Atomic cluster expansion potential for large scale simulations of hydrocarbons under shock compression.

We present an Atomic Cluster Expansion (ACE) machine learned potential developed for high-fidelity atomistic simulations of hydrocarbons, targeting pressures and temperatures near and above supercritical fluid regimes for molecular fluids. A diverse set of stoichiometries were covered in training, including 1:0 (pure carbon), 1:4 (methane), and 1:1 (benzene), and rich bonding environments sampled at supercritical temperatures, hydrogen rich, reactive mixtures where metastable stoichiometries arise, including 1:2 (ethylene) and 1:3 (ethane). A high-fidelity training database was constructed by performing large-scale quantum molecular dynamic simulations [density functional theory (DFT) MD] of diamond, graphite, methane, and benzene. A novel approach to selecting structures from DFT MD is also presented, which allows for the rapid selection of unique DFT MD frames from complex trajectories. Comparisons to DFT and experimental data demonstrate that the presented ACE potential accurately reproduces isotherms, carbon melting curves, radial distribution functions, and shock Hugoniots for carbon and hydrocarbon systems for pressures up to 100 GPa and temperatures up to 6000 K for hydrocarbon systems and up to 9000 K for pure carbon systems. This work delivers a potential that can be used for accurate, large-scale simulations of shocked hydrocarbons and demonstrates a methodology for fitting and validating machine learning interatomic potentials to complex molecular environments, which can be applied to energetic materials in future works.

Accuracy, transferability, and computational efficiency of interatomic potentials for simulations of carbon under extreme conditions.

Large-scale atomistic molecular dynamics (MD) simulations provide an exceptional opportunity to advance the fundamental understanding of carbon under extreme conditions of high pressures and temperatures. However, the fidelity of these simulations depends heavily on the accuracy of classical interatomic potentials governing the dynamics of many-atom systems. This study critically assesses several popular empirical potentials for carbon, as well as machine learning interatomic potentials (MLIPs), in their ability to simulate a range of physical properties at high pressures and temperatures, including the diamond equation of state, its melting line, shock Hugoniot, uniaxial compressions, and the structure of liquid carbon. Empirical potentials fail to accurately predict the behavior of carbon under high pressure-temperature conditions. In contrast, MLIPs demonstrate quantum accuracy, with Spectral Neighbor Analysis Potential (SNAP) and atomic cluster expansion (ACE) being the most accurate in reproducing the density functional theory results. ACE displays remarkable transferability despite not being specifically trained for extreme conditions. Furthermore, ACE and SNAP exhibit superior computational performance on graphics processing unit-based systems in billion atom MD simulations, with SNAP emerging as the fastest. In addition to offering practical guidance in selecting an interatomic potential with a fine balance of accuracy, transferability, and computational efficiency, this work also highlights transformative opportunities for groundbreaking scientific discoveries facilitated by quantum-accurate MD simulations with MLIPs on emerging exascale supercomputers.

Neutrophil to Lymphocyte Ratio and Periprosthetic Joint Infection: A Systematic Review and Meta-Analysis.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) has shown promising results as a diagnostic tool for periprosthetic joint infection (PJI) after total joint arthroplasty. We conducted a systematic review and meta-analysis to determine the utility of NLR in the diagnosis of PJI. METHODS: We searched PubMed, Scopus, and Web of Science from inception up to 2022 and evaluated the quality of the included literature. RESULTS: Based on the 12 eligible studies, NLR levels were significantly higher in patients who had PJI compared to those who had aseptic loosening (standard mean difference (SMD) = 1.05, 95% Confidence Interval (CI) = 0.71 to 1.40, P < .001). In the subgroup analysis according to type of PJI, NLR levels were significantly higher in patients who had either acute (SMD = 1.04, 95% CI = 0.05 to 2.03, P < .001) or chronic PJI (SMD = 1.08, 95% CI = 0.55 to 1.61, P < .001), compared to those who had aseptic loosening. According to type of arthroplasty, NLR levels were significantly higher in patients who had either total knee arthroplasty (SMD = 1.81, 95% CI = 1.48 to 2.13, P < .001) or total hip arthroplasty (SMD = 1.76, 95% CI = 1.54 to 1.98, P < .001) compared to aseptic loosening. The pooled sensitivity of the 12 studies was 0.73 (95% CI, 0.65 to 0.79), and the pooled specificity was 0.75 (95% CI, 0.71 to 0.78). The pooled positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio of NLR were 2.94 (95% CI = 2.44 to 3.54), 0.35 (95% CI = 0.27 to 0.46), and 8.26 (95% CI = 5.42 to 12.58), respectively. CONCLUSION: In summary, this meta-analysis indicates that NLR is a reliable marker in the diagnosis of PJI.

Prognostic Role of Neutrophil to Lymphocyte Ratio in Contrast-Induced Nephropathy: A Systematic Review and Meta-analysis.

This meta-analysis assessed the use of the neutrophil-to-lymphocyte ratio (NLR) as a means of early detection of contrast-induced nephropathy (CIN) following diagnostic or therapeutic procedures. We used Web of Science, PubMed, and Scopus to conduct a systematic search. There was no limitation regarding language or date of publication. We reported standardized mean difference (SMD) with a 95% confidence interval (CI). Due to high heterogeneity, a random-effects model was used, and the Newcastle-Ottawa scale was used for quality assessment. Thirty-one articles were included in the analysis. Patients in the CIN group had elevated levels of NLR compared with those in the non-CIN group (SMD = 0.78, 95% CI = 0.52-1.04, P < .001). Similar results were observed in either prospective (SMD = 1.03, 95% CI = 0.13-1.93, P = .02) or retrospective studies (SMD = 0.70, 95% CI = 0.45-0.96, P < .001). The pooled sensitivity of NLR was 74.02% (95% CI = 66.54%-81.02%), and the pooled specificity was 60.58% (95% CI = 53.94%-66.84%). NLR shows potential as a cost-effective biomarker for predicting CIN associated with contrast-involved treatments. This could help implement timely interventions to mitigate CIN and improve outcomes.

Extreme Metastability of Diamond and its Transformation to the BC8 Post-Diamond Phase of Carbon.

Diamond possesses exceptional physical properties due to its remarkably strong carbon-carbon bonding, leading to significant resilience to structural transformations at very high pressures and temperatures. Despite several experimental attempts, synthesis and recovery of the theoretically predicted post-diamond BC8 phase remains elusive. Through quantum-accurate multimillion atom molecular dynamics (MD) simulations, we have uncovered the extreme metastability of diamond at very high pressures, significantly exceeding its range of thermodynamic stability. We predict the post-diamond BC8 phase to be experimentally accessible only within a narrow high pressure-temperature region of the carbon phase diagram. The diamond to BC8 transformation proceeds through premelting followed by BC8 nucleation and growth in the metastable carbon liquid. We propose a double-shock compression pathway for BC8 synthesis, which is currently being explored in experiments at the National Ignition Facility.

"Timing of percutaneous endoscopic gastrostomy tube placement in post-stroke patients does not impact mortality, complications, or outcomes": Commentary.

In this commentary, we summarize some of the key points of the original paper "Timing of percutaneous endoscopic gastrostomy tube placement in post-stroke patients does not impact mortality, complications, or outcomes" and offer support for the proposed results. Specifically, we address how early percutaneous endoscopic gastrostomy (PEG) tube placement may reduce hospital length of stay and costs. We also discuss topics related to the article including PEG weaning and post-stroke nutritional formulation. However, we note that concerns purported by previous studies that early PEG placement may worsen outcomes are not fully addressed, and further research is needed.

Stem Cell Scaffolds for the Treatment of Spinal Cord Injury-A Review.

Spinal cord injury (SCI) is a profoundly debilitating yet common central nervous system condition resulting in significant morbidity and mortality rates. Major causes of SCI encompass traumatic incidences such as motor vehicle accidents, falls, and sports injuries. Present treatment strategies for SCI aim to improve and enhance neurologic functionality. The ability for neural stem cells (NSCs) to differentiate into diverse neural and glial cell precursors has stimulated the investigation of stem cell scaffolds as potential therapeutics for SCI. Various scaffolding modalities including composite materials, natural polymers, synthetic polymers, and hydrogels have been explored. However, most trials remain largely in the preclinical stage, emphasizing the need to further develop and refine these treatment strategies before clinical implementation. In this review, we delve into the physiological processes that underpin NSC differentiation, including substrates and signaling pathways required for axonal regrowth post-injury, and provide an overview of current and emerging stem cell scaffolding platforms for SCI.

Review of meningioma diagnosis and management.

Meningiomas are the most common intracranial tumors in adult patients. Although the majority of meningiomas are diagnosed as benign, approximately 20% of cases are high-grade tumors that require significant clinical treatment. The gold standard for grading central nervous system tumors comes from the World Health Organization Classification of Tumors of the central nervous system. Treatment options also depend on the location, imaging, and histopathological features of the tumor. This review will cover diagnostic strategies for meningiomas, including 2021 updates to the World Health Organization's grading of meningiomas. Meningioma treatment plans are variable and highly dependent on tumor grading. This review will also update the reader on developments in the treatment of meningiomas, including surgery, radiation therapy and monoclonal antibody treatment.

Update for astrocytomas: medical and surgical management considerations.

Astrocytomas include a wide range of tumors with unique mutations and varying grades of malignancy. These tumors all originate from the astrocyte, a star-shaped glial cell that plays a major role in supporting functions of the central nervous system (CNS), including blood-brain barrier (BBB) development and maintenance, water and ion regulation, influencing neuronal synaptogenesis, and stimulating the immunological response. In terms of epidemiology, glioblastoma (GB), the most common and malignant astrocytoma, generally occur with higher rates in Australia, Western Europe, and Canada, with the lowest rates in Southeast Asia. Additionally, significantly higher rates of GB are observed in males and non-Hispanic whites. It has been suggested that higher levels of testosterone observed in biological males may account for the increased rates of GB. Hereditary syndromes such as Cowden, Lynch, Turcot, Li-Fraumeni, and neurofibromatosis type 1 have been linked to increased rates of astrocytoma development. While there are a number of specific gene mutations that may influence malignancy or be targeted in astrocytoma treatment, O 6-methylguanine-DNA methyltransferase (MGMT) gene function is an important predictor of astrocytoma response to chemotherapeutic agent temozolomide (TMZ). TMZ for primary and bevacizumab in the setting of recurrent tumor formation are two of the main chemotherapeutic agents currently approved in the treatment of astrocytomas. While stereotactic radiosurgery (SRS) has debatable implications for increased survival in comparison to whole-brain radiotherapy (WBRT), SRS demonstrates increased precision with reduced radiation toxicity. When considering surgical resection of astrocytoma, the extent of resection (EoR) is taken into consideration. Subtotal resection (STR) spares the margins of the T1 enhanced magnetic resonance imaging (MRI) region, gross total resection (GTR) includes the margins, and supramaximal resection (SMR) extends beyond the margin of the T1 and into the T2 region. Surgical resection, radiation, and chemotherapy are integral components of astrocytoma treatment.

Endocrine resistant breast cancer: brain metastasis.

Endocrine resistant breast cancer metastasis continues to serve as a significant clinical challenge with high morbidity and mortality for patients. As the number of breast cancer cases continues to rise, the rate of brain metastasis has also increased. For single lesions or a large symptomatic lesion with other smaller lesions, surgical resection is a viable option in non-eloquent regions. Stereotactic radiosurgery is a great option for post-operative therapy or for 10 or fewer small lesions (< 3 cm in size). Whole-brain radiation can be used sparingly for large tumor burdens but should encompass hippocampus sparing techniques. Chemotherapy options have remained relatively limited due to decreased permeability of the blood-brain barrier. Emerging monoclonal antibody treatments have offered initial promise, especially for endocrine resistant breast cancer metastasis.

Secondary Mechanisms of Neurotrauma: A Closer Look at the Evidence.

Traumatic central nervous system injury is a leading cause of neurological injury worldwide. While initial neuroresuscitative efforts are focused on ameliorating the effects of primary injury through patient stabilization, secondary injury in neurotrauma is a potential cause of cell death, oxidative stress, and neuroinflammation. These secondary injuries lack defined therapy. The major causes of secondary injury in neurotrauma include endoplasmic reticular stress, mitochondrial dysfunction, and the buildup of reactive oxygen or nitrogenous species. Stress to the endoplasmic reticulum in neurotrauma results in the overactivation of the unfolded protein response with subsequent cell apoptosis. Mitochondrial dysfunction can lead to the release of caspases and the buildup of reactive oxygen species; several characteristics make the central nervous system particularly susceptible to oxidative damage. Together, endoplasmic reticulum, mitochondrial, and oxidative stress can have detrimental consequences, beginning moments and lasting days to months after the primary injury. Understanding these causative pathways has led to the proposal of various potential treatment options.

Neurotrauma Prevention Review: Improving Helmet Design and Implementation.

Neurotrauma continues to contribute to significant mortality and disability. The need for better protective equipment is apparent. This review focuses on improved helmet design and the necessity for continued research. We start by highlighting current innovations in helmet design for sport and subsequent utilization in the lay community for construction. The current standards by sport and organization are summarized. We then address current standards within the military environment. The pathophysiology is discussed with emphasis on how helmets provide protection. As innovative designs emerge, protection against secondary injury becomes apparent. Much research is needed, but this focused paper is intended to serve as a catalyst for improvement in helmet design and implementation to provide more efficient and reliable neuroprotection across broad arenas.

Gut microbiome and neurosurgery: Implications for treatment.

Introduction: The aim of this review is to summarize the current understanding of the gut-brain axis (GBA), its impact on neurosurgery, and its implications for future treatment. Background: An abundance of research has established the existence of a collection of pathways between the gut microbiome and the central nervous system (CNS), commonly known as the GBA. Complicating this relationship, the gut microbiome bacterial diversity appears to change with age, antibiotic exposure and a number of external and internal factors. Methods: In this paper, we present the current understanding of the key protective and deleterious roles the gut microbiome plays in the pathogenesis of several common neurosurgical concerns. Results: Specifically, we examine how spinal cord injury, traumatic brain injury and stroke may cause gut microbial dysbiosis. Furthermore, this link appears to be bidirectional as gut dysbiosis contributes to secondary CNS injury in each of these ailment settings. This toxic cycle may be broken, and the future secondary damage rescued by timely, therapeutic, gut microbiome modification. In addition, a robust gut microbiome appears to improve outcomes in brain tumour treatment. There are several primary routes by which microbiome dysbiosis may be ameliorated, including faecal microbiota transplant, oral probiotics, bacteriophages, genetic modification of gut microbiota and vagus nerve stimulation. Conclusion: The GBA represents an important component of patient care in the field of neurosurgery. Future research may illuminate ideal methods of therapeutic microbiome modulation in distinct pathogenic settings.

Improving Gene Therapy for Angelman Syndrome with Secreted Human UBE3A.

The rare genetic neurodevelopmental disease Angelman syndrome (AS) is caused by the loss of function of UBE3A, a ubiquitin ligase. The disease results in a lifetime of severe symptoms, including intellectual disability and motor impairments for which there are no effective treatments. One avenue of treatment for AS is the use of gene therapy to reintroduce a functional copy of the UBE3A gene. Our group had previously shown that recombinant adeno-associated virus (rAAV) expressing mouse Ube3a could rescue deficits in a mouse model of AS. Here, we expand on this work and show that this approach could be successfully replicated in a second AS model using the human UBE3A gene. Furthermore, we address the challenge of limited vector distribution in the brain by developing a novel modified form of UBE3A. This modified protein, termed STUB, was designed with a secretion signal and a cell-penetrating peptide. This allowed transduced cells to act as factories for the production of UBE3A protein that could be taken up by neighboring non-transduced cells, thus increasing the number of neurons receiving the therapeutic protein. Combining this construct with intracerebroventricular injections to maximize rAAV distribution within the brain, we demonstrate that this novel approach improves the recovery of behavioral and electrophysiological deficits in the AS rat model. More importantly, a comparison of rAAV-STUB to a rAAV expressing the normal human UBE3A gene showed that STUB was a more effective therapeutic. These data suggest that rAAV-STUB is a new potential approach for the treatment of AS.

An Approach to Improving Clinical Morale: Targeting a Positive Culture.

Establishing a positive work environment is critical for successful outcomes and optimized performance. In a high-stakes arena such as healthcare, having all individuals engaged and ready to be part of the team is crucial. In this paper, we highlight a novel strategy for establishing effective communication and breaking down barriers. Through the implementation of a positive culture committee the neurosurgical department will improve relationships and performance. Goals and different strategies are addressed in the discussion. As implementation is underway, we plan to measure improved performance metrics in the coming years.

Identification of UBE3A Protein in CSF and Extracellular Space of the Hippocampus Suggest a Potential Novel Function in Synaptic Plasticity.

Disruptions to the maternally inherited allele UBE3A, encoding for an E3 ubiquitin ligase, leads to the manifestation of Angelman Syndrome (AS). While this disorder is rare, the symptoms are severe and lifelong including but not limited to: intractable seizures, abnormal EEG's, ataxic gait, lack of speech, and most notably an abnormally happy demeanor with easily provoked laughter. Currently, little is known about the neurophysiological underpinnings of UBE3A leading to such globally severe phenotypes. Utilizing the newest AS rat model, comprised of a full UBE3A deletion, we aimed to elucidate novel mechanistic actions and potential therapeutic targets. This report demonstrates for the first time that catalytically active UBE3A protein is detectable within cerebrospinal fluid (CSF) of wild type rats but distinctly absent in AS rat CSF. Microdialysis within the rat hippocampus also showed that UBE3A protein is located in the interstitial fluid of wild type rat brains but absent in AS animals. This protein maintains catalytic activity and appears to be regulated in a dynamic activity-dependent manner. LAY SUMMARY: Angelman syndrome (AS) is a rare genetic disorder caused by the loss of the UBE3A gene within the central nervous system. Although we have identified the gene responsible for AS, we still have a long way to go to fully understand its function in vivo. Here we report that UBE3A is present within normal cerebrospinal fluid (CSF) but distinctly absent in AS CSF. Furthermore, we demonstrate that UBE3A is secreted and that this may occur in a dynamic activity-dependent fashion. Extracellular UBE3A maintained its ubiquitinating activity, thus suggesting that UBE3A may have a novel role outside of neurons. Autism Res 2021, 14: 645-655. © 2021 International Society for Autism Research and Wiley Periodicals LLC.

Generation of a Novel Rat Model of Angelman Syndrome with a Complete Ube3a Gene Deletion.

Angelman syndrome (AS) is a rare genetic disorder characterized by severe intellectual disability, seizures, lack of speech, and ataxia. The gene responsible for AS was identified as Ube3a and it encodes for E6AP, an E3 ubiquitin ligase. Currently, there is very little known about E6AP's mechanism of action in vivo or how the lack of this protein in neurons may contribute to the AS phenotype. Elucidating the mechanistic action of E6AP would enhance our understanding of AS and drive current research into new avenues that could lead to novel therapeutic approaches that target E6AP's various functions. To facilitate the study of AS, we have generated a novel rat model in which we deleted the rat Ube3a gene using CRISPR. The AS rat phenotypically mirrors human AS with loss of Ube3a expression in the brain and deficits in motor coordination as well as learning and memory. This model offers a new avenue for the study of AS. Autism Res 2020, 13: 397-409. © 2020 International Society for Autism Research,Wiley Periodicals, Inc. LAY SUMMARY: Angelman syndrome (AS) is a rare genetic disorder characterized by severe intellectual disability, seizures, difficulty speaking, and ataxia. The gene responsible for AS was identified as UBE3A, yet very little is known about its function in vivo or how the lack of this protein in neurons may contribute to the AS phenotype. To facilitate the study of AS, we have generated a novel rat model in which we deleted the rat Ube3a gene using CRISPR. The AS rat mirrors human AS with loss of Ube3a expression in the brain and deficits in motor coordination as well as learning and memory. This model offers a new avenue for the study of AS.