ItemNational Institutes of Health Stroke Scale (NIHSS) scoring inconsistencies between neurologists and emergency room nurses(Frontiers, 2022) Comer, Amber R.; Templeton, Evan; Glidden, Michelle; Bartlett, Stephanie; D'Cruz, Lynn; Nemati, Donya; Zabel, Samantha; Slaven, James E.BACKGROUND: Little is known about the consistency of initial NIHSS scores between neurologists and RNs in clinical practice. METHODS: A cohort study of patients with a code stroke was conducted at an urban academic Primary Stroke Center in the Midwest between January 1, 2018, and December 31, 2019 to determine consistency in National Institutes of Health Stroke Scale Scores (NIHSS) between neurologists and registered nurses (RNs). RESULTS: Among the 438 patients included in this study 65.3% (n = 286) of neurologist-RN NIHSS scoring pairs had congruent scores. One-in-three, (34.7%, n = 152) of neurologist-RN NIHSS scoring pairs had a clinically meaningful scoring difference of two points or greater. Higher NIHSS (p ≤ 0.01) and aphasia (p ≤ 0.01) were each associated with incongruent scoring between neurologist and emergency room RN pairs. CONCLUSIONS: One-in-three initial NIHSS assessed by both a neurologist and RN had a clinically meaningful score difference between providers. More severe stroke, as indicated by a higher NIHSS was associated with scoring inconsistency between neurologist-RN pairs. Subjective scoring measures, especially those involving a patient having aphasia, was associated with greater score incongruency. Score differences may be attributed to differences in NIHSS training requirements between neurologists and RNs. ItemA Novel ZIP4-HDAC4-VEGFA Axis in High-Grade Serous Ovarian Cancer(MDPI, 2021-07-29) Fan, Qipeng; Li, Lihong; Wang, Tian-Li; Emerson, Robert E.; Xu, Yan; Obstetrics and Gynecology, School of MedicineWe have recently identified ZIP4 as a novel cancer stem cell (CSC) marker in high-grade serous ovarian cancer (HGSOC). While it converts drug-resistance to cisplatin (CDDP), we unexpectedly found that ZIP4 induced sensitization of HGSOC cells to histone deacetylase inhibitors (HDACis). Mechanistically, ZIP4 selectively upregulated HDAC IIa HDACs, with little or no effect on HDACs in other classes. HDAC4 knockdown (KD) and LMK-235 inhibited spheroid formation in vitro and tumorigenesis in vivo, with hypoxia inducible factor-1 alpha (HIF1α) and endothelial growth factor A (VEGFA) as functional downstream mediators of HDAC4. Moreover, we found that ZIP4, HDAC4, and HIF1α were involved in regulating secreted VEGFA in HGSOC cells. Furthermore, we tested our hypothesis that co-targeting CSC via the ZIP4-HDAC4 axis and non-CSC using CDDP is necessary and highly effective by comparing the effects of ZIP4-knockout/KD, HDAC4-KD, and HDACis, in the presence or absence of CDDP on tumorigenesis in mouse models. Our results showed that the co-targeting strategy was highly effective. Finally, data from human HGSOC tissues showed that ZIP4 and HDAC4 were upregulated in a subset of recurrent tumors, justifying the clinical relevance of the study. In summary, our study provides a new mechanistic-based targeting strategy for HGSOC. ItemCharacterization and assessment of lung and bone marrow derived endothelial cells and their bone regenerative potential(Frontiers, 2022) de Lima Perini, Mariana Moraes; Valuch, Conner R.; Dadwal, Ushashi C.; Awosanya, Olatundun D.; Mostardo, Sarah L.; Blosser, Rachel J.; Knox, Adam M.; McGuire, Anthony C.; Battina, Hanisha L.; Nazzal, Murad; Kacena, Melissa A.; Li, Jiliang; Biology, School of ScienceAngiogenesis is important for successful fracture repair. Aging negatively affects the number and activity of endothelial cells (ECs) and subsequently leads to impaired bone healing. We previously showed that implantation of lung-derived endothelial cells (LECs) improved fracture healing in rats. In this study, we characterized and compared neonatal lung and bone marrow-derived endothelial cells (neonatal LECs and neonatal BMECs) and further asses3sed if implantation of neonatal BMECs could enhance bone healing in both young and aged mice. We assessed neonatal EC tube formation, proliferation, and wound migration ability in vitro in ECs isolated from the bone marrow and lungs of neonatal mice. The in vitro studies demonstrated that both neonatal LECs and neonatal BMECs exhibited EC traits. To test the function of neonatal ECs in vivo, we created a femoral fracture in young and aged mice and implanted a collagen sponge to deliver neonatal BMECs at the fracture site. In the mouse fracture model, endochondral ossification was delayed in aged control mice compared to young controls. Neonatal BMECs significantly improved endochondral bone formation only in aged mice. These data suggest BMECs have potential to enhance aged bone healing. Compared to LECs, BMECs are more feasible for translational cell therapy and clinical applications in bone repair. Future studies are needed to examine the fate and function of BMECs implanted into the fracture sites. ItemPhenoDEF: a corpus for annotating sentences with information of phenotype definitions in biomedical literature(Springer, 2022) Binkheder, Samar; Wu, Heng-Yi; Quinney, Sara K.; Zhang, Shijun; Zitu, Md. Muntasir; Chiang, Chien-Wei; Wang, Lei; Jones, Josette; Li, Lang; BioHealth Informatics, School of Informatics and ComputingBackground Adverse events induced by drug-drug interactions are a major concern in the United States. Current research is moving toward using electronic health record (EHR) data, including for adverse drug events discovery. One of the first steps in EHR-based studies is to define a phenotype for establishing a cohort of patients. However, phenotype definitions are not readily available for all phenotypes. One of the first steps of developing automated text mining tools is building a corpus. Therefore, this study aimed to develop annotation guidelines and a gold standard corpus to facilitate building future automated approaches for mining phenotype definitions contained in the literature. Furthermore, our aim is to improve the understanding of how these published phenotype definitions are presented in the literature and how we annotate them for future text mining tasks. Results Two annotators manually annotated the corpus on a sentence-level for the presence of evidence for phenotype definitions. Three major categories (inclusion, intermediate, and exclusion) with a total of ten dimensions were proposed characterizing major contextual patterns and cues for presenting phenotype definitions in published literature. The developed annotation guidelines were used to annotate the corpus that contained 3971 sentences: 1923 out of 3971 (48.4%) for the inclusion category, 1851 out of 3971 (46.6%) for the intermediate category, and 2273 out of 3971 (57.2%) for exclusion category. The highest number of annotated sentences was 1449 out of 3971 (36.5%) for the “Biomedical & Procedure” dimension. The lowest number of annotated sentences was 49 out of 3971 (1.2%) for “The use of NLP”. The overall percent inter-annotator agreement was 97.8%. Percent and Kappa statistics also showed high inter-annotator agreement across all dimensions. Conclusions The corpus and annotation guidelines can serve as a foundational informatics approach for annotating and mining phenotype definitions in literature, and can be used later for text mining applications. ItemRates of Tobacco Use Disorder, Pharmacologic Treatment, and Associated Mental Health Disorders in a Medicaid Claim Review Among Youth in Indiana, USA(Sage, 2022) McBrayer, Kimberly; Ouyang, Fangqian; Adams, Zachary; Hulvershorn, Leslie; Aalsma, Matthew C.; Pediatrics, School of MedicinePurpose This study delineates a number of Medicaid youth with tobacco use disorder (TUD), prescribing habits for treatment, and associated externalizing disorders. Methods Youth Medicaid claims from 2007-2017 processed in a large Midwestern city were analyzed for a diagnosis of TUD, related pharmacotherapy, and externalizing mental health and substance use disorders. Results Claims connected 6541 patients with 42 890 visits. Mean age was 16.4 with 40% female. 1232 of the 6541 charts contained a TUD diagnosis equating to 1848 visits. A comorbid diagnosis of ADHD, cannabis use, and conduct disorder were more common in males (3.9% vs 1.3% in females; 3.4% vs .8%; and 2.8% vs .8%; P < .05). 808 scripts were provided to 152 of the 1232 youths, with 4.7% of those scripts a nicotine replacement product. Conclusions Pharmacotherapy is underutilized in this Medicaid claims data set. Certain externalizing factors were associated with males with TUD more than females. ItemThe Ex Vivo Human Translaminar Autonomous System to Study Spaceflight Associated Neuro-ocular Syndrome Pathogenesis(Nature, 2022-10) Peng, Michael; Curry, Stacy M.; Liu, Yang; Lohawala, Husain; Sharma, Gaurav; Sharma, Tasneem P.; Ophthalmology, School of MedicineSpaceflight-Associated Neuro-ocular Syndrome (SANS) is a significant unexplained adverse reaction to long-duration spaceflight. We employ an ex vivo translaminar autonomous system (TAS) to recreate a human ocular ground-based spaceflight analogue model to study SANS pathogenesis. To recapitulate the human SANS conditions, human ocular posterior segments are cultured in the TAS model for 14 days. Translaminar pressure differentials are generated by simulating various flow rates within intracranial pressure (ICP) and intraocular (IOP) chambers to maintain hydrostatic pressures of ICP: IOP (12:16, 15:16, 12:21, 21:16 mmHg). In addition, optic nerves are mechanically kinked by 6- and 10-degree tilt inserts for the ICP: IOP;15:16 mmHg pressure paradigm. The TAS model successfully maintains various pressure differentials for all experimental groups over 14 days. Post culture, we determine inflammatory and extracellular component expression changes within posterior segments. To further characterize the SANS pathogenesis, axonal transport capacity, optic nerve degeneration and retinal functional are measured. Identifiable pathogenic alterations are observed in posterior segments by morphologic, apoptotic, and inflammatory changes including transport and functional deficits under various simulated SANS conditions. Here we report our TAS model provides a unique preclinical application system to mimic SANS pathology and a viable therapeutic testing device for countermeasures. ItemThe current state of lesbian, gay, bisexual and transgender (LGBT) cultural competency among U.S. dermatology residents(Wolters Kluwer, 2022-10) Nowaskie, Dustin Z.; Garcia-Dehbozorgi, Sara; Cortez, Jose L.; Medicine, School of MedicineBackground: Lesbian, gay, bisexual, and transgender (LGBT) people interface with dermatology providers for many reasons. Implementing culturally competent LGBT dermatologic care necessitates evaluating provider competency to identify where gaps remain. Objectives: To assess the LGBT cultural competency among U.S. dermatology residents. Methods: A self-reporting, cross-sectional survey was emailed to U.S. dermatology program coordinators (N = 143). LGBT patient exposure, LGBT educational hours, and LGBT cultural competency via the LGBT-Development of Clinical Skills Scale (with the subscales Clinical Preparedness, Attitudinal Awareness, and Basic Knowledge) were measured. Results: Dermatology residents (N = 119) across the United States completed the survey. They reported caring for less than 20 LGBT patients per year and receiving less than 75 minutes of LGBT education per year. They reported significantly higher Attitudinal Awareness than both Clinical Preparedness and Basic Knowledge; they reported significantly higher Basic Knowledge than Clinical Preparedness. They reported significantly less adequate clinical training and supervision, experience, and competence to assess transgender patients compared to lesbian, gay, and bisexual patients. In general, dermatology residents who reported more LGBT patients and LGBT education also reported higher LGBT cultural competency. Limitations: A larger national sample of U.S. dermatology residents is necessary for generalizability. Conclusions: Currently, there is a lack of LGBT education in U.S. dermatology residency curricula, which may delay addressing the health disparities that exist in this patient population. Due to such dearth of standardized LGBT education, dermatology residents likely do not feel adequately knowledgeable or prepared to address LGBT needs. Both LGBT education and LGBT patient experiences may help alleviate these shortcomings and help LGBT patients feel affirmed in their dermatologic care. ItemTranscriptome Profiling of the Hippocampal Seizure Network Implicates a Role for Wnt Signaling during Epileptogenesis in a Mouse Model of Temporal Lobe Epilepsy(MDPI, 2022-10) Mardones, Muriel D.; Gupta, Kunal; Neurological Surgery, School of MedicineMesial temporal lobe epilepsy (mTLE) is a life-threatening condition characterized by recurrent hippocampal seizures. mTLE can develop after exposure to risk factors such as febrile seizure, trauma, and infection. Within the latent period between exposure and onset of epilepsy, pathological remodeling events occur that contribute to epileptogenesis. The molecular mechanisms responsible are currently unclear. We used the mouse intrahippocampal kainite model of mTLE to investigate transcriptional dysregulation in the ipsilateral and contralateral dentate gyrus (DG), representing the epileptogenic zone (EZ) and peri-ictal zone (PIZ). DG were analyzed after 3, 7, and 14 days by RNA sequencing. In both the EZ and PIZ, transcriptional dysregulation was dynamic over the epileptogenic period with early expression of genes representing cell signaling, migration, and proliferation. Canonical Wnt signaling was upregulated in the EZ and PIZ at 3 days. Expression of inflammatory genes differed between the EZ and PIZ, with early expression after 3 days in the PIZ and delayed expression after 7–14 days in the EZ. This suggests that critical gene changes occur early in the hippocampal seizure network and that Wnt signaling may play a role within the latent epileptogenic period. These findings may help to identify novel therapeutic targets that could prevent epileptogenesis. ItemThe orchestrated cellular and molecular responses of the kidney to endotoxin define a precise sepsis timeline(eLife Sciences, 2021-01-15) Janosevic, Danielle; Myslinski, Jered; McCarthy, Thomas W.; Zollman, Amy; Syed, Farooq; Xuei, Xiaoling; Gao, Hongyu; Liu, Yun-Long; Collins, Kimberly S.; Cheng, Ying-Hua; Winfree, Seth; El-Achkar, Tarek M.; Maier, Bernhard; Ferreira, Ricardo Melo; Eadon, Michael T.; Hato, Takashi; Dagher, Pierre C.; Medicine, School of MedicineSepsis is a dynamic state that progresses at variable rates and has life-threatening consequences. Staging patients along the sepsis timeline requires a thorough knowledge of the evolution of cellular and molecular events at the tissue level. Here, we investigated the kidney, an organ central to the pathophysiology of sepsis. Single-cell RNA-sequencing in a murine endotoxemia model revealed the involvement of various cell populations to be temporally organized and highly orchestrated. Endothelial and stromal cells were the first responders. At later time points, epithelial cells upregulated immune-related pathways while concomitantly downregulating physiological functions such as solute homeostasis. Sixteen hours after endotoxin, there was global cell-cell communication failure and organ shutdown. Despite this apparent organ paralysis, upstream regulatory analysis showed significant activity in pathways involved in healing and recovery. This rigorous spatial and temporal definition of murine endotoxemia will uncover precise biomarkers and targets that can help stage and treat human sepsis. ItemSerologic Presentation of Lamotrigine-Induced Lupus(Hindawi, 2022) Dempsey, Hannah; Aitcheson, Gabriella; Goble, Gretchen; Snook, Riley; Medicine, School of MedicineThis paper discusses the presentation of a rare drug side effect, a case of drug-induced lupus presenting with weight loss, weakness, hepatitis, and pancreatitis. A 24-year-old male with a history of major depressive disorder and childhood seizures presented to the ER with symptoms of abdominal pain, significant weight loss, and weakness. Initial workup revealed acute pancreatitis, elevated liver function enzymes (LFTs), and abnormal anti-double-stranded DNA antibody (anti-dsDNA) 1 : 640. He showed no classical clinical signs of lupus including rash, arthritis, or photosensitivity. He had multiple hospitalizations in the previous 6 months for excessive weight loss, malnutrition, weakness, and altered mental status. He had been taking lamotrigine for seizure prevention and mood stabilization while on a selective serotonin reuptake inhibitor (SSRI) and had a decline in health since the lamotrigine dose was increased. Antihistone antibodies were positive suggesting a drug-induced lupus syndrome. We hope to bring awareness to the possible rare complication of lamotrigine-induced lupus.