Disparate Outcomes, Biologic and Therapeutic Differences in Pediatric versus Adult Patients with Ewing Sarcoma.

INTRODUCTION: Ewing sarcoma (ES) is a small blue round cell sarcoma affecting a wide age spectrum. Clinical advances predominately stem from pediatric research consortia clinical trials. In most series, adults have poorer outcomes when compared to children. The aim of this study was to perform a detailed evaluation of factors potentially accounting for this difference. METHODS: A single institution retrospective chart review was conducted on patients with ES diagnosed from 2005 to 2015, identified using a free-text search engine with the keywords "Ewing sarcoma" as well as a corresponding pathologic database. Data were analyzed based on age, pediatric (age <18) and adult (age >18 years), using a multivariate analysis model. RESULTS: Eighty-eight ES patients (34 pediatric, 54 adult) were identified with a median age of 13 (range 3-18) and 31 (range 19-70) in their respective cohorts. Five-year overall survival (OS) was higher in pediatric patients (73.5% vs. 48.1%, p = 0.0213). By stage, 5-year OS in pediatric versus adult patients was 65% versus 20% (p = 0.0530) in metastatic (n = 32) and 68.1% versus 58.8% (p = 0.278) in localized (n = 56) patients. Lung-only metastases were present in 83% of metastatic pediatric patients versus 35% of adult metastatic patients. Pediatric patients received more cycles of first-line chemotherapy (13.8 vs. 11.4, p = 0.001), independent of stage. More cycles of chemotherapy correlated with improved OS (HR: 0.864, CI: 0.773-0.967) and progression-free survival (HR: 0.897, CI: 0.808-0.996). CONCLUSIONS: Outcome differences were most notable in patients with metastatic disease, although not statistically significant. Our series found differences in presentation between pediatric and adult populations with adult patients receiving fewer cycles of chemotherapy. This may suggest that both variations in underlying disease biology and potentially differences in treatment may account for outcome disparities.

Electrically Fueled Active Supramolecular Materials.

Fuel-driven dissipative self-assemblies play essential roles in living systems, contributing both to their complex, dynamic structures and emergent functions. Several dissipative supramolecular materials have been created using chemicals or light as fuel. However, electrical energy, one of the most common energy sources, has remained unexplored for such purposes. Here, we demonstrate a new platform for creating active supramolecular materials using electrically fueled dissipative self-assembly. Through an electrochemical redox reaction network, a transient and highly active supramolecular assembly is achieved with rapid kinetics, directionality, and precise spatiotemporal control. As electronic signals are the default information carriers in modern technology, the described approach offers a potential opportunity to integrate active materials into electronic devices for bioelectronic applications.

Traumatic stress symptoms predict restraint incidents in children and adolescents in psychiatric residential treatment.

The early identification of youth at risk for restraint incidents is an important next step to reducing the likelihood of such incidents. Yet, the extant research has not comprehensively investigated the idiographic factors that contribute to the restraint of youth in psychiatric residential treatment facilities (PRTFs). The current study investigated client-level predictors of restraint incidents, with specific emphasis on youth client trauma history and traumatic stress symptoms as assessed at admission. Participants were children and adolescents (N = 150; 55.3% female, 66.7% White, 33.3% Black or biracial) aged 6-17 (M = 11.8 years) admitted to a PRTF in the northeastern United States. A negative binomial regression with maximum likelihood estimation was conducted to examine the relative contributions of age, gender, length of stay, number of psychiatric diagnoses, body mass index (BMI), and traumatic stress symptoms at intake to the frequency of restraint incidents. The model was significant, χ2 (6, N = 150) = 30.326, p < .001, and both length of stay, ß = .005, p < .001, IRR = 1.005, and traumatic stress symptoms at intake, ß = .072, p = .007, IRR = 1.074, were identified as significant predictors within the model. Although length of stay is an obvious predictor of restraint incidents, the current study is the first of which we are aware to identify traumatic stress symptoms at intake as a potential indicator of restraint frequency following admission. Clinical implications of these results are discussed.

Population Health Innovations and Payment to Address Social Needs Among Patients and Communities With Diabetes.

Policy Points Population health efforts to improve diabetes care and outcomes should identify social needs, support social needs referrals and coordination, and partner health care organizations with community social service agencies and resources. Current payment mechanisms for health care services do not adequately support critical up-front investments in infrastructure to address medical and social needs, nor provide sufficient incentives to make addressing social needs a priority. Alternative payment models and value-based payment should provide up-front funding for personnel and infrastructure to address social needs and should incentivize care that addresses social needs and outcomes sensitive to social risk. CONTEXT: Increasingly, health care organizations are implementing interventions to improve outcomes for patients with complex health and social needs, including diabetes, through cross-sector partnerships with nonmedical organizations. However, fee-for-service and many value-based payment systems constrain options to implement models of care that address social and medical needs in an integrated fashion. We present experiences of eight grantee organizations from the Bridging the Gap: Reducing Disparities in Diabetes Care initiative to improve diabetes outcomes by transforming primary care and addressing social needs within evolving payment models. METHODS: Analysis of eight grantees through site visits, technical assistance calls, grant applications, and publicly available data from US census data (2017) and from Health Resources and Services Administration Uniform Data System Resources data (2018). Organizations represent a range of payment models, health care settings, market factors, geographies, populations, and community resources. FINDINGS: Grantees are implementing strategies to address medical and social needs through augmented staffing models to support high-risk patients with diabetes (e.g., community health workers, behavioral health specialists), information technology innovations (e.g., software for social needs referrals), and system-wide protocols to identify high-risk populations with gaps in care. Sites identify and address social needs (e.g., food insecurity, housing), invest in human capital to support social needs referrals and coordination (e.g., embedding social service employees in clinics), and work with organizations to connect to community resources. Sites encounter challenges accessing flexible up-front funding to support infrastructure for interventions. Value-based payment mechanisms usually reward clinical performance metrics rather than measures of population health or social needs interventions. CONCLUSIONS: Federal, state, and private payers should support critical infrastructure to address social needs and incentivize care that addresses social needs and outcomes sensitive to social risk. Population health strategies that address medical and social needs for populations living with diabetes will need to be tailored to a range of health care organizations, geographies, populations, community partners, and market factors. Payment models should support and incentivize these strategies for sustainability.

Cation-chloride cotransporters and the polarity of GABA signalling in mouse hippocampal parvalbumin interneurons.

KEY POINTS: Cation-chloride cotransporters (CCCs) play a critical role in controlling the efficacy and polarity of GABAA receptor (GABAA R)-mediated transmission in the brain, yet their expression and function in GABAergic interneurons has been overlooked. We compared the polarity of GABA signalling and the function of CCCs in mouse hippocampal pyramidal neurons and parvalbumin-expressing interneurons. Under resting conditions, GABAA R activation was mostly depolarizing and yet inhibitory in both cell types. KCC2 blockade further depolarized the reversal potential of GABAA R-mediated currents often above action potential threshold. However, during repetitive GABAA R activation, the postsynaptic response declined independently of the ion flux direction or KCC2 function, suggesting intracellular chloride build-up is not responsible for this form of plasticity. Our data demonstrate similar mechanisms of chloride regulation in mouse hippocampal pyramidal neurons and parvalbumin interneurons. ABSTRACT: Transmembrane chloride gradients govern the efficacy and polarity of GABA signalling in neurons and are usually maintained by the activity of cation-chloride cotransporters, such as KCC2 and NKCC1. Whereas their role is well established in cortical principal neurons, it remains poorly documented in GABAergic interneurons. We used complementary electrophysiological approaches to compare the effects of GABAA receptor (GABAA R) activation in adult mouse hippocampal parvalbumin interneurons (PV-INs) and pyramidal cells (PCs). Loose cell-attached, tight-seal and gramicidin-perforated patch recordings all show GABAA R-mediated transmission is slightly depolarizing and yet inhibitory in both PV-INs and PCs. Focal GABA uncaging in whole-cell recordings reveal that KCC2 and NKCC1 are functional in both PV-INs and PCs but differentially contribute to transmembrane chloride gradients in their soma and dendrites. Blocking KCC2 function depolarizes the reversal potential of GABAA R-mediated currents in PV-INs and PCs, often beyond firing threshold, showing KCC2 is essential to maintain the inhibitory effect of GABAA Rs. Finally, we show that repetitive 10 Hz activation of GABAA Rs in both PV-INs and PCs leads to a progressive decline of the postsynaptic response independently of the ion flux direction or KCC2 function. This suggests intraneuronal chloride build-up may not predominantly contribute to activity-dependent plasticity of GABAergic synapses in this frequency range. Altogether our data demonstrate similar mechanisms of chloride regulation in mouse hippocampal PV-INs and PCs and suggest KCC2 downregulation in the pathology may affect the valence of GABA signalling in both cell types.

The Cal-DSH diversion guidelines.

The Cal-DSH Diversion Guidelines provide 10 general guidelines that jurisdictions should consider when developing diversion programs for individuals with a serious mental illness (SMI) who become involved in the criminal justice system. Screening for SMI in a jail setting is reviewed. In addition, important treatment interventions for SMI and substance use disorders are highlighted with the need to address criminogenic risk factors highlighted.

Design and fabrication of prototype piezoelectric adjustable X-ray mirrors.

Lynx, a next generation X-ray observatory concept currently under study, requires lightweight, high spatial resolution X-ray mirrors. Here we detail the development and fabrication of one of the candidate technologies for Lynx, piezoelectric adjustable X-ray optics. These X-ray mirrors are thin glass shell mirrors with Cr/Ir X-ray reflective coatings on the mirror side and piezoelectric thin film actuators on the actuator side. Magnetron sputtering was used to deposit metal electrodes and metal-oxide piezoelectric layers. The piezoelectric (Pb0.995(Zr0.52Ti0.48)0.99Nb0.01O3) was divided into 112 independent piezoelectric actuators, with 100% yield achieved. We discuss the fabrication procedure, residual thermal stresses and tuning of the Cr/Ir coating stress for the purposes of stress balancing.

Neuronal morphology generates high-frequency firing resonance.

The attenuation of neuronal voltage responses to high-frequency current inputs by the membrane capacitance is believed to limit single-cell bandwidth. However, neuronal populations subject to stochastic fluctuations can follow inputs beyond this limit. We investigated this apparent paradox theoretically and experimentally using Purkinje cells in the cerebellum, a motor structure that benefits from rapid information transfer. We analyzed the modulation of firing in response to the somatic injection of sinusoidal currents. Computational modeling suggested that, instead of decreasing with frequency, modulation amplitude can increase up to high frequencies because of cellular morphology. Electrophysiological measurements in adult rat slices confirmed this prediction and displayed a marked resonance at 200 Hz. We elucidated the underlying mechanism, showing that the two-compartment morphology of the Purkinje cell, interacting with a simple spiking mechanism and dendritic fluctuations, is sufficient to create high-frequency signal amplification. This mechanism, which we term morphology-induced resonance, is selective for somatic inputs, which in the Purkinje cell are exclusively inhibitory. The resonance sensitizes Purkinje cells in the frequency range of population oscillations observed in vivo.

Illustrative cases to support the Cal-VAT guidelines.

There is increasing interest in developing more nuanced methods for managing aggression and violence in long-term psychiatric inpatient settings. However, the dearth of controlled studies has, at times, hampered presentation of viable options. Following the publication of guidelines developed in the California State Hospital forensic system, the authors present a group of 7 cases illustrating different approaches to violence management, including pharmacological, psychotherapeutic, and environmental interventions.

Flow diversion versus conventional treatment for carotid cavernous aneurysms.

BACKGROUND AND PURPOSE: Several endovascular treatment options are available for cavernous carotid aneurysms. We compared pipeline embolization device (PED) versus conventional endovascular treatment in terms of evolution of mass effect, complications, recurrence, and retreatment rate. METHODS: One hundred fifty-seven patients harboring 167 cavernous carotid aneurysms were treated using PED placement, coiling, stent-assisted coiling, and carotid vessel destruction. Procedural complications, angiographic results, and clinical outcomes were analyzed and compared. RESULTS: There were no difference in age, sex, and mean aneurysm size between those treated with PED and those treated with conventional endovascular procedures. The patients treated with PED had a significantly lower proportion of small-size aneurysms (<10 mm) and a shorter follow-up duration. Multivariate analysis revealed treatment other than PED (PED: odds ratio [OR], 0.03; P=0.002) and size >15 mm (OR, 4.27; P=0.003) to be predictors of no improvement in symptoms. The rate of complete occlusion was 81.36% (48 of 59) for PED, 42.25% (39 of 71) for stent-assisted coiling, 27.27% (6 of 22) for coiling, and 73.33% (11 of 15) for carotid vessel destruction. Retreatment was needed in patients with aneurysm size >15 mm (OR, 2.67; P=0.037) and those who were not treated with PED (PED: OR, 0.16; P=0.006). The rate of major complications was 6.6% (11 of 167). Patients who were treated with PED or stent-assisted coiling had 3.84 lower odds to develop complications (OR, 0.26; P<0.05). CONCLUSIONS: The use of PED should be encouraged, especially in symptomatic patients. We found PED to be associated with less need for future treatment, higher improvement in symptoms rate, and lower rate of complications.

California State Hospital Violence Assessment and Treatment (Cal-VAT) guideline.

Here we provide comprehensive guidelines for the assessment and treatment of violence and aggression of various etiologies, including psychotic aggression and impulsive aggression due to schizophrenia, mood disorders, ADHD, or trauma, and predatory aggression due to psychopathy and other personality disorders. These guidelines have been developed from a collection of prescribing recommendations, clinical trial results, and years of clinical experience in treating patients who are persistently violent or aggressive in the California Department of State Hospital System. Many of the recommendations provided in these guidelines employ off-label prescribing practices; thus, sound clinical judgment based on individual patient needs and according to institution formularies must be considered when applying these guidelines in clinical practice.

California State Hospital Violence Assessment and Treatment (Cal-VAT) guidelines.

Here we provide comprehensive guidelines for the assessment and treatment of violence and aggression of various etiologies, including psychotic aggression and impulsive aggression due to schizophrenia, mood disorders, ADHD, or trauma, and predatory aggression due to psychopathy and other personality disorders. These guidelines have been developed from a collection of prescribing recommendations, clinical trial results, and years of clinical experience in treating patients who are persistently violent or aggressive in the California Department of State Hospital System. Many of the recommendations provided in these guidelines employ off-label prescribing practices; thus, sound clinical judgment based on individual patient needs and according to institution formularies must be considered when applying these guidelines in clinical practice.

Predictors of infections following cranioplasty: a retrospective review of a large single center study.

INTRODUCTION: The variables that predispose to postcranioplasty infections are poorly described in the literature. We formulated a multivariate model that predicts the risk of infection in patients undergoing cranioplasty. METHOD: Retrospective review of all patients who underwent cranioplasty following craniectomy from January, 2000, to December, 2011. Tested predictors were age, sex, diabetic status, hypertensive status, reason for craniectomy, urgency status of craniectomy, location of cranioplasty, reoperation for hematoma, hydrocephalus postcranioplasty, and material type. A multivariate logistic regression analysis was performed. RESULTS: Three hundred forty-eight patients met the study criteria. Infection rate was 26.43% (92/348). Of these cases with infection, 56.52% (52/92) were superficial (supragaleal), 43.48% (40/92) were deep (subgaleal), and 31.52% (29/92) were present in both the supragaleal and subgaleal spaces. The predominant pathogen was coagulase-negative staphylococcus (30.43%) followed by methicillin-resistant Staphylococcus aureus (22.83%) and methicillin-sensitive Staphylococcus aureus (15.22%). Approximately 15.22% of all cultures were polymicrobial. Multivariate analysis revealed convex craniectomy, hemorrhagic stroke, and hydrocephalus to be associated with an increased risk of infection (OR = 14.41; P < 0.05, OR = 4.33; P < 0.05, OR = 1.90; P = 0.054, resp.). CONCLUSION: Many of the risk factors for infection after cranioplasty are modifiable. Recognition and prevention of the risk factors would help decrease the infection's rate.

Comparative life cycle assessment of copper and gold recovery from waste printed circuit boards: Pyrometallurgy, chemical leaching and bioleaching.

Printed circuit boards (PCBs) make up a substantial amount of electronic waste (e-waste) generated annually. Waste PCBs contain high quantities of copper and gold in comparison to natural ores. As such, "urban mining" of waste PCBs to recover these metals is of commercial interest. In this work, we used life cycle assessment to compare the environmental impact of four copper and gold recovery processes. We evaluated pyrometallurgy, chemical leaching, and bioleaching, as well as a hybrid leaching process that uses bioleaching to recover copper and chemical leaching to recover gold. Furthermore, we considered differences in environmental impact based on differences in electricity sources. If electricity comes from fossil fuels, the pyrometallurgical process results in the lowest environmental impact in all impact categories studied. If electricity comes from carbon-free sources, the pyrometallurgical process results in the lowest environmental impact in all categories studied except global warming, where the hybrid leaching process results in the lowest impact. In all cases, metal recovery from waste PCBs leads to lower environmental impact than primary metal production. Our goal is to guide e-waste recyclers towards more environmentally sustainable metal recovery processes and to provide knowledge gaps in the field to guide future research.

Observing the Dynamics of an Electrochemically Driven Active Material with Liquid Electron Microscopy.

Electrochemical liquid electron microscopy has revolutionized our understanding of nanomaterial dynamics by allowing for direct observation of their electrochemical production. This technique, primarily applied to inorganic materials, is now being used to explore the self-assembly dynamics of active molecular materials. Our study examines these dynamics across various scales, from the nanoscale behavior of individual fibers to the micrometer-scale hierarchical evolution of fiber clusters. To isolate the influences of the electron beam and electrical potential on material behavior, we conducted thorough beam-sample interaction analyses. Our findings reveal that the dynamics of these active materials at the nanoscale are shaped by their proximity to the electrode and the applied electrical current. By integrating electron microscopy observations with reaction-diffusion simulations, we uncover that local structures and their formation history play a crucial role in determining assembly rates. This suggests that the emergence of nonequilibrium structures can locally accelerate further structural development, offering insights into the behavior of active materials under electrochemical conditions.

NMDA receptors with incomplete Mg²âº block enable low-frequency transmission through the cerebellar cortex.

The cerebellar cortex coordinates movements and maintains balance by modifying motor commands as a function of sensory-motor context, which is encoded by mossy fiber (MF) activity. MFs exhibit a wide range of activity, from brief precisely timed high-frequency bursts, which encode discrete variables such as whisker stimulation, to low-frequency sustained rate-coded modulation, which encodes continuous variables such as head velocity. While high-frequency MF inputs have been shown to activate granule cells (GCs) effectively, much less is known about sustained low-frequency signaling through the GC layer, which is impeded by a hyperpolarized resting potential and strong GABA(A)-mediated tonic inhibition of GCs. Here we have exploited the intrinsic MF network of unipolar brush cells to activate GCs with sustained low-frequency asynchronous MF inputs in rat cerebellar slices. We find that low-frequency MF input modulates the intrinsic firing of Purkinje cells, and that this signal transmission through the GC layer requires synaptic activation of Mg²âº-block-resistant NMDA receptors (NMDARs) that are likely to contain the GluN2C subunit. Slow NMDAR conductances sum temporally to contribute approximately half the MF-GC synaptic charge at hyperpolarized potentials. Simulations of synaptic integration in GCs show that the NMDAR and slow spillover-activated AMPA receptor (AMPAR) components depolarize GCs to a similar extent. Moreover, their combined depolarizing effect enables the fast quantal AMPAR component to trigger action potentials at low MF input frequencies. Our results suggest that the weak Mg²âº block of GluN2C-containing NMDARs enables transmission of low-frequency MF signals through the input layer of the cerebellar cortex.

Lipolysis of triglyceride-rich lipoproteins, vascular inflammation, and atherosclerosis.

Epidemiological and interventional studies have implicated elevated triglyceride-rich lipoprotein (TGRL) levels as a risk factor for cardiovascular disease and vascular inflammation, though the results have not been entirely consistent. This appears particularly relevant in model systems where the lipolysis occurs in the setting of established inflammation (e.g., in pre-existing atherosclerotic plaques), rather than in the tissue capillary beds where lipolysis normally occurs. Two main mechanisms seem to link TGRL lipolysis to vascular inflammation. First, lipolysis of TGRL leaves behind partially lipolyzed remnant particles which are better able to enter the vessel wall than nascent TGRL, have a rate of egress substantially lower than their rate of entry, and contain 5-20 times more cholesterol per particle than LDL. Furthermore, remnants do not require oxidation or other modifications to be phagocytized by macrophages, enhancing foam cell formation. Second, saturated fatty acids and oxidized phospholipids released by lipolysis induce inflammation by activating Toll-like receptors of the innate immune system, via oxidative stress, or by greatly amplifying existing pro-inflammatory signals (caused by subclinical endotoxemia) via mitogen-activated protein kinases. However, n-3 and unbound n-9 unsaturated fatty acids released by lipolysis have anti-inflammatory effects. Thus, the contribution of TGRL lipolysis to inflammation likely depends less on the TGRL concentration than on the balance between pro- and anti-inflammatory factors, and on the setting in which the lipolysis occurs. In the setting of the typical "Western" diet, enriched in saturated and oxidized fatty acids and excessive in size, this balance is likely to be tilted towards increased vascular inflammation and atherosclerosis. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.

Habenular Neurons Expressing Mu Opioid Receptors Promote Negative Affect in a Projection-Specific Manner.

BACKGROUND: The mu opioid receptor (MOR) is central to hedonic balance and produces euphoria by engaging reward circuits. MOR signaling may also influence aversion centers, notably the habenula (Hb), where the receptor is highly dense. Our previous data suggest that the inhibitory activity of MOR in the Hb may limit aversive states. To investigate this hypothesis, we tested whether neurons expressing MOR in the Hb (Hb-MOR neurons) promote negative affect. METHODS: Using Oprm1-Cre knockin mice, we combined tracing and optogenetics with behavioral testing to investigate consequences of Hb-MOR neuron stimulation for approach/avoidance (real-time place preference), anxiety-related responses (open field, elevated plus maze, and marble burying), and despair-like behavior (tail suspension). RESULTS: Optostimulation of Hb-MOR neurons elicited avoidance behavior, demonstrating that these neurons promote aversive states. Anterograde tracing showed that, in addition to the interpeduncular nucleus, Hb-MOR neurons project to the dorsal raphe nucleus. Optostimulation of Hb-MOR/interpeduncular nucleus terminals triggered avoidance and despair-like responses with no anxiety-related effect, whereas light-activation of Hb-MOR/dorsal raphe nucleus terminals increased levels of anxiety with no effect on other behaviors, revealing 2 dissociable pathways controlling negative affect. CONCLUSIONS: Together, the data demonstrate that Hb neurons expressing MOR facilitate aversive states via 2 distinct Hb circuits, contributing to despair-like behavior (Hb-MOR/interpeduncular nucleus) and anxiety (Hb-MOR/dorsal raphe nucleus). The findings support the notion that inhibition of these neurons by either endogenous or exogenous opioids may relieve negative affect, a mechanism that would have implications for hedonic homeostasis and addiction.

Mechanisms of simultaneous linear and nonlinear computations at the mammalian cone photoreceptor synapse.

Neurons enhance their computational power by combining linear and nonlinear transformations in extended dendritic trees. Rich, spatially distributed processing is rarely associated with individual synapses, but the cone photoreceptor synapse may be an exception. Graded voltages temporally modulate vesicle fusion at a cone's ~20 ribbon active zones. Transmitter then flows into a common, glia-free volume where bipolar cell dendrites are organized by type in successive tiers. Using super-resolution microscopy and tracking vesicle fusion and postsynaptic responses at the quantal level in the thirteen-lined ground squirrel, Ictidomys tridecemlineatus, we show that certain bipolar cell types respond to individual fusion events in the vesicle stream while other types respond to degrees of locally coincident events, creating a gradient across tiers that are increasingly nonlinear. Nonlinearities emerge from a combination of factors specific to each bipolar cell type including diffusion distance, contact number, receptor affinity, and proximity to glutamate transporters. Complex computations related to feature detection begin within the first visual synapse.