Search

The potential of antiferroelectrics to exhibit a negative capacitance regime has been largely overlooked as all the attention focused on their polar counterparts, ferroelectrics. We use nonequilibrium first-principles-based molecular dynamics to probe a negative capacitance regime in prototypical antiferroelectric PbZrO 3. Simulations predict that this antiferroelectric can exhibit a negative capacitance/susceptibility regime in response of polarization to an internal electric field, which is a superposition of applied and residual depolarizing fields. Consequently, the regime emerges when the polarization surface charge in the polar phase of antiferroelectric is not fully screened, as is often the case in thin films and nanostructures. The negative capacitance regime occurs below the Curie temperature and disappears in the paraelectric phase. We find that the time the material spends in the negative capacitance regime is proportional to the time needed to complete antipolar–polar (or its reverse) transition and shortens as the frequency of the applied field increases. Moreover, a negative susceptibility value exhibits strong dependence on the quality of surface charge screening with the largest in magnitude values occurring in the vicinity of the transition into a negative capacitance regime. [ABSTRACT FROM AUTHOR]

The potential of antiferroelectrics to exhibit a negative capacitance regime has been largely overlooked as all the attention focused on their polar counterparts, ferroelectrics. We use nonequilibrium first-principles-based molecular dynamics to probe a negative capacitance regime in prototypical antiferroelectric PbZrO 3. Simulations predict that this antiferroelectric can exhibit a negative capacitance/susceptibility regime in response of polarization to an internal electric field, which is a superposition of applied and residual depolarizing fields. Consequently, the regime emerges when the polarization surface charge in the polar phase of antiferroelectric is not fully screened, as is often the case in thin films and nanostructures. The negative capacitance regime occurs below the Curie temperature and disappears in the paraelectric phase. We find that the time the material spends in the negative capacitance regime is proportional to the time needed to complete antipolar–polar (or its reverse) transition and shortens as the frequency of the applied field increases. Moreover, a negative susceptibility value exhibits strong dependence on the quality of surface charge screening with the largest in magnitude values occurring in the vicinity of the transition into a negative capacitance regime. [ABSTRACT FROM AUTHOR]

Introduction: Zuranolone (ZRN) is a positive allosteric modulator of both synaptic and extrasynaptic gamma-aminobutyric acid type A receptors and a neuroactive steroid approved as an oral, once-daily, 14-day treatment course for adults with postpartum depression in the US and under investigation for adults with major depressive disorder (MDD). The randomised, double-blind, placebo-controlled, Phase 3 CORAL Study assessed the efficacy and safety of ZRN 50 mg vs placebo, each co-initiated with an open-label standard-of-care antidepressant (ADT). Patients who completed CORAL could roll over into open-label SHORELINE, which assessed the safety and tolerability of ZRN 50 mg and need for repeat treatment courses in adults with MDD. Objectives: To assess the safety and tolerability (primary endpoint) and need for repeat ZRN 50 mg treatment courses (secondary endpoint) in adults with MDD who previously enrolled in CORAL. Methods: CORAL enrolled adults (18–64 years) with MDD and 17-item Hamilton Rating Scale for Depression (HAMD-17) total score ≥24. After completing the 6-week CORAL Study, patients who enrolled in SHORELINE could enter a 46-week observation period to assess the safety and need for 14-day repeat ZRN treatment course(s), with a total of ≤4 repeat treatment courses permitted. Patients were screened every 2 weeks with the 9-item Patient Health Questionnaire, and scores ≥10 prompted a HAMD-17 assessment within 1 week. Patients with HAMD-17 total score ≥20 were eligible for repeat ZRN course(s) ≥8 weeks after completing the prior ZRN treatment course. Results: Among the 190 patients from CORAL who rolled over into SHORELINE and received ≥1 ZRN treatment course in either study, 133 (70.0%) had received ZRN+ADT and 57 (30.0%) received placebo+ADT in CORAL. Overall, 118 rollover patients received ≥1 open-label ZRN treatment course in SHORELINE. For patients who received ≥1 ZRN treatment course in either study, 76.8% received 1 (54.2%; 103/190) or 2 (22.6%; 43/190) total ZRN treatment courses across both studies in up to 1 year in study. The most common (>5%) treatment-emergent adverse events (TEAEs) during treatment and 14 days following the last ZRN dose were somnolence (16.1% of patients), dizziness (8.5%), headache (8.5%), fatigue (7.6%), sedation (5.9%), and nausea (5.1%); study-period TEAEs (73.7%; 87/118) for the majority of patients were mild/moderate (69.5%; 82/118) in severity and occurred primarily during the treatment period (58.5%; 69/118). No signals for increased suicidal ideation/behaviour were observed. Conclusions: Safety and tolerability among rollover patients were consistent with previous studies; most of the TEAEs reported by adults with MDD who received ZRN were mild/moderate in severity. Most patients who rolled over from CORAL to SHORELINE received ≤2 total treatment courses in up to 1 year in study. Disclosure of Interest: G. Mattingly Grant / Research support from: Akili, Alkermes, Allergan (now AbbVie), Axsome, Boehringer, Janssen, Lundbeck, Medgenics, NLS-1 Pharma AG, Otsuka, Reckitt Benckiser, Roche, Sage, Sunovion, Supernus, Takeda, and Teva, Consultant of: Akili, Alkermes, Allergan (now AbbVie), Axsome, Ironshore, Intra-Cellular Therapies, Janssen, Lundbeck, Neos Therapeutics, Otsuka, Purdue, Rhodes, Sage, Sunovion, Takeda, and Teva, Speakers bureau of: Alkermes, Allergan (now AbbVie), Ironshore, Janssen, Lundbeck, Otsuka, Sunovion, and Takeda, S. Mathew Grant / Research support from: Biohaven Pharmaceuticals, Boehringer-Ingelheim, Janssen, Merck, Sage Therapeutics, Inc., and VistaGen Therapeutics, Consultant of: Allergan (now AbbVie), Alkermes, Almatica Pharma, Axsome Therapeutics, BioXcel Therapeutics, Boehringer-Ingelheim, Clexio Biosciences, COMPASS Pathways, Eleusis, EMA Wellness, Engrail Therapeutics, Greenwich Biosciences, Intra-Cellular Therapies, Janssen, Levo Therapeutics, Perception Neurosciences, Praxis Precision Medicines, Neumora, Neurocrine, Relmada Therapeutics, Sage Therapeutics, Inc., Seelos Therapeutics, Signant Health, and Sunovion, S. Parikh Grant / Research support from: Aifred, Assurex, Janssen, Mensante, Sage Therapeutics, Inc., and Takeda, S. Aaronson Grant / Research support from: COMPASS Pathways and Neuronetics; has served as a consultant to Genomind, Inc., Janssen, LivaNova PLC, Neuronetics; and Sage Therapeutics, Inc., Speakers bureau of: Janssen and Sunovion Pharmaceuticals, Inc., B. Baune Speakers bureau of: Angelini, AstraZeneca, Biogen, Bristol Myers Squibb, Janssen, LivaNova, Lundbeck, Novartis, Otsuka, Pfizer, Servier, Sumitomo Pharma, Wyeth, and Boehringer-Ingelheim, A. Czysz Shareolder of: Sage Therapeutics, Inc., Employee of: Sage Therapeutics, Inc., I. Nandy Shareolder of: Sage Therapeutics, Inc., Employee of: Sage Therapeutics, Inc., V. Ona Shareolder of: Sage Therapeutics, Inc., Employee of: Sage Therapeutics, Inc., C. Brown Shareolder of: Sage Therapeutics, Inc., Employee of: Sage Therapeutics, Inc., S. Kyaga Employee of: Biogen Inc., F. Forrestal Employee of: Biogen Inc., S. Levin Employee of: Biogen Inc., J. Doherty Shareolder of: Sage Therapeutics, Inc., Employee of: Sage Therapeutics, Inc., G. Mattingly: None Declared [ABSTRACT FROM AUTHOR]

Dorsal root ganglion (DRG) toxicity has been consistently reported as a potential safety concern after delivery of adeno-associated viruses (AAVs) containing gene replacement vectors but has yet to be reported for RNAi-based vectors. Here, we report DRG toxicity after AAV intra-CSF delivery of an RNAi expression construct-artificial miRNA targeting superoxide dismutase 1 (SOD1)-in nonhuman primates (NHPs) and provide evidence this can be recapitulated within mice. Histopathology evaluation showed that NHPs and mice develop DRG toxicity after AAV delivery, including DRG neuron degeneration and necrosis, and nerve fiber degeneration that were associated with increases in cerebrospinal fluid (CSF) and serum phosphorylated neurofilament heavy chain (pNF-H). RNA-seq analysis of DRGs showed that dysregulated pathways were preserved between NHPs and mice, including increases in innate/adaptive immune responses, and decreases in mitochondrial- and neuronal-related genes following AAV treatment. Finally, endogenous miR-21-5p was upregulated in DRGs of AAV-treated NHPs and mice. Increases in miR-21-5p were also identified within the CSF of NHPs, which significantly correlated with pNF-H, implicating miR-21-5p as a potential biomarker of DRG toxicity in conjunction with other molecular analytes. This work highlights the importance of assessing safety concerns related to DRG toxicity when developing RNAi-based AAV vectors for therapeutic purposes., (Copyright © 2024 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Accurate quantification of lung density, in Hounsfield Units (HU), is of high importance to monitor progression of diseases such as emphysema using chest CT imaging. Reproducibility of HU quantification on independent photon counting detector CT (PCD-CT) systems with a focus on lung imaging have not yet been evaluated. We thus aimed to evaluate HU reproducibility on 2 independent PCD-CT systems using a repeatable phantom setup with identical acquisition and image reconstruction settings. A COPDGene phantom comprising densities of air, water and lung was scanned on 2 independent PCCT systems using 3 different radiation exposures, 2 medium-sharpness reconstruction kernels (Br40 and Qr36), with and without iterative reconstruction (levels 0 vs 3). Our results demonstrate that acquisitions performed with full dose (3.2 mGy), half dose (1.6 mGy), and one-eighth dose (0.4 mGy) had minimal influence on HU accuracy (<6 HU) when using Br40 and Qr36 kernels. The level of iterative reconstruction also has a minimal impact (<6 HU) with the same kernels. Between the 2 PCD-CT systems evaluated, reproducible HU quantification was achieved for changes to CTDI vol , iterative reconstruction level and reconstruction kernel., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors are all employees of Siemens Medical Solutions., (Copyright © 2024 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

Background: Applying graph convolutional networks (GCN) to the classification of free-form natural language texts leveraged by graph-of-words features (TextGCN) was studied and confirmed to be an effective means of describing complex natural language texts. However, the text classification models based on the TextGCN possess weaknesses in terms of memory consumption and model dissemination and distribution. In this paper, we present a fast message passing network (FastMPN), implementing a GCN with message passing architecture that provides versatility and flexibility by allowing trainable node embedding and edge weights, helping the GCN model find the better solution. We applied the FastMPN model to the task of clinical information extraction from cancer pathology reports, extracting the following six properties: main site, subsite, laterality, histology, behavior, and grade., Results: We evaluated the clinical task performance of the FastMPN models in terms of micro- and macro-averaged F1 scores. A comparison was performed with the multi-task convolutional neural network (MT-CNN) model. Results show that the FastMPN model is equivalent to or better than the MT-CNN., Conclusions: Our implementation revealed that our FastMPN model, which is based on the PyTorch platform, can train a large corpus (667,290 training samples) with 202,373 unique words in less than 3 minutes per epoch using one NVIDIA V100 hardware accelerator. Our experiments demonstrated that using this implementation, the clinical task performance scores of information extraction related to tumors from cancer pathology reports were highly competitive., (© 2024. The Author(s).)

Introduction: Compassion fatigue (CF), the physical, emotional, and psychological impact of helping others, is composed of three domains: compassion satisfaction (CS), secondary traumatic stress (STS), and burnout (BO). Trauma surgeons (TSs) experience work-related stress resulting in high rates of CF, which can manifest as physical and psychological disorders. We hypothesized that TSs experience CF and there are potentially modifiable systemic factors to mitigate its symptoms., Methods: All TSs in a major metropolitan area were eligible. Personal and professional demographic information was obtained. Each participant completed six validated surveys: (1) Professional Quality of Life scale, (2) Perceived Stress Scale, (3) Multidimensional Scale of Perceived Social Support, (4) Adverse Childhood Events Questionnaire, (5) Brief Coping Inventory, and (6) Toronto Empathy Questionnaire. Compassion fatigue subscale risk scores (low, <23; moderate, 23-41; high, >41) were recorded. Linear regression analysis assessed the demographic and environmental factors association with BO, STS, and CS. Variables significant on univariate analysis were included in multivariate models to determine the independent influence on BO, STS, and CS. Significance was p ≤ 0.05., Results: There were 57 TSs (response rate, 75.4% [n = 43]; White, 65% [n = 28]; male, 67% [n = 29]). Trauma surgeons experienced CF (BO, 26 [interquartile range (IQR), 21-32]; STS, 23 [IQR, 19-32]; CS, 39 [IQR, 34-45]). The Perceived Stress Scale score was significantly associated with increased BO (coefficient [coef.], 0.52; 95% confidence interval [CI], 0.28-0.77) and STS (coef., 0.44; 95% CI, 0.15-0.73), and decreased CS (coef., -0.51; 95% CI, -0.80 to -0.23) ( p < 0.01). Night shifts were associated with higher BO (coef., 1.55; 95% CI, 0.07-3.03; p = 0.05); conversely, day shifts were associated with higher STS (coef., 1.94; 95% CI, 0.32-3.56; p = 0.03). Higher Toronto Empathy Questionnaire scores were associated with greater CS (coef., 0.33; 95% CI, 0.12-0.55; p < 0.01)., Conclusion: Trauma surgeons experience moderate BO and STS associated with modifiable system- and work-related stressors. Efforts to reduce CF should focus on addressing sources of workplace stress and promoting empathic care., Level of Evidence: Prognostic and Epidemiological; Level III., (Copyright © 2024 American Association for the Surgery of Trauma.)

A widely accepted view is that errorless learning is essential for supporting new learning in people with anterograde amnesia, but findings are mixed for those with a broader range of memory impairments. People at a chronic stage of recovery from brain injury (BI) with impaired memory and executive function ( N  = 26) were compared with adults in a comparison group without any known risks to brain function ( N  = 25). Learning techniques were compared using a "Generate-and-correct" and "Read-only" condition when learning novel word pairs. At test, both groups scored above chance and showed benefits of Generate-and-correct (error ful learning). Poor learners in the BI group were classified from "flat" learning slopes extracted from an independent word-pair learning task. Critically, poor learners showed no benefit, but also no decrement to learning, using the Generate-and-correct method. No group was harmed by errorful learning; all, except the poorest learners, benefitted from errorful learning. This study indicates, that in some rehabilitation settings, encouraging clients to guess the meaning of unfamiliar material (e.g., from cards, magazines, newspapers) and then correct their errors, could have benefits for recognition memory. Determining when and how errorful learning benefits learning is a key aim for future research.