A 3D printable alloy designed for extreme environments.

Multiprincipal-element alloys are an enabling class of materials owing to their impressive mechanical and oxidation-resistant properties, especially in extreme environments1,2. Here we develop a new oxide-dispersion-strengthened NiCoCr-based alloy using a model-driven alloy design approach and laser-based additive manufacturing. This oxide-dispersion-strengthened alloy, called GRX-810, uses laser powder bed fusion to disperse nanoscale Y2O3 particles throughout the microstructure without the use of resource-intensive processing steps such as mechanical or in situ alloying3,4. We show the successful incorporation and dispersion of nanoscale oxides throughout the GRX-810 build volume via high-resolution characterization of its microstructure. The mechanical results of GRX-810 show a twofold improvement in strength, over 1,000-fold better creep performance and twofold improvement in oxidation resistance compared with the traditional polycrystalline wrought Ni-based alloys used extensively in additive manufacturing at 1,093 °C5,6. The success of this alloy highlights how model-driven alloy designs can provide superior compositions using far fewer resources compared with the 'trial-and-error' methods of the past. These results showcase how future alloy development that leverages dispersion strengthening combined with additive manufacturing processing can accelerate the discovery of revolutionary materials.

Predicting the functional state of protein kinases using interpretable graph neural networks from sequence and structural data.

Protein kinases are central to cellular activities and are actively pursued as drug targets for several conditions including cancer and autoimmune diseases. Despite the availability of a large structural database for kinases, methodologies to elucidate the structure-function relationship of these proteins (without manual intervention) are lacking. Such techniques are essential in structural biology and to accelerate drug discovery efforts. Here, we implement an interpretable graph neural network (GNN) framework for classifying the functionally active and inactive states of a large set of protein kinases by only using their tertiary structure and amino acid sequence. We show that the GNN models can classify kinase structures with high accuracy (>97%). We implement the Gradient-weighted Class Activation Mapping for graphs (Graph Grad-CAM) to automatically identify structurally important residues and residue-residue contacts of the kinases without any a priori input. We show that the motifs identified through the Graph Grad-CAM methodology are functionally critical, consistent with the existing kinase literature. Notably, the highly conserved DFG and HRD motifs of the well-known hydrophobic spine are identified by the interpretable framework in addition to some of the lesser known motifs. Further, using Grad-CAM maps as the vector embedding of the protein structures, we identify the subtle differences in the crystal structures among different sub-classes of kinases in the Protein Data Bank (PDB). Frameworks such as the one implemented here, for high-throughput identification of protein structure-function relationships are essential in designing targeted small molecules therapies as well as in engineering new proteins for novel applications.

Clustered mutations in the GRIK2 kainate receptor subunit gene underlie diverse neurodevelopmental disorders.

Kainate receptors (KARs) are glutamate-gated cation channels with diverse roles in the central nervous system. Bi-allelic loss of function of the KAR-encoding gene GRIK2 causes a nonsyndromic neurodevelopmental disorder (NDD) with intellectual disability and developmental delay as core features. The extent to which mono-allelic variants in GRIK2 also underlie NDDs is less understood because only a single individual has been reported previously. Here, we describe an additional eleven individuals with heterozygous de novo variants in GRIK2 causative for neurodevelopmental deficits that include intellectual disability. Five children harbored recurrent de novo variants (three encoding p.Thr660Lys and two p.Thr660Arg), and four children and one adult were homozygous for a previously reported variant (c.1969G>A [p.Ala657Thr]). Individuals with shared variants had some overlapping behavioral and neurological dysfunction, suggesting that the GRIK2 variants are likely pathogenic. Analogous mutations introduced into recombinant GluK2 KAR subunits at sites within the M3 transmembrane domain (encoding p.Ala657Thr, p.Thr660Lys, and p.Thr660Arg) and the M3-S2 linker domain (encoding p.Ile668Thr) had complex effects on functional properties and membrane localization of homomeric and heteromeric KARs. Both p.Thr660Lys and p.Thr660Arg mutant KARs exhibited markedly slowed gating kinetics, similar to p.Ala657Thr-containing receptors. Moreover, we observed emerging genotype-phenotype correlations, including the presence of severe epilepsy in individuals with the p.Thr660Lys variant and hypomyelination in individuals with either the p.Thr660Lys or p.Thr660Arg variant. Collectively, these results demonstrate that human GRIK2 variants predicted to alter channel function are causative for early childhood development disorders and further emphasize the importance of clarifying the role of KARs in early nervous system development.

Determination of γ/γ' interface free energy for solid state precipitation in Ni-Al alloys from molecular dynamics simulation.

Interface free energy is a fundamental material parameter needed to predict the nucleation and growth of new phases. The high cost of experimentally determining this parameter makes it an ideal target for calculation through a physically informed simulation. Direct determination of interface free energy has many challenges, especially for solid-solid transformations. Indirect determination of the interface free energy from the nucleation data has been done in the case of solidification. However, a slow on molecular dynamics (MD) simulation time scale atomic diffusion makes this method not applicable to the case of nucleation from the solid phase when precipitate composition is different from that in matrix. To address this challenge, we outline the development of a new technique for determining the critical nucleus size from an MD simulation using a recently developed method to accelerate solid-state diffusion. The accuracy of our approach for the Ni-Al system for Ni3Al (γ') precipitates in a Ni-Al (γ) matrix is demonstrated well within experimental accuracy and greatly improves upon previous computational methods [Herrnring et al., Acta Mater. 215(8), 117053 (2021)].

Acute Effects of Sprint Interval Training and Blood Flow Restriction on Neuromuscular and Muscle Function.

BFR) applied during sprint interval training (SIT) on performance and neuromuscular function. METHODS: Fifteen men completed a randomized bout of SIT with CBFR, IBFR, and without BFR (No-BFR), consisting of 2, 30-s maximal sprints on a cycle ergometer with a resistance of 7.5% of body mass. Concentric peak torque (CPT), maximal voluntary isometric contraction (MVIC) torque, and muscle thickness (MT) were measured before and after SIT, including surface electromyography (sEMG) recorded during the strength assessments. Peak and mean revolutions per minute (RPM) were measured during SIT and power output was examined relative to physical working capacity at the fatigue threshold (PWCFT). RESULTS: CPT and MVIC torque decreased from pre-SIT (220.3±47.6 Nm and 355.1±72.5 Nm, respectively) to post-SIT (147.9±27.7 Nm and 252.2±45.5 Nm, respectively, all P<0.05), while MT increased (1.77±0.31 cm to 1.96±0.30 cm). sEMG mean power frequency decreased during CPT (-12.8±10.5%) and MVIC (-8.7±10.2%) muscle actions. %PWCFT was greater during No-BFR (414.2±121.9%) than CBFR (375.9±121.9%). CONCLUSION: SIT with or without BFR induced comparable alterations in neuromuscular fatigue and sprint performance across all conditions, without affecting neuromuscular function.

Blood flow restriction increases necessary muscle excitation of the elbow flexors during a single high-load contraction.

PURPOSE: To investigate the effects of blood flow restriction (BFR) on electromyographic amplitude (EMGRMS)-force relationships of the biceps brachii (BB) during a single high-load muscle action. METHODS: Twelve recreationally active males and eleven recreationally active females performed maximal voluntary contractions (MVCs), followed by an isometric trapezoidal muscle action of the elbow flexors at 70% MVC. Surface EMG was recorded from the BB during BFR and control (CON) visits. For BFR, cuff pressure was 60% of the pressure required to completely occlude blood at rest. Individual b (slope) and a terms (gain) were calculated from the log-transformed EMGRMS-force relationships during the linearly increasing and decreasing segments of the trapezoid. EMGRMS during the steady force segment was normalized to MVC EMGRMS. RESULTS: For BFR, the b terms were greater during the linearly increasing segment than the linearly decreasing segment (p < 0.001), and compared to the linearly increasing segment for CON (p < 0.001). The a terms for BFR were greater during the linearly decreasing than linearly increasing segment (p = 0.028). Steady force N-EMGRMS was greater for BFR than CON collapsed across sex (p = 0.041). CONCLUSION: BFR likely elicited additional recruitment of higher threshold motor units during the linearly increasing- and steady force-segment. The differences between activation and deactivation strategies were only observed with BFR, such as the b terms decreased and the a terms increased for the linearly decreasing segment in comparison to the increasing segment. However, EMGRMS-force relationships during the linearly increasing- and decreasing-segments were not different between sexes during BFR and CON.

Progression and perceptual responses to blood flow restriction resistance training among people with multiple sclerosis.

PURPOSE: Resistance exercise can attenuate muscular impairments associated with multiple sclerosis (MS), and blood flow restriction (BFR) may provide a viable alternative to prescribing heavy training loads. The purpose of this investigation was to examine the progression of upper and lower body low-load (30% of one-repetition maximum [1RM]) resistance training (RT) with BFR applied intermittently during the exercise intervals (RT + BFR) versus volume-matched heavy-load (65% of 1RM) RT. METHODS: Men and women with MS (n = 16) were randomly assigned to low-load RT + BFR (applied intermittently) or heavy-load RT and completed 12 weeks (2 × /week) of RT that consisted of bilateral chest press, seated row, shoulder press, leg press, leg extension, and leg curl exercises. Exercise load, tonnage, and rating of perceived exertion were assessed at baseline and every 6 weeks. RESULTS: Training load increased to a greater extent and sometimes earlier for RT + BFR (57.7-106.3%) than heavy-load RT (42.3-54.3%) during chest press, seated row, and leg curl exercises, while there were similar increases (63.5-101.1%) for shoulder press, leg extension, and leg press exercises. Exercise tonnage was greater across all exercises for RT + BFR than heavy-load RT, although tonnage only increased during the chest press (70.7-80.0%) and leg extension (89.1%) exercises. Perceptions of exertion (4.8-7.2 au) and compliance (97.9-99.0%) were similar for both interventions. CONCLUSION: The training-induced increases in load, high compliance, and moderate levels of exertion suggested that RT + BFR and heavy-load RT are viable interventions among people with MS. RT + BFR may be a preferred modality if heavy loads are not well tolerated and/or to promote early-phase training responses.

A Moderate Blood Flow Restriction Pressure Does Not Affect Maximal Strength or Neuromuscular Responses.

ABSTRACT: Lubiak, SM, Lawson, JE, Gonzalez Rojas, DH, Proppe, CE, Rivera, PM, Hammer, SM, Trevino, MA, Dinyer-McNeely, TK, Montgomery, TR, Olmos, AA, Sears, KN, Bergstrom, HC, Succi, PJ, Keller, JL, and Hill, EC. A moderate blood flow restriction pressure does not affect maximal strength or neuromuscular responses. J Strength Cond Res XX(X): 000-000, 2024-The purpose of this study was to examine the acute effects of blood flow restriction (BFR) applied at 60% of total arterial occlusion pressure (AOP) on maximal strength. Eleven college-aged female subjects completed two testing sessions of maximal unilateral concentric, isometric, and eccentric leg extension muscle actions performed with and without BFR. Separate 3 (mode [isometric, concentric, eccentric]) × 2 (condition [BFR, no BFR]) × 2 (visit [2, 3]) repeated-measures analysis of variances were used to examine mean differences in maximal strength, neuromuscular function, rating of perceived exertion (RPE), and pain. For maximal strength (collapsed across condition and visit), isometric (128.5 ± 22.7 Nm) and eccentric (114.5 ± 35.4 Nm) strength were greater than concentric maximal strength (89.3 ± 22.3 Nm) (p < 0.001-0.041). Muscle excitation relative (%) to isometric non-BFR was greater during the concentric (108.6 ± 31.5%) than during the eccentric (86.7 ± 29.2%) (p = 0.045) assessments but not different than isometric (93.4 ± 17.9%) (p = 0.109) assessments, collapsed across condition and visit. For RPE, there was an interaction such that RPE was greater during non-BFR (4.3 ± 1.7) than during BFR (3.7 ± 1.7) (p = 0.031) during the maximal concentric strength assessments. Furthermore, during maximal strength assessments performed with BFR, isometric RPE (5.8 ± 1.9) was greater than concentric (3.7 ± 1.7) (p = 0.005) and eccentric (4.6 ± 1.9) (p = 0.009) RPE. Finally, pain was greater during the isometric (2.8 ± 2.1 au) than during the concentric (1.8 ± 1.5 au) (p = 0.016), but not eccentric, maximal strength assessments (2.1 ± 1.6 au) (p = 0.126), collapsed across condition and visit. The application of BFR at 60% AOP did not affect concentric, isometric, or eccentric maximal strength or neuromuscular function. Trainers, clinicians, and researchers can prescribe exercise interventions relative to a restricted (when using a moderate AOP) or nonrestricted assessment of maximal strength.

Acute effects of low load blood flow restricted and non restricted exercise on muscle excitation, neuromuscular efficiency, and average torque.

OBJECTIVES: The purpose of this investigation was to examine the acute effects of low-load blood flow restriction (LLBFR) and low-load (LL) resistance exercise on muscle excitation, neuromuscular efficiency, and average torque. METHODS: Eleven men (age±SD=22±3yrs) randomly performed LLBFR and LL that consisted of 30 unilateral leg extensions at 30% of one-repetition maximum while surface electromyography (sEMG) and torque were simultaneously assessed. Polynomial regression analyses and slope comparisons were performed to examine patterns of responses and rates of change. RESULTS: sEMG amplitude increased for LLBFR (9 of 11) and LL (8 of 11) and between composite responses (R2=0.939-0.981). For LLBFR, sEMG amplitude increased to a greater extent for 5 of the 11 individual and for the composite responses. Similarly, neuromuscular efficiency decreased for LLBFR (8 of 11) and LL (5 of 11) as well as the composite responses r2=0.902-0.929, but the decrease was larger for LLBFR than LL for the individual (4 of 11) responses. For average submaximal concentric torque, there were individual increases, decreases, and no changes for the composite responses (R2=0.198-0.325). CONCLUSION: LLBFR elicited greater fatigue-induced increases in muscle excitation and decreases in neuromuscular efficiency than LL, but neither LLBFR nor LL affected average submaximal concentric torque.

GenomicDistributions: fast analysis of genomic intervals with Bioconductor.

BACKGROUND: Epigenome analysis relies on defined sets of genomic regions output by widely used assays such as ChIP-seq and ATAC-seq. Statistical analysis and visualization of genomic region sets is essential to answer biological questions in gene regulation. As the epigenomics community continues generating data, there will be an increasing need for software tools that can efficiently deal with more abundant and larger genomic region sets. Here, we introduce GenomicDistributions, an R package for fast and easy summarization and visualization of genomic region data. RESULTS: GenomicDistributions offers a broad selection of functions to calculate properties of genomic region sets, such as feature distances, genomic partition overlaps, and more. GenomicDistributions functions are meticulously optimized for best-in-class speed and generally outperform comparable functions in existing R packages. GenomicDistributions also offers plotting functions that produce editable ggplot objects. All GenomicDistributions functions follow a uniform naming scheme and can handle either single or multiple region set inputs. CONCLUSIONS: GenomicDistributions offers a fast and scalable tool for exploratory genomic region set analysis and visualization. GenomicDistributions excels in user-friendliness, flexibility of outputs, breadth of functions, and computational performance. GenomicDistributions is available from Bioconductor ( https://bioconductor.org/packages/release/bioc/html/GenomicDistributions.html ).

Nature of the Electrical Double Layer on Suspended Graphene Electrodes.

The structure of interfacial water near suspended graphene electrodes in contact with aqueous solutions of Na2SO4, NH4Cl, and (NH4)2SO4 has been studied using confocal Raman spectroscopy, sum frequency vibrational spectroscopy, and Kelvin probe force microscopy. SO42- anions were found to preferentially accumulate near the interface at an open circuit potential (OCP), creating an electrical field that orients water molecules below the interface, as revealed by the increased intensity of the O-H stretching peak of H-bonded water. No such increase is observed with NH4Cl at the OCP. The intensity of the dangling O-H bond stretching peak however remains largely unchanged. The degree of orientation of the water molecules as well as the electrical double layer strength increased further when positive voltages are applied. Negative voltages on the other hand produced only small changes in the intensity of the H-bonded water peaks but affected the intensity and frequency of dangling O-H bond peaks. The TOC figure is an oversimplified representation of the system in this work.

Methotrexate-related central neurotoxicity: clinical characteristics, risk factors and genome-wide association study in children treated for acute lymphoblastic leukemia.

Symptomatic methotrexate-related central neurotoxicity (MTX neurotoxicity) is a severe toxicity experienced during acute lymphoblastic leukemia (ALL) therapy with potential long-term neurologic complications. Risk factors and long-term outcomes require further study. We conducted a systematic, retrospective review of 1,251 consecutive Australian children enrolled on Berlin-Frankfurt-Münster or Children's Oncology Group-based protocols between 1998-2013. Clinical risk predictors for MTX neurotoxicity were analyzed using regression. A genome-wide association study (GWAS) was performed on 48 cases and 537 controls. The incidence of MTX neurotoxicity was 7.6% (n=95 of 1,251), at a median of 4 months from ALL diagnosis and 8 days after intravenous or intrathecal MTX. Grade 3 elevation of serum aspartate aminotransferase (P=0.005, odds ratio 2.31 [range, 1.28-4.16]) in induction/consolidation was associated with MTX neurotoxicity, after accounting for the only established risk factor, age ≥10 years. Cumulative incidence of CNS relapse was increased in children where intrathecal MTX was omitted following symptomatic MTX neurotoxicity (n=48) compared to where intrathecal MTX was continued throughout therapy (n=1,174) (P=0.047). Five-year central nervous system relapse-free survival was 89.2 4.6% when intrathecal MTX was ceased compared to 95.4 0.6% when intrathecal MTX was continued. Recurrence of MTX neurotoxicity was low (12.9%) for patients whose intrathecal MTX was continued after their first episode. The GWAS identified single-nucletide polymorphism associated with MTX neurotoxicity near genes regulating neuronal growth, neuronal differentiation and cytoskeletal organization (P<1x10-6). In conclusion, increased serum aspartate aminotransferase and age ≥10 years at diagnosis were independent risk factors for MTX neurotoxicity. Our data do not support cessation of intrathecal MTX after a first MTX neurotoxicity event.

Efficacy and safety of cannabidivarin treatment of epilepsy in girls with Rett syndrome: A phase 1 clinical trial.

OBJECTIVE: Rett syndrome (RTT), commonly caused by methyl-CpG-binding protein 2 (MECP2) pathogenic variants, has many comorbidities. Fifty to ninety percent of children with RTT have epilepsy, which is often drug-resistant. Cannabidivarin (CBDV), a non-hallucinogenic phytocannabinoid, has shown benefit in MECP2 animal models. This phase 1 trial assessed the safety and tolerability of CBDV in female children with RTT and drug-resistant epilepsy, as well as the effect on mean monthly seizure frequency (MMSF), the electroencephalogram (EEG), and non-epilepsy comorbid symptoms. METHODS: Five female children with drug-resistant epilepsy and a pathogenic MECP2 variant were enrolled. Baseline clinical and laboratory assessments, including monthly seizure frequency, were recorded. CBDV oral solution (50 mg/ml) was prescribed and titrated to 10 mg/kg/day. Data collected included pharmacokinetics, seizure type and frequency, adverse events, EEG, and responses to the Rett Syndrome Behaviour Questionnaire and Rett Syndrome Symptom Severity Index, and were compared to baseline data. RESULTS: All five children reached the maximum CBDV dose of 10 mg/kg/day and had a reduction in MMSF (median = 79% reduction). Three children had MMSF reduction > 75%. This corresponded to an overall reduction in seizure frequency from 32 to 7.2 seizures per month. Ninety-one percent of adverse events were mild or moderate, and none required drug withdrawal. Sixty-two percent were judged to be unrelated to CBDV. Thirty-one percent of adverse events were identified as possibly related, of which nearly all were mild, and the remainder were later assessed as RTT symptoms. Hypersomnolence and drooling were identified as related to CBDV. No serious adverse events reported were related to CBDV. No significant change was noted in EEG or non-epilepsy-related symptoms of RTT. SIGNIFICANCE: A dose of 10 mg/kg/day of CBDV is safe and well tolerated in a pediatric RTT cohort and suggests improved seizure control in children with MECP2-related RTT.

Expert advice for prescribing cannabis medicines for patients with epilepsy-drawn from the Australian clinical experience.

There is international interest for consensus advice for prescribers working in the field of drug resistant epilepsy intending to trial potential therapies that are nonregistered or off-label. Cannabinoids are one such therapy. In 2017, the New South Wales State Government (Australia) set up a cannabinoid prescribing guidance service for a wide variety of indications, based on known pharmacology together with the relevant new literature as it became available. Increasing interest in cannabis medicines use outside this State over the following 5 years together with a paucity of registration-standard clinical trials, lack of information around dosing issues, drug interactions and biological plausibility meant there remained a large unmet need for such advice. To address the unmet need in epilepsy, and until medicines were registered or regulator quality data were available, it was agreed to bring together a working group comprising paediatric and adult epilepsy specialists, clinical pharmacists., clinical pharmacologists and cannabis researchers from across Australia to develop interim consensus advice for prescribers. Although interim, this consensus advice addresses much of the current practice gap by providing an informed overview of the different cannabis medicines currently available for use in the treatment of epilepsy in paediatric and adult settings, with information on dose, drug interactions, toxicity, type of seizure and frequency of symptom relief. As such it supplements the limited evidence currently available from clinical trials with experience from front-line practice. It is expected that this consensus advice will be updated as new evidence emerges and will provide guidance for a subsequent Guideline.

Accelerated long-term forgetting in children with temporal lobe epilepsy: A timescale investigation of material specificity and executive skills.

Recently, children with temporal lobe epilepsy (TLE) were found to be at risk of accelerated long-term forgetting (ALF). In this study, we examined the temporal trajectory of ALF, while exploring the relationship between ALF, executive skills, and epilepsy variables. Fifty-one children, (23 with TLE and 28 typically developing) completed a battery of neuropsychological tests of verbal and visual memory, executive skills, and two experimental memory tasks (verbal and visual) involving recall after short (30-min) and extended (1-day and 2-week) delays. Side of seizure focus and hippocampal integrity were considered. On the visual task (Scene Memory), children with TLE performed comparably to typically developing children following a 30-min and 1-day delay, although worse than typically developing children at 2 weeks: ALF was observed in children with right TLE focus. The two groups did not differ on the experimental verbal memory task. Children with TLE also had worse performance than typically developing children on standardized verbal memory test and on tests of executive skills (i.e., verbal generativity, inhibition, working memory, complex attention). Only complex attention was associated with visual ALF. ALF was present for visuo-spatial materials in children with TLE at two weeks, and children with right TLE were most susceptible. A relationship was identified between complex attention and long-term forgetting. The findings extend our understanding of difficulties in long-term memory formation experienced by children with TLE.

Modeling Singlet Oxygen-Induced Degradation Pathways Including Environmental Effects of 1,2-Dimethoxyethane in Li-O2 Batteries through Density Functional Theory.

We employ density functional theory (DFT) to examine reaction mechanisms involving singlet oxygen 1Δg (1O2) and 1,2-dimethoxyethane (DME) to probe potential parasitic reactions occurring in Li-O2 batteries. First, we investigate the attack of 1O2 on the ethylene group (-CH2-CH2-) to form H2O2 and a C-C double bond in a single step. Second, we look at hydroperoxide formation that occurs via a two-step mechanism. We employ an implicit solvent model, Li+ coordination, and external electric fields to model the complex electrolyte environment near the cathode of a Li-O2 battery. The initial barriers for these reactions are decreasing functions of the dielectric constant of the implicit solvent model as well as the strength of the electric field. These initial barriers range between 17 and 26 kcal mol-1 for large dielectric constants and in the presence of electric fields. We discuss the implications of these results on ether-based electrolytes for Li-O2 batteries.

The need for improved management of status epilepticus in children in Australia: Time from seizure onset to treatment is consistently delayed.

AIM: To determine if the management of paediatric status epilepticus (SE) follows accepted clinical practice guidelines. METHODS: Retrospective, consecutive series of patients with SE who attended the emergency departments from two NSW sites over a 12-month period. SE was defined as a convulsive seizure, 5 min or more in duration. Time to presentation to the ED, time to first- and second-line treatment, number of benzodiazepine (BZD) doses given prior to intubation and adherence to guidelines were evaluated. The outcomes included seizure duration, need for respiratory support, admission to intensive care, morbidity and mortality. RESULTS: The time from onset of seizure to ED presentation was a median (p25-p75) time of 22 (15-40) min. Forty-eight of 59 presentations received pre-hospital midazolam. The median (p25-p75) time to first-line treatment was 15 (8-25) min and to second-line treatment was 43.5 (35-59) min. There was no significant difference in the results in the two hospitals. The total number of BZD doses ranged from 1 to 7 (median 3). There was non-adherence to the clinical practice guidelines in 55 (93.2%) of 59 presentations. CONCLUSIONS: We found excessive benzodiazepine use and delay in both definitive treatment of status epilepticus and in escalation from first- to second-line anticonvulsant treatment. This raises the need for rapid escalation of treatment. We propose a 'status epilepticus code' for emergency departments.

Adjunctive everolimus therapy for tuberous sclerosis complex-associated refractory seizures: Results from the postextension phase of EXIST-3.

OBJECTIVE: Epilepsy is highly prevalent in patients with tuberous sclerosis complex (TSC). Everolimus showed higher efficacy than placebo for seizures in the primary analysis of the EXIST-3 study. Here, we present the long-term outcomes of everolimus at the end of the postextension phase (PEP; data cutoff date: October 25, 2017). METHODS: After completion of the extension phase, patients were invited to continue everolimus in the PEP with everolimus (targeted trough concentration = 5-15 ng/ml, investigator-judged). Efficacy assessments included changes in seizure status during the PEP collected at 12-week intervals as parent/caregiver-reported data through a structured questionnaire. RESULTS: Among 361 patients, 343 entered the extension phase and 249 entered the PEP. After 12 weeks in the PEP, 18.9% (46/244) of patients were seizure-free since the last visit of the extension phase and 64.8% (158/244) had a stable/improved seizure status. At 24 weeks, the corresponding percentages were 18.2% (42/231) and 64.5% (149/231). Among 244 patients, the response rate was 32.8% (80/244) during the 12-week maintenance period of the core phase and 63.9% (156/244) at the end of the extension phase. Of the 149 responders at the end of the extension phase, 70.5% were seizure-free or had stable/improved seizure status. Long-term efficacy data showed persistent responses were observed in 183 of 361 patients (50.7%); 63.9% of these patients had a response that lasted at least 48 weeks. The most frequent Grade 3-4 adverse events (≥2% incidence) reported throughout the study were pneumonia, status epilepticus, seizure, stomatitis, neutropenia, and gastroenteritis. Four patients died during the study. SIGNIFICANCE: The final analysis of EXIST-3 demonstrated the sustained efficacy of everolimus as adjunctive therapy in patients with TSC-associated treatment-refractory seizures, with a tolerable safety profile.

Congenital subpendymal giant cell astrocytoma in children with tuberous sclerosis complex: growth patterns and neurological outcome.

BACKGROUND: Literature regarding congenital subependymal giant cell astrocytomas (SEGA) is limited, and suggests they are at risk of rapid growth and complications. We sought to characterise the growth patterns of congenital SEGA. The second part of the study was an exploratory analysis of congenital SEGA as a possible biomarker for poor neurological outcome. METHODS: This single-centre case series describes ten patients with TSC who had SEGA diagnosed before 12 months. SEGA diameter and volumetric growth were analysed using serial MRIs. Neurological outcomes were compared to a genotype-matched group. RESULTS: All children with congenital SEGA had a TSC2 mutation. Patients were followed for 1-8.7 years, during which median SEGA growth rate was 1.1 mm/yr in diameter or 150 mm3/yr volumetrically. SEGA with volume > 500 mm3 had a significantly higher growth rate compared with smaller SEGA (462 mm3/yr vs. 42 mm3/yr, p = 0.0095). Children with congenital SEGA had a high prevalence of severe epilepsy, developmental disability and autism spectrum disorder. CONCLUSION: Congenital SEGA can follow a relatively benign course with a lower growth rate compared with published literature. Frequent neuroimaging surveillance is recommended for congenital SEGA with volumes exceeding 500 mm3. IMPACT: Congenital SEGA occur in 9.2% of paediatric patients with tuberous sclerosis complex. There are few published cases of congenital SEGA to date. This case series of ten patients adds our experience seen in a tertiary referral hospital over 10 years. Congenital SEGA can follow a relatively benign course with a lower growth rate compared with published literature. Congenital SEGA with volume exceeding 500 mm3 had a significantly higher growth rate compared with smaller SEGA and should have more frequent neuroimaging surveillance.

Reaction of Singlet Oxygen with the Ethylene Group: Implications for Electrolyte Stability in Li-Ion and Li-O2 Batteries.

Recent experimental and computational evidence indicates that singlet oxygen (1O2) attacks the ethylene group (-CH2-CH2-) in ethylene carbonate (EC) leading to degradation in Li-ion batteries employing EC as the electrolyte solvent [J. Phys. Chem. A 2018, 122, 8828-8839]. Here, we employ computational quantum chemistry to explore this mechanism in detail for a large set of organic molecules. Benchmark calculations comparing density functional theory to the complete active space second-order perturbation theory and internally contracted multireference configuration interaction indicate that the M11 functional adequately captures trends in the transition-state energies for this mechanism. Based on our results, we recommend that solvents which include the ethylene group should be avoided in Li-ion and Li-O2 batteries where 1O2 is generated unless neighboring functional groups raise the reaction barrier to avoid this decomposition pathway.