Rapid Electroencephalography and Artificial Intelligence in the Detection and Management of Nonconvulsive Seizures.

STUDY OBJECTIVE: Nonconvulsive status epilepticus is a commonly overlooked cause of altered mental status. This study assessed nonconvulsive status epilepticus prevalence in emergency department (ED) patients with acute neurologic presentations using limited electroencephalogram (EEG) coupled with artificial intelligence (AI)-enhanced seizure detection technology. We then compared the accuracy of the AI EEG interpretations to those performed by an epileptologist. METHODS: In a prospective observational cohort analysis, adult patients with unexplained mental status changes identified by emergency physicians received expedited placement of a limited EEG. Data collected encompassed patient demographics, clinical history, EEG interpretations by the AI algorithm and epileptologists, treatments, and disposition determinations. RESULTS: There were 134 device applications on 132 patients (2 received the device twice) enrolled in the study, but 16 were missing data critical for identification or analysis and 9 did not meet the selection criteria. Of the 108 limited EEGs interpreted by an epileptologist, 69 were abnormal (diffuse slowing, highly epileptiform patterns, or spikes and sharps), 41 were normal, 5 were uninterpretable, and 3 captured episodes of seizure or status epilepticus. Limited EEG AI interpretation detected >90% seizure burden in 2 of 3 cases of seizure or status epilepticus as well as in 2 abnormal EEGs and 1 normal EEG, providing a sensitivity of 66.7% (95% confidence interval 9.4 to 99.2), a specificity of 97.0% (95% confidence interval 91.5 to 99.4), and a disease prevalence of 2.9%. CONCLUSION: Limited AI-enhanced EEG can detect nonconvulsive status epilepticus in the ED; however, the technology tended to overestimate seizure burden in our cohort. This study found a lower nonconvulsive status epilepticus prevalence compared to prior literature reports.

Underrepresentation of Women and Minorities in the United States IR Academic Physician Workforce.

PURPOSE: To assess the United States interventional radiology (IR) academic physician workforce diversity and comparative specialties. METHODS: Public registries were used to assess demographic differences among 2012 IR faculty and fellows, diagnostic radiology (DR) faculty and residents, DR subspecialty fellows (pediatric, abdominal, neuroradiology, and musculoskeletal), vascular surgery and interventional cardiology trainees, and 2010 US medical school graduates and US Census using binomial tests with .001 significance level (Bonferroni adjustment for multiple comparisons). Significant trends in IR physician representation were evaluated from 1992 to 2012. RESULTS: Women (15.4%), blacks (2.0%), and Hispanics (6.2%) were significantly underrepresented as IR fellows compared with the US population. Women were underrepresented as IR (7.3%) versus DR (27.8%) faculty and IR fellows (15.4%) versus medical school graduates (48.3%), DR residents (27.8%), pediatric radiology fellows (49.4%), and vascular surgery trainees (27.7%) (all P < .001). IR ranked last in female representation among radiologic subspecialty fellows. Blacks (1.8%, 2.1%, respectively, for IR faculty and fellows); Hispanics (1.8%, 6.2%); and combined American Indians, Alaska Natives, Native Hawaiians, and Pacific Islanders (1.8%, 0) showed no significant differences in representation as IR fellows compared with IR faculty, DR residents, other DR fellows, or interventional cardiology or vascular surgery trainees. Over 20 years, there was no significant increase in female or black representation as IR fellows or faculty. CONCLUSIONS: Women, blacks, and Hispanics are underrepresented in the IR academic physician workforce relative to the US population. Given prevalent health care disparities and an increasingly diverse society, research and training efforts should address IR physician workforce diversity.

Ovariectomy-Induced Arterial Stiffening Differs From Vascular Aging and Is Reversed by GPER Activation.

BACKGROUND: Arterial stiffness is a cardiovascular risk factor and dramatically increases as women transition through menopause. The current study assessed whether a mouse model of menopause increases arterial stiffness in a similar manner to aging and whether activation of the G-protein-coupled estrogen receptor could reverse stiffness. METHODS: Female C57Bl/6J mice were ovariectomized at 10 weeks of age or aged to 52 weeks, and some mice were treated with G-protein-coupled estrogen receptor agonists. RESULTS: Ovariectomy and aging increased pulse wave velocity to a similar extent independent of changes in blood pressure. Aging increased carotid wall thickness, while ovariectomy increased material stiffness without altering vascular geometry. RNA-sequencing analysis revealed that ovariectomy downregulated smooth muscle contractile genes. The enantiomerically pure G-protein-coupled estrogen receptor agonist, LNS8801, reversed stiffness in ovariectomy mice to a greater degree than the racemic agonist G-1. In summary, ovariectomy and aging induced arterial stiffening via potentially different mechanisms. Aging was associated with inward remodeling, while ovariectomy-induced material stiffness independent of geometry and a loss of the contractile phenotype. CONCLUSIONS: This study enhances our understanding of the impact of estrogen loss on vascular health in a murine model and warrants further studies to examine the ability of LNS8801 to improve vascular health in menopausal women.

Ovariectomy-Induced Arterial Stiffening Differs from Vascular Aging and is Reversed by GPER Activation.

Arterial stiffness is a cardiovascular risk factor and dramatically increases as women transition through menopause. The current study assessed whether a mouse model of menopause increases arterial stiffness in a similar manner to aging, and whether activation of the G protein-coupled estrogen receptor (GPER) could reverse stiffness. Female C57Bl/6J mice were ovariectomized (OVX) at 10 weeks of age or aged to 52 weeks, and some mice were treated with GPER agonists. OVX and aging increased pulse wave velocity to a similar extent independent of changes in blood pressure. Aging increased carotid wall thickness, while OVX increased material stiffness without altering vascular geometry. RNA-Seq analysis revealed that OVX downregulated smooth muscle contractile genes. The enantiomerically pure GPER agonist, LNS8801, reversed stiffness in OVX mice to a greater degree than the racemic agonist G-1. In summary, OVX and aging induced arterial stiffening via potentially different mechanisms. Aging was associated with inward remodeling while OVX induced material stiffness independent of geometry and a loss of the contractile phenotype. This study helps to further our understanding of the impact of menopause on vascular health and identifies LNS8801 as a potential therapy to counteract this detrimental process in women.

A Virtual Book Club for Professional Development in Emergency Medicine.

INTRODUCTION: Professional development is an important component of graduate medical education, but it is unclear how to best deliver this instruction. Book clubs have been used outside of medicine as a professional development tool. We sought to create and evaluate a virtual professional development book club for emergency medicine interns. METHODS: We designed and implemented a virtual professional development book club during intern orientation. Afterward, participants completed an evaluative survey consisting of Likert and free-response items. Descriptive statistics were reported. We analyzed free-response data using a thematic approach. RESULTS: Of 15 interns who participated in the book club, 12 (80%) completed the evaluative survey. Most (10/12; 83.3%) agreed or strongly agreed that the book club showed them the importance of professional development as a component of residency training and helped them reflect on their own professional (11/12; 91.7%) and personal development (11/12; 91.7%). Participants felt the book club contributed to bonding with their peers (9/12; 75%) and engagement with the residency program (9/12; 75%). Our qualitative analysis revealed five major themes regarding how the book club contributed to professional and personal development: alignment with developmental stage; deliberate practice; self-reflection; strategies to address challenges; and communication skills. CONCLUSION: A virtual book club was feasible to implement. Participants identified multiple ways the book club positively contributed to their professional development. These results may inform the development of other book clubs in graduate medical education.

Disrupting the CD47-SIRPα anti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric brain tumors.

Morbidity and mortality associated with pediatric malignant primary brain tumors remain high in the absence of effective therapies. Macrophage-mediated phagocytosis of tumor cells via blockade of the anti-phagocytic CD47-SIRPα interaction using anti-CD47 antibodies has shown promise in preclinical xenografts of various human malignancies. We demonstrate the effect of a humanized anti-CD47 antibody, Hu5F9-G4, on five aggressive and etiologically distinct pediatric brain tumors: group 3 medulloblastoma (primary and metastatic), atypical teratoid rhabdoid tumor, primitive neuroectodermal tumor, pediatric glioblastoma, and diffuse intrinsic pontine glioma. Hu5F9-G4 demonstrated therapeutic efficacy in vitro and in vivo in patient-derived orthotopic xenograft models. Intraventricular administration of Hu5F9-G4 further enhanced its activity against disseminated medulloblastoma leptomeningeal disease. Notably, Hu5F9-G4 showed minimal activity against normal human neural cells in vitro and in vivo, a phenomenon reiterated in an immunocompetent allograft glioma model. Thus, Hu5F9-G4 is a potentially safe and effective therapeutic agent for managing multiple pediatric central nervous system malignancies.

Anti-CD47 Treatment Stimulates Phagocytosis of Glioblastoma by M1 and M2 Polarized Macrophages and Promotes M1 Polarized Macrophages In Vivo.

Tumor-associated macrophages (TAMs) represent an important cellular subset within the glioblastoma (WHO grade IV) microenvironment and are a potential therapeutic target. TAMs display a continuum of different polarization states between antitumorigenic M1 and protumorigenic M2 phenotypes, with a lower M1/M2 ratio correlating with worse prognosis. Here, we investigated the effect of macrophage polarization on anti-CD47 antibody-mediated phagocytosis of human glioblastoma cells in vitro, as well as the effect of anti-CD47 on the distribution of M1 versus M2 macrophages within human glioblastoma cells grown in mouse xenografts. Bone marrow-derived mouse macrophages and peripheral blood-derived human macrophages were polarized in vitro toward M1 or M2 phenotypes and verified by flow cytometry. Primary human glioblastoma cell lines were offered as targets to mouse and human M1 or M2 polarized macrophages in vitro. The addition of an anti-CD47 monoclonal antibody led to enhanced tumor-cell phagocytosis by mouse and human M1 and M2 macrophages. In both cases, the anti-CD47-induced phagocytosis by M1 was more prominent than that for M2. Dissected tumors from human glioblastoma xenografted within NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice and treated with anti-CD47 showed a significant increase of M1 macrophages within the tumor. These data show that anti-CD47 treatment leads to enhanced tumor cell phagocytosis by both M1 and M2 macrophage subtypes with a higher phagocytosis rate by M1 macrophages. Furthermore, these data demonstrate that anti-CD47 treatment alone can shift the phenotype of macrophages toward the M1 subtype in vivo.

The diverse surgeons' initiative: longitudinal assessment of a successful national program.

BACKGROUND: The Diverse Surgeons Initiative (DSI) is a program that was created to provide underrepresented minority surgical residents with the clinical knowledge and minimally invasive surgical skills necessary to excel in surgical residency and successfully transition into surgical practice. The early success of the graduates of the program has been published; however, a more longitudinal assessment of the program was suggested and warranted. This study provides a 5-year follow-up of the 76 physicians that participated in the DSI from 2002 to 2009 to determine if the trend toward fellowship placement and academic appointments persisted. Additionally, this extended evaluation yields an opportunity to assess these young surgeons' professional progress and contributions to the field. STUDY DESIGN: The most current professional development and employment information was obtained for the 76 physicians that completed the DSI from 2002 to 2009. The percentage of DSI graduates completing surgical residency, obtaining subspecialty fellowships, attaining board certification, receiving fellowship in the American College of Surgeons, contributing to the peer-reviewed literature, acquiring academic faculty positions, and ascending to professional leadership roles were calculated and compared with the original assessment. RESULTS: Of the 76 DSI graduates, 99% completed general surgery residency. Of those eligible, 87% completed subspecialty fellowships; 87% were board certified; 50% received fellowship in the American College of Surgeons; 76% had contributed to the peer-reviewed literature; 41% had obtained faculty positions; and 18% held local, regional, or national professional leadership positions. CONCLUSIONS: This longitudinal analysis has revealed sustained success of the DSI in preparing underrepresented minority residents to excel in their training and transition into practice, obtain postsurgical fellowships, acquire faculty appointments, and contribute to the advancement of the field of surgery.

Neural Placode Tissue Derived From Myelomeningocele Repair Serves as a Viable Source of Oligodendrocyte Progenitor Cells.

BACKGROUND: The presence, characteristics, and potential clinical relevance of neural progenitor populations within the neural placodes of myelomeningocele patients remain to be studied. Neural stem cells are known to reside adjacent to ependyma-lined surfaces along the central nervous system axis. OBJECTIVE: Given such neuroanatomic correlation and regenerative capacity in fetal development, we assessed myelomeningocele-derived neural placode tissue as a potentially novel source of neural stem and progenitor cells. METHODS: Nonfunctional neural placode tissue was harvested from infants during the surgical repair of myelomeningocele and subsequently further analyzed by in vitro studies, flow cytometry, and immunofluorescence. To assess lineage potential, neural placode-derived neurospheres were subjected to differential media conditions. Through assessment of platelet-derived growth factor receptor α (PDGFRα) and CD15 cell marker expression, Sox2+Olig2+ putative oligodendrocyte progenitor cells were successfully isolated. RESULTS: PDGFRαCD15 cell populations demonstrated the highest rate of self-renewal capacity and multipotency of cell progeny. Immunofluorescence of neural placode-derived neurospheres demonstrated preferential expression of the oligodendrocyte progenitor marker, CNPase, whereas differentiation to neurons and astrocytes was also noted, albeit to a limited degree. CONCLUSION: Neural placode tissue contains multipotent progenitors that are preferentially biased toward oligodendrocyte progenitor cell differentiation and presents a novel source of such cells for use in the treatment of a variety of pediatric and adult neurological disease, including spinal cord injury, multiple sclerosis, and metabolic leukoencephalopathies.

Decoupling of tumor-initiating activity from stable immunophenotype in HoxA9-Meis1-driven AML.

Increasing evidence suggests tumors are maintained by cancer stem cells; however, their nature remains controversial. In a HoxA9-Meis1 (H9M) model of acute myeloid leukemia (AML), we found that tumor-initiating activity existed in three, immunophenotypically distinct compartments, corresponding to disparate lineages on the normal hematopoietic hierarchy--stem/progenitor cells (Lin(-)kit(+)) and committed progenitors of the myeloid (Gr1(+)kit(+)) and lymphoid lineages (Lym(+)kit(+)). These distinct tumor-initiating cells (TICs) clonally recapitulated the immunophenotypic spectrum of the original tumor in vivo (including cells with a less-differentiated immunophenotype) and shared signaling networks, such that in vivo pharmacologic targeting of conserved TIC survival pathways (DNA methyltransferase and MEK phosphorylation) significantly increased survival. Collectively, H9M AML is organized as an atypical hierarchy that defies the strict lineage marker boundaries and unidirectional differentiation of normal hematopoiesis. Moreover, this suggests that in certain malignancies tumor-initiation activity (or "cancer stemness") can represent a cellular state that exists independently of distinct immunophenotypic definition.