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This study identified CYP2C variants, including CYP2C9*3, known to reduce drug clearance, as important genetic factors associated with phenytoin-related severe cutaneous adverse reactions.

Summary:Purpose: The anterior nucleus of the thalamus (ANT) modulates temporal lobe and hypothalamic activities, and relays information to the cingulate gyrus and entorhinal cortex. Deep brain stimulation (DBS) of the ANT has been reported to decrease seizure activity in a limited number of human subjects. However, long-term effect of chronic ANT stimulation on such patients remains unknown. We report long-term follow-up results in four patients receiving ANT stimulation for intractable epilepsy.Methods: Four patients underwent stereotactic implantation of quadripolar stimulating electrodes in the bilateral ANT, guided by single-unit microelectrode recording. Electrode location was confirmed by postoperative magnetic resonance imaging (MRI). The stimulator was activated 2-4 weeks following electrode insertion; initial stimulation parameters were 4-5 V, 90-110 Hz, and 60-90 µs. Seizure frequency was monitored and compared with preimplantation baseline frequency. Intelligence quotient (IQ) test and auditory P300 response were performed before and after implantation of electrodes.Results: Four patients (one man with generalized seizures, and three women with partial seizures and secondary generalization) aged 18-45 years old were studied with mean followup period of 43.8 months. The four patients demonstrated a sustained effect of 49% (range, 35-76%) seizure reduction to ANT stimulation. Simple insertion of DBS electrodes (Sham period, no stimulation) produced a mean reduction in seizures of 67% (range, 44-94%). One patient was seizure-free for 15 months with anticonvulsant medications. One patient had a small frontal hemorrhage and a second patient had extension erosion over scalp; no resultant major or permanent neurological deficit was observed. Preoperative IQ index and auditory P300 were not significantly different with those after electrodes implantation.Conclusions: Implantation of electrodes in the ANT and subsequent stimulation is associated with a significant reduction in seizure frequency. However, our study could not differentiate whether the implantation itself, the subsequent stimulation or postimplantation drug manipulation had the greatest impact. These experimental results prompt further controlled study in a large patient population.

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Our findings suggest that HLA-B*15:02 is significantly associated with OXC-SJS in Asian populations (Chinese and Thai). However, the severity and incidence of OXC-SJS/TEN are less than that of CBZ-SJS/TEN. The need for preemptive HLA-B*15:02 screening should be evaluated further.

We present and evaluate a large-scale malware detection system integrating machine learning with expert reviewers, treating reviewers as a limited labeling resource. We demonstrate that even in small numbers, reviewers can vastly improve the system's ability to keep pace with evolving threats. We conduct our evaluation on a sample of VirusTotal submissions spanning 2.5 years and containing 1.1 million binaries with 778GB of raw feature data. Without reviewer assistance, we achieve 72% detection at a 0.5% false positive rate, performing comparable to the best vendors on VirusTotal. Given a budget of 80 accurate reviews daily, we improve detection to 89% and are able to detect 42% of malicious binaries undetected upon initial submission to VirusTotal. Additionally, we identify a previously unnoticed temporal inconsistency in the labeling of training datasets. We compare the impact of training labels obtained at the same time training data is first seen with training labels obtained months later. We find that using training labels obtained well after samples appear, and thus unavailable in practice for current training data, inflates measured detection by almost 20 percentage points. We release our cluster-based implementation, as well as a list of all hashes in our evaluation and 3% of our entire dataset.

The PERaMpanel pooled analysIs of effecTiveness and tolerability (PERMIT) study was a pooled analysis of data from 44 real-world studies from 17 countries, in which people with epilepsy (PWE; focal and generalized) were treated with perampanel (PER). Retention and effectiveness were assessed after 3, 6, and 12 months, and at the last visit (last observation carried forward). Effectiveness assessments included 50% responder rate (≥ 50% reduction in seizure frequency from baseline) and seizure freedom rate (no seizures since at least the prior visit); in PWE with status epilepticus, response was defined as seizures under control. Safety and tolerability were assessed by evaluating adverse events (AEs) and discontinuation due to AEs. The Full Analysis Set included 5193 PWE. Retention, effectiveness and safety/tolerability were assessed in 4721, 4392 and 4617, respectively. Retention on PER treatment at 3, 6, and 12 months was 90.5%, 79.8%, and 64.2%, respectively. Mean retention time on PER treatment was 10.8 months. The 50% responder rate was 58.3% at 12 months and 50.0% at the last visit, and the corresponding seizure freedom rates were 23.2% and 20.5%, respectively; 52.7% of PWE with status epilepticus responded to PER treatment. Overall, 49.9% of PWE reported AEs and the most frequently reported AEs (≥ 5% of PWE) were dizziness/vertigo (15.2%), somnolence (10.6%), irritability (8.4%), and behavioral disorders (5.4%). At 12 months, 17.6% of PWEs had discontinued due to AEs. PERMIT demonstrated that PER is effective and generally well tolerated when used to treat people with focal and/or generalized epilepsy in everyday clinical practice.

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