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During the first hours after stroke onset, neurological deficits can be highly unstable: some patients rapidly improve, while others deteriorate. This early neurological instability has a major impact on long-term outcome. Here, we aimed to determine the genetic architecture of early neurological instability measured by the difference between the National Institutes of Health Stroke Scale (NIHSS) within 6 h of stroke onset and NIHSS at 24 h. A total of 5876 individuals from seven countries (Spain, Finland, Poland, USA, Costa Rica, Mexico and Korea) were studied using a multi-ancestry meta-analyses. We found that 8.7% of NIHSS at 24 h of variance was explained by common genetic variations, and also that early neurological instability has a different genetic architecture from that of stroke risk. Eight loci (1p21.1, 1q42.2, 2p25.1, 2q31.2, 2q33.3, 5q33.2, 7p21.2 and 13q31.1) were genome-wide significant and explained 1.8% of the variability suggesting that additional variants influence early change in neurological deficits. We used functional genomics and bioinformatic annotation to identify the genes driving the association from each locus. Expression quantitative trait loci mapping and summary data-based Mendelian randomization indicate that ADAM23 (log Bayes factor = 5.41) was driving the association for 2q33.3. Gene-based analyses suggested that GRIA1 (log Bayes factor = 5.19), which is predominantly expressed in the brain, is the gene driving the association for the 5q33.2 locus. These analyses also nominated GNPAT (log Bayes factor = 7.64) ABCB5 (log Bayes factor = 5.97) for the 1p21.1 and 7p21.1 loci. Human brain single-nuclei RNA-sequencing indicates that the gene expression of ADAM23 and GRIA1 is enriched in neurons. ADAM23, a presynaptic protein and GRIA1, a protein subunit of the AMPA receptor, are part of a synaptic protein complex that modulates neuronal excitability. These data provide the first genetic evidence in humans that excitotoxicity may contribute to early neurological instability after acute ischaemic stroke., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The cost associated with incorporating standardized observational assessments and diagnostic interviews in large-scale epidemiologic studies of autism spectrum disorders (ASD) risk factors can be substantial. Streamlined approaches for confirming ASD case status would benefit these studies. We conducted a multi-site, cross-sectional criterion validity study in a convenience sample of 382 three-year olds scheduled for neurodevelopmental evaluation. ASD case classification as determined by three novel assessment instruments (the Early Video-guided Autism Screener E-VAS; the Autism Symptom Interview, ASI; the Screening Tool for Autism in Toddlers Expanded, STAT-E) each designed to be administered in less than 30 minutes by lay staff, was compared to ADOS scores and DSM-based diagnostic assessment from a qualified clinician. Sensitivity and specificity of each instrument alone and in combination were estimated. Alternative cutpoints were identified under different criteria and two-stage cross validation was used to avoid overfitting. Findings were interpreted in the context of a large, prospective pregnancy cohort study utilizing a two-stage approach to case identification. Under initial cutpoints, sensitivity ranged from 0.63 to 0.92 and specificity from 0.35 to 0.70. Cutpoints giving equal weight to sensitivity and specificity resulted in sensitivity estimates ranging from 0.45 to 0.83 and specificity ranging from 0.49 to 0.86. Several strategies were well-suited for application as a second-stage case-confirmation. These included the STAT-E alone and the parallel administration of both the E-VAS and the ASI. Use of more streamlined methods of case-confirmation in large-scale prospective cohort epidemiologic investigations of ASD risk factors appears feasible. Autism Res 2017, 10: 485-501. © 2016 International Society for Autism Research, Wiley Periodicals, Inc., (© 2016 International Society for Autism Research, Wiley Periodicals, Inc.)

Background & Aims: Drug-induced liver injury (DILI), especially from antimicrobial agents, is an important cause of serious liver disease. Amoxicillin-clavulanate (AC) is a leading cause of idiosyncratic DILI, but little is understood about genetic susceptibility to this adverse reaction., Methods: We performed a genome-wide association study using 822,927 single nucleotide polymorphism (SNP) markers from 201 White European and US cases of DILI following AC administration (AC-DILI) and 532 population controls, matched for genetic background., Results: AC-DILI was associated with many loci in the major histocompatibility complex. The strongest effect was with an HLA class II SNP (rs9274407, P=4.8×10(-14)), which correlated with rs3135388, a tag SNP of HLA-DRB1*1501-DQB1*0602 that was previously associated with AC-DILI. Conditioned on rs3135388, rs9274407 is still significant (P=1.1×10(-4)). An independent association was observed in the class I region (rs2523822, P=1.8×10(-10)), related to HLA-A*0201. The most significant class I and II SNPs showed statistical interaction (P=.0015). High-resolution HLA genotyping (177 cases and 219 controls) confirmed associations of HLA-A*0201 (P=2×10(-6)) and HLA-DQB1*0602 (P=5×10(-10)) and their interaction (P=.005). Additional, population-dependent effects were observed in HLA alleles with nominal significance. In an analysis of autoimmune-related genes, rs2476601 in the gene PTPN22 was associated (P=1.3×10(-4))., Conclusions: Class I and II HLA genotypes affect susceptibility to AC-DILI, indicating the importance of the adaptive immune response in pathogenesis. The HLA genotypes identified will be useful in studies of the pathogenesis of AC-DILI but have limited utility as predictive or diagnostic biomarkers because of the low positive predictive values., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: With increasing research on system integration for image-guided therapy (IGT), there has been a strong demand for standardized communication among devices and software to share data such as target positions, images and device status., Method: We propose a new, open, simple and extensible network communication protocol for IGT, named OpenIGTLink, to transfer transform, image and status messages. We conducted performance tests and use-case evaluations in five clinical and engineering scenarios., Results: The protocol was able to transfer position data with submillisecond latency up to 1024 fps and images with latency of <10 ms at 32 fps. The use-case tests demonstrated that the protocol is feasible for integrating devices and software., Conclusion: The protocol proved capable of handling data required in the IGT setting with sufficient time resolution and latency. The protocol not only improves the interoperability of devices and software but also promotes transitions of research prototypes to clinical applications., (Copyright (c) 2009 John Wiley & Sons, Ltd.)