Neurosurgery
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Checkpoint molecules like programmed death-1 (PD-1) and T-cell immunoglobulin mucin-3 (TIM-3) act as negative regulators of the immune system and can be upregulated in the setting of glioblastoma multiforme (GBM). Combined PD-1 blockade and stereotactic radiosurgery (SRS) have been shown to improve antitumor immunity and produce long-term survivors in a murine glioma model. However, tumor-infiltrating lymphocytes can express multiple checkpoints (including TIM-3), and expression of 2 or more checkpoints corresponds to a more exhausted T-cell phenotype. Here, we hypothesized that the addition of a second checkpoint-blocking antibody could achieve additive or synergistic antitumor effects. ⋯ Combining anti-TIM-3 with anti-PD-1 and radiation was synergistic and conferred a significant survival benefit.
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Microglia, the resident immune cells of the central nervous system, play a critical role in health and disease. Following injury, microglia upregulate inducible nitric oxide synthase (iNOS), and can exert neurotoxic effects by releasing large quantities of nitric oxide (NO). Expression of iNOS, and many other proinflammatory genes, is regulated in part by Ca influx and Ca-dependent transcription factors. The expression of the nonselective cation channel Sur1-Trpm4 may be 1 molecular mechanism by which microglia dynamically modulate Ca influx. We hypothesized that microglial Sur1-Trpm4 plays a role in microglial-mediated neuroinflammation by regulating the calcium-sensitive induction of iNOS. ⋯ Our results strongly support our hypothesis that Sur1-Trpm4 regulates the calcium-sensitive induction of iNOS by controlling NFAT activity. These observations have impactful therapeutic implications. Inhibition of Sur1-Trpm4 using the well-tolerated sulfonylurea glibenclamide (a.k.a. glyburide) may be a promising approach to limit the deleterious effects of microglial-mediated neuroinflammation.
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Brain-machine interface neuroprosthetic arms for people with upper limb impairment are developing quickly, but could be improved through intelligent computer-vision-based assistance. Grasping and manipulating objects requires very accurate control of a prosthetic arm and hand, and is required for these limbs to eventually be used clinically. With the computer helping to stabilize the hand during grasping, the user's control would not need to be as accurate, and they would be free to concentrate on the larger goals of the arm movements. ⋯ By integrating brain-machine interface-based high-level control with computer-vision-based low-level control of a robotic arm, people with tetraplegia showed improved functional use of the arm. This result highlights the importance of combining neuroscience- and robotic-based assistive technologies to create a highly flexible and effective neuroprosthetic arm for people with upper limb impairment.
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The optimal site for placement of tissue oxygen probes following traumatic brain injury (TBI) remains unresolved. We studied brain tissue oxygen tension (PbtO2) at the sites of contusion, proximal and distal to contusion, and in the contralateral hemisphere to determine the effect of probe location on PbtO2 and to assess the effects of physiological interventions on PbtO2 at these different sites. ⋯ PbtO2 measurements are strongly influenced by the distance from the site of focal injury. Physiological alterations, including hyperoxia, hyperventilation, and hypoventilation substantially affect PbtO2 values distal to the site of injury, but have little effect in and around the site of contusion.
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Recent efforts to improve health care quality have focused on variations in outcomes such as 30-day readmissions (30d-R). Pay-for-performance programs hold providers accountable to reduce these variations, with the assumption that variations are due to discretionary practices of providers and can be influenced by changes in reimbursement. We examined variations in length of stay (LOS) and 30d-R among the surgeons for elective lumbar spine surgery for degenerative conditions to determine if these outcomes are a valid target for pay for performance programs. ⋯ We found significant variations in LOS by surgeon after adjusting for patient characteristics and type of surgery. This suggests that surgeon practice varies and impacts length of stay. Yet, we found no variation in 30d-R by surgeon, implying that surgeon practice variation does not affect 30d-R. Thus, pay-for-performance programs aimed at providers are unlikely to improve 30d-R.