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The diverse composition of mammalian tissues poses challenges for understanding the cell-cell interactions required for organ homeostasis and how spatial relationships are perturbed during disease. Existing methods such as single-cell genomics, lacking a spatial context, and traditional immunofluorescence, capturing only two to six molecular features, cannot resolve these issues. Imaging technologies have been developed to address these problems, but each possesses limitations that constrain widespread use. Here we report a method that overcomes major impediments to highly multiplex tissue imaging. "Iterative bleaching extends multiplexity" (IBEX) uses an iterative staining and chemical bleaching method to enable high-resolution imaging of >65 parameters in the same tissue section without physical degradation. IBEX can be employed with various types of conventional microscopes and permits use of both commercially available and user-generated antibodies in an "open" system to allow easy adjustment of staining panels based on ongoing marker discovery efforts. We show how IBEX can also be used with amplified staining methods for imaging strongly fixed tissues with limited epitope retention and with oligonucleotide-based staining, allowing potential cross-referencing between flow cytometry, cellular indexing of transcriptomes and epitopes by sequencing, and IBEX analysis of the same tissue. To facilitate data processing, we provide an open-source platform for automated registration of iterative images. IBEX thus represents a technology that can be rapidly integrated into most current laboratory workflows to achieve high-content imaging to reveal the complex cellular landscape of diverse organs and tissues., Competing Interests: Competing interest statement: J.C. is an employee of BioLegend, which manufactures and sells TotalSeq-A antibodies that are used in one of the workflows described in this paper.

Objective: Infantile spasms (IS) is a severe epilepsy in early childhood. Early treatment of IS provides the best chance of seizure remission and favorable developmental outcome. We aimed to develop a prediction rule to accurately predict which neonates with acute symptomatic seizures will develop IS., Methods: We used data from the Neonatal Seizure Registry, a prospective, multicenter cohort of infants with acute symptomatic neonatal seizures born from July 2015 to March 2018. Neonates with acute symptomatic seizures who received clinical electroencephalography (EEG) and magnetic resonance imaging (MRI) and were younger than 2 years of age at the time of enrollment were included. We evaluated the association of neonatal EEG, MRI, and clinical factors with subsequent IS using bivariate analysis and best subsets logistic regression. We selected a final model through a consensus process that balanced statistical significance with clinical relevance., Results: IS developed in 12 of 204 infants (6%). Multiple potential predictors were associated with IS, including Apgar scores, EEG features, seizure characteristics, MRI abnormalities, and clinical status at hospital discharge. The final model included three risk factors: (a) severely abnormal EEG or ≥3 days with seizures recorded on EEG, (b) deep gray or brainstem injury on MRI, and (c) abnormal tone on discharge exam. The stratified risk of IS was the following: no factors 0% (0/82, 95% confidence interval [CI] 0%-4%), one or two factors 4% (4/108, 95% CI 1%-9%), and all three factors 57% (8/14, 95% CI 29%-83%)., Significance: IS risk after acute symptomatic neonatal seizures can be stratified using commonly available clinical data. No child without risk factors, vs >50% of those with all three factors, developed IS. This risk prediction rule may be valuable for clinical counseling as well as for selecting participants for clinical trials to prevent post-neonatal epilepsy. This tailored approach may lead to earlier diagnosis and treatment and improve outcomes for a devastating early life epilepsy., (© 2020 International League Against Epilepsy.)

Background: Neonatal seizures are associated with death and neurological morbidity; however, little is known about how neonates with seizures die., Methods: This was a prospective, observational cohort study of neonates with seizures treated at seven sites of the Neonatal Seizure Registry. We characterized the mode of death, evaluated the association between infant characteristics and mode of death, and evaluated predictors of death or transfer to hospice., Results: We enrolled 611 consecutive neonates with seizures, and 90 neonates (15%) died before hospital discharge at a median age of 11 days (range: 1 to 163 days); 32 (36%) died in the first postnatal week. An additional 19 neonates (3%) were transferred to hospice. The most common mode of in-hospital death was death after extubation amidst concerns for poor neurological prognosis, in the absence of life-threatening physiologic instability (n = 43, 48%). Only one infant died while actively receiving cardiopulmonary resuscitation. In an adjusted analysis, premature birth (odds ratio: 3.06, 95% confidence interval 1.59 to 5.90) and high seizure burden (odds ratio: 4.33, 95% confidence interval 1.88 to 9.95) were associated with increased odds of death or transfer to hospice., Conclusion: In a cohort of neonates with seizures, death occurred predominantly after decisions to withdraw or withhold life-sustaining intervention(s). Future work should characterize how these decisions occur and develop optimized approaches to support families and clinicians caring for newborns with seizures., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Neonates with seizures have a high risk of mortality and neurological morbidity. We aimed to describe the experience of parents caring for neonates with seizures., Design: This prospective, observational and multicentre ( Neonatal Seizure Registry ) study enrolled parents of neonates with acute symptomatic seizures. At the time of hospital discharge, parents answered six open-ended response questions that targeted their experience. Responses were analysed using a conventional content analysis approach., Results: 144 parents completed the open-ended questions (732 total comments). Four themes were identified. Sources of strength : families valued medical team consensus, opportunities to contribute to their child's care and bonding with their infant. Uncertainty : parents reported three primary types of uncertainty, all of which caused distress: (1) the daily uncertainty of the intensive care experience; (2) concerns about their child's uncertain future and (3) lack of consensus between members of the medical team. Adapting family life : parents described the many ways in which they anticipated their infant's condition would lead to adaptations in their family life, including adjusting their family's lifestyle, parenting approach and routine. Many parents described financial and work challenges due to caring for a child with medical needs. Emotional and physical toll : parents reported experiencing anxiety, fear, stress, helplessness and loss of sleep., Conclusions: Parents of neonates with seizures face challenges as they adapt to and find meaning in their role as a parent of a child with medical needs. Future interventions should target facilitating parent involvement in clinical and developmental care, improving team consensus and reducing the burden associated with prognostic uncertainty., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Childhood epilepsy with centrotemporal spikes (CECTS) is a common, focal, transient, developmental epilepsy syndrome characterized by unilateral or bilateral, independent epileptiform spikes in the Rolandic regions of unknown etiology. Given that CECTS presents during a period of dramatic white matter maturation and thatspikes in CECTS are activated during non-rapid eye movement (REM) sleep, we hypothesized that children with CECTS would have aberrant development of white matter connectivity between the thalamus and the Rolandic cortex. We further tested whether Rolandic thalamocortical structural connectivity correlates with spike rate during non-REM sleep., Methods: Twenty-three children with CECTS (age = 8-15 years) and 19 controls (age = 7-15 years) underwent 3-T structural and diffusion-weighted magnetic resonance imaging and 72-electrode electroencephalographic recordings. Thalamocortical structural connectivity to Rolandic and non-Rolandic cortices was quantified using probabilistic tractography. Developmental changes in connectivity were compared between groups using bootstrap analyses. Longitudinal analysis was performed in four subjects with 1-year follow-up data. Spike rate was quantified during non-REM sleep using manual and automated techniques and compared to Rolandic connectivity using regression analyses., Results: Children with CECTS had aberrant development of thalamocortical connectivity to the Rolandic cortex compared to controls (P = .01), where the expected increase in connectivity with age was not observed in CECTS. There was no difference in the development of thalamocortical connectivity to non-Rolandic regions between CECTS subjects and controls (P = .19). Subjects with CECTS observed longitudinally had reductions in thalamocortical connectivity to the Rolandic cortex over time. No definite relationship was found between Rolandic connectivity and non-REM spike rate (P > .05)., Significance: These data provide evidence that abnormal maturation of thalamocortical white matter circuits to the Rolandic cortex is a feature of CECTS. Our data further suggest that the abnormalities in these tracts do not recover, but are increasingly dysmature over time, implicating a permanent but potentially compensatory process contributing to disease resolution., (© 2020 International League Against Epilepsy.)

Our recent work characterized the movement of single blood cells within the retinal vasculature (Joseph et al. 2019) using adaptive optics ophthalmoscopy. Here, we apply this technique to the context of acute inflammation and discover both infiltrating and tissue-resident immune cells to be visible without any labeling in the living mouse retina using near-infrared light alone. Intravital imaging of immune cells can be negatively impacted by surgical manipulation, exogenous dyes, transgenic manipulation and phototoxicity. These confounds are now overcome, using phase contrast and time-lapse videography to reveal the dynamic behavior of myeloid cells as they interact, extravasate and survey the mouse retina. Cellular motility and differential vascular responses were measured noninvasively and in vivo across hours to months at the same retinal location, from initiation to the resolution of inflammation. As comparable systems are already available for clinical research, this approach could be readily translated to human application., Competing Interests: AJ Received funding support from Hoffman-La Roche Inc Hold patents and/or patent applications on adaptive optics technology filed through the University of Rochester. US Patent Application Number: US20190114790A1, "Rapid assessment and visual reporting of local particle velocity". CC No competing interests declared, GF, KD Received funding support from Hoffman-La Roche Inc, JS Received funding support from Hoffman-La Roche Inc Hold patents and/or patent applications on adaptive optics technology filed through the University of Rochester. US Patent #9,844,320 Issued: 12/19/2017, "System and Method for Observing an Object in a Blood Vessel". US Patent Application Number: US20190114790A1, "Rapid assessment and visual reporting of local particle velocity"., (© 2020, Joseph et al.)

Background: Osteochondral (OC) repair presents a significant challenge to clinicians. However, whether the use of acellular spongy poly(lactic-co-glycolic acid) (PLGA) scaffolding plus treadmill exercise as a rehabilitation program regenerates OC defects in a large-animal model has yet to be determined., Hypothesis: PLGA scaffolding plus treadmill exercise may offer improved OC repair for both high and low weightbearing regions in a minipig model., Study Design: Controlled laboratory study., Methods: A total of 9 mature minipigs (18 knees) were randomly divided into the treadmill exercise (TRE) group or sedentary (SED) group. All pigs received critically sized OC defects in a higher weightbearing region of the medial condyle and a lower weightbearing region of the trochlear groove. In each minipig, a PLGA scaffold was placed in the defect of the right knee (PLGA subgroup), and the defect of the left knee was untreated (empty defect [ED] subgroup). The TRE group performed exercises in 3 phases: warm-up, 3 km/h for 5 minutes; main exercise, 4 km/h for 20 minutes; and cool-down, 3 km/h for 5 minutes. The total duration was about 30 minutes whenever possible. The SED group was allowed free cage activity., Results: At 6 months, the TRE-PLGA group showed the highest gross morphology scores and regenerated a smooth articular surface covered with new hyaline-like tissue, while the defects of the other groups remained and contained nontransparent tissue. Histologically, the TRE-PLGA group also revealed sound OC integration, chondrocyte-like cells embedded in lacunae, abundant glycosaminoglycans, a sound collagen structure, and modest inflammatory cells with an inflammatory response (ie, tumor necrosis factor-α, interleukin-6). In addition, in the medial condyle region, the TRE-PLGA group (31.80 ± 3.03) had the highest total histological scores (TRE-ED: 20.20 ± 5.76; SED-PLGA: 10.25 ± 6.24; SED-ED: 11.75 ± 6.50; P = .004). In the trochlear groove region, the TRE-PLGA group (30.20 ± 6.42) displayed significantly higher total histological scores (TRE-ED: 19.60 ± 7.00; SED-PLGA: 10.00 ± 5.42; SED-ED: 11.25 ± 5.25; P = .006). In contrast, the SED-PLGA and SED-ED groups revealed an irregular surface with abrasion, fibrotic tissue with an empty void and inflammatory cells, disorganized collagen fibers, and less glycosaminoglycan deposition. Micro-computed tomography analysis revealed that the TRE-PLGA group had integrated OC interfaces with continued remodeling in the subchondral bone. Furthermore, comparing the 2 defect regions, no statistically significant differences in cartilage regeneration were detected, indicating the suitability of this regenerative approach for both high and low weightbearing regions., Conclusion: Implanting an acellular PLGA scaffold plus treadmill exercise promoted articular cartilage regeneration for both high and low weightbearing regions in minipigs., Clinical Relevance: This study suggests the use of a cell-free porous PLGA scaffold and treadmill exercise rehabilitation as an alternative therapeutic strategy for OC repair in a large-animal knee joint model. This combined effect may pave the way for biomaterials and exercise regimens in the application of OC repair.

PRéCIS:: A large cohort undergoing cataract extraction was retrospectively analyzed to ascertain the degree of real-world intraocular pressure (IOP) reduction in normal eyes and those with glaucoma, and a predictive formula was developed., Purpose: The purpose of this study was to define the real-world degree of IOP reduction after cataract extraction to guide its role as an isolated intervention for glaucoma., Materials and Methods: A retrospective analysis was carried out of clinical data collected in 8 clinical sites in the United Kingdom from an electronic medical record system between January 2006 and May 2015. A total of 20,508 eyes without known pathology and 2251 eyes from patients with glaucoma undergoing phacoemulsification and intraocular lens insertion were included. Eyes with intraoperative complications, undergoing additional procedures, axial lengths outside 22 to 26.5 mm, preoperative IOP under 6 mm Hg or over 30 mm Hg, and copathology, except for amblyopia or glaucoma, were excluded. The main outcome measure was the change in preoperative IOP compared with the next recorded visit for up to 12 weeks., Results: In eyes without pathology, the mean reduction in IOP was 1.40 mm Hg (±3.74) compared with 1.03 (±5.02), P-value <0.001, in eyes with a diagnosis of glaucoma. A multiple linear regression model identified preoperative IOP, a glaucoma diagnosis, preoperative corrected visual acuity, age, and axial length as determinants of IOP reduction. The model was validated against an independent cohort., Conclusions: We quantify mean IOP reduction achieved in a real-world setting from cataract surgery alone. In glaucomatous eyes where angle closure is not differentiated, phacoemulsification alone yields only a modest reduction of IOP.

A batch of biochar was produced from pyrolysis of Typha angustifolia (TBCs) at 200-500℃ for 2 h and 6 h to investigate the effects of pyrolytic temperature and heating retention time on the physico-chemical properties. Moreover, Escherichia coli ( E. coli ) HB101 and the seeds of Helianthus annuus were used to preliminarily test the ecological risk of the TBCs. Results showed that the heating retention time (i.e., 2 and 6 h) had no significant effect on the properties of TBCs, while pyrolytic temperature significantly affected TBCs' characteristics. As the pyrolysis temperature increased from 200 to 500℃, the mass yield and contents of hydrogen (H) and oxygen (O) decreased, while the contents of carbon (C) and ash increased. The pH and surface pores also increased with increasing pyrolytic temperature, whereas the O-containing functional group (e.g., -COOH and -OH) decreased. These results indicated the increased carbonization and aromatization of the TBCs. For the inherent nutrients of TBCs, the total phosphorus (TP) and available potassium (K) contents significantly increased as temperature increased. The main components of dissolved organic matter (DOM) of TBCs were humic acid-like and fulvic acid-like organic compounds. As the pyrolysis temperature increased, the content of humic acid-like organic compounds decreased, while the content of fulvic acid-like organic compounds increased. All the TBCs had no significant effect on the growth of E. coli HB101 and the seed germination of Helianthus annuus , indicating the little ecological risk of TBCs under the experimental conditions. These findings provide an alternative way for resource utilization of waste wetland biomass and provide important theoretical data for screening biochar in soil reclamation.

While current technology permits inference of dynamic brain networks over long time periods at high temporal resolution, the detailed structure of dynamic network communities during human seizures remains poorly understood. We introduce a new methodology that addresses critical aspects unique to the analysis of dynamic functional networks inferred from noisy data. We propose a dynamic plex percolation method (DPPM) that is robust to edge noise, and yields well-defined spatiotemporal communities that span forward and backwards in time. We show in simulation that DPPM outperforms existing methods in accurately capturing certain stereotypical dynamic community behaviors in noisy situations. We then illustrate the ability of this method to track dynamic community organization during human seizures, using invasive brain voltage recordings at seizure onset. We conjecture that application of this method will yield new targets for surgical treatment of epilepsy, and more generally could provide new insights in other network neuroscience applications.

Hypochlorous acid has played several functions in the biological system. However, excess HOCl can cause damage to biomolecules and result in some diseases. Accordingly, a new fluorescent probe, BSP, has been developed for fast recognition of HOCl through the HOCl-induced oxidation of methyl phenyl sulfide to sulfoxide. The reaction of BSP with HOCl caused a 22-fold fluorescence enhancement (quantum yield increase from 0.006 to 0.133). The detection limit of HOCl is found to be 30 nM (S/N = 3). The fluorescence enhancement is due to the suppression of the photo-induced electron transfer from the methyl phenyl sulfide moiety to BODIPY. Eventually, the cellular fluorescence imaging experiment showed that BSP could be effectively used for monitoring HOCl in living cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: To characterize and determine risk factors for key dimensions of well-being at hospital discharge in families of neonates with acute symptomatic seizures., Study Design: This prospective, observational cohort study enrolled 144 parent-infant dyads among neonates with acute symptomatic seizures from 9 pediatric hospitals in the Neonatal Seizure Registry. One parent per family completed a discharge survey, which included measures of anxiety and depression, health-related quality of life, and impact on the family. Multivariable regression analyses adjusted for site were constructed to examine parent and infant characteristics associated with well-being., Results: At discharge, 54% of parents reported symptoms of anxiety and 32% reported symptoms of depression. Parents of infants with hypoxic-ischemic encephalopathy reported more depression and worse quality of life than parents of infants with other seizure etiologies. Parental quality of life was also lower with greater infant age at discharge. A higher level of maternal education was associated with greater impact on the family. All these differences were medium to large effect sizes, ranging from 0.52 to 0.78., Conclusions: Symptoms of anxiety and depression are common in parents of infants with neonatal seizures, and several parent and infant characteristics are associated with poorer parental quality of life and family well-being. These findings are a call to action to improve mental health screening and services for parents of infants with neonatal seizures., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A new flexible memory element is crucial for mobile and wearable electronics. A new concept for memory operation and innovative device structure with new materials is certainly required to address the bottleneck of memory applications now and in the future. We report a new nonvolatile molecular memory with a new operating mechanism based on two-dimensional (2D) material nanochannel field-effect transistors (FETs). The smallest channel length for our 2D material nanochannel FETs was approximately 30 nm. The modified molecular configuration for charge induced in the nanochannel of the MoS 2 FET can be tuned by applying an up-gate voltage pulse, which can vary the channel conductance to exhibit memory states. Through controlling the amounts of triggered molecules through either different gate voltage pulses or gate duration time, multilevel states were obtained in the molecular memory. These new molecular memory transistors exhibited an erase/program ratio of more than three orders of current magnitude and high sensitivity, of a few picoamperes, at the current level. Reproducible operation and four-level states with stable retention and endurance were achieved. We believe this prototype device has potential for use in future memory devices.

Intravenous third-line anaesthetic agents are typically titrated in refractory status epilepticus to achieve either seizure suppression or burst suppression on continuous EEG. However, the optimum treatment paradigm is unknown and little data exist to guide the withdrawal of anaesthetics in refractory status epilepticus. Premature withdrawal of anaesthetics risks the recurrence of seizures, whereas the prolonged use of anaesthetics increases the risk of treatment-associated adverse effects. This study sought to measure the accuracy of features of EEG activity during anaesthetic weaning in refractory status epilepticus as predictors of successful weaning from intravenous anaesthetics. We prespecified a successful anaesthetic wean as the discontinuation of intravenous anaesthesia without developing recurrent status epilepticus, and a wean failure as either recurrent status epilepticus or the resumption of anaesthesia for the purpose of treating an EEG pattern concerning for incipient status epilepticus. We evaluated two types of features as predictors of successful weaning: spectral components of the EEG signal, and spatial-correlation-based measures of functional connectivity. The results of these analyses were used to train a classifier to predict wean outcome. Forty-seven consecutive anaesthetic weans (23 successes, 24 failures) were identified from a single-centre cohort of patients admitted with refractory status epilepticus from 2016 to 2019. Spectral components of the EEG revealed no significant differences between successful and unsuccessful weans. Analysis of functional connectivity measures revealed that successful anaesthetic weans were characterized by the emergence of larger, more densely connected, and more highly clustered spatial functional networks, yielding 75.5% (95% confidence interval: 73.1-77.8%) testing accuracy in a bootstrap analysis using a hold-out sample of 20% of data for testing and 74.6% (95% confidence interval 73.2-75.9%) testing accuracy in a secondary external validation cohort, with an area under the curve of 83.3%. Distinct signatures in the spatial networks of functional connectivity emerge during successful anaesthetic liberation in status epilepticus; these findings are absent in patients with anaesthetic wean failure. Identifying features that emerge during successful anaesthetic weaning may allow faster and more successful anaesthetic liberation after refractory status epilepticus., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Glaucoma is a common cause of blindness, yet current therapeutic options are imperfect. Clinical trials have invariably shown that reduction in intraocular pressure (IOP) regardless of disease subtype prevents visual loss. Reducing ciliary body aqueous humor production can lower IOP, and the adeno-associated virus ShH10 serotype was identified as able to transduce mouse ciliary body epithelium following intravitreal injection. Using ShH10 to deliver a single vector CRISPR-Cas9 system disrupting Aquaporin 1 resulted in reduced IOP in treated eyes (10.4 ± 2.4 mmHg) compared with control (13.2 ± 2.0 mmHg) or non-injected eyes (13.1 ± 2.8 mmHg; p < 0.001; n = 12). Editing in the aquaporin 1 gene could be detected in ciliary body, and no off-target increases in corneal or retinal thickness were identified. In experimental mouse models of corticosteroid and microbead-induced ocular hypertension, IOP could be reduced to prevent ganglion cell loss (32 ± 4 /mm 2 ) compared with untreated eyes (25 ± 5/mm 2 ; p < 0.01). ShH10 could transduce human ciliary body from post-mortem donor eyes in ex vivo culture with indel formation detectable in the Aquaporin 1 locus. Clinical translation of this approach to patients with glaucoma may permit long-term reduction of IOP following a single injection., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

It is not currently possible to reliably visualise and track immune cells in the human central nervous system or eye. Previous work demonstrated that indocyanine green (ICG) dye could label immune cells and be imaged after a delay during disease in the mouse retina. We report a pilot study investigating if ICG can similarly label immune cells within the human retina. Twelve adult participants receiving ICG angiography as part of routine standard of care were recruited. Baseline retinal images were obtained prior to ICG administration then repeated over a period ranging from 2 hours to 9 days. Matched peripheral blood samples were obtained to examine systemic immune cell labelling and activation from ICG by flow cytometry with human macrophage cultures as positive controls. Differences between the delayed near infrared ICG imaging and 488 nm autofluorescence was observed across pathologies, likely arising from the retinal pigment epithelium (RPE). Only one subject demonstrated ICG signal on peripheral blood myeloid cells and only three distinct cell-sized signals appeared over time within the retina of three participants. No significant increase in immune cell activation markers were detected after ICG administration. ICG accumulated in the endosomes of macrophage cultures and was detectable above a minimum concentration, suggesting cell labelling is possible. ICG can label RPE and may be used as an additional biomarker for RPE health across a range of retinal disorders. Standard clinical doses of intravenous ICG do not lead to robust immune cell labelling in human blood or retina and further optimisation in dose and route are required., Competing Interests: I have read the journal's policy and the authors of the manuscript have the following competing interests: M. Fruttiger and D.A. Sim: Patent (expired). The remaining authors have declared that no competing interests exist.

Objective: Childhood epilepsy with centrotemporal spikes (CECTS) (formally benign epilepsy with centrotemporal spikes, BECTS) is a common childhood epilepsy syndrome characterized by psychiatric, behavioral, and cognitive abnormalities and self-limited seizures. Although CECTS is one of the most well-characterized electroclinical epilepsy syndromes, the natural history of neuropsychiatric outcomes is poorly understood. We report the psychiatric, behavioral, and cognitive profiles over the course of disease from a large, prospectively-enrolled, longitudinal cohort of children with CECTS. We further characterize the detailed seizure course and test the relationship between several proposed risk factors and neuropsychiatric and seizure outcomes in these children., Methods: Patients diagnosed with CECTS were enrolled as part of a community-based study and followed from diagnosis through disease resolution (16.0 ± 3.1 years, N = 60). Twenty sibling controls were also recruited. We report the natural history of premorbid neuropsychiatric concerns, postmorbid neuropsychiatric diagnoses, long-term neuropsychological performance, seizure course, antiseizure medication (ASM) treatment response, and the relationship between duration seizure-free and remission. Age at onset and premorbid neuropsychiatric concerns were tested as predictors of seizure count, epilepsy duration, postmorbid neuropsychiatric diagnoses, and long-term neuropsychological performance. Antiseizure medication treatment duration, seizure count, and epilepsy duration were tested as predictors of postmorbid neuropsychiatric diagnoses and long-term neuropsychological performance., Results: Children with CECTS had a high incidence of ADD/ADHD symptoms (18.3%) or learning difficulties (21.7%) before diagnosis. New or persistent ADHD (20%), mood disorders (23.6%), learning difficulties (14.5%), and behavioral disorders (7.3%) were common after CECTS diagnosis. At 9-year follow-up, performance on formal neuropsychological testing was comparable to population statistics and sibling controls. More than two-thirds of treated children experienced at least one seizure during treatment. Most children (61.7%) had entered terminal resolution after 12 months seizure-free. Among all children, for each month seizure-free, there was a 6-7% increase in the probability of achieving terminal remission (p < 1e-10). The presence of a premorbid neurodevelopmental concern predicted a longer epilepsy duration (p = 0.02), higher seizure count (p = 0.02), and a postmorbid psychiatric or neurodevelopmental diagnosis (p = 0.002). None of the tested features predicted long-term neuropsychological performance., Significance: Children are at high risk of neuropsychiatric symptoms along the course of the disease in CECTS, however, long-term cognitive performance is favorable. The majority of children had a seizure while being treated with ASMs, suggesting that CECTS is not as pharmacoresponsive as assumed or that treatment approaches are not optimized. Among treated and untreated children, future seizure-risk can be estimated from duration seizure-free. The presence of a premorbid neuropsychiatric concern predicted a more severe disease course in CECTS., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Whether retinal microglia can maintain or restore immune homeostasis during and after inflammation is unclear. We performed single-eye mRNA-sequencing on microglia at different timepoints following a single inflammatory stimulus to characterise their transcriptome during and after resolution of endotoxin-induced uveitis (EIU). Experimental Approach: Cx3cr1 CreER :R26-tdTomato (C57BL/6) male heterozygotes were administered tamoxifen via different regimes at 4-5 weeks of age. Four weeks post-tamoxifen, mice were injected intravitreally with 10 ng lipopolysaccharide (endotoxin induced uveitis, EIU). Six-hundred retinal microglia were obtained by FACS from individual naïve retinas and at 4 h, 18 h, and 2 weeks following EIU induction. Samples were sequenced to a depth of up to 16.7 million reads using the SMART-Seq v4 Ultra Low Input RNA kit. The data was analysed using Partek software and Ingenuity Pathway Analysis. Genes were considered differentially-expressed (DEG) if the FDR step-up p -value was ≤0.05 and the fold-change was ≥±2. Results: Flow cytometric analysis indicates that the Cx3cr1 CreER :R26-tdTomato strain is both sensitive (>95% tagging) and specific (>95% specificity) for microglia when tamoxifen is administered topically to the eye for 3 days. During "early" activation, 613 DEGs were identified. In contrast, 537 DEGs were observed during peak cellular infiltrate and none at 2 weeks, compared to baseline controls (1,069 total unique DEGs). Key marker changes were validated by qPCR, flow cytometry, and fluorescence microscopy. C5AR1 was identified and validated as a robust marker of differentiating microglial subsets during an LPS response. Conclusion: Using EIU to provide a single defined inflammatory stimulus, mRNA-Seq identified acute transcriptional changes in retinal microglia which returned to their original transcriptome after 2 weeks. Yolk-sac derived microglia are capable of restoring their homeostatic state after acute inflammation., (Copyright © 2020 Bell, Copland, Ward, Nicholson, Lange, Chu and Dick.)

Background: Immunosuppressant-related acceleration of fibrosis has been documented in chronic hepatitis C (CHC) patients who receive organ transplantation (Tx), and sustained virological response (SVR) rates for these patients by pegylated interferon (IFN)-based therapy are generally poor and associated with unfavorable safety profiles. In addition, IFN treatment varies by patient and poses a high risk of post-renal Tx graft rejection. This study was aimed to investigate the efficacy and safety of all oral direct acting antivirals (DAAs) for CHC patients following organ Tx., Methods: A total of 32 organ Tx (liver: 17, kidney: 13, kidney then liver: 1, and heart: 1) patients with CHC on an oral DAA (paritaprevir/ritonavir, ombitasvir, and dasabuvir: 11, daclatasvir and asunaprevir: 4, sofosbuvir-based: 17) were enrolled in the study. DAAs regimen was based by genotype/subtype, patient characteristics, drug interaction profiles, and health insurance coverage., Results: Mean patient age was 61.4 ± 9.5 years, 50.0% male, and 15.6% with cirrhosis. Fourteen (43.7%) patients experienced unsuccessful IFN treatment. Genotype distribution was as follows: 1a: 6, 1b: 17, 2: 7, 3: 1, and 6: 1. Mean time between Tx and DAAs therapy was 77.3 ± 11.0 months. Baseline HCV RNA before DAAs was 6.20 ± 0.19 log10 IU/mL. After DAAs, the distribution of week 2 HCV RNA was as follows: <15 IU/mL (53.1%), 15 to 50 IU/mL (15.6%), 50 to 100 IU/mL (6.3%), and >100 IU/mL (25.0%), respectively. The rates of undetectable HCV RNA (<15 IU/mL) at week 4 and end-of-treatment were 93.8% and 100%, respectively. Subjective adverse events during therapy were generally mild, with no treatment terminations. After posttreatment follow-up, all 32 patients (100%) achieved SVR12., Conclusion: Highly responsive treatment and favorable tolerability were achieved by all oral DAAs in this difficult-to-treat patient population.

Purpose: Electrical source imaging may yield ambiguous results in multilesional epilepsy. The aim of this study was to test the clinical utility of lesion-constrained electrical source imaging in epilepsy surgery in children with tuberous sclerosis complex., Methods: Lesion-constrained electrical source imaging is a novel method based on a proposed head model in which the source solution is constrained to lesions. Using a goodness of fit analysis, we rank-ordered individual tubers by their ability to approximate interictal and ictal EEG data. The overlap with the surgical resection cavity was determined qualitatively, and placed findings in the context of epilepsy surgical outcome, and compared with the low-resolution brain electromagnetic tomography solution., Results: Low-resolution brain electromagnetic tomography predicted the surgical cavity in only one patient with good outcome (true positive) and localized to outside of the cavity in two patients with a good outcome (false negative). In one patient with a poor outcome, the interictal low-resolution brain electromagnetic tomography solution overlapped with the cavity (false positive). Lesion-constrained electrical source imaging of ictal EEG data identified tubers concordant with the resection zone in three patients with a good surgical outcome (true positive) and appropriately discordant in three other patients with a poor outcome (true negative)., Conclusions: Lesion-constrained electrical source imaging on low-resolution EEG data provides complementary information in the presurgical workup for patients with tuberous sclerosis complex, although further validation is required. In the appropriate clinical context, the yield of source localization on low-resolution EEG data may be increased by reduction of the solution space.

Objective: We evaluated the impact of monitoring indication, early electroencephalography (EEG), and clinical features on seizure risk in all neonates undergoing continuous EEG (cEEG) monitoring following a standardized monitoring protocol., Methods: All cEEGs from unique neonates 34-48 weeks postmenstrual age monitored from 1/2011-10/2017 (n = 291) were included. We evaluated the impact of cEEG monitoring indication (acute neonatal encephalopathy [ANE], suspicious clinical events [SCEs], or other high-risk conditions [OHRs]), age, medication status, and early EEG abnormalities (including the presence of epileptiform discharges and abnormal background continuity, amplitude, asymmetry, asynchrony, excessive sharp transients, and burst suppression) on time to first seizure and overall seizure risk using Kaplan-Meier survival curves and multivariable Cox proportional hazards models., Results: Seizures occurred in 28% of high-risk neonates. Discontinuation of monitoring after 24 hours of seizure-freedom would have missed 8.5% of neonates with seizures. Overall seizure risk was lower in neonates monitored for ANE compared to OHR (P = .004) and trended lower compared to SCE (P = .097). The time course of seizure presentation varied by group, where the probability of future seizure was less than 1% after 17 hours of seizure-free monitoring in the SCE group, but required 42 hours in the OHR group, and 73 hours in the ANE group. The presence of early epileptiform discharges increased seizure risk in each group (ANE: adjusted hazard ratio [aHR] 4.32, 95% confidence interval [CI] 1.23-15.13, P = .022; SCE: aHR 10.95, 95% CI 4.77-25.14, P < 1e-07; OHR: aHR 56.90, 95% CI 10.32-313.72, P < 1e-05)., Significance: Neonates who undergo cEEG are at high risk for seizures, and risk varies by monitoring indication and early EEG findings. Seizures are captured in nearly all neonates undergoing monitoring for SCE within 24 hours of cEEG monitoring. Neonates monitored for OHR and ANE can present with delayed seizures and require longer durations of monitoring. Early epileptiform discharges are the best early EEG feature to predict seizure risk., (Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.)

Background: Based on the previously published results, 12 weeks of sofosbuvir (SOF) 400 mg/day plus ribavirin (RBV), the current direct antiviral agent regimen reimbursed by Bureau-of National-Health-Insurance (BNHI) of Taiwan for genotype-2 chronic hepatitis C (CHC), is suboptimal in efficacy, especially for difficult-to-treat subpopulations such as liver cirrhosis, previous interferon (IFN) treatment failure, and high viral-load. This study aimed to evaluate the efficacy and safety of SOF plus daclatasvir (DCV) for Taiwanese genotype-2 CHC patients., Methods: Between March 2017 and December 2018, a total of 50 consecutive genotype-2 CHC patients who completed 12 weeks combination of SOF (400 mg/day) plus DCV (60 mg/day) with or without RBV by investigators were enrolled for analyses. When RBV was added, weight-based (800-1200 mg/day) approach was applied. Sustained virological response (SVR12) was defined by undetectable HCV RNA (<15 IU/mL) at the end and 12 weeks after completion of therapy., Results: The mean age was 62.0 ± 11.4 years, 16 (32.0%) of them were males and 20 (40.0%) of them failed to previous IFN. Severity of liver diseases was as follows: ≤F2 fibrosis: 24.0%; F3 fibrosis: 40.0%, Child-Pugh A cirrhosis: 30.0%; and Child-Pugh B-C cirrhosis: 6.0%. The mean baseline HCV RNA level was 6.19 ± 0.91 log10 IU/mL and 30 (60.0%) had baseline HCV RNA ≥ 2 million IU/mL. The rates of undetectable HCV RNA (<15 IU/mL) at weeks 2, 4, and end-of-treatment were 40%, 94%, and 100%, respectively. Majority (66.7%) of patients with detectable HCV RNA at week 2 belonged to low-level viremia (<50 IU/mL). Subjective adverse events (AEs) and laboratory abnormalities were more common for patients combining RBV. Grades of AEs were generally mild and all patients finished therapy without interruption. After post-treatment follow-up, all 50 patients (100%) achieved SVR12., Conclusion: Our real-world cohort of Taiwan showed that a 12-week SOF/DCV-based treatment was well-tolerated and highly effective for genotype-2 CHC patients with or without liver cirrhosis.

Rationale: Early-life epilepsies (ELEs) include some of the most challenging forms of epilepsy to manage. Given recent diagnostic and therapeutic advances, a contemporary assessment of the immediate short-term outcomes can provide a valuable framework for identifying priorities and benchmarks for evaluating quality improvement efforts., Methods: Children with newly diagnosed epilepsy and onset <3 years were prospectively recruited through 17 US hospitals, from 2012 to 2015 and followed for 1 year after diagnosis. Short-term outcome included mortality, drug resistance, evolution of nonsyndromic epilepsy to infantile spasms (IS) and from IS to other epilepsies, and developmental decline. Multivariable analyses assessed the risk of each outcome., Results: Seven hundred seventy-five children were recruited, including 408 (53%) boys. Median age at onset was 7.5 months (interquartile range (IQR): 4.2-16.5), and 509 (66%) had onset in the first year of life. Of 22 deaths that occurred within one year of epilepsy diagnosis, 21 were children with epilepsy onset in infancy (<12 months). Of 680 children followed ≥6 months, 239 (35%) developed drug-resistant seizures; 34/227 (15%) infants with nonsyndromic epilepsy developed IS, and 48/210 (23%) initially presenting with IS developed additional seizure types. One hundred of 435 (23%) with initially typical development or only mild/equivocal delays at seizure onset, had clear developmental impairment within one year after initial diagnosis. Each outcome had a different set of predictors; however, younger age and impaired development at seizure onset were broadly indicative of poorer outcomes. Type of epilepsy and early identification of underlying cause were not reliable predictors of these outcomes., Conclusion: Early-life epilepsies carry a high risk of poor outcome which is evident shortly after epilepsy diagnosis. Onset in infancy and developmental delay is associated with an especially high risk, regardless of epilepsy type. The likelihood of poor outcomes is worrisome regardless of specific clinical profiles., (Copyright © 2019. Published by Elsevier Inc.)

Treatment of chronic hepatitis C virus infection has evolved rapidly in recent years due to the invention of interferon-free direct antiviral agents (DAAs). However, evidence and recommendations for acute hepatitis C (AHC) virus infection by DAAs are still limited, especially for those whose disease presents with hepatic decompensation. Here, we report a case with genotype 1b AHC virus infection, complicated by hepatic decompensation and the patient received sofosbuvir and daclatasvir plus low dose ribavirin for 12 weeks. Serum hepatitis C virus RNA significantly declines after therapy and became undetectable at week 8 and it remained undetectable at 12 weeks after finishing therapy; sustained virological response was impressed. Our findings support that combination of sofosbuvir and daclatasvir plus ribavirin can be used for genotype 1b, AHC virus infection patients with overt hepatic decompensation.

In the past decade, brief bursts of fast oscillations in the ripple range have been identified in the scalp EEG as a promising non-invasive biomarker for epilepsy. However, investigation and clinical application of this biomarker have been limited because standard approaches to identify these brief, low amplitude events are difficult, time consuming, and subjective. Recent studies have demonstrated that ripples co-occurring with epileptiform discharges ('spike ripple events') are easier to detect than ripples alone and have greater pathological significance. Here, we used objective techniques to quantify spike ripples and test whether this biomarker predicts seizure risk in childhood epilepsy. We evaluated spike ripples in scalp EEG recordings from a prospective cohort of children with a self-limited epilepsy syndrome, benign epilepsy with centrotemporal spikes, and healthy control children. We compared the rate of spike ripples between children with epilepsy and healthy controls, and between children with epilepsy during periods of active disease (active, within 1 year of seizure) and after a period of sustained seizure-freedom (seizure-free, >1 year without seizure), using semi-automated and automated detection techniques. Spike ripple rate was higher in subjects with active epilepsy compared to healthy controls (P = 0.0018) or subjects with epilepsy who were seizure-free ON or OFF medication (P = 0.0018). Among epilepsy subjects with spike ripples, each month seizure-free decreased the odds of a spike ripple by a factor of 0.66 [95% confidence interval (0.47, 0.91), P = 0.021]. Comparing the diagnostic accuracy of the presence of at least one spike ripple versus a classic spike event to identify group, we found comparable sensitivity and negative predictive value, but greater specificity and positive predictive value of spike ripples compared to spikes (P = 0.016 and P = 0.006, respectively). We found qualitatively consistent results using a fully automated spike ripple detector, including comparison with an automated spike detector. We conclude that scalp spike ripple events identify disease and track with seizure risk in this epilepsy population, using both semi-automated and fully automated detection methods, and that this biomarker outperforms analysis of spikes alone in categorizing seizure risk. These data provide evidence that spike ripples are a specific non-invasive biomarker for seizure risk in benign epilepsy with centrotemporal spikes and support future work to evaluate the utility of this biomarker to guide medication trials and tapers in these children and predict seizure risk in other at-risk populations., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aims: To evaluate retinal vasculature changes in primary open-angle glaucoma (POAG) and whether the functional visual loss correlates with parameters obtained using optical coherence tomography angiography (OCTA)., Materials and Methods: OCT and OCTA images were collected from 116 POAG eyes and 40 normal eyes in a prospective, cross-sectional observational study. Glaucomatous eyes were further divided into three groups according to a Glaucoma Staging System. Measurements of macular vessel density, ganglion cell complex (GCC), and disk retinal nerve fiber layer (RNFL) thickness were compared among groups., Results: The macular vessel density, GCC, and RNFL are significantly reduced in POAG compared to normal eyes that also corresponds to the severity of glaucoma (Kruskal-Wallis test with Dunnett's correction; p < 0.0001). Visual field mean deviation correlates significantly with macular vessel density (p = 0.0028, r = 0.3), GCC (p < 0.0001, r = 0.6), and RNFL (p = 0.008, r = 0.36) in POAG. There are significant correlations between GCC and RNFL (p < 0.0001, r = 0.76) as well as macular vessel density (p < 0.0001, r = 0.48). Increased age also correlates with reduced macular vessel density in both normal (p = 0.0002, r = 0.49) and glaucomatous eyes (p < 0.0001, r = 0.48), but a greater proportionate reduction of vessel density is seen in glaucomatous eyes., Conclusion: Reduced macular vessel density occurs in POAG despite of age-related changes, which also correlates with reductions in RNFL and GCC measurements. OCTA can detect microstructural defects and offers potential to facilitate diagnosis of glaucoma.

The cognitive control network (CCN) is a network responsible for multiple executive functions, which are impaired in covert hepatic encephalopathy (CHE). We aimed to use functional connectivity (FC) magnetic resonance imaging to test the hypothesis that CHE manifested with disconnection within the CCN, which is associated with impaired neuropsychiatric and biochemical profiles. CHE was detected with abnormally low psychometric hepatic encephalopathy scores (PHES) (total cut-off score <-4). Two seeds in the dorsal anterior cingulate cortex (dACC) and the dorsolateral prefrontal cortex (DLPFC) were used to calculate the FC map within the CCN. Pearson correlation analysis was performed between the CCN and psychometric, biochemical profiles including ammonia, Interleukin (IL)-6, and tumor necrosis factor (TNF)-α. Eighteen CHE, 36 non-HE (NHE) cirrhotic patients and 36 controls were studied. Significant differences in FC were noted among groups, which revealed CHE patients had a lower FC in the bilateral lateral occipital cortex (seed in the bilateral dACC) and in the right lateral occipital and precuneus cortices (seed in the left DLPFC) (P < 0.05, corrected) compared with NHE. Progressively decreased FC in the left precentral gyrus within the CCN was noted from control, NHE to CHE. PHES positively and biochemistry negatively correlated with FC in the CCN. In conclusion, CHE patients showed aberrant FC within the CCN which is correlated with both cognitive dysfunction and biochemical profiles. Ammonia and pro-inflammatory cytokines may contribute to the occurrence of aberrant connectivity. Impaired FC within the CCN may serve as a complementary biomarker for CHE.

Introduction: Benign epilepsy with centrotemporal spikes (BECTS) is a common form of childhood epilepsy with the majority of those afflicted remitting during their early teenage years. Seizures arise from the lower half of the sensorimotor cortex of the brain (e.g. seizure onset zone) and the abnormal epileptiform discharges observed increase during NREM sleep. To date no clinical factors reliably predict disease course, making determination of ongoing seizure risk a significant challenge. Prior work in BECTS have shown abnormalities in beta band (14.9-30 Hz) oscillations during movement and rest. Oscillations in this frequency band are modulated by state of consciousness and thought to reflect intrinsic inhibitory mechanisms., Methods: We used high density EEG and source localization techniques to examine beta band activity in the seizure onset zone (sensorimotor cortex) in a prospective cohort of children with BECTS and healthy controls during sleep. We hypothesized that beta power in the sensorimotor cortex would be different between patients and healthy controls, and that beta abnormalities would improve with resolution of disease in this self-limited epilepsy syndrome. We further explored the specificity of our findings and correlation with clinical features. Statistical testing was performed using logistic and standard linear regression models., Results: We found that beta band power in the seizure onset zone is different between healthy controls and BECTS patients. We also found that a longer duration of time spent seizure-free (corresponding to disease remission) correlates with lower beta power in the seizure onset zone. Exploratory spatial analysis suggests this effect is not restricted to the sensorimotor cortex. Exploratory frequency analysis suggests that this phenomenon is also observed in alpha and gamma range activity. We found no relationship between beta power and the presence or rate of epileptiform discharges in the sensorimotor cortex or a test of sensorimotor performance., Conclusion: These results provide evidence that cortical beta power in the seizure onset zone may provide a dynamic physiological biomarker of disease in BECTS., (© 2019 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.)

Background: Treatment of chronic hepatitis C (CHC) evolved rapidly due to the invention of interferon-free direct antiviral agents. Previous clinical trials showed combination therapy with paritaprevir/ritonavir, ombitasvir, and dasabuvir (PrOD) with or without ribavirin (RBV) can cure over 95% of genotype 1 CHC patients, regardless with cirrhosis or not. However, real-world data regarding the efficacy and safety of PrOD-based therapy in Asian HCV genotype 1 CHC patients are limited, especially for advanced-fibrotic patients who failed previous therapy with pegylated interferon (PEG-IFN) plus RBV., Methods: Between January and October 2017, 60 advanced fibrotic (≥F3) genotype 1 CHC patients who failed previous therapy with PEG-IFN and received PrOD-based therapy for 12 weeks were retrospectively enrolled. Weight-based RBV 800 to 1200 mg/d was added for genotype 1b patients with cirrhosis and all genotype 1a patients. Sustained virological response (SVR) was defined by undetectable HCV RNA at the end and 12 weeks after the completion of therapy., Results: The mean age was 63.2 ± 9.3 years, 26 (43.3%) of them were males and 20 (33.3%) were diagnosed to have liver cirrhosis. The mean baseline HCV RNA level was 6.19 ± 0.88 log10 IU/mL and 86.7% (52/60) of patients were infected by HCV genotype 1b. After PrOD-based therapy, the rates undetectable HCV RNA (<15 IU/mL) at week 2, 4, and 12 were 61.7%, 90.0%, and 100%, respectively; 69.6% (16/23) of patients with detectable HCV RNA at week 2 were < 100 IU/mL. Pruritus, fatigue, headache, insomnia, and dizziness were the most common patient-reported adverse events. Grade 2 hyperbilirubinemia were found in 21.6% (13/60) of patients during study period and all belonged to unconjugated hyperbilirubinemia. After posttherapy follow up, all 60 patients (100%) achieved SVR., Conclusion: Our real-world data in Taiwan revealed that PrOD-based rescue therapy is well-tolerated and highly effective for genotype 1 CHC patients with advanced fibrosis failing previous therapy with PEG-IFN plus RBV.

In a prospective cohort of 534 neonates with acute symptomatic seizures, 66% had incomplete response to the initial loading dose of antiseizure medication (ASM). Treatment response did not differ by gestational age, sex, medication, or dose. The risk of incomplete response was highest for seizures due to intracranial hemorrhage and lowest for hypoxic-ischemic encephalopathy, although the difference was not significant after adjusting for high seizure burden and therapeutic hypothermia treatment. Future trial design may test ASMs in neonates with all acute symptomatic seizure etiologies and could target neonates with seizures refractory to an initial ASM., (Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.)

Benign epilepsy with centrotemporal spikes is a common childhood epilepsy syndrome that predominantly affects boys, characterized by self-limited focal seizures arising from the perirolandic cortex and fine motor abnormalities. Concurrent with the age-specific presentation of this syndrome, the brain undergoes a developmentally choreographed sequence of white matter microstructural changes, including maturation of association u-fibres abutting the cortex. These short fibres mediate local cortico-cortical communication and provide an age-sensitive structural substrate that could support a focal disease process. To test this hypothesis, we evaluated the microstructural properties of superficial white matter in regions corresponding to u-fibres underlying the perirolandic seizure onset zone in children with this epilepsy syndrome compared with healthy controls. To verify the spatial specificity of these features, we characterized global superficial and deep white matter properties. We further evaluated the characteristics of the perirolandic white matter in relation to performance on a fine motor task, gender and abnormalities observed on EEG. Children with benign epilepsy with centrotemporal spikes ( n  = 20) and healthy controls ( n  = 14) underwent multimodal testing with high-resolution MRI including diffusion tensor imaging sequences, sleep EEG recordings and fine motor assessment. We compared white matter microstructural characteristics (axial, radial and mean diffusivity, and fractional anisotropy) between groups in each region. We found distinct abnormalities corresponding to the perirolandic u-fibre region, with increased axial, radial and mean diffusivity and fractional anisotropy values in children with epilepsy ( P  = 0.039, P  = 0.035, P  = 0.042 and P  = 0.017, respectively). Increased fractional anisotropy in this region, consistent with decreased integrity of crossing sensorimotor u-fibres, correlated with inferior fine motor performance ( P  = 0.029). There were gender-specific differences in white matter microstructure in the perirolandic region; males and females with epilepsy and healthy males had higher diffusion and fractional anisotropy values than healthy females ( P  ≤ 0.035 for all measures), suggesting that typical patterns of white matter development disproportionately predispose boys to this developmental epilepsy syndrome. Perirolandic white matter microstructure showed no relationship to epilepsy duration, duration seizure free, or epileptiform burden. There were no group differences in diffusivity or fractional anisotropy in superficial white matter outside of the perirolandic region. Children with epilepsy had increased radial diffusivity ( P  = 0.022) and decreased fractional anisotropy ( P  = 0.027) in deep white matter, consistent with a global delay in white matter maturation. These data provide evidence that atypical maturation of white matter microstructure is a basic feature in benign epilepsy with centrotemporal spikes and may contribute to the epilepsy, male predisposition and clinical comorbidities observed in this disorder., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Purpose: To analyze the visual outcomes and rate of intraoperative complications of phacoemulsification surgery after prior pars plana vitrectomy (PPV)., Design: Retrospective, multicenter database study., Participants: Eyes that underwent phacoemulsification between June 2005 and March 2015 at 8 sites in the United Kingdom., Methods: Study eyes were classified as vitrectomized (prior PPV group) or nonvitrectomized (reference group) depending on the vitreous state at the time of cataract surgery. Eyes with multiple intraocular surgeries or history of ocular diseases known to cause cataract progression or increased risk of intraoperative complications during phacoemulsification were excluded., Main Outcome Measures: Logarithm of the minimum angle of resolution (logMAR) visual acuity (VA), rate of intraoperative complications, and time interval to cataract surgery., Results: Eyes in the prior PPV group (n = 2221) had worse preoperative logMAR VA (0.96±0.60 vs. 0.62±0.52, P < 0.0001), were from younger patients, and had longer axial lengths than the nonvitrectomized group (n = 136 533). At all postoperative time points measured up to 24 weeks, mean vision was poorer in the prior PPV group (0.41±0.47 vs. 0.17±0.29 at 4-12 weeks, P < 0.0001) and a smaller proportion of eyes achieved postoperative VA ≤0.30 logMAR (Snellen, ≥20/40) (60.8% vs. 86.5% at 4-12 weeks, P < 0.0001). The rate of posterior capsular rupture was not different between the prior PPV (1.5%) and the nonvitrectomized (1.7%) groups, but the incidences of zonular dialysis (1.3% vs. 0.6%) and dropped nuclear fragments (0.6% vs. 0.2%) were higher in the prior PPV group (P < 0.0001). The mean time interval between PPV and cataract surgery was 399 days., Conclusions: We found a significant improvement in VA with postvitrectomy cataract surgery. However, compared with eyes without prior PPV, there was a worse mean postoperative vision of 0.2 logMAR units, a higher rate of zonular dialysis and dropped nuclear fragments, and a similar rate of posterior capsule rupture., (Copyright © 2018 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: How the human brain coordinates network activity to support cognition and behavior remains poorly understood. New high-resolution recording modalities facilitate a more detailed understanding of the human brain network. Several approaches have been proposed to infer functional networks, indicating the transient coordination of activity between brain regions, from neural time series. One category of approach is based on statistical modeling of time series recorded from multiple sensors (e.g., multivariate Granger causality). However, fitting such models remains computationally challenging as the history structure may be long in neural activity, requiring many model parameters to fully capture the dynamics., New Method: We develop a method based on Granger causality that makes the assumption that the history dependence varies smoothly. We fit multivariate autoregressive models such that the coefficients of the lagged history terms are smooth functions. We do so by modelling the history terms with a lower dimensional spline basis, which requires many fewer parameters than the standard approach and increases the statistical power of the model., Results: We show that this procedure allows accurate estimation of brain dynamics and functional networks in simulations and examples of brain voltage activity recorded from a patient with pharmacoresistant epilepsy., Comparison With Existing Method: The proposed method has more statistical power than the Granger method for networks of signals that exhibit extended and smooth history dependencies., Conclusions: The proposed tool permits conditional inference of functional networks from many brain regions with extended history dependence, furthering the applicability of Granger causality to brain network science., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: We assessed the adherence to neuroimaging guidelines and the diagnostically relevant yield of neuroimaging in newly presenting early life epilepsy (ELE)., Methods: There were 775 children with a new diagnosis of epilepsy (<3 years old at onset) who were recruited through the ELE study at 17 US pediatric epilepsy centers (2012-2015) and managed prospectively for 1 year. The data were analyzed to assess the proportion of children who underwent neuroimaging, the type of neuroimaging, and abnormalities., Results: Of 725 children (93.5%) with neuroimaging, 714 had an MRI (87% with seizure protocols) and 11 had computed tomography or ultrasound only. Etiologically relevant abnormalities were present in 290 individuals (40%) and included: an acquired injury in 97 (13.4%), malformations of cortical development in 56 (7.7%), and other diffuse disorders of brain development in 51 (7.0%). Neuroimaging was abnormal in 160 of 262 (61%) children with abnormal development at diagnosis versus 113 of 463 (24%) children with typical development. Neuroimaging abnormalities were most common in association with focal seizure semiology (40%), spasms (47%), or unclear semiology (42%). In children without spasms or focal semiology with typical development, 29 of 185 (16%) had imaging abnormalities. Pathogenic genetic variants were identified in 53 of 121 (44%) children with abnormal neuroimaging in whom genetic testing was performed., Conclusions: Structural abnormalities occur commonly in ELE, and adherence to neuroimaging guidelines is high at US pediatric epilepsy centers. These data support the universal adoption of imaging guidelines because the yield is substantially high, even in the lowest risk group., Competing Interests: POTENTIAL CONFLICT OF INTEREST: Dr Wirrell has received a consulting fee from Biomarin; Dr Knupp has served as a consultant for Zogenix and has an additional grant funded by the Pediatric Epilepsy Research Foundation; Dr Sullivan has served as an expert witness in various cases that involve seizures in children in which he was not subpoenaed. Subjects who were enrolled in this study by Dr Sullivan were seen as part of routine clinical care; Dr Patel discloses consulting with Greenwich Biosciences, UCB Pharma, Supernus, and LivaNova. He has pending or active grants with the Pediatric Epilepsy Research Foundation, Upsher-Smith, Greenwich Biosciences, and LivaNova; Dr Loddenkemper discloses board membership service on the council (and as president) of the American Clinical Neurophysiology Society and the American Board of Clinical Neurophysiology. He serves as committee chair at the American Epilepsy Society (Special Interest Group and Investigator Workshop committees) and as founder and consortium principal investigator of the pediatric Status Epilepticus Research Group. He received grant support from federal epilepsy-related groups as well as from pharmaceutical companies, including research support from the National Institutes of Health, the Patient-Centered Outcomes Research Institute, the Epilepsy Research Fund, the American Epilepsy Society, the Epilepsy Foundation of America, the Epilepsy Therapy Project, the Pediatric Epilepsy Research Foundation, and Citizens United for Research in Epilepsy, and he received research grants from Lundbeck, Eisai, Upsher-Smith, Mallinckrodt, Sage, and Pfizer. Dr Loddenkemper is part of pending patent applications to detect and predict seizures and to diagnose epilepsy; the other authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)

Objective: Benign epilepsy with centrotemporal spikes (BECTS) is a common, self-limited epilepsy syndrome affecting school-age children. Classic interictal epileptiform discharges (IEDs) confirm diagnosis, and BECTS is presumed to be pharmacoresponsive. As seizure risk decreases in time with this disease, we hypothesize that the impact of IEDs and anticonvulsive drug (ACD) treatment on the risk of subsequent seizure will differ based on disease duration., Methods: We calculate subsequent seizure risk following diagnosis in a large retrospective cohort of children with BECTS (n = 130), evaluating the impact of IEDs and ACD treatment in the first, second, third, and fourth years of disease. We use a Kaplan-Meier survival analysis and logistic regression models. Patients were censored if they were lost to follow-up or if they changed group status., Results: Two-thirds of children had a subsequent seizure within 2 years of diagnosis. The majority of children had a subsequent seizure within 3 years despite treatment. The presence of IEDs on electroencephalography (EEG) did not impact subsequent seizure risk early in the disease. By the fourth year of disease, all children without IEDs remained seizure free, whereas one-third of children with IEDs at this stage had a subsequent seizure. Conversely, ACD treatment corresponded with lower risk of seizure early in the disease but did not impact seizure risk in later years., Significance: In this cohort, the majority of children with BECTS had a subsequent seizure despite treatment. In addition, ACD treatment and IEDs predicted seizure risk at specific points of disease duration. Future prospective studies are needed to validate these exploratory findings.

Background: Treating articular cartilage lesions is clinically challenging. However, whether the addition of autologous platelet-rich plasma (PRP) to bioimplants along with early rehabilitation exercise provides therapeutic effects and regenerates the osteochondral defect remains uninvestigated., Hypothesis: The addition of PRP to a polylactic-co-glycolic acid (PLGA) scaffold along with continuous passive motion (CPM) in osteochondral defects may offer beneficial in situ microenvironment changes to facilitate hyaline cartilage and subchondral bone tissue repair., Study Design: Controlled laboratory study., Methods: In 26 rabbits, 52 critical osteochondral defects were created in bilateral femoral trochlear grooves. The rabbits were allocated to 1 of the following 3 groups: PRP gel (PG group), PRP + PLGA scaffold (PP group), and PRP + PLGA scaffold + CPM (PPC group). At 4 and 12 weeks after surgery, the specimens were assessed by a macroscopic examination, a histological evaluation with immunohistochemical staining, and micro-computed tomography., Results: The PPC group exhibited the most favorable therapeutic outcomes in terms of hyaline cartilage regeneration. At week 4, the PPC group exhibited significantly higher levels of glycosaminoglycan (GAG) and collagen (COL) II and modest increases in COL I, matrix metalloproteinase-3 (MMP-3), and inflammatory cells with tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). At week 12, the PPC group had significantly higher tissue repair scores, corresponding to a sound articular cartilage surface and chondrocyte and collagen arrangement. This group demonstrated restored hyaline cartilage and mineralized bone volume per tissue volume, which had an integrating structure in the repair site. However, the PG and PP groups exhibited mainly fibrous tissue and fibrocartilage, corresponding to higher expressions of COL I, TNF-α, IL-6, and MMP-3., Conclusion: PRP with a PLGA graft along with early CPM exercise is promising for the repair of osteochondral defects in rabbit knee joints., Clinical Relevance: This study demonstrates the efficacy of a triad therapy involving the addition of PRP to bioimplants along with early CPM intervention for hyaline cartilage and subchondral regeneration. However, PRP alone (with or without PLGA implants) is limited to osteochondral defect repair without significant regeneration.

Background: Angelman syndrome (AS) is a neurodevelopmental disorder characterized by intellectual disability, speech and motor impairments, epilepsy, abnormal sleep, and phenotypic overlap with autism. Individuals with AS display characteristic EEG patterns including high-amplitude rhythmic delta waves. Here, we sought to quantitatively explore EEG architecture in AS beyond known spectral power phenotypes. We were motivated by studies of functional connectivity and sleep spindles in autism to study these EEG readouts in children with AS., Methods: We analyzed retrospective wake and sleep EEGs from children with AS (age 4-11) and age-matched neurotypical controls. We assessed long-range and short-range functional connectivity by measuring coherence across multiple frequencies during wake and sleep. We quantified sleep spindles using automated and manual approaches., Results: During wakefulness, children with AS showed enhanced long-range EEG coherence across a wide range of frequencies. During sleep, children with AS showed increased long-range EEG coherence specifically in the gamma band. EEGs from children with AS contained fewer sleep spindles, and these spindles were shorter in duration than their neurotypical counterparts., Conclusions: We demonstrate two quantitative readouts of dysregulated sleep composition in children with AS-gamma coherence and spindles-and describe how functional connectivity patterns may be disrupted during wakefulness. Quantitative EEG phenotypes have potential as biomarkers and readouts of target engagement for future clinical trials and provide clues into how neural circuits are dysregulated in children with AS., Competing Interests: All EEG studies and analyses were performed with institutional review board (IRB) approval.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Importance: More than half of infants with new-onset epilepsy have electroencephalographic and clinical features that do not conform to known electroclinical syndromes (ie, nonsyndromic epilepsy). Levetiracetam and phenobarbital are the most commonly prescribed medications for epilepsy in infants, but their comparative effectiveness is unknown., Objective: To compare the effectiveness of levetiracetam vs phenobarbital for nonsyndromic infantile epilepsy., Design, Setting, and Participants: The Early Life Epilepsy Study-a prospective, multicenter, observational cohort study conducted from March 1, 2012, to April 30, 2015, in 17 US medical centers-enrolled infants with nonsyndromic epilepsy and a first afebrile seizure between 1 month and 1 year of age., Exposures: Use of levetiracetam or phenobarbital as initial monotherapy within 1 year of the first seizure., Main Outcomes and Measures: The binary outcome was freedom from monotherapy failure at 6 months, defined as no second prescribed antiepileptic medication and freedom from seizures beginning within 3 months of initiation of treatment. Outcomes were adjusted for demographics, epilepsy characteristics, and neurologic history, as well as for observable selection bias using propensity score weighting and for within-center correlation using generalized estimating equations., Results: Of the 155 infants in the study (81 girls and 74 boys; median age, 4.7 months [interquartile range, 3.0-7.1 months]), those treated with levetiracetam (n = 117) were older at the time of the first seizure than those treated with phenobarbital (n = 38) (median age, 5.2 months [interquartile range, 3.5-8.2 months] vs 3.0 months [interquartile range, 2.0-4.4 months]; P < .001). There were no other significant bivariate differences. Infants treated with levetiracetam were free from monotherapy failure more often than those treated with phenobarbital (47 [40.2%] vs 6 [15.8%]; P = .01). The superiority of levetiracetam over phenobarbital persisted after adjusting for covariates, observable selection bias, and within-center correlation (odds ratio, 4.2; 95% CI, 1.1-16; number needed to treat, 3.5 [95% CI, 1.7-60])., Conclusions and Relevance: Levetiracetam may have superior effectiveness compared with phenobarbital for initial monotherapy of nonsyndromic epilepsy in infants. If 100 infants who received phenobarbital were instead treated with levetiracetam, 44 would be free from monotherapy failure instead of 16 by the estimates in this study. Randomized clinical trials are necessary to confirm these findings.

Infantile spasms are the defining seizures of West syndrome, a severe form of early life epilepsy with poorly-understood pathophysiology. We present a novel comparative analysis of infants with spasms versus other seizure-types and identify clinical, etiological, and molecular-genetic factors preferentially predisposing to spasms. We compared ages, clinical etiologies, and associated-genes between spasms and non-spasms groups in a multicenter cohort of 509 infants (<12months) with newly-diagnosed epilepsy. Gene ontology and pathway enrichment analysis of clinical laboratory-confirmed pathogenic variant-harboring genes was performed. Pathways, functions, and cellular compartments between spasms and non-spasms groups were compared. Spasms onset age was similar in infants initially presenting with spasms (6.1 months) versus developing spasms as a later seizure type (6.9 months) but lower in the non-spasms group (4.7 months, p<0.0001). This pattern held across most etiological categories. Gestational age negatively correlated with spasms onset-age (r = -0.29, p<0.0001) but not with non-spasm seizure age. Spasms were significantly preferentially associated with broad developmental and regulatory pathways, whereas motor functions and pathways including cellular response to stimuli, cell motility and ion transport were preferentially enriched in non-spasms. Neuronal cell-body organelles preferentially associated with spasms, while, axonal, dendritic, and synaptic regions preferentially associated with other seizures. Spasms are a clinically and biologically distinct infantile seizure type. Comparative clinical-epidemiological analyses identify the middle of the first year as the time of peak expression regardless of etiology. The inverse association with gestational age suggests the preterm brain must reach a certain post-conceptional, not just chronological, neurodevelopmental stage before spasms manifest. Clear differences exist between the biological pathways leading to spasms versus other seizure types and suggest that spasms result from dysregulation of multiple developmental pathways and involve different cellular components than other seizure types. This deeper level of understanding may guide investigations into pathways most critical to target in future precision medicine efforts.

Background & Aims: There have been reports of reactivation of hepatitis B virus (HBV) infection during treatment of hepatitis C virus (HCV) infection with direct-acting antiviral agents. We performed a prospective study of risks and outcomes of HCV infection treatment with ledipasvir and sofosbuvir in patients with HBV infection., Methods: We performed a phase 3b, multicenter, open-label study in Taiwan of 111 patients with HCV infection (61% HCV genotype 1, 39% HCV genotype 2 infection; 62% women, 16% with compensated cirrhosis) along with HBV infection. All but 1 were positive for the hepatitis B surface antigen (HBsAg); 1 patient who was HBsAg-positive at screening was found to be HBsAg-negative at baseline. Overall, 33% of participants had received prior treatment for HCV and 5% had previously been treated for HBV; no patient was on HBV therapy at the start of the study. All patients received a fixed-dose combination of 90 mg of the HCV NS5A inhibitor ledipasvir with 400 mg of the NS5B nucleotide analogue inhibitor sofosbuvir, once daily for 12 weeks. The primary endpoint was sustained virologic response 12 weeks after the end of therapy., Results: All 111 patients (100%) achieved a sustained virologic response. Of the 37 patients with baseline HBV DNA below 20 IU/mL, 31 (84%) had at least 1 episode of quantifiable HBV DNA through posttreatment week 12. Of the 74 patients with baseline HBV DNA levels of 20 IU/mL or more, 39 (53%) had increases of HBV DNA greater than 1 log 10 IU/mL through posttreatment week 12. Overall, 5 patients had increased levels of HBV DNA concomitant with a level of alanine aminotransferase >2 times the upper limit of normal through posttreatment week 12. Of these, 3 patients started HBV treatment. In addition, 1 patient with HBV reactivation since week 8 and concomitant alanine aminotransferase elevation >2 times upper limit of normal at posttreatment week 48 started treatment at posttreatment week 53. This patient had clinical signs and symptoms associated with HBV reactivation. The most common adverse events were headache, upper respiratory infection, and fatigue., Conclusions: In a prospective study, the combination of ledipasvir and sofosbuvir for 12 weeks produced a sustained virologic response in 100% of patients with HCV infection who were coinfected with HBV. Most patients had an increase in level of HBV DNA not associated with signs or symptoms. ClinicalTrials.gov no: NCT02613871., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Importance: Primary epiretinal membrane (ERM) is a common retinal disorder with a prevalence of 4% to 18.5%. Although ERM and cataracts commonly occur together, to our knowledge, no studies have investigated the outcome of cataract surgery alone in this setting., Objective: To analyze the visual outcome and cystoid macular edema risk with cataract surgery in eyes with primary ERM., Design, Setting, and Participants: In this retrospective clinical database study, data were collected from July 2003 to March 2015 from 8 locations in the United Kingdom. Cataract surgery data of 217 557 eyes were extracted from the electronic medical record of the UK National Health Service. After exclusion of 57 561 eyes with combined surgery, prior vitrectomy, copathology, and complications, 812 eyes with primary ERM and 159 184 reference eyes were analyzed., Main Outcomes and Measures: We report on visual acuity (VA), the incidence of cystoid macular edema, and the need for ERM surgery., Results: The mean (SD) age of patients in the ERM group was 73.7 (9.23) years, and 395 of 812 were men (46.8%). The mean (SD) age of patients in the reference group was 74.4 (12.19) years, and 65 265 of 159 184 were men (41%). Epiretinal membrane eyes assessed at 4 to 12 weeks postoperatively gained 0.27 (0.32) logMAR (approximately 3 Snellen lines), with 200 of 448 (44.6%) improving by 0.30 logMAR or more (≥3 Snellen lines) and 32 of 448 (7.1%) worsening by 0.30 logMAR or more. Reference eyes gained a mean (SD) of 0.44 (0.26) logMAR (approximately 4 Snellen lines), with 48 583 of 77 408 (62.8%) improving by 0.30 logMAR or more and 2125 of 77 408 (2.7%) worsening by 0.30 logMAR or more. Although all eyes with preoperative VA of 20/40 or less improved, only reference eyes with preoperative VA of more than 20/40 showed improvement. Cystoid macular edema developed in 57 of 663 ERM eyes (8.6%) (95% CI, 6.69-10.98) and 1731 of 125 435 reference eyes (1.38%) (95% CI, 1.32-1.45) (P < .001). Epiretinal membrane surgery was performed in 43 of 663 (6.5%) ERM eyes., Conclusions and Relevance: On average, VA improved 0.27 logMAR (approximately 3 Snellen lines) in eyes with ERM. Eyes with ERM and VA of 20/40 or less showed more benefit after cataract surgery than those with better preoperative vision. However, compared with eyes without ERM, higher rates of cystoid macular edema and a lower postoperative VA gain were noted.

Objective: The multicenter National Infantile Spasms Consortium prospective cohort was used to compare outcomes and phenotypic features of patients with infantile spasms with and without hypsarrhythmia., Methods: Patients aged 2 months to 2 years were enrolled prospectively with new-onset infantile spasms. Treatment choice and categorization of hypsarrhythmia were determined clinically at each site. Response to therapy was defined as resolution of clinical spasms (and hypsarrhythmia if present) without relapse 3 months after initiation., Results: Eighty-two percent of patients had hypsarrhythmia, but this was not associated with gender, mean age, preexisting developmental delay or epilepsy, etiology, or response to first-line therapy. Infants with hypsarrhythmia were more likely to receive standard treatment (adrenocorticotropic hormone, prednisolone, or vigabatrin [odds ratio (OR) 2.6, 95% confidence interval (CI) 1.4-4.7] and preexisting epilepsy reduced the likelihood of standard treatment (OR 3.2, 95% CI 1.9-5.4). Hypsarrhythmia was not a determinant of response to treatment. A logistic regression model demonstrated that later age of onset (OR 1.09 per month, 95% CI 1.03-1.15) and absence of preexisting epilepsy (OR 1.7, 95% CI 1.06-2.81) had a small impact on the likelihood of responding to the first-line treatment. However, receiving standard first-line treatment increased the likelihood of responding dramatically: vigabatrin (OR 5.2 ,95% CI 2-13.7), prednisolone (OR 8, 95% CI 3.1-20.6), and adrenocorticotropic hormone (ACTH; OR 10.2, 95% CI 4.1-25.8) ., Significance: First-line treatment with standard therapy was by far the most important variable in determining likelihood of response to treatment of infantile spasms with or without hypsarrhythmia., (Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.)

Background and Aim: This multinational (Taiwan, South Korea, Russia) phase 3 study evaluated the all-oral, ribavirin-free, fixed-dose combination (DCV-TRIO) of daclatasvir (NS5A inhibitor) 30 mg, asunaprevir (NS3 inhibitor) 200 mg, and beclabuvir (NS5B inhibitor) 75 mg, in patients with chronic hepatitis C virus genotype-1 infection, with or without compensated cirrhosis., Methods: UNITY-4 (NCT02170727) was an open-label, two-cohort study in which 169 patients, treatment-naive (n = 138) or treatment-experienced (n = 31), received twice-daily DCV-TRIO for 12 weeks with 24 weeks of post-treatment follow-up. The primary efficacy end point was sustained virologic response at post-treatment week 12 (SVR12) in treatment-naive patients., Results: Eighty-eight (52%) patients were men, 81 (48%) Taiwanese, 78 (46%) Korean, and 10 (6%) Russian; 23 (14%) had compensated cirrhosis, and 52 (31%) were IL28B (rs1297860) non-CC genotype. Baseline resistance-associated NS5A polymorphisms (L31 and/or Y93) were detected in 25/165 (15%) patients with available genotype-1 sequencing data. SVR12 was achieved by 98.6% (136/138; 95% confidence interval: 94.9-99.8%) of treatment-naive and 100% (31/31; 95% confidence interval: 88.8-100%) of treatment-experienced patients. Both virologic failures were found to be infected with hepatitis C virus genotype-6g; 100% SVR12 was observed for genotype-1a (n = 8) and genotype-1b (n = 157). Two patients experienced serious adverse events. Eight (5%) patients experienced reversible grade 3/4 alanine aminotransferase or aspartate aminotransferase elevations, leading to discontinuation in four (2%); all achieved SVR12. There were no grade 3/4 total bilirubin increases and no deaths., Conclusions: Twelve weeks of DCV-TRIO was well tolerated and provided 100% SVR12 in treatment-naive and treatment-experienced patients with genotype-1 infection, with or without cirrhosis, including those with baseline NS5A-L31 or NS5A-Y93 resistance-associated substitutions., (© 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Objective: There are no evidence-based guidelines on the preferred approach to treating early-life epilepsy. We examined initial therapy selection in a contemporary US cohort of children with newly diagnosed, nonsyndromic, early-life epilepsy (onset before age three years)., Methods: Seventeen pediatric epilepsy centers participated in a prospective cohort study of children with newly diagnosed epilepsy with onset under 36 months of age. Details regarding demographics, seizure types, and initial medication selections were obtained from medical records., Results: About half of the 495 enrolled children with new-onset, nonsyndromic epilepsy were less than 12 months old at the time of diagnosis (n = 263, 53%) and about half (n = 260, 52%) had epilepsy with focal features. Of 464 who were treated with monotherapy, 95% received one of five drugs: levetiracetam (n = 291, 63%), oxcarbazepine (n = 67, 14%), phenobarbital (n = 57, 12%), topiramate (n = 16, 3.4%), and zonisamide (n = 13, 2.8%). Phenobarbital was prescribed first for 50 of 163 (31%) infants less than six months old versus seven of 300 (2.3%) of children six months or older (P < 0.0001). Although the first treatment varied across study centers (P < 0.0001), levetiracetam was the most commonly prescribed medication regardless of epilepsy presentation (focal, generalized, mixed/uncertain). Between the first and second treatment choices, 367 (74%) of children received levetiracetam within the first year after diagnosis., Conclusions: Without any specific effort, the pediatric epilepsy community has developed an unexpectedly consistent approach to initial treatment selection for early-life epilepsy. This suggests that a standard practice is emerging and could be utilized as a widely acceptable basis of comparison in future drug studies., (Copyright © 2017 Elsevier Inc. All rights reserved.)

PurposeThe aim of this study was to determine a sequence of structural changes in acute posterior multifocal placoid pigment epitheliopathy (APMPPE) using optical coherence tomography-angiography (OCT-A) and comparing with other imaging modalities.Patients and methodsPatients with a new diagnosis of acute-onset APMPPE referred to a regional specialist centre from October 2015 to October 2016 were included. Multimodal imaging employed on all patients from diagnosis included the following: fundus fluorescein angiography, indocyanine green angiography, fundus autofluorescence, spectral domain-OCT (SD-OCT), and OCT-A. All non-invasive imaging processes were repeated during follow-up.ResultsTen eyes of five patients were included in the study, three males and two females, with a mean age of 26.2 years (range: 21-32) and a mean follow-up of 6.4 months (range: 2.6-13.3). All patients presented with bilateral disease and macular involving lesions. OCT-A imaging of the choriocapillaris was supportive of hypoperfusion at the site of APMPPE lesions during the acute phase of this condition with normalisation of choroidal vasculature during follow-up. Multimodal imaging consistently highlighted four sequential phases from presentation to resolution of active disease.ConclusionsMultimodal imaging in patients with APMPPE in acute and long-term follow-up demonstrates a reversible choroidal hypoperfusion supporting the primary inciting pathology as a choriocapillaritis. The evolution shows resolution of the ischaemia through a defined sequence that results in persistent changes at the level of the retinal pigment epithelium and outer retina. OCT-A was able to detect preclinical changes and chart resolution at the level of the choriocapillaris.

See Schiff (doi:10.1093/awx209) for a scientific commentary on this article. Patients with acute severe traumatic brain injury may recover consciousness before self-expression. Without behavioural evidence of consciousness at the bedside, clinicians may render an inaccurate prognosis, increasing the likelihood of withholding life-sustaining therapies or denying rehabilitative services. Task-based functional magnetic resonance imaging and electroencephalography techniques have revealed covert consciousness in the chronic setting, but these techniques have not been tested in the intensive care unit. We prospectively enrolled 16 patients admitted to the intensive care unit for acute severe traumatic brain injury to test two hypotheses: (i) in patients who lack behavioural evidence of language expression and comprehension, functional magnetic resonance imaging and electroencephalography detect command-following during a motor imagery task (i.e. cognitive motor dissociation) and association cortex responses during language and music stimuli (i.e. higher-order cortex motor dissociation); and (ii) early responses to these paradigms are associated with better 6-month outcomes on the Glasgow Outcome Scale-Extended. Patients underwent functional magnetic resonance imaging on post-injury Day 9.2 ± 5.0 and electroencephalography on Day 9.8 ± 4.6. At the time of imaging, behavioural evaluation with the Coma Recovery Scale-Revised indicated coma (n = 2), vegetative state (n = 3), minimally conscious state without language (n = 3), minimally conscious state with language (n = 4) or post-traumatic confusional state (n = 4). Cognitive motor dissociation was identified in four patients, including three whose behavioural diagnosis suggested a vegetative state. Higher-order cortex motor dissociation was identified in two additional patients. Complete absence of responses to language, music and motor imagery was only observed in coma patients. In patients with behavioural evidence of language function, responses to language and music were more frequently observed than responses to motor imagery (62.5-80% versus 33.3-42.9%). Similarly, in 16 matched healthy subjects, responses to language and music were more frequently observed than responses to motor imagery (87.5-100% versus 68.8-75.0%). Except for one patient who died in the intensive care unit, all patients with cognitive motor dissociation and higher-order cortex motor dissociation recovered beyond a confusional state by 6 months. However, 6-month outcomes were not associated with early functional magnetic resonance imaging and electroencephalography responses for the entire cohort. These observations suggest that functional magnetic resonance imaging and electroencephalography can detect command-following and higher-order cortical function in patients with acute severe traumatic brain injury. Early detection of covert consciousness and cortical responses in the intensive care unit could alter time-sensitive decisions about withholding life-sustaining therapies., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Importance: Early-life epilepsies are often a consequence of numerous neurodevelopmental disorders, most of which are proving to have genetic origins. The role of genetic testing in the initial evaluation of these epilepsies is not established., Objective: To provide a contemporary account of the patterns of use and diagnostic yield of genetic testing for early-life epilepsies., Design, Setting, and Participants: In this prospective cohort, children with newly diagnosed epilepsy with an onset at less than 3 years of age were recruited from March 1, 2012, to April 30, 2015, from 17 US pediatric hospitals and followed up for 1 year. Of 795 families approached, 775 agreed to participate. Clinical diagnosis of the etiology of epilepsy were characterized based on information available before genetic testing was performed. Added contributions of cytogenetic and gene sequencing investigations were determined., Exposures: Genetic diagnostic testing., Main Outcomes and Measures: Laboratory-confirmed pathogenic variant., Results: Of the 775 patients in the study (367 girls and 408 boys; median age of onset, 7.5 months [interquartile range, 4.2-16.5 months]), 95 (12.3%) had acquired brain injuries. Of the remaining 680 patients, 327 (48.1%) underwent various forms of genetic testing, which identified pathogenic variants in 132 of 327 children (40.4%; 95% CI, 37%-44%): 26 of 59 (44.1%) with karyotyping, 32 of 188 (17.0%) with microarrays, 31 of 114 (27.2%) with epilepsy panels, 11 of 33 (33.3%) with whole exomes, 4 of 20 (20.0%) with mitochondrial panels, and 28 of 94 (29.8%) with other tests. Forty-four variants were identified before initial epilepsy presentation. Apart from dysmorphic syndromes, pathogenic yields were highest for children with tuberous sclerosis complex (9 of 11 [81.8%]), metabolic diseases (11 of 14 [78.6%]), and brain malformations (20 of 61 [32.8%]). A total of 180 of 446 children (40.4%), whose etiology would have remained unknown without genetic testing, underwent some testing. Pathogenic variants were identified in 48 of 180 children (26.7%; 95% CI, 18%-34%). Diagnostic yields were greater than 15% regardless of delay, spasms, and young age. Yields were greater for epilepsy panels (28 of 96 [29.2%]; P < .001) and whole exomes (5 of 18 [27.8%]; P = .02) than for chromosomal microarray (8 of 101 [7.9%])., Conclusions and Relevance: Genetic investigations, particularly broad sequencing methods, have high diagnostic yields in newly diagnosed early-life epilepsies regardless of key clinical features. Thorough genetic investigation emphasizing sequencing tests should be incorporated into the initial evaluation of newly presenting early-life epilepsies and not just reserved for those with severe presentations and poor outcomes.

Objective: Although individual neonatal epilepsy syndromes are rare, as a group they represent a sizable subgroup of neonatal seizure etiologies. We evaluated the profile of neonatal epilepsies in a prospective cohort of newborns with seizures., Methods: Consecutive newborns with seizures were enrolled in the Neonatal Seizure Registry (an association of 7 US children's hospitals). Treatment and diagnostic testing were at the clinicians' discretion. Neonates with seizures related to epileptic encephalopathies (without structural brain abnormalities), brain malformations, or benign familial epilepsies were included in this analysis., Results: Among 611 consecutive newborns with seizures, 79 (13%) had epilepsy (35 epileptic encephalopathy, 32 congenital brain malformations, 11 benign familial neonatal epilepsy [BFNE], 1 benign neonatal seizures). Twenty-nine (83%) with epileptic encephalopathy had genetic testing and 24/29 (83%) had a genetic etiology. Pathogenic or likely pathogenic KCNQ2 variants (n = 10) were the most commonly identified etiology of epileptic encephalopathy. Among 23 neonates with brain malformations who had genetic testing, 7 had putative genetic etiologies. Six infants with BFNE had genetic testing; 3 had pathogenic KCNQ2 variants and 1 had a pathogenic KCNQ3 variant. Comorbid illnesses that predisposed to acute symptomatic seizures occurred in 3/35 neonates with epileptic encephalopathy vs 10/32 with brain malformations ( p = 0.03). Death or discharge to hospice were more common among newborns with brain malformations (11/32) than those with epileptic encephalopathy (3/35, p = 0.01)., Conclusions: Neonatal epilepsy is often due to identifiable genetic causes. Genetic testing is now warranted for newborns with epilepsy in order to guide management and inform discussions of prognosis., (© 2017 American Academy of Neurology.)

Background/aims: Cataract is an important source of visual loss in patients with uveitis. Whether or not outcomes of cataract surgery in eyes with uveitis are worse compared with non-uveitic eyes have to date been compromised by lack of reliable estimates of benefit and harm, which require data from large cohorts., Methods: Electronic medical record data were extracted from eight independent UK clinical sites for eyes undergoing cataract extraction between January 2010 and December 2014. 1173 eyes with a recorded diagnosis of uveitis were compared with a reference group of 95 573 eyes from the same dataset., Results: Uveitic eyes represented 1.2% of all eyes undergoing cataract surgery. Eyes in the uveitic group had worse preoperative visual acuity (0.87 vs 0.65 logarithm of the minimum angle of resolution (logMAR) units), were from younger patients and had shorter axial lengths and a higher incidence of ocular copathology including glaucoma. A greater number had documented small pupils, required additional surgical procedures, developed more intraoperative complications and had poorer postoperative visual acuity at all time points measured up to 6 months (0.41 vs 0.27 logMAR units at 12-24 weeks)., Conclusions: This large study cohort of eyes with a diagnosis of uveitis undergoing cataract surgery highlights more precisely the complex surgical demands, copathology and worse visual outcomes in this group. These data will allow more accurate preoperative counselling and planning. Although improvement in visual acuity is achieved in most cases, prognosis should be guarded, so that patient expectations are met. Compared with the non-uveitic population, the mean postoperative visual acuity is between one and two lines worse at all time points., Competing Interests: Competing interests: There are no direct competing interests relating to this manuscript. Alcon (Fort Worth, TX, USA) provided a research grant to cover the cost of the initial data extraction, but has not played any role in the study design or conduct. All authors have completed ICMJE disclosure forms. RLJ is a shareholder and the Medical Director of Medisoft Limited., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)