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SummaryObjectivePharmacokinetics (PK) of a drug drive its exposure, efficacy, and tolerability. A thorough preclinical PK assessment of antiseizure medications (ASMs) is therefore essential to evaluate the clinical potential. We tested protection against evoked seizures of prototype ASMs in conjunction with analysis of plasma and brain PK as a proof-of-principle study to enhance our understanding of drug efficacy and duration of action using rodent seizure models.MethodsIn vivo seizure protection assays were performed in adult male CF-1 mice and Sprague-Dawley rats. Clobazam (CLB), N-desmethylclobzam (NCLB), carbamazepine (CBZ), carbamazepine-10,11-epoxide (CBZE), valproic acid (VPA), and levetiracetam (LEV) concentrations were quantified in plasma and brain using liquid chromatography-tandem mass spectrometry. Mean concentrations of each analyte were calculated and used to determine PK parameters via non-compartmental analysis in Phoenix WinNonLin.ResultsNCLB concentrations were approximately 10-fold greater than CLB in mice. The antiseizure profile of CLB was partially sustained by NCLB in mice. CLB concentrations were lower in rats than in mice. CBZE plasma exposures were approximately 70% of CBZ in both mice and rats, likely contributing to the antiseizure effect of CBZ. VPA showed a relatively short half-life in both mice and rats, which correlated with a sharp decline in efficacy. LEV had a prolonged brain and plasma half-life, associated with a prolonged duration of action in mice.SignificanceThe study demonstrates the utility of PK analyses for understanding the seizure protection time-course in mice and rats. The data indicate that distinct PK profiles of ASMs between mice and rats likely drive differences in drug efficacy between rodent models.Key PointsThere exist potential contributions of active metabolites to the efficacy of some ASMs.The utility of preclinical PK assessment of ASM is critical to guide our insight into a drug efficacy profile and provide a framework for subchronic dosing strategies.Species-specific variations in PK profiles of ASMs in rodent models of epilepsy may underpin the differences in antiseizure effect in these models.Pre-clinical drug screening of ASMs should include a (sub)chronic dosing paradigm to better mimic the dosing regimen in the clinic.

BACKGROUND: Employment is associated with greater quality of life (QOL) for people with disabilities. Yet, for individuals with traumatic brain injury (TBI), the benefits of work are not often realized given high rates of unemployment. OBJECTIVE: This study examined the unique impact of psychosocial variables and employment status (working vs. not working) on self-reported QOL among adults with TBI. METHODS: Participants included 116 adults with TBI between the ages of 18-65, recruited through state brain injury associations in the United States to complete an anonymous online survey. Hierarchical regression analysis was used to examine the incremental impact of psychosocial variables (sense of community, social support, social network, and problem-solving confidence) and employment status on QOL controlling for age and symptom severity. RESULTS: In the final model, employment status, informal and formal support network ties, problem-solving confidence, sense of community, and emotional support explained 59% of the variance in QOL, which is considered a large effect size. Employment status uniquely explained 5% of the variance in QOL. CONCLUSIONS: Findings support the positive benefits of work for adults with TBI. Rehabilitation services that emphasize vocational considerations and employment supports are needed to impact work status and ultimately QOL for individuals with TBI.

Objective Infection with Theiler's Murine Encephalomyelitis Virus (TMEV) in C57Bl/6J mice results in handling-induced seizures and is useful for evaluating compounds effective against infection-induced seizures. However, to date only a few compounds have been evaluated in this model, and a comprehensive study of antiseizure medications (ASMs) has not yet been performed. Furthermore, as the TMEV infection produces marked neuroinflammation, an evaluation of prototype anti-inflammatory compounds is needed as well. Methods Male C57Bl/6J mice were inoculated with TMEV (day 0) followed by daily administrations of test compounds (day 3-7) and subsequent handling sessions (day 3-7). Doses of ASMs, comprising several mechanistic classes, were selected based on previously published data demonstrating the effect of these compounds in reducing seizures in the 6 Hz model of pharmacoresistant seizures. Doses of anti-inflammatory compounds, comprising several mechanistic classes, were selected based on published evidence of reduction of inflammation or inflammation-related endpoints. Results Several prototype ASMs reduced acute seizures following TMEV infection: lacosamide, phenytoin, ezogabine, phenobarbital, tiagabine, gabapentin, levetiracetam, topiramate, and sodium valproate. Of these, phenobarbital and sodium valproate had the greatest effect (>95% seizure burden reduction). Prototype anti-inflammatory drugs celecoxib, dexamethasone, and prednisone also moderately reduced seizure burden. Significance The TMEV model is utilized by the Epilepsy Therapy Screening Program (ETSP) as a tool for evaluation of novel compounds. Compounds reducing seizures in the TMEV comprise distinct mechanistic classes, some with mechanisms of action that extend beyond traditional ASMs.

Highlights • NURTURE is an ongoing study of nusinersen started in a presymptomatic stage of SMA. • All infants were ≥25 months old, and alive without permanent ventilation. • All infants achieved independent sitting and 88% (22/25) were walking alone. • Nusinersen demonstrated durability of effect with a median 2.9 years of follow up. • Nusinersen was well tolerated with no new safety concerns over extended follow up., Spinal muscular atrophy (SMA) is a neurodegenerative disease associated with severe muscle atrophy and weakness in the limbs and trunk. We report interim efficacy and safety outcomes as of March 29, 2019 in 25 children with genetically diagnosed SMA who first received nusinersen in infancy while presymptomatic in the ongoing Phase 2, multisite, open-label, single-arm NURTURE trial. Fifteen children have two SMN2 copies and 10 have three SMN2 copies. At last visit, children were median (range) 34.8 [25.7–45.4] months of age and past the expected age of symptom onset for SMA Types I or II; all were alive and none required tracheostomy or permanent ventilation. Four (16%) participants with two SMN2 copies utilized respiratory support for ≥6 h/day for ≥7 consecutive days that was initiated during acute, reversible illnesses. All 25 participants achieved the ability to sit without support, 23/25 (92%) achieved walking with assistance, and 22/25 (88%) achieved walking independently. Eight infants had adverse events considered possibly related to nusinersen by the study investigators. These results, representing a median 2.9 years of follow up, emphasize the importance of proactive treatment with nusinersen immediately after establishing the genetic diagnosis of SMA in presymptomatic infants and emerging newborn screening efforts.

Dravet syndrome (DS) is a rare childhood epilepsy disorder resulting in spontaneous, recurrent seizures (SRS) and behavioral co-morbidities. To facilitate the discovery and development of anti-seizure drugs for DS, the contract site of the NINDS Epilepsy Therapy Screening Program (ETSP) has continued to evaluate a mouse model of DS. Scn1aA1783V/WT mice exhibited increased hyperactivity, thigmotaxis, and deficits in nest-building behavior. Ex-vivo brain slice electrophysiology experiments revealed increased excitability of hippocampal CA1 neurons specifically due to increased action potential firing frequency in response to brief depolarizations and decreased frequency of spontaneous GABAergic synaptic events. A video-EEG study revealed mice had on average, 1 seizure per day, with males seizing significantly more frequently than females. Increased proportion of seizure activity occurred during the dark phase of the light/dark cycle in both sexes. While clobazam, a drug commonly prescribed to patients with DS, had no effect on SRS activity at the tested doses, the seizure history and frequency observed in this study aids in determining the sample sizes and experimental timeline needed for adequately powered preclinical drug studies. Overall, this study provides a broad description of the Scn1aA1783V/WT mouse and highlights the utility of this model in therapy discovery.

SummaryObjectiveDravet syndrome (DS) is a rare, but catastrophic genetic epilepsy, with 80% of patients with carrying a mutation in the SCN1A gene. Currently, no anti-seizure drug (ASD) exists that adequately controls seizures. Patients with DS often present clinically with a febrile seizure and generalized tonic-clonic seizures that continue throughout life. To facilitate the development of ASDs for DS, the contract site of the NINDS Epilepsy Therapy Screening Program (ETSP) has evaluated a mouse model of DS using the conditional knock-in Scn1aA1783V/WT mouse.MethodsSurvival rates and temperature thresholds for Scn1aA1783V/WT were determined. Prototype ASDs were administered via intraperitoneal injections at the time-to-peak effect, which was previously determined, prior to the induction of hyperthermia-induced seizures. Protection was determined if ASDs significantly increased the temperature at which Scn1aA1783V/WT mice seized.ResultsApproximately 50% of Scn1aA1783V/WT survive to adulthood and all have hyperthermia-induce seizures. The results suggest that hyperthermia-induced seizures in this model of DS are highly refractory to a battery of ASDs. Exceptions were clobazam, tiagabine, and the combination of clobazam and valproic acid with add-on stiripentol, which elevated seizure thresholdsSignificanceOverall, the data demonstrate the proposed model for DS is suitable for screening novel compounds for the ability to block hyperthermia-induced seizures and heterozygous mice can be evaluated repeatedly over the course of several weeks, allowing for higher throughput screening.Key PointsScn1aA1783V/WT mice have a 50% survival rate and all have hyperthermia-induced seizures.Common DS treatments such as CLB and combinatorial therapy of CLB, VPA, and STP increase temperature thresholds in Scn1aA1783V/WT mice.Sodium channel blockers, such as CBZ and LTG, decrease temperature thresholds of Scn1aA1783V/WT mice as predicted.Scn1aA1783V/WT mice are highly pharmacoresitant to common ASDsThe Scn1aA1783V/WT may be a useful preclinical drug screening platform for the treatment of DS.

Immigrants enrich the United States through economic contributions and unique perspectives. Immigrants find themselves navigating a new culture, a complicated health care system, unfamiliar social programs, and an ever-changing policy environment. They may be discouraged by unmet expectations of life in the United States, changing family dynamics, and discrimination. Screening for the social determinants of health is crucial, as not all patients will proactively seek the advice of their health care provider for these issues. Health care providers can assist and empower immigrants to navigate these challenges, as well as serve as advocates on a broader scale.

What explains subnational policy choices over tax cut after decentralization? We test two different explanations in the context of the 2002 tax reform in Russia. A popular strand of literature suggests that decentralization induces more regional competition over investment, motivating subnational tax cuts. A second body of literature suggests that personal business interests of regional governors can account for their different policy choices. Governors with personal business ties refrain from tax cuts because they increase market competition. We find no support for the regional competition hypothesis, but strong statistical evidence for the business connection hypothesis. Our findings have important implications for research on fiscal decentralization and on the connections between business interests of leaders and their policy choices.

Do states use trade to reward and punish partners? WTO rules and the pressures of globalization restrict states’ capacity to manipulate trade policies, but we argue that governments can link political goals with economic outcomes using less direct avenues of influence over firm behavior. Where governments intervene in markets, politicization of trade is likely to occur. In this paper, we examine one important form of government control: state ownership of firms. Taking China and India as examples, we use bilateral trade data by firm ownership type, as well as measures of bilateral political relations based on diplomatic events and UN voting to estimate the effect of political relations on import and export flows. Our results support the hypothesis that imports controlled by state-owned enterprises (SOEs) exhibit stronger responsiveness to political relations than imports controlled by private enterprises. A more nuanced picture emerges for exports; while India’s exports through SOEs are more responsive to political tensions than its flows through private entities, the opposite is true for China. This research holds broader implications for how we should think about the relationship between political and economic relations going forward, especially as a number of countries with partially state-controlled economies gain strength in the global economy.

Objective The lamotrigine‐resistant amygdala kindling model uses repeated administration of a low dose of lamotrigine during the kindling process to produce resistance to lamotrigine, which also extends to some other antiseizure drugs (ASDs). This model of pharmacoresistant epilepsy has been incorporated into the testing scheme utilized by the Epilepsy Therapy Screening Program (ETSP). Although some ASDs have been evaluated in this model, a comprehensive evaluation of ASD prototypes has not been reported. Methods Following depth electrode implantation and recovery, rats were exposed to lamotrigine (5 mg/kg, i.p.) prior to each stimulation during the kindling development process (~3 weeks). A test dose of lamotrigine was used to confirm that fully kindled rats were lamotrigine‐resistant. Efficacy (unambiguous protection against electrically elicited convulsive seizures) was defined as a Racine score

It is a worldwide challenge to detect planet gear bore-rim cracking using vibration data analytics, especially for large helicopters like the Airbus Super Puma that has experienced two fatal accidents since 2009 due to planet gear bore-rim cracking. For helicopter safety, it is of vital importance to equip helicopter vibration health monitoring systems with the capability of detecting and monitoring the progression of planet gear bore-rim cracking. When a crack reaches sufficient size in the rim of the gear, the weakening stiffness caused by the crack allows the planet gear teeth near the crack to distort as they come into and out of mesh, resulting in vibration impacts. A key challenge for detecting a planet gear bore-rim crack lies in isolating these impacts from the dominating gear mesh harmonics. In this paper, we propose a method of vibration data analytics based on enhanced planet gear time synchronous averaging (EP-TSA). The method takes advantage of visualizing the impacts from planet-ring and planet-sun gear meshes over the planet-ring hunting tooth period of the planetary gear system. We firstly process the raw vibration signal using time-synchronous averaging with respect to the relative rotation of the planet gear over a number of hunting tooth periods. The method employs a novel resampling scheme, termed boosted synchronous resampling scheme (BSRS), which facilitates simultaneous removal of multiple shaft and gear mesh harmonics and their intermodulation components using the spectrum of the averaged signal in order to derive a residual signal. By construction, the BSRS facilitates three-dimensional (3-D) plotting of the squared envelope of the residual signal, comprising multiple individual revolutions of the planet gear over the hunting tooth period. With crack-induced impacts visualized in 3-D, we can identify those planet gear revolutions where the crack-induced impacts are in close proximity to the vibration transducer to obtain a final feature signal reflecting the characteristics of the bore-rim cracking. We call the final feature signal the enhanced planet residual signals (EPRS), which is those individual residual signals at the selected planet gear revolutions with the largest kurtoses above a certain threshold. Where possible we should look at multiple planet gear revolutions to reinforce the detection of vibration impacts. Lastly, we confirm the detection of planet gear bore-rim cracking by the consistent pattern of two spikes in each planet revolution that are associated with the planet-ring and planet-sun gear meshes. The method is validated using vibration data generated from a small industrial planetary gearbox with simulated cracks inserted in the bore-rim from one side of a planet gear. The results show that the BSRS can be very effective in removing multiple sets of shaft harmonics and their intermodulation sidebands. We have demonstrated that the visualization tool can provide strong evidence of the crack-induced impacts. In comparison to other methods our results have shown that we can detect the planet gear bore-rim crack more effectively using the enhanced planet time synchronous averaging method.

Ethics and professionalism standards are essential components of health and welfare training programs, yet data on effective ethics training methods remain elusive. We studied two different delivery methods of ethics education in the Gynecology and Obstetrics rotation of medical school: case-based instructor-facilitated discussion only and case-based discussion following student-led presentations. This paper describes results of the focus group we held with student participants from both methods. Students participated in a mixed 1-hour focus group. The focus group moderator transcribed the meeting, which became the data for the analysis. The research team analyzed the data using grounded theory. Two themes emerged from the data: (1) the ways in which students progressed in their ability to identify and assess ethical questions and (2) the degree to which students were engaged with the course material, peers, and facilitators. In addition, two main categories emerged from overlap among the codes identified...

The successful identification of promising investigational therapies for the treatment of epilepsy can be credited to the use of numerous animal models of seizure and epilepsy for over 80 years. In this time, the maximal electroshock test in mice and rats, the subcutaneous pentylenetetrazol test in mice and rats, and more recently the 6 Hz assay in mice, have been utilized as primary models of electrically or chemically-evoked seizures in neurologically intact rodents. In addition, rodent kindling models, in which chronic network hyperexcitability has developed, have been used to identify new agents. It is clear that this traditional screening approach has greatly expanded the number of marketed drugs available to manage the symptomatic seizures associated with epilepsy. In spite of the numerous antiseizure drugs (ASDs) on the market today, the fact remains that nearly 30% of patients are resistant to these currently available medications. To address this unmet medical need, the National Institute of Neurological Disorders and Stroke (NINDS) Epilepsy Therapy Screening Program (ETSP) revised its approach to the early evaluation of investigational agents for the treatment of epilepsy in 2015 to include a focus on preclinical approaches to model pharmacoresistant seizures. This present report highlights the in vivo and in vitro findings associated with the initial pharmacological validation of this testing approach using a number of mechanistically diverse, commercially available antiseizure drugs, as well as several probe compounds that are of potential mechanistic interest to the clinical management of epilepsy.

IntroductionOpicinumab is a human monoclonal antibody against LINGO-1, a negative regulator of oligodendrocyte differentiation and axonal regeneration. The phase 2 SYNERGY study identified a patient subpopulation with a potentially enhanced response to opicinumab treatment.MethodsAFFINITY (NCT03222973) is an ongoing, randomised, double-blind, placebo-controlled phase 2 study to evaluate the efficacy/safety of opicinumab vs placebo as an add-on to disease-modifying therapies in a targeted population. Inclusion criteria include: age 18–58; relapsing multiple sclerosis (MS) with ≤20-year duration; Expanded Disability Status Scale (EDSS) score 2.0–6.0; evidence of disease activity within 24 months prior to enrolment; brain MRI criteria suggestive of low myelin content but preserved tissue integrity in pre-existing T2 lesions; stably treated ≥24 weeks with interferon-beta, dimethyl fumarate, or natalizumab. Primary endpoint is the multicomponent Overall Response Score (based on EDSS, Timed 25-Foot Walk, and 9-Hole Peg Test). Secondary endpoints will evaluate confirmed improvement in disability measures.ResultsEnrolment began in September 2017 and was completed in September 2018. Participant baseline demographic, disease, and MRI characteristics will be presented.ConclusionsAFFINITY will further investigate the efficacy and safety of opicinumab in a subpopulation of MS patients.Support: Biogen. Disclosures to be included on poster.

Do states use trade to reward and punish partners? WTO rules and the pressures of globalization restrict states’ capacity to manipulate trade policies, but we argue that governments can link political goals with economic outcomes using less direct avenues of influence over firm behavior. Where governments intervene in markets, politicization of trade is likely to occur. In this paper, we examine one important form of government control: state ownership of firms. Taking China and India as examples, we use bilateral trade data by firm ownership type, as well as measures of bilateral political relations based on diplomatic events and UN voting to estimate the effect of political relations on import and export flows. Our results support the hypothesis that imports controlled by state-owned enterprises (SOEs) exhibit stronger responsiveness to political relations than imports controlled by private enterprises. A more nuanced picture emerges for exports; while India’s exports through SOEs are more responsive to political tensions than its flows through private entities, the opposite is true for China. This research holds broader implications for how we should think about the relationship between political and economic relations going forward, especially as a number of countries with partially state-controlled economies gain strength in the global economy.

This study examined the ways in which depression affects immigrant Latina women residing in an emerging Latino immigrant community in the United States. Three Spanish-language focus groups were conducted within a community-based participatory research framework. Latina women expressed concerns about their immigration status, separation from family in their native countries, and about finances and inabilities to meet family obligations. They expressed fears for their children in the United States. Their sociopolitical, economic, and familial explanations for depression differ from the individual, biological explanations of depression common today. Implications for policymakers, community organizers, health care providers, public health educators, and school counselors are presented.

Severe self-injurious behavior in a boy with severe mental retardation and autistic disorder was successfully treated with a behavioral treatment package following a trial of naltrexone to reduce self-injurious behavior. The subject was a 7-year-old boy who was hospitalized for self-injurious behavior, aggression, and a reported increased irritability. During baseline assessment, the subject was physically and verbally interrupted and redirected whenever he engaged in self-injurious behavior. During the first treatment phase, pediatric “no-no” splints were applied and systematic splint fading began. In addition, differential reinforcement of other behaviors (DRO) and a brief hand restraint were implemented. In the second treatment phase, naltrexone was administered with the continued use of systematic point fading, DRO and brief hand restraint. The third treatment phase consisted of a placebo trial and the same behavioral treatment. In the final phase, restraint fading continued and reinforcement was faded to a variable interval (VI)-3 minute schedule, as well as the use of brief hand restraint. This treatment package was effective in reducing this boy’s severe self-injurious behavior to zero upon discharge from the hospital. Follow-up data from the school indicated continued success with the use of the brief contingent hand restraint as well as reinforcement delivered on a VI-3 min schedule.

A 13-year-old boy with attention-deficit hyperactivity disorder and conduct disorder developed manic symptoms during a trial of fluoxetine. A prior methylphenidate trial had failed, and induced irritable and dysphoric effects at 0.5 mg/kg daily. In view of the mood symptoms, a trial of tricyclic antidepressants was recommended, but the family rejected the recommendation and preferred a trial of fluoxetine. Fluoxetine was initiated at 5 mg daily and increased at weekly intervals by 5 mg. The symptoms of ADHD were not improving, but no adverse effects were attributed to the medication. After 2 days on fluoxetine 20 mg, clear-cut symptoms of mania emerged. The manic symptoms did not subside after discontinuation of fluoxetine, but were controlled by lithium and carbamazepine. The manic symptoms returned when these medications were discontinued by the family, and were again controlled when lithium was reinstituted. The episode fulfilled DSM-III-R criteria for nonpsychotic mania. By history, this patient had not experienced a depressive, hypomanic, or manic episode prior to treatment with fluoxetine. Retrospectively, it appears that the patient began to show evidence of hypomania or mania during the second week of fluoxetine treatment while on 10 mg daily. It is recommended that clinicians be alert to the possibility of a manic switch appearing during fluoxetine treatment, even at low doses of medication.

This Public Policy Brief presents analysis of the labor market by economic research staff at the Federal Reserve Bank of Boston. It is based on materials originally presented to the Board of Directors of the Boston Fed on April 8, 2004, with selective updates incorporating data reported in early June. Contributors to this brief include David DeRemer, Jeffrey C. Fuhrer, Kristina Johnson, Jane Sneddon Little, Radoslav Raykov, Scott Schuh, Geoffrey M.B. Tootell, Robert Triest, and Anne van Grondelle. Views expressed in this brief do not necessarily reflect the views of the Federal Reserve System.

In Beijing, 64 percent of families rate owning a car above owning a home. But can they afford either one?

In a clinical trial, 20 children and adolescents with developmental disorders (age range 8 through 17 years) refractory to previous psychotropic treatments were administered the atypical neuroleptic risperidone (dose range 1.5 to 10 mg/day). In a follow-up period ranging from 8 to 15 months, risperidone demonstrated clinical efficacy in 13 children. Twelve patients were free of side effects and two had minor ones. Three patients had marked weight increase, and galactorrhea developed in two adolescent girls. In this open study, risperidone was associated with clinical improvement. However, controlled studies are needed to determine its relative efficacy and safety in this special population.

The practical limit on the storage capacity of photorefractive media is estimated for a given bit error rate and read out bandwidth.