Feline Epilepsy: An Update

Millions of users share their experiences, thoughts, and interests online, through social media sites (e.g., Twitter, Flickr, YouTube). As a result, these sites host a substantial number of user-contributed documents (e.g., textual messages, photographs, videos) for a wide variety of events (e.g., concerts, political demonstrations, earthquakes). In this dissertation, we present techniques for leveraging the wealth of available social media documents to identify and characterize events of different types and scale. By automatically identifying and characterizing events and their associated user-contributed social media documents, we can ultimately offer substantial improvements in browsing and search quality for event content. To understand the types of events that exist in social media, we first characterize a large set of events using their associated social media documents. Specifically, we develop a taxonomy of events in social media, identify important dimensions along which they can be categorized, and determine the key distinguishing features that can be derived from their associated documents. We quantitatively examine the computed features for different categories of events, and establish that significant differences can be detected across categories. Importantly, we observe differences between events and other non-event content that exists in social media. We use these observations to inform our event identification techniques. To identify events in social media, we follow two possible scenarios. In one scenario, we do not have any information about the events that are re ected in the data. In this scenario, we use an online clustering framework to identify these unknown events and their associated social media documents. To distinguish between event and non-event content, we develop event classification techniques that rely on a rich family of aggregate cluster statistics, including temporal, social, topical, and platform-centric characteristics. In addition, to tailor the clustering framework to the social media domain, we develop similarity metric learning techniques for social media documents, exploiting the variety of document context features, both textual and non-textual. In our alternative event identification scenario, the events of interest are known, through user-contributed event aggregation platforms (e.g., Last.fm events, EventBrite, Facebook events). In this scenario, we can identify social media documents for the known events by exploiting known event features, such as the event title, venue, and time. While this event information is generally helpful and easy to collect, it is often noisy and ambiguous. To address this challenge, we develop query formulation strategies for retrieving event content on different social media sites. Specifically, we propose a two-step query formulation approach, with a first step that uses highly specific queries aimed at achieving high-precision results, and a second step that builds on these high-precision results, using term extraction and frequency analysis, with the goal of improving recall. Importantly, we demonstrate how event-related documents from one social media site can be used to enhance the identification of documents for the event on another social media site, thus contributing to the diversity of information that we identify. The number of social media documents that our techniques identify for each event is potentially large. To avoid overwhelming users with unmanageable volumes of event information, we design techniques for selecting a subset of documents from the total number of documents that we identify for each event. Specifically, we aim to select high-quality, relevant documents that re ect useful event information. For this content selection task, we experiment with several centrality-based techniques that consider the similarity of each event-related document to the central theme of its associated event and to other social media documents that correspond to the same event. We then evaluate both the relative and overall user satisfaction with the selected social media documents for each event. The existing tools to find and organize social media event content are extremely limited. This dissertation presents robust ways to organize and filter this noisy but powerful event information. With our event identification, characterization, and content selection techniques, we provide new opportunities for exploring and interacting with a diverse set of social media documents that re ect timely and revealing event content. Overall, the work presented in this dissertation provides an essential methodology for organizing social media documents that re ect event information, towards improved browsing and search for social media event data.

Is Tolerance to Antiepileptic Drugs Clinically Relevant?

There are established drugs for the treatment of status epilepticus (SE) but their potentially hazardous side-effects are well known. Levetiracetam (LEV) is a novel anticonvulsant available for intravenous (i.v.) application. It could be an alternative when standard drugs fail or should be avoided. We retrospectively identified patients from two German teaching hospitals who were treated with LEV i.v. for SE. Their charts were reviewed regarding sociodemographic data, type, etiology, onset and duration of SE, dose of LEV, concurrent antiepileptic drugs (AED) treatment, tolerability, and outcome. Thirty-two patients (15 female) were found who were treated with i.v. LEV for SE (median age 71 years). Two patients were exclusively treated with LEV. Eight received a low and further 20 patients a high dose of benzodiazepines before LEV. Two patients were treated with LEV to enable discontinuation of narcosis. SE was generalized convulsive in five, nonconvulsive in 20, and simple focal in seven patients. Etiology was acute 13 times and remote symptomatic 16 times; three SE were of unknown etiology. Therapy was initiated within a median time of 3 h and LEV i.v. was applied within a median time of 6 h. Median LEV bolus was 2,000 mg; median total dose on day 1 was 3,500 mg. Benzodiazepines plus i.v. LEV terminated SE in 23 patients without application of additional anticonvulsants, 10 within 30 min. LEV could not terminate SE in seven patients. We documented nausea and emesis in one and elevation of liver enzymes in another patient that were likely to be attributed to LEV. LEV i.v. seems to be safe with relevant efficiency for the treatment of SE in elderly and multimorbid patients when comorbidity and respiratory insufficiency precludes high doses of benzodiazepines or phenytoin.

Background: Most of the hard outcomes in epilepsy can be avoided by controlling seizures with the continued use of antiepileptic drugs (AEDs). Some of these medications are distributed through the Specialized Component of Pharmaceutical Assistance (CEAF). Most states currently offer 8 drugs for the treatment of epilepsy: Primidone (PRM), Clobazam (CLB), Vigabatrin (VGB), Ethosuximide (ESM), Gabapentin (GBP), Lamotrigine (LTG), Topiramate (TPM) and Levetiracetam (LEV). Objective: To analyze the distribution of AEDs made available by CEAF and identify drugs with the highest tendency to be prescribed for each type of crisis. Methods: A retrospective study was conducted using data recorded in the SIA available by DATASUS regarding AEDs distributed by the CEAF since its creation in 2009. The analysis was performed using regression for each drug according to the subdivision into groups for the best indication of each AED: Drugs with action on generalized crises (LGT and PMS), focal (GBP and LEV), absence (ESM), and refractory (PRM, CBZ, GBV). Results: Over the 14 years of CEAF activity, the most distributed AED was LTG (33%), followed by GBP (30%), and TPM (23%). Except for VGB (APC: -20.6; CI95%: -32.6 to -7.2; p<0.005), all drugs showed an increasing distribution trend at the end of the study period. Although LEV was identified as the AED with the highest trend, more samples are needed to achieve statistical significance (APC: 729%; p=0.15). Considering the groups, LTG was the main choice for generalized crises (60%), with a change in trend in 2017 (APC 14.2; 95%CI: 10.6 to 25.7; p<0.001). ESM was the only drug evaluated in the absence group, with a trend change in 2012 (APC: 15; 95%CI: 10.6 to 19.5; p<0.001). Although LTG also has an effect on this type of crisis, it was placed in the group of generalized crises because of its higher prevalence. In the focal seizure group, the most widely distributed drug was GBP, with two points of change: 2012 (APC: 51.7; 95%CI 42.7 to 66.5; p<0.001) and 2016 (APC 19.4; CI95%: 14.8 to 23; p<0.001). It is important to highlight that LEV was included in the program only in 2016, and that GBP has a wide distribution because it is also effective in the treatment of neuropathic pain. In the refractoriness group, VGB and PRM maintained their stationery trends, whereas CBZ was the most distributed drug, with trend modification in 2012 (APC: 15.8; 95%CI: 12.5 to 18.1; p<0.001), although it is important to note that CBZ is also prescribed as a pure anxiolytic. Conclusion: Although there is an overlap of drug indications in the context of type of epilepsy, when separating groups according to their main indication, we found that LTG is the most distributed AED. LTG was also the most frequent option for generalized seizures, while ESM was the most prescribed for absence seizures, GBP among AEDs for focal seizures, and CBZ in the refractoriness group. Except for VGB, all the drugs showed an increasing distribution trend.

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 events in folding can determine if a protein is going to fold, misfold, or aggregate. Understanding these deterministic events is paramount for de novo protein engineering, the enhancement of biopharmaceutical stabilities, and understanding neurodegenerative diseases including amyotrophic lateral sclerosis and Alzheimer's disease. However, the physicochemical and structural biases within high energy states of protein biopolymers are poorly understood. A combined experimental and computational study was conducted on the small β/α-repeat protein CheY to determine the structural basis of its submillisecond misfolding reaction to an off-pathway intermediate. Using permutations, we were able to discriminate between the roles of two proposed mechanisms of folding; a nucleation condensation model, and a hydrophobic collapse model driven by the formation of clusters of isoleucine, leucine, and valine (ILV) residues. We found that by altering the ILV cluster connectivity we could bias the early folding events to either favor on or off-pathway intermediates. Structural biases were also experimentally observed in the unfolded state of a de novo designed synthetic β/α-repeat protein, Di-III_14. Although thermodynamically and kinetically 2-state, Di-III_14 has a well structured unfolded state that is only observable under native-favoring conditions. This unfolded state appears to retain native-like structure, consisting of a hydrophobic 7 core (69% ILV) stabilized by solvent exposed polar groups and long range electrostatic interactions. Together, these results suggest that early folding events are largely deterministic in these two systems. Generally, low contact order ILV clusters favor local compaction and, in specific cases, long range electrostatic interactions may have stabilizing effects in higher energy states.

PURPOSE Levetiracetam (LEV) is a new antiepileptic drug which is increasingly being used intravenously as acute therapy for epileptic seizures and status epilepticus. Due to its minimal adverse events and the lack of a hepatic metabolism it is a suitable alternative in the emergency treatment of elderly patients. This study examines the tolerability and pharmacokinetics of fast intravenous infusions of LEV with elderly epileptic patients. PATIENTS AND METHODS Thirteen patients with a mean age of 72 years were treated with LEV IV for acute epileptic seizures or status epilepticus. 2000 mg were given within a period of 15 or 5 minutes. The LEV level was determined within 30 to 60 minutes after administration as well as 6, 12 and 24 hours later. Level of consciousness, respiration and cardiovascular functions were monitored. RESULTS 30 to 60 minutes following administration the mean plasma level of LEV was 48 mg/L; after 6, 12 and 24 hours 31, 20 and 17 mg/L, respectively. Eight out of the thirteen patients showed a cessation of ictal activity among which five were definitely responders to LEV. Alterations in the level of consciousness, respiration and cardiovascular functions did not occur. CONCLUSION 2000 mg LEV IV can be given to elderly and multimorbid patients within a period of 5 - 15 minutes without experiencing major adverse events. With this infusion rate plasma concentrations are > 40 mg/L immediately after infusion and 24 hours later > 10 mg/L. For half of the patients with status epilepticus LEV was an effective antiepileptic drug.

Cluster tools play an important role in the semiconductor fabrication industry. Optimization of an individual cluster tool maximizes productivity of mass fabrication. Optimizing the scheduler results in increased throughput. The cluster tool is a real-time, dynamic environment in which different parts interact. That is why it is necessary to have a dynamic scheduler that makes its decisions online and within an acceptable computation time in the presence of unexpected sporadic events. Our contribution is to develop and implement a scheduler for a cluster tool. Attributes of the scheduler are predictive, periodic and dynamic to satisfy real-time characteristics of the cluster tool. The major characteristic of the scheduler is that it is optimized to produce high throughput and low complexity, i.e. time to schedule as overhead. First steady-state and transient-state of the cluster tool are analyzed. Then different scheduling algorithms are experimented with and compared. As the results of experiments demonstrate, throughput is optimized in steady-state and transient-state of the scheduler with low overhead.

BackgroundClobazam (CLB) is a well characterized antiepileptic drug (AED) that differs from other benzodiazepines by its basic chemical structure and pharmacodynamic properties. Only one previous study examined the efficacy of CLB as add-on therapy in refractory status epilepticus (RSE).MethodsWe analyzed RSE episodes treated in our institution between 2001 and 2012. Successful treatment with CLB was scored if CLB was the last AED added to therapy before RSE termination. We assessed the differences between patients with and without CLB and correlated CLB with outcome. Among patients treated with CLB, we studied responders and non-responders and compared our CLB cohort with recently published data.ResultsCLB was part of the AED regimen in 24/70 (34.3 %) RSE episodes. In six of these (25.0 %) RSE resolution was attributed to CLB. Baseline characteristics of episodes with and without CLB treatment showed no significant differences and RSE termination rates were very similar (83.3 % vs. 80.4 %). CLB was administered in clinically more complex RSE with longer RSE duration and worse outcome, but CLB was not related independently to outcome. Comparison of our results with previously published data revealed that baseline characteristics as well as CLB maintenance doses and time of treatment initiation were similar in both cohorts. CLB was less frequently the last AED added to RSE therapy in our patients indicating a lower treatment success rate than previously reported.ConclusionsCLB represents a reasonable AED and promising add-on agent for treatment of RSE. However, rates of successful CLB response were substantially lower than in a recently published study. Differing RSE characteristics and treatment strategies may account for the discrepancy between study results, as RSE etiologies and seizures types associated with unfavorable prognosis were more common in our cohort, while anesthetics tended to be less frequently applied to achieve seizure control.

In the current study, methods and techniques of Biostatistics were used, to evaluate the efficacy and safety of the antiepileptic drug, Brivaracetam in epilepsy patients. This is a multicenter, retrospective study and the data was based on medical questionnaires filled by the treating physician. Firstly, a descriptive and graphic analysis of all variables was conducted, in order to collect essential information that will complete the findings of the statistical inference. We used contingency tables to determine the association between the response variables (efficacy, safety) and other variables. Finally, we evaluate the existence of predictive variables for the efficacy and safety of Brivaracetam, using generalized linear models. At the end of the study, we aim to find robust evidence that Brivaracetam affects the reduction of the seizure frequency, without patients reporting adverse events, especially serious adverse events. For all analyses IBM SPSS Statistics, Version 25.0 and R Programming Language were used.

The pharmacokinetics of brivaracetam (BRV), added to its effectiveness observed in animal models of status epilepticus (SE), makes this drug attractive for use in emergency situations. Our objective was to evaluate the use of intravenous BRV in a multicenter study. A retrospective multicenter registry of SE cases treated with BRV was created. These patients were evaluated between January and December 2018 at seven hospitals in Spain. Demographic variables, SE characteristics, concomitant drugs, loading doses, and response to treatment were collected. Forty-three patients were registered. The mean age was 56±23.1years, 51.2% were male, 29 had previous epilepsy, 24 (55.8%) had prominent motor symptoms, and 19 had nonconvulsive symptoms. Regarding the etiology, 19 (44.2%) were considered acute symptomatic, 16 (17.2%) remote symptomatic, four (9.3%) progressive symptomatic, and four (9.3%) cryptogenic. Regarding concomitant antiepileptic drugs (AEDs), 17 had previously received levetiracetam (LEV). In 14 patients, BRV was used early (first or second AED). The median loading dose was 100mg (range = 50-400), and the weight-adjusted dose was 1.8mg/kg (range = 0.4-7.3). BRV was effective in 54% (n=23), and a response was observed in <6hours in 13 patients. We observed a tendency for it to be more effective when administered earlier (P=0.09), but there were no differences regarding SE type and the concomitant use of LEV. In those with the fastest responses, we observed that both the total administered dose (300mg vs 100mg, P=0.008) and the weight-adjusted dose (3.85mg vs 1.43mg, P=0.006) were significantly higher. The receiver operating characteristic curve showed that the best cutoff point for a faster response was 1.82mg/kg. BRV is useful for the treatment of SE, even when patients are already being treated with LEV. The response rate seems higher when it is administered earlier and at higher doses (>1.82mg/kg).

Error handling in multimodal voice-enabled interfaces of tour-guide robots using graphical models

Psychiatric and behavioral side effects of anti-epileptic drugs in adolescents and children with epilepsy.

Objective To understand the incidences of adverse reactions on cognition, language, and bone metabolism related to 8 commonly used antiepileptic drugs in China using SIDER database. Methods The integrated incidences of adverse reactions on cognition, language, and bone metabolism related to 8 commonly used antiepileptic drugs (carbamazepine, oxcarbazepine, valproate, clonazepam, lamotrigine, levetiracetam, topiramate, and zonisamide) marketed in China was searched in the SIDER database. Results The main drugs that affected cognition were topiramate and valproate. The incidences of memory impairment caused by topiramate and abnormal thinking related to valproate were 1.2%-10.8% and 6.0%, respectively. Topiramate was the main drug that affected language. The incidences of dysarthria and speech disorder caused by topiramate were 1.6%-6.2% and 1.0%-16.8%, respectively. The main antiepileptic drugs that affected bone metabolism were carbamazepine, oxcarbazepine, and valproate. But there was no incidence information because of the limited small amount of literature reports after marketing. Conclusions The results of data analysis in this database indicate that different antiepileptic drugs have different effects on cognitive function, language function and bone metabolism, and the frequency of adverse reactions is different. The clinical use of antiepileptic drugs needs to weigh the advantages and disadvantages according to the specific situation of patients. Key words: Drug-related side effects and adverse reactions; Epilepsy; Anticonvulsants; Cognition; Language; Osteoporosis; Fractures, bone

Subjective handicap in people with epilepsy in Georgia and Turkey