Tumor-associated macrophages (TAMs) constitute up to 50% of tumor bulk in glioblastoma (GBM) and play an important role in tumor maintenance and progression. The recently discovered differences between invading tumour periphery and hypoxic tumor core implies that macrophage biology is also distinct by location. This may provide further insight into the observed treatment resistance to immune modulation. We hypothesize that macrophage activation occurs through processes that are distinct in tumor periphery versus core. We therefore investigated regional differences in TAM recruitment and evolution in GBM by combining open source single cell and bulk gene expression data. We used single cell gene expression data from 4 glioblastomas (total of 3589 cells) and 122 total bulk samples obtained from 10 different patients. Cell identity, ontogeny (bone-marrow derived macrophages-BMDM vs microglia), and macrophage activation state were inferred using verified gene expression signatures. We captured the spectrum of immune states using cell trajectory analysis with pseudotime ordering. In keeping with previous studies, TAMs carrying BMDM identity were more abundant in tumor bulk while microglia-derived TAMs dominated the tumor periphery across all macrophage activation states including pre-activation. We note that core TAMs evolve towards a pro-inflammatory state and identify a subpopulation of cells based on a gene program exhibiting strong, opposing correlation with Programmed cell Death-1 (PD-1) signaling, which may correlate to their response to PD-1 inhibition. By contrast, peripheral TAMs evolve towards anti-inflammatory phenotype and contains a population of cells strongly associated with NFkB signaling. Our preliminary analysis suggests important regional differences in TAMs with regard to recruitment and evolution. We identify regionally distinct and potentially actionable cell subpopulations and advocate the need for a multi-targeted approach to GBM therapeutics.

Objective. Recording and stimulating from the peripheral nervous system are becoming important components in a new generation of bioelectronics systems. Although neurostimulation has seen a history of successful chronic applications in humans, peripheral nerve recording in humans chronically remains a challenge. Multi-contact nerve cuff electrode configurations have the potential to improve recording selectivity. We introduce the idea of using a convolutional neural network (CNN) to associate recordings of individual naturally evoked compound action potentials (CAPs) with neural pathways of interest, by exploiting the spatiotemporal patterns in multi-contact nerve cuff recordings. Approach. Nine Long-Evan rats were implanted with a 56-channel nerve cuff electrode on the sciatic nerve and afferent activity was selectively evoked in different fascicles (tibial, peroneal, sural) using mechanical stimuli. A recurrent neural network was then used to predict joint angles based on the predicted firing patterns from the CNN. Performance was measured based on the classification accuracy, F1-score and the ability to track the ankle joint angle. Main results. Classification accuracy and F1-score of the best CNN configuration were and 0.747  ±  0.114, respectively. The mean Pearson correlation coefficient between the manually measured ankle angle and the angle predicted from the estimated firing rate was Significance. The proposed method demonstrates that CAP-based classification can be achieved with high accuracy and can be used to track a physiological meaningful measure (e.g. joint angle). These results provide a promising direction for realizing more effective and intuitive neuroprosthetic systems.

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Objectives: Sepsis and trauma are common health problems and provide great challenges in critical care. Diverse patient responses to these conditions further complicate patient management and outcome prediction. Whole blood transcriptomics provides a unique opportunity to follow the molecular response in the critically ill. Prior results show robust and diverse genomic signal in the acute phase and others have found shared biological mechanisms across divergent disease etiologies. We hypothesize that selected transcriptomics responses, particularly immune mechanisms are shared across disease etiologies. We further hypothesize that these processes may identify homogenous patient subgroups with shared clinical course in critical illness deciphering disease heterogeneity. These processes may serve as universal markers for predicting a complicated clinical course and/or risk of a poor outcome. Design: We present a system level, data driven, genome-wide analysis of whole blood gene expression for a total of 382 patients suffering from either abdominal sepsis (49), pulmonary sepsis (107) or trauma (158) and compare these to gene expression in healthy controls (68). Patients and Setting: We relied on available open genetic data from gene expression omnibus for patients diagnosed with abdominal sepsis, community-acquired pneumonia, or trauma which also included healthy control patients. Measurements and Main Results: Our results confirm that immune processes are shared across disease etiologies in critical illnesses. We identify two consistent and distinct patient subgroups through deconvolution of serum transcriptomics: 1) increased neutrophils and naïve CD4 cell fractions and 2) suppressed neutrophil fraction. Furthermore, we found immune and inflammatory processes were downregulated in subgroup 2, a configuration previously shown to be more susceptible to multiple organ failure. Correspondingly, this subgroup had significantly higher mortality rates in all three etiologies of illness (0% vs 6.1%, p = 3.1 × 10–39 for trauma; 15.0% vs 25.4%, p = 4.4 × 10–9 for community-acquired pneumonia, and 7.1% vs 20.0%, p = 3.4 × 10–7 for abdominal sepsis). Conclusions: We identify two consistent subgroups of critical illness based on serum transcriptomics and derived immune cell fractions, with significantly different survival rates. This may serve as a universal predictor of complicated clinical course or treatment response and, importantly, may identify opportunities for subgroup-specific immunomodulatory intervention.

Modulation of tumor microenvironment is an emerging frontier for new therapeutics. However in meningiomas, the most frequent adult brain tumor, the correlation of microenvironment with tumor phenotype is scarcely studied. We applied a variety of systems biology approaches to bulk tumor transcriptomics to explore the immune environments of both skull base and convexity (hemispheric) meningiomas. We hypothesized that the more benign biology of skull base meningiomas parallels the relative composition and activity of immune cells that oppose tumor growth and/or survival. We firstly applied gene co-expression networks to tumor bulk transcriptomics from 107 meningiomas (derived from 3 independent studies) and found immune processes to be the sole biological mechanism correlated with anatomical location while correcting for tumour grade. We then derived tumor immune cell fractions from bulk transcriptomics data and examined the immune cell-cytokine interactions using a network-based approach. We demonstrate that oncolytic Gamma-Delta T cells dominate skull base meningiomas while mast cells and neutrophils, known to play a role in oncogenesis, show greater activity in convexity tumors. Our results are the first to suggest the importance of tumor microenvironment in meningioma biology in the context of anatomic location and immune landscape. These findings may help better inform surgical decision making and yield location-specific therapies through modulation of immune microenvironment.

Agender pay gap in physician incomes has been described across numerous jurisdictions. 1 Previous analy ses have found income differences between women and men in the general physician population, among academic physicians and among physicians within the same specialty, 2-8 and when controlling for years of experience, hours worked, geographic location, race and practice type. [9][10][11][12][13] Although the difference in physician income between women and men is well described in the United States, fewer studies have looked at a Canadian cohort. An analysis of surgeons in Ontario found that female surgeons earned less per hour spent operating than male surgeons, and suggested that female physicians were more likely to perform less lucrative procedures than male physicians. 14 A recent report released by the Ontario Medical Association highlighted income disparity between men and women physicians in Ontario, but did not provide a detailed breakdown by specialty. 15 Transparent and detailed reporting on gender differences in physician payments can provide data to guide advocacy for greater pay equity.In this study, we aimed to describe payments to physicians across the province of Ontario by gender when controlling for specialty choice, career stage and physician demographics. Methods ContextOntario has a publicly funded, single-payer health care system for physician services. About 70% of physician payments are paid through a fee-for-service model for claims to the Ontario Health Insurance Plan (OHIP). The remainder of physician payments come from alternative payment plans, which can consist of salaries, hourly rates, capitation models or contract-based payments. 16 A physician's salary can comprise a combination of

There are limited data pertaining to current practices in timing of surgical decompression for acute thoracolumbar spinal cord injury (SCI). We conducted a retrospective cohort study to evaluate variability in timing between- and within-trauma centers in North America; and to identify patient- and hospital-level factors associated with treatment delay. Adults with acute thoracolumbar SCI who underwent decompressive surgery within five days of injury at participating trauma centers in the American College of Surgeons Trauma Quality Improvement Program were included. Mixed-effects regression with a random intercept for trauma center was used to model the outcome of time to surgical decompression and assess risk-adjusted variability in surgery timeliness across centers. 3,948 patients admitted to 214 TQIP centers were eligible. 28 centers were outliers, with a significantly shorter or longer time to surgery than average. Case-mix and hospital characteristics explained < 1% of between-hospital variability in surgical timing. Moreover, only 7% of surgical timing variability within-centers was explained by case-mix characteristics. The adjusted intraclass correlation coefficient of 12% suggested poor correlation of surgical timing for patients with similar characteristics treated at the same center. These findings support the need for further research into the optimal timing of surgical intervention for thoracolumbar SCI.

This systematic review evaluates the role of methotrexate (MTX) as an adjunctive intravitreal agent for the prevention and treatment of proliferative vitreoretinopathy (PVR) in rhegmatogenous retinal detachment. Articles investigating the use of MTX in ≥5 patients with PVR or high risk of PVR were identified via searches of OVID MED-LINE, EMBASE, and Cochrane Library. Eight studies and 240 eyes were included. Patients received an average 2.2 MTX injections with doses ranging from 250 to 400 µg. After 10 months of follow-up in the three controlled trials, there was an 80% retinal re-attachment rate and 0.63 logMAR improvement in visual acuity for patients receiving MTX ( n = 106), compared to an 83% reattachment rate and 0.30 logMAR improvement for controls ( n = 91). Three mild complications related to MTX were reported. Further research is required given the low number of studies and quality of evidence, heterogenous case selection and treatment regimens, high risk of bias, and lack of randomization. [ Ophthalmic Surg Lasers Imaging Retina 2022;53:561–568.]