In-State Retention Rates of Female Neurosurgery Graduates.

OBJECTIVE: We sought to determine the rate of retaining female neurosurgery graduates in the same states as their medical education and identify medical school and state characteristics associated with high retention rates. METHODS: Database from the Centers for Medicare & Medicaid Services was used to extract female physicians indicating "neurosurgery" as their specialty. The top 25 medical schools with the highest number of female neurosurgery graduates were selected. Descriptive analysis was used to determine the retention rate of female neurosurgery graduates. Univariable and multivariable analyses were used to identify medical school and state characteristics associated with high retention rates. RESULTS: Medical schools with the highest retention rate included the University of California, San Francisco (60%), the University of Alabama (60%), and the University of Pennsylvania (60%). Univariable and multivariable analysis showed the number of female neurosurgery attendings (ß = 0.036, 95% confidence interval [CI] = 0.003 to 0.070, P = 0.04 and ß = 0.036, CI = 0.001 to 0.071, P = 0.04.) and the healthcare employment rate (ß = 0.098, CI = 0.011 to 0.186, P = 0.03 and ß = 0.117, CI = 0.021 to 0.212, P = 0.02) to be positively associated with the retention rate of female neurosurgery graduates. CONCLUSIONS: Retaining female neurosurgery graduates within a state is essential for addressing the physician shortage and gender inequality. To encourage female medical students to practice in the same state, medical schools and states should work collectively to improve the visibility of female neurosurgeons and increase employment opportunities.

Defining blood-induced microglia functions in neurodegeneration through multiomic profiling.

Blood protein extravasation through a disrupted blood-brain barrier and innate immune activation are hallmarks of neurological diseases and emerging therapeutic targets. However, how blood proteins polarize innate immune cells remains largely unknown. Here, we established an unbiased blood-innate immunity multiomic and genetic loss-of-function pipeline to define the transcriptome and global phosphoproteome of blood-induced innate immune polarization and its role in microglia neurotoxicity. Blood induced widespread microglial transcriptional changes, including changes involving oxidative stress and neurodegenerative genes. Comparative functional multiomics showed that blood proteins induce distinct receptor-mediated transcriptional programs in microglia and macrophages, such as redox, type I interferon and lymphocyte recruitment. Deletion of the blood coagulation factor fibrinogen largely reversed blood-induced microglia neurodegenerative signatures. Genetic elimination of the fibrinogen-binding motif to CD11b in Alzheimer's disease mice reduced microglial lipid metabolism and neurodegenerative signatures that were shared with autoimmune-driven neuroinflammation in multiple sclerosis mice. Our data provide an interactive resource for investigation of the immunology of blood proteins that could support therapeutic targeting of microglia activation by immune and vascular signals.

Zika virus-based immunotherapy enhances long-term survival of rodents with brain tumors through upregulation of memory T-cells.

Zika virus (ZIKV) exhibits a tropism for brain tumor cells and has been used as an oncolytic virus to target brain tumors in mice with modest effects on extending median survival. Recent studies have highlighted the potential for combining virotherapy and immunotherapy to target cancer. We postulated that ZIKV could be used as an adjuvant to enhance the long-term survival of mice with malignant glioblastoma and generate memory T-cells capable of providing long-term immunity against cancer remission. To test this hypothesis mice bearing malignant intracranial GL261 tumors were subcutaneously vaccinated with irradiated GL261 cells previously infected with the ZIKV. Mice also received intracranial injections of live ZIKV, irradiation attenuated ZIKV, or irradiated GL261 cells previously infected with ZIKV. Long-term survivors were rechallenged with a second intracranial tumor to examine their immune response and look for the establishment of protective memory T-cells. Mice with subcutaneous vaccination plus intracranial irradiation attenuated ZIKV or intracranial irradiated GL261 cells previously infected with ZIKV exhibited the greatest extensions to overall survival. Flow cytometry analysis of immune cells within the brains of long-term surviving mice after tumor rechallenge revealed an increase in the number of T-cells, including CD4+ and tissue-resident effector/ effector memory CD4+ T-cells, in comparison to long-term survivors that were mock-rechallenged, and in comparison to naïve untreated mice challenged with intracranial gliomas. These results suggest that ZIKV can serve as an adjuvant to subcutaneous tumor vaccines that enhance long-term survival and generate protective tissue-resident memory CD4+ T-cells.

Orientation selective deep brain stimulation of the subthalamic nucleus in rats.

Deep brain stimulation (DBS) has become an important tool in the management of a wide spectrum of diseases in neurology and psychiatry. Target selection is a vital aspect of DBS so that only the desired areas are stimulated. Segmented leads and current steering have been shown to be promising additions to DBS technology enabling better control of the stimulating electric field. Recently introduced orientation selective DBS (OS-DBS) is a related development permitting sensitization of the stimulus to axonal pathways with different orientations by freely controlling the primary direction of the electric field using multiple contacts. Here, we used OS-DBS to stimulate the subthalamic nucleus (STN) in healthy rats while simultaneously monitoring the induced brain activity with fMRI. Maximal activation of the sensorimotor and basal ganglia-thalamocortical networks was observed when the electric field was aligned mediolaterally in the STN pointing in the lateral direction, while no cortical activation was observed with the electric field pointing medially to the opposite direction. Such findings are consistent with mediolateral main direction of the STN fibers, as seen with high resolution diffusion imaging and histology. The asymmetry of the OS-DBS dipolar field distribution using three contacts along with the potential stimulation of the internal capsule, are also discussed. We conclude that OS-DBS offers an additional degree of flexibility for optimization of DBS of the STN which may enable a better treatment response.

Interspecies Organogenesis for Human Transplantation.

Blastocyst complementation combined with gene editing is an emerging approach in the field of regenerative medicine that could potentially solve the worldwide problem of organ shortages for transplantation. In theory, blastocyst complementation can generate fully functional human organs or tissues, grown within genetically engineered livestock animals. Targeted deletion of a specific gene(s) using gene editing to cause deficiencies in organ development can open a niche for human stem cells to occupy, thus generating human tissues. Within this review, we will focus on the pancreas, liver, heart, kidney, lung, and skeletal muscle, as well as cells of the immune and nervous systems. Within each of these organ systems, we identify and discuss (i) the common causes of organ failure; (ii) the current state of regenerative therapies; and (iii) the candidate genes to knockout and enable specific exogenous organ development via the use of blastocyst complementation. We also highlight some of the current barriers limiting the success of blastocyst complementation.