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We sought to examine cardiovascular toxicities associated with tyrosine kinase inhibitors in pediatrics. We examined 1624 pediatric adverse events with imatinib, dasatinib, sorafenib, pazopanib, crizotinib, and ruxolitinib reported to the Food and Drug Administration between January 1, 2015, and August 14, 2020. There were 102 cardiovascular event reports. Hypertension was the most commonly reported cardiovascular event and was most frequently associated with sorafenib and pazopanib. The presence of infection increased the reporting odds of cardiovascular events overall and specifically cardiac arrest, heart failure, and hypertension. These data provide early insight into cardiovascular toxicities with tyrosine kinase inhibitor use in pediatrics.

We find compelling evidence that integrating environment, social and governance (ESG) analyses into ongoing investment practices in Australia does not harm risk‐adjusted returns. High‐ESG‐rated portfolios consistently provide superior outperformance, diversification efficiencies, and lower overall risk compared to low‐ESG‐rated portfolios. In contrast to low‐rated portfolios, we find no evidence that high‐ESG‐rated portfolios underperform the market. All results remain robust to alternative time periods, market cycles, seasonality effects, ratings method and the inclusion of trading costs and management fees. Overall, our findings suggest that a simple ESG integration strategy may provide a natural hedge against the risks that arise from the evolving fiduciary responsibilities of professional investment managers relating to ESG risks.

The development and survival of spiral ganglion neurons (SGNs) are dependent on multiple trophic factors as well as membrane electrical activity. Semaphorins (Sema) constitute a family of membrane-associated and secreted proteins that have garnered significant attention as a potential SGN "navigator" during cochlea development. Previous studies using mutant mice demonstrated that Sema3A plays a role in the SGN pathfinding. The mechanisms, however, by which Sema3A shapes SGNs firing behavior are not known. In these studies, we found that Sema3A plays a novel role in regulating SGN resting membrane potential and excitability. Using dissociated SGN from pre-hearing (P3-P5) and post-hearing mice (P12-P15), we recorded membrane potentials using whole-cell patch clamp recording techniques in apical and basal SGN populations. Recombinant Sema3A was applied to examine the effects on intrinsic membrane properties and action potentials evoked by current injections. Apical and basal SGNs from newborn mice treated with recombinant Sema3A (100 ng/ml) displayed a higher resting membrane potential, higher threshold, decreased amplitude, and prolonged latency and duration of spikes. Although a similar phenomenon was observed in SGNs from post-hearing mice, the resting membrane potential was essentially indistinguishable before and after Sema3A exposure. Sema3A-mediated changes in membrane excitability were associated with a significant decrease in K+ and Ca2+ currents. Sema3A acts through linopirdine-sensitive K+ channels in apical, but not in the basal SGNs. Therefore, Sema3A induces differential effects in SGN membrane excitability that are dependent on age and location, and constitutes an additional early and novel effect of Sema3A SGNs in vitro.

We have examined the expression of glutamate transporters in primary and immortalized glial precursors (GRIPs). We subsequently transduced these cells with the GLT1 glutamate transporter and examined the ability of these cells to protect motor neurons in an organotypic spinal cord culture. We show that glial restricted precursors and GRIP-derived astrocytes predominantly express glutamate transporters GLAST and GLT1. Oligodendrocyte differentiation of GRIPs results in downregulation of all glutamate transporter subtypes. Having identified these precursor cells as potential vectors for delivering glutamate transporters to regions of interest, we engineered a line of GRIPS that overexpress the glutamate transporter GLT1. These cells (G3 cells) have a nearly fourfold increase in glutamate transporter expression and at least a twofold increase in the V(max) for glutamate transport. To assess whether G3 seeding can protect motor neurons from chronic glutamate neurotoxicity, G3s were seeded onto rat organotypic spinal cord cultures. These cultures have previously been used extensively to understand pathways involved in chronic glutamate neurotoxicity of motor neurons. After G3 seeding, cells integrated into the culture slice and resulted in levels of glutamate transport sufficient to enhance total glutamate uptake. To test whether neuroprotection was related to glutamate transporter overexpression, we isolated GRIPS from the GLT1 null mouse to serve as controls. The seeding of G3s resulted in a reduction of motor neuron cell death. Hence, we believe that these cells may potentially play a role in cell-based neuroprotection from glutamate excitotoxicity.

Objective To compare family physicians', obstetricians' and midwives' self-reported practices, attitudes and beliefs about central issues in childbirth. Design Mail-out questionnaire. Setting/Population All registered midwives in the province, and a sample of family physicians and obstetricians in a maternity care teaching hospital. Response rates: 91% (n= 50), 69% (n= 97) and 89% (n= 34), respectively. Methods A postal survey. Main outcome measures Twenty-three five-point Likert scale items (strongly agree to strongly disagree) addressing attitudes toward routine electronic fetal monitoring, induction of labour, epidural analgesia, episiotomy, doulas, vaginal birth after caesarean section (VBACs), birth centres, provision educational material, birth plans and caesarean section. Results Cluster analysis identified three distinct clusters based on similar response to the questions. The ‘MW’ cluster consisted of 100% of midwives and 26% of the family physicians. The ‘OB’ cluster was composed of 79% of the obstetricians and 16% of the family physicians. The ‘FP’ cluster was composed of 58% the family physicians and 21% the obstetricians. Members of the ‘OB’ cluster more strongly believed that women had the right to request a caesarean section without maternal/fetal indications (P < 0.001), that epidurals early in labour were not associated with development of fetal malpositions (P < 0.001) and that increasing caesarean rates were a sign of improvement in obstetrics (P < 0.001). The ‘OB’ cluster members were more likely to say they would induce women as soon as possible after 41 3/7 weeks of gestation (P < 0.001) and were least likely to encourage the use of birth plans (P < 0.001). The ‘MW’ cluster's views were the opposite of the ‘OBs’ while the ‘FP’ cluster's views fell between the ‘MW’ and ‘OB’ clusters. Conclusions In our environment, obstetricians were the most attached to technology and interventions including caesarean section and inductions, midwives the least, while family physicians fell in the middle. While generalisations can be problematic, obstetricians and midwives generally follow a defined and different approach to maternity care. Family physicians are heterogeneous, sometimes practising more like midwives and sometimes more like obstetricians.

Glutamate is the major neurotransmitter of the brain, whose extracellular levels are tightly controlled by glutamate transporters. Five glutamate transporters in the human brain (EAAT1-5) are present on both astroglia and neurons. We characterize the profile of three different human astroglial progenitors in vitro: human glial restricted precursors (HGRP), human astrocyte precursors (HAPC), and early-differentiated astrocytes. EAAT 1, EAAT3, and EAAT4 are all expressed in GRPs with a subsequent upregulation of EAAT1 following differentiation of GRPs into GRP-derived astrocytes in the presence of bone morphogenic protein (BMP-4). This corresponds to a significant increase in the glutamate transport capacity of these cells. EAAT2, the transporter responsible for the bulk of glutamate transport in the adult brain, is not expressed as a full-length protein, nor does it appear to have functional significance (as determined by the EAAT2 inhibitor dihydrokainate) in these precursors. A splice variant of EAAT2, termed EAAT2b, does appear to be present in low levels, however. EAAT3 and EAAT4 expression is reduced as glial maturation progresses both in astrocyte precursors and early-differentiated astrocytes and is consistent with their role in adult tissues as primarily neuronal glutamate transporters. These human glial precursors offer several advantages as tools for understanding glial biology because they can be passaged extensively in the presence of mitogens, afford the potential to study the temporal changes in glutamate transporter expression in a tightly controlled fashion, and are cultured in the absence of neuronal coculture, allowing for the independent study of astroglial biology.

Background NTRK fusions are known oncogenic drivers and have recently been effectively targeted by investigational agents in adults. We sought to assess the frequency of NTRK fusions in a large series of pediatric and adolescent patients with advanced cancers. Procedure Genomic profiles from 2,031 advanced cancers from patients less than 21 years old who were assayed with comprehensive genomic profiling were reviewed to identify NTRK fusions. Results Total of nine cases (0.44%) harbored NTRK fusions, including novel partners. Four of these cases were in children less than 2 years old for which infantile fibrosarcoma was considered as a diagnosis, and two harbored the canonical ETV6-NTRK3. The remaining cases carried other diagnoses, at least one that carried the diagnosis of inflammatory myofibroblastic tumor. Conclusions NTRK fusions occur in a subset of young patients with mesenchymal or sarcoma-like tumors at a low frequency, and are eminently druggable targets via either investigational agents or approved drugs.