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IntroductionFor children who present to emergency departments (EDs) due to blunt head trauma, ED clinicians must decide who requires computed tomography (CT) scanning to evaluate for traumatic brain injury (TBI). The Pediatric Emergency Care Applied Research Network (PECARN) derived and validated two age-based prediction rules to identify children at very low risk of clinically-important traumatic brain injuries (ciTBIs) who do not typically require CT scans. In this case report, we describe the strategy used to implement the PECARN TBI prediction rules via electronic health record (EHR) clinical decision support (CDS) as the intervention in a multicenter clinical trial.MethodsThirteen EDs participated in this trial. The 10 sites receiving the CDS intervention used the Epic(®) EHR. All sites implementing EHR-based CDS built the rules by using the vendor's CDS engine. Based on a sociotechnical analysis, we designed the CDS so that recommendations could be displayed immediately after any provider entered prediction rule data. One central site developed and tested the intervention package to be exported to other sites. The intervention package included a clinical trial alert, an electronic data collection form, the CDS rules and the format for recommendations.ResultsThe original PECARN head trauma prediction rules were derived from physician documentation while this pragmatic trial led each site to customize their workflows and allow multiple different providers to complete the head trauma assessments. These differences in workflows led to varying completion rates across sites as well as differences in the types of providers completing the electronic data form. Site variation in internal change management processes made it challenging to maintain the same rigor across all sites. This led to downstream effects when data reports were developed.ConclusionsThe process of a centralized build and export of a CDS system in one commercial EHR system successfully supported a multicenter clinical trial.

Background: The Women's Health Needs Study (WHNS) collected information on the health characteristics, needs, and experiences, including female genital mutilation (FGM) experiences, attitudes, and beliefs, of women aged 18 to 49 years who were born, or whose mothers were born, in a country where FGM is prevalent living in the US. The purpose of this paper is to describe the WHNS design, methods, strengths and limitations, as well as select demographic and health-related characteristics of participants. Methods: We conducted a cross-sectional survey from November 2020 –June 2021 in four US metropolitan areas, using a hybrid venue-based sampling (VBS) and respondent-driven sampling (RDS) approach to identify women for recruitment. Results: Of 1,132 participants, 395 were recruited via VBS and 737 RDS. Most were born, or their mothers were born, in either a West African country (Burkina Faso, Guinea, Mali, Mauritania, Sierra Leone, The Gambia) (39.0%) or Ethiopia (30.7%). More than a third were aged 30–39 years (37.5%) with a majority who immigrated at ages ≥13 years (86.6%) and had lived in the United States for ≥5 years (68.9%). Medicaid was the top health insurer (52.5%), followed by private health insurance (30.5%); 17% of participants had no insurance. Nearly half of women reported 1–2 healthcare visits within the past 12 months (47.7%). One in seven did not get needed health care due to cost (14.8%). Over half have ever used contraception (52.1%) to delay or avoid pregnancy and 76.9% had their last pelvic and/or Papanicolaou (pap) exam within the past 3 years. More than half experienced FGM (55.0%). Nearly all women believed that FGM should be stopped (92.0%). Conclusion: The VBS/RDS approach enabled recruitment of a diverse study population. WHNS advances research related to the health characteristics, needs, and experiences of women living in the US from countries where FGM is prevalent. [ABSTRACT FROM AUTHOR]

Thioredoxin-interacting protein (TxNIP) is an endogenous inhibitor of thioredoxin, a ubiquitous thiol oxidoreductase, that regulates cellular redox status. Diabetic mice exhibit increased expression of TxNIP in pancreatic islets, and recent studies suggest that TxNIP is a proapoptotic factor in [beta]-cells that may contribute to the development of diabetes. Here, we examined the role of TxNIP deficiency in vivo in the development of insulin-deficient diabetes and whether it impacted on pancreatic [beta]-cell mass and/or insulin secretion. TxNIP-deficient (Hcb-19/[TxNIP.sup.-/-]) mice had lower baseline glycemia, higher circulating insulin concentrations, and higher total pancreatic insulin content and [beta]-cell mass than control mice (C3H). Hcb-19/[TxNIP.sup.-/-] did not develop hyperglycemia when injected with standard multiple low doses of streptozotocin (STZ), in contrast to C3H controls. Surprisingly, although [beta]-cell mass remained higher in Hcb-19/[TxNIP.sup.-/-] mice compared with C3H after STZ exposure, the relative decrease induced by STZ was as great or even greater in the TxNIP-deficient animals. Consistently, cultured pancreatic INS-1 cells transfected with small-interfering RNA against TxNIP were more sensitive to cell death induced by direct exposure to STZ or to the combination of inflammatory cytokines interleukin-1[[beta], interferon-[gamma], and tumor necrosis factor-[alpha]. Furthermore, when corrected for insulin content, isolated pancreatic islets from [TxNIP.sup.-/-] mice exhibited reduced glucose-induced insulin secretion. These data indicate that TxNIP functions as a regulator of [beta]-cell mass and influences insulin secretion. In conclusion, the relative resistance of TxNIP-deficient mice to STZ-induced diabetes appears to be because of an increase in [beta]-cell mass. However, TxNIP deficiency is associated with sensitization to STZ- and cytokine-induced [beta]-cell death, indicating complex regulatory roles of TxNIP under different physiological and pathological conditions. thioredoxin interacting protein; pancreatic [beta]-cell; apoptosis; insulin secretion

Conversion of normally quiescent mesangial cells into extracellular matrix-overproducing myofibroblasts in response to high ambient glucose and transforming growth factor (TGF)-[[beta].sub.1] is central to the pathogenesis of diabetic nephropathy. Previously, we reported that mesangial cells respond to high glucose by generating reactive oxygen species (ROS) from NADPH oxidase dependent on protein kinase C (PKC)-[zeta] activation. We investigated the role of TGF-[[beta].sub.1] in this action of high glucose on primary rat mesangial cells within 1-48 h. Both high glucose and exogenous TGF-[[beta].sub.1] stimulated PKC-[zeta] kinase activity, as measured by an immune complex kinase assay and immunofluorescence confocal cellular imaging. In high glucose, Akt Ser473 phosphorylation appeared within 1 h and Smad2/3 nuclear translocation was prevented with neutralizing TGF-[[beta].sub.1] antibodies. Neutralizing TGF-[[beta].sub.1] antibodies, or a TGF-[beta] receptor kinase inhibitor (LY364947), or a phosphatidylinositol 3,4,5-trisphosphate (PI3) kinase inhibitor (wortmannin), prevented PKC-[zeta] activation by high glucose. TGF-[[beta].sub.1] also stimulated cellular membrane translocation of PKC-[alpha], -[[beta].sub.1], -[delta], and -[epsilon], similar to high glucose. High glucose and TGF-[[beta].sub.1] enhanced ROS generation by mesangial cell NADPH oxidase, as detected by 2,7-dichlorofluorescein immunofluorescence. This response was abrogated by neutralizing TGF-[[beta].sub.1] antibodies, LY364947, or a specific PKC-[zeta] pseudosubstrate peptide inhibitor. Expression of constitutively active PKC-[zeta] in normal glucose caused upregulation of [p22.sup.phox], a likely mechanism of NADPH oxidase activation. We conclude that very early responses of mesangial cells to high glucose include autocrine TGF-[[beta].sub.1] stimulation of PKC isozymes including PI3 kinase activation of PKC-[zeta] and consequent generation of ROS by NADPH oxidase. reactive oxygen species; transforming growth factor-[[beta].sub.1]; PI3 kinase

Vascular endothelial growth factor (VEGF) is implicated in the development of proteinuria in diabetic nephropathy. High ambient glucose present in diabetes stimulates VEGF expression in several cell types, but the molecular mechanisms are incompletely understood. Here primary cultured rat mesangial cells served as a model to investigate the signal transduction pathways involved in high-glucose-induced VEGF expression. Exposure to high glucose (25 mM) significantly increased VEGF mRNA evaluated by real-time PCR by 3 h, VEGF cellular protein content assessed by immunoblotting or immunofluorescence within 24 h, and VEGF secretion by 24 h. High-glucose-induced VEGF expression was blocked by an antioxidant, Tempol, and antisense oligonucleotides directed against [p22.sup.phox], a NADPH oxidase subunit. Inhibition of protein kinase C (PKC)-[[beta].sub.1] with the specific pharmacological inhibitor LY-333531 or inhibition of PKC-[zeta] with a cell permeable specific pseudosubstrate peptide also prevented enhanced VEGF expression in high glucose. Enhanced VEGF secretion in high glucose was prevented by Tempol, PKC-[beta], or PKC-[zeta] inhibition. In normal glucose (5.6 mM), overexpression of [p22.sup.phox] or constitutively active PKC-[zeta] enhanced VEGF expression. Hypoxia inducible factor-1[alpha] protein was significantly increased in high glucose only by 24 h, suggesting a possible contribution to high-glucose-stimulated VEGF expression at later time points. Thus reactive oxygen species generated by NADPH oxidase, and both PKC-[[beta].sub.1] and -[zeta], play important roles in high-glucose-stimulated VEGF expression and secretion by mesangial cells. NADPH oxidase; vascular endothelial growth factor; [p22.sup.phox]; protein kinase C-[beta]; protein kinase C-[zeta]

Byline: Jawed Shaikh, MB, BS, ARDMS (York Hospital, York, Pennsylvania, jwdshk@hotmail.com); Amy Steinmetz, ARDMS (York Hospital, York, Pennsylvania); Howard Goldberg, MD (York Hospital, York, Pennsylvania) Keywords: celiac artery aneurysm; celiac [...]

Mesangial cell filamentous actin disassembly and hypocontractility in high glucose are mediated by PKC-[zeta]. Am J Physiol Renal Physiol 282: F151-F163, 2002. First published August 15, 2001; 10.1152/ajprenal.00055.2001.--In high glucose (HG), mesangial cells (MCs) lose their contractile response to endothelin-1 (ET-1) coincidently with filamentous (F)-actin disassembly. We postulated that these MC phenotypic changes are mediated by altered protein kinase C (PKC) isozyme activity, myosin light chain (ML[C.sub.20]) phosphorylation, or [Ca.sup.2+] signaling. MCs were growth arrested for 24 h in 0.5% fetal bovine serum (FBS)-DMEM in 5.6 (normal glucose; NG) or 30 mM glucose (high glucose; HG). In HG, the planar area was reduced [2,608 [+ or -] 135 vs. 3,952 [+ or -] 225 (SE) [micro][m.sup.2] in NG, P < 0.01, n = 31] with no contractile response to 0.1 [micro]M ET-1. Mannitol did not affect cell size or ET-1 response. Confocal imaging of fluo 3- loaded cells revealed that the peak intensity of ET-1-induced [Ca.sup.2+] signaling was not altered in HG vs. NG. Immunoblotting of phosphorylated ML[C.sub.20] showed that HG increased mono- and decreased unphosphorylated ML[C.sub.20] (42 [+ or -] 16 and 49 [+ or -] 15 vs. 13 [+ or -] 3 and 80 [+ or -] 4% of total in NG, P < 0.05, n = 3), but the peak phosphorylation responses to ET-1 were identical in NG and HG. ET-1 stimulated translocation of PKC-[delta] and -[epsilon] from cytosolic to membrane and particulate fractions identically in NG and HG but did not cause PKC-[zeta] translocation. In HG, membrane accumulation of PKC-[zeta] was observed. Membrane PKC-[zeta] activity measured by immunoprecipitation and [sup.32]P phosphorylation of PKC-[epsilon] pseudosubstrate peptide was 190 [+ or -] 18% of NG (P < 0.01, n = 4), which was completely inhibited by pretreatment with a myristoylated peptide inhibitor (ZI). In HG, pretreatment with ZI for 24 h restored normal MC size and contractile and F-actin disassembly responses to ET-1. In conclusion, in HG, decreased MC size is due to decreased F-actin assembly, and loss of contractile response to ET-1 occurs in the presence of normal [Ca.sup.2+] signaling and normal ML[C.sub.20] phosphorylation. In HG, altered F-actin and contractile functions in MCs are mediated by PKC-[zeta]. endothelin-1; calcium signaling; myosin light chain phosphorylation; protein kinase C-[zeta]