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Background and ObjectiveTo characterize trends in antiseizure medication (ASM) fills and total prescription costs in people with epilepsy.MethodsThis was a retrospective cohort study of beneficiaries with epilepsy (ASM, plus ICD codes) in a 20% random Medicare sample, with continuous Fee-For-Service coverage (Parts A, B, and D) in 2008–2018. We summed the number of pill days and costs (adjusted to 2018 dollars) per person-year for each ASM. ASMs were categorized into brand vs generic, first vs newer generation, and enzyme inducers vs noninducers.ResultsThere were 77,000–133,000 beneficiaries with epilepsy per year. The most common ASM was phenytoin in 2008, which shifted to levetiracetam in 2018 (2008: phenytoin 25%, levetiracetam 14%; 2018: phenytoin 9%, levetiracetam 27%). Brand name (2008: 56%; 2018: 14%), first-generation (2008: 55%; 2018: 32%), and enzyme-inducing ASMs (2008: 44%; 2018: 24%) each decreased over time as a proportion of pill days. The number of brand pill days per person-year initially decreased (e.g., 2008: 250; 2009: 121; 2010: 96) but then plateaued (2013–2018: between 66 and 69) given a notable increase in lacosamide pill days per person (2008: 0; 2018: 20). Total brand name costs per year initially decreased 2008–2010 (2008: $150 million; 2010: $72 million) but then increased after 2010 (2018: $256 million). In 2018, brand name ASMs represented 79% of costs despite representing only 14% of pill days, a 1-year pill supply became 277% more expensive for brand name medications but 42% less expensive for generic medications over time (2008: brand ∼$2,800 vs generic ∼$800; 2018: brand ∼$10,700 vs generic ∼$460), and many common brand name ASMs cost approximately 10-fold more per pill day than their generic equivalents.DiscussionFirst-generation and enzyme-inducing ASMs waned from 2008 to 2018. Although brand name ASMs initially waned translating into lower costs and potentially higher value care, after 2010, brand name costs markedly increased because of increasing use of lacosamide plus a 277% increase in per-pill cost of brand name ASMs. Brand name ASMs represented a minority of prescriptions, but the majority of costs.

Solution-processed transparent conductive oxides offer the advantages of low-cost, high-throughput fabrication of electronic devices compared to the specific requirements of vacuum deposition techniques. However, adapting the current state of the art to ink deposition calls for optimization of the precursor ink composition and the postdeposition process. Solution processing of indium tin oxide films can be accomplished at reduced temperatures (250-400 °C) by annealing soluble precursor metal salts together with a fuel/oxidizer, causing an exothermic reaction with elevated local temperatures. Following layer-by-layer cycles of deposition and annealing, a postprocessing step is required via heating (300 °C) under a 5% H

Supplementary Data from HYD1-induced increase in reactive oxygen species leads to autophagy and necrotic cell death in multiple myeloma cells

HYD1 is a D–amino acid peptide that was previously shown to inhibit adhesion of prostate cancer cells to the extracellular matrix. In this study, we show that in addition to inhibiting adhesion of multiple myeloma (MM) cells to fibronectin, HYD1 induces cell death in MM cells as a single agent. HYD1-induced cell death was necrotic in nature as shown by: (a) decrease in mitochondrial membrane potential (Δψm), (b) loss of total cellular ATP, and (c) increase in reactive oxygen species (ROS) production. Moreover, HYD1 treatment does not result in apoptotic cell death because it did not trigger the activation of caspases or the release of apoptosis-inducing factor and endonuclease G from the mitochondria, nor did it induce double-stranded DNA breaks. HYD1 did initiate autophagy in cells; however, autophagy was found to be an adaptive response contributing to cell survival rather than the cause of cell death. We were further able to show that N-acetyl-L-cysteine, a thiol-containing free radical scavenger, partially protects MM cells from HYD1-induced death. Additionally, N-acetyl-L-cysteine blocked HYD1-induced as well as basal levels of autophagy, suggesting that ROS can potentially trigger both cell death and cell survival pathways. Taken together, our data describe an important role of ROS in HYD1-induced necrotic cell death in MM cells. [Mol Cancer Ther 2009;8(8):2441–51]

Background and ObjectivesAlthough moderate and severe traumatic brain injury (TBI) can cause posttraumatic epilepsy (PTE), many patients with functional seizures (FS) also report a history of mild TBI. To determine whether features of TBI history differ between patients with epileptic seizures (ES) and FS, we compared patient reports of TBI severity, symptoms, and causes of injury.MethodsWe recruited patients undergoing video-EEG evaluation for the diagnosis of ES, FS, mixed ES and FS, or physiologic seizure-like events at an academic, tertiary referral center. Patients and their caregivers were interviewed before final video-EEG diagnosis regarding their TBI histories, including concussive symptoms and causes of injury.ResultsOf 506 patients, a greater percentage of patients with FS reported a history of TBI than patients with ES (70% vs 59%, aOR = 1.75 [95% CI: 1.00–3.05],p= 0.047). TBI with loss of consciousness (LOC) lasting less than 30 minutes was more frequently reported among patients with FS than with ES (27% vs 13%, aOR = 2.38 [1.26–4.47],p< 0.01). The proportion of patients reporting other neurologic symptoms immediately after TBI was not significantly different between FS and ES (40% vs 29%,p= 0.08). Causes of TBI were found to differ, with TBIs caused by falls from a height (17% vs 10%, aOR = 2.24 [1.06–4.70],p= 0.03) or motor vehicle collisions (27% vs 11%, aOR = 2.96 [1.54–5.67],p< 0.01) reported more frequently in FS than ES.DiscussionOur findings further the association of mild TBI with FS and prompt reconsideration of typical assumptions regarding the significance of a reported TBI history in patients with previously undifferentiated seizures. Although common in both groups, TBI with LOC less than 30 minutes and causes of injury that are commonly believed to be more severe were reported more frequently in FS than ES. This suggests that a patient or caregiver reporting of these features does not imply that PTE is a more probable diagnosis than FS. Although a history of TBI with LOC and presumed high-risk causes of injury intuitively raises suspicion for PTE, clinicians should be cautioned that these historical factors also were a frequent finding in patients with FS.

BackgroundChoosing candidates for antiseizure medication (ASM) withdrawal in well- controlled epilepsy is challenging. We evaluated 1) the correlation between neurologists’ seizure risk estimation (“clinician predictions”) versus calculated predictions, 2) how viewing calculated predictions influenced recommendations, and 3) barriers to using risk calculation.MethodsWe asked neurologists to predict two-year seizure risk after ASM withdrawal for hypothetical vignettes. We compared withdrawal recommendations ASMs before versus after viewing calculated predictions using generalized linear models.ResultsThree-hundred forty-six responded. There was moderate correlation between clinician and calculated predictions (Spearman coefficient 0.42). Clinician predictions varied widely, e.g., predictions ranged 5%-100% for a two-year seizure-free adult without epileptiform abnormalities. Mean clinician predictions exceeded calculated predictions for vignettes with epileptiform abnormalities (e.g., childhood absence epilepsy: clinician 65%, 95% confidence interval [CI] 57%-74%; calculated 46%) and surgical vignettes (e.g., focal cortical dysplasia six-months seizure-free mean clinician 56%, 95% CI 52%-60%; calculated 28%). Clinicians overestimated the influence of epileptiform EEG findings on withdrawal risk (26%, 95% CI 24%-28%) compared with calculators (14%, 95% 13%-14%). Viewing calculated predictions slightly reduced willingness to withdraw (−0.8/10 change, 95% CI -1.0 to -0.7), particularly without epileptiform abnormalities. The greatest barrier to calculator use was doubting its accuracy (44%).ConclusionsClinicians overestimated the influence of abnormal EEGs particularly for low-risk patients and overestimated risk and the influence of seizure-free duration for surgical patients, compared with calculators. These data may question widespread ordering of EEGs or time-based seizure-free thresholds for surgical patients. Viewing calculated predictions reduced willingness to withdraw particularly without epileptiform abnormalities.What is already known on this topicFor the two-thirds of patients with epilepsy who become seizure-free on antiseizure medications (ASMs), a key question is whether ASMs are necessary indefinitely after attaining seizure-freedom. An individualized post-withdrawal seizure risk calculator exists,[1,2] which has demonstrated moderate external validity, and one 1993 study suggested that viewing results from an older version of such a calculator slightly reduced patients’ willingness to withdraw.What this study addsBefore our study, it was unknown how closely clinicians’ intuitive estimates of post-withdrawal seizure risk (“clinician predictions”) align with model (“calculated”) predictions, and no study had previously evaluated the influence of viewing calculated risk on clinician recommendations. We found 1) moderate correlation between clinician and calculated predictions (Spearman coefficient 0.42), 2) clinician predictions and recommendations varied widely, 3) clinicians tended to overestimate risk compared with calculators for vignettes with epileptiform abnormalities and surgical cases, 4) viewing calculated predictions slightly reduced willingness to withdraw particularly without epileptiform abnormalities, and 5) the greatest endorsed barrier to calculator use was doubting its accuracy.How this study might affect research, practice or policyOur study suggests patient scenarios in which viewing calculator results may be most useful or be most likely to change clinical practice. These data may also question widespread ordering of EEGs or time-based seizure-free thresholds for surgical patients given calculated risk differences were smaller than clinician predictions. We also provide preliminary data guiding future work to improve calculator implementation such as targeting educational efforts to improve knowledge of its development, improving its accuracy, and integrating it into the electronic medical record.

biBackground:/i/bThe spread of emerging tick-borne pathogens has steadily increased in Canada with the widespread establishment of tick vectors and vertebrate hosts. At present,iBorrelia burgdorferi/i, the bacterium causing Lyme disease, is the most common tick-borne pathogen in Canada and primarily transmitted byiIxodes scapularis/i. A low prevalence of other emerging tick-borne pathogens, such asiAnaplasma phagocytophilum/i,iBabesia/ispecies,iBorrelia miyamotoi/i, andiFrancisella tularensis/ihave also been detected through surveillance efforts in Canada. AlthoughiRickettsia rickettsii/ihas been historically detected iniHaemaphysalis leporispalustris/iin Canada, the current prevalence and geographic extent of this pathogen is unknown.biMaterial and Methods:/i/bIn this study, we assessed the presence and prevalence of several emerging tick-borne pathogens in ticks and hosts collected through tick dragging and small mammal trapping in Central Canada.biResults:/i/bNested PCR testing detected three pathogen species in ticks, withiBabesia odocoilei/iandiB. burgdorferi/iiniI. scapularis/iin addition toiR. rickettsii/iiniH. leporispalustris/i. Three pathogen species were detected in small mammals by nested PCR includingiB. odocoilei/iiniBlarina brevicauda/i,iBabesia microti/iiniPeromyscus leucopus/i, and aiHepatozoon/ispecies iniP. leucopus/iandiPeromyscus maniculatus/i.iB. burgdorferi/iandiBabesia/ispecies were the pathogens most often detected in our samples, suggesting they are widely distributed across Central Canada. We also detectediB. odocoilei/iandiR. rickettsii/ibeyond their known geographic distribution.biConclusions:/i/bOur results provide evidence that emerging tick-borne pathogens may be present outside defined risk areas identified by current surveillance efforts in Canada. As a result, emerging tick-borne pathogens introduced by the dispersal of infected ticks by migratory birds or maintained by hosts and vectors through cryptic transmission cycles may go undetected. More comprehensive testing including all tick life stages and additional tick-borne pathogens will help detect the spread and potential risk of emerging or re-emerging tick-borne pathogens for human and wildlife populations throughout Canada.

To evaluate the exploratory time to exceed pre-randomization seizure count (T-PSC) in the determination of efficacy of adjunctive perampanel in participants with primary generalized tonic-clonic (PGTC) seizures in generalized-onset epilepsy.In this multicenter, double-blind study (ClinicalTrials.gov identifier: NCT01393743), participants ≥12 years of age with treatment-resistant idiopathic generalized epilepsy were randomized to receive placebo or adjunctive perampanel (≤8 mg/day) across a 17-week double-blind treatment phase (4-week titration; 13-week maintenance). We evaluated the pre-planned exploratory end point of the T-PSC using a Kaplan-Meier analysis. We also re-evaluated the correspondence of the primary end points of median percent seizure frequency change (MPC) and 50% responder rate (50RR) calculated at T-PSC and at the end of the trial.The exploratory end point of median T-PSC on placebo was 43 days and120 days on perampanel (log-rank p .001). The primary end points calculated at T-PSC did not differ significantly from the end points at the end of the trial (MPC -31% vs -42% at T-PSC; 50RR 32% vs 51% at T-PSC). After T-PSC was reached, participants had a median (interquartile range) of 5 (3-13) additional seizures on placebo and 5 (2-10) on perampanel.The exploratory end point of T-PSC demonstrated the effectiveness of perampanel despite a shorter duration of monitoring. The seizures that occurred after T-PSC did not influence the conclusions of the trial; therefore, T-PSC may be a viable alternative to traditional trial end points that reduces the risk to participants.

Health Education England (HEE) is responsible for educating and training the health workforce in England, ensuring the workforce has the right numbers, skills, values, and behaviours to support patients. This includes developing a multi-professional dental care workforce able to meet the needs of current and future service requirements. The recognised challenge will be to train and develop clinicians to address the changing needs concomitant with the population demographics.

OBJECTIVES Since 2000, medical treatment for epilepsy and cardiovascular risk-reduction strategies have advanced significantly in the United States (US). However, seizure-free rates remain unchanged, and people with epilepsy are at higher risk than the general population for heart disease and stroke. The purpose of this study is to determine how cardiovascular, epilepsy-related, and other causes of death are changing in epilepsy in comparison with the US population. MATERIALS & METHODS Changes in the 15 underlying causes of death in epilepsy (ICD-10 G40-G40.9) and the US population were analyzed and compared from 2000 to 2018. The CDC multiple cause-of-death database was utilized as the primary data source. Changes in the relative proportions for each cause-of-death over were evaluated using logistic regression. RESULTS The proportions of deaths in epilepsy due to heart disease declined 34.4% (p

To prioritize areas for conservation, biologists and managers need information on species diversity in threatened habitats. The resources available for such inventories remain severely limited, increasing the need to develop speedier ways to estimate the status of target habitats. We present a study of the use of such techniques in the highly fragmented oak savannas of southern Ontario, including selection of indicator taxa, use of rapid biodiversity assessment based on morphospecies, and analysis of community structure. We found that butterflies and skippers can be used to predict richness among Hymenoptera in the study sites, which is consistent with the hypothesis that these easily surveyed Lepidoptera are good candidates for indicator status. Richness values for hymenoptera morphospecies in these savanna remnants were strongly correlated with species richness scores as estimated by systematists, although nonspecialists tended to “split” species into more than one morphospecies. Finally, both the Hymenoptera and Lepidoptera communities in these oak savannas exhibited a high degree of nestedness, suggesting that local extinctions, mostly undocumented, are important determinants of the richness patterns across these widely separated savanna study sites. We found no evidence of significant spatial autocorrelation, probably because of the wide separation of study sites. Resumen: Para priorizar areas para la conservacion, los biologos y manejadores necesitan informacion sobre la diversidad de especies en habitats amenazados. La disponibilidad de recursos para llevar a cabo tales inventarios es aun muy limitada, incrementando la necesidad de desarrollar formas rapidas de estimar la situacion de los habitats que son objeto del estudio. Presentamos un estudio sobre el uso de estas tecnicas en las sabanas altamente fragmentadas de robles del sur de Ontario, incluyendo la seleccion de taxones indicadores, el uso de evaluaciones rapidas de la biodiversidad basadas en morfoespecies y un analisis de la estructura comunitaria. Encontramos que las mariposas y saltadores pueden ser usados como predictores de la riqueza entre himenopteros en los sitios de estudio, lo cual es consecuente con la hipotesis de que estos lepidopteros facilmente muestreables son buenos candidatos para ser considerados indicadores. Los valores de la riqueza de morfoespecies de himenopteros para estos remanentes de sabana estuvieron fuertemente correlacionados con datos de riqueza de especies estimados por sistematistas, a pesar de que los sistematistas tienden a “dividir” especies en mas de una morfoespecie. Finalmente, tanto las comunidades de himenopteros como de lepidopteros de estas sabanas de robles exhibieron un nivel alto de anidamiento, sugiriendo que las extinciones locales, mayormente no documentadas, son determinantes importantes de los patrones de riqueza a lo largo de estos sitios de estudio de sabana ampliamente separados. No encontramos evidencia de una autocorrelacion espacial significativa, probablemente debido a la amplia separacion entre sitios de estudio.

Toe joints play an important functional role in able-bodied walking; however, for prosthesis users, the effect of adding a toe joint to a passive prosthetic foot remains largely unknown. The current study explores the kinematics, kinetics, rate of oxygen consumption and user preference of nine individuals with below-knee limb loss. Participants walked on a passive prosthetic foot in two configurations: with a Flexible, articulating toe joint and with a Locked-out toe joint. During level treadmill gait, participants exhibited a decrease in Push-Off work when using the Flexible toe joint prosthesis versus the Locked toe joint prosthesis: 16% less from the prosthesis (p = 0.004) and 10% less at the center of mass level (p = 0.039). However, between configurations, participants exhibited little change in other gait kinematics or kinetics, and no apparent or consistent difference in the rate of oxygen consumption (p = 0.097). None of the traditional biomechanical or metabolic outcomes seemed to explain user preference. However, an unexpected and intriguing observation was that all participants who wore the prosthesis on their dominant limb preferred the Flexible toe joint, and every other participant preferred the Locked configuration. Although perhaps coincidental, such findings may suggest a potential link between user preference and limb dominance, offering an interesting avenue for future research.

Environmental decision-makers and practitioners need and deserve high-quality environmental evidence for effective decision-making. We collate and share a suite of best practices for applied environmental researchers to support their capacity to inform such decision-making processes. This raises a number of important questions: What does “relevant” and informative evidence look like? How do we know when evidence has been applied? We assembled an experienced team of knowledge generators and users in Canada to identify insights that have emerged from their work and that could serve as guideposts for others who seek to apply environmental research to policy challenges. By reflecting on successes and failures, we define “success” in applied environmental science as respectfully conducted, partner-relevant research that is accessible, understandable, and shared and that can create opportunities for change (e.g., in policy, behaviour, management). Next, we generated a list of best practices for delivering “successful” applied environmental research. Our guidance emphasizes the importance of engaging early and often, in a respectful manner, with partners, generating high-quality, relevant research (which requires flexibility), having a plan for communicating and sharing outputs, and being transparent about uncertainties and limitations. Other important considerations include acknowledging partners for involvement and training early career researchers in applied partnership research. Finally, we generated a list of specific, measurable indicators for evaluating success, including quality and quantity of scientific outputs, the relationship with the partner(s), relevance and connectedness of the research, accessibility and availability of outputs to users, provision of outputs that are digestible and usable by different audiences, training and capacity building, and ultimate outcomes (e.g., including social, environmental, and economic outcomes, as well as partner satisfaction). We encourage those embarking on applied environmental research to consider embracing the strategies, to continuously reflect on progress toward shared research goals, and to be flexible. Doing so will increase the likelihood of delivering research that is “successful” and in doing so contribute to overcoming and addressing environmental issues and problems.

Objective The 1991 Medical Research Council (MRC) Study compared seizure relapse for seizure-free patients randomized to withdraw vs continue of antiseizure medications (ASMs). We re-analyzed this trial to account for crossover between arms using contamination-adjusted intention to treat (CA ITT) methods, to explore dose-response curves, and to validate predictions against external data. ITT assesses the effect of being randomized to withdraw, as-treated analysis assesses the confounded effect of withdrawing, but CA ITT assesses the unconfounded effect of actually withdrawing. Methods CA ITT involves two stages. First, we used randomized arm to predict whether patients withdrew their ASM (logistic) or total daily ASM dose (linear). Second, we used those values to predict seizure occurrence (logistic). Results The trial randomized 503 patients to withdraw and 501 patients to continue ASMs. We found that 316 of 376 patients (88%) who were randomized to withdraw decreased their dose at every pre-seizure visit, compared with 35 of 424 (8%) who were randomized to continue (p < .01). Adjusted odds ratios of a 2-year seizure for those who withdrew vs those who did not was 1.3 (95% confidence interval [CI] 0.9–1.9) in the as-treated analysis, 2.5 (95% CI 1.9–3.4) comparing those randomized to withdraw vs continue for ITT, and 3.1 (95% CI 2.1–4.5) for CA ITT. Probabilities (withdrawal vs continue) were 28% vs 24% (as-treated), 40% vs 22% (ITT), and 43% vs 21% (CA ITT). Differences between ITT and CA ITT were greater when varying the predictor (reaching zero ASMs) or outcome (1-year seizures). As-treated dose-response curves demonstrated little to no effects, but larger effects in CA ITT analysis. MRC data overpredicted risk in Lossius data, with moderate discrimination (areas under the curve ~0.70). Significance CA ITT results (the effect of actually withdrawing ASMs on seizures) were slightly greater than ITT effects (the effect of recommend withdrawing ASMs on seizures). How these findings affect clinical practice must be individualized.

The impact of multitrophic interactions on metacommunity structure, despite extensive theory and modeling/manipulative studies, has remained largely unexplored within naturally occurring metacommunities. We investigated the impacts of mutualistic partners and predators on a butterfly metacommunity, as well as the impacts that local and landscape characteristics have across three trophic levels: flowering plants, butterflies, and butterfly predators. Using data for butterfly diversity/richness, flowering plant diversity/richness, and butterfly predation (on clay butterfly models) across 15 grassland sites, we posed 3 questions. (1) How do mutualist metacommunity structure, predation pressure, and local and regional habitat characteristics affect butterfly metacommunity structure? (2) How do local and regional habitat characteristics affect flowering plant metacommunity structure? (3) How do local and regional habitat characteristics affect predation pressure? Floral diversity and richness had a positive effect on butterfly diversity and richness (Question 1). Site size positively affected floral diversity and richness (Question 2), and through this relationship site size had an indirect positive effect on butterfly diversity and richness (Question 1). In contrast to previous work, no other variables impacted butterfly diversity/richness. This result was particularly surprising for predation pressure: Our results suggest that within our study system, butterfly community diversity and richness are not strongly impacted by predation. Predator attacks occurred more in larger and more isolated sites (Question 3), suggesting that predators respond more strongly to landscape characteristics than abundance or diversity of butterfly prey species. This decoupling of predation pressure and butterfly communities suggests that conserving and restoring healthy predator populations may not negatively impact butterfly communities. If diverse plant communities are maintained, even small and isolated habitat patches can be valuable for butterfly conservation, which may influence reserve design and habitat restoration strategies.