative outcomes (incidence rate ratio: untreated persons/treated persons), including medical events and health care resource utilization., Results: In the primary study, 59,970 persons met selection (or inclusion) criteria; 36.7% of persons with newly diagnosed epilepsy remained untreated up to 3 years after diagnosis. In the validation study (N = 30,890), 31.8% of persons remained untreated up to 3 years after diagnosis. Lack of AED treatment was associated with an adjusted incidence rate ratio (95% confidence interval) of 1.2 (1.2-1.3) for medical events, 2.3 (2.2-2.3) for hospitalizations, and 2.8 (2.7-2.9) for emergency department visits., Conclusions: One-third of newly diagnosed persons remain untreated up to 3 years after epilepsy diagnosis. The increased risk of medical events and health care utilization highlights the consequences of delayed treatment after epilepsy diagnosis, which might be preventable., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)