Diagnostic Performance, Triage Safety, and Usability of a Clinical Decision Support System Within a University Hospital Emergency Department: Algorithm Performance and Usability Study.

Background: Computerized clinical decision support systems (CDSSs) are increasingly adopted in health care to optimize resources and streamline patient flow. However, they often lack scientific validation against standard medical care. Objective: The purpose of this study was to assess the performance, safety, and usability of a CDSS in a university hospital emergency department setting in Kuopio, Finland. Methods: Patients entering the emergency department were asked to voluntarily participate in this study. Patients aged 17 years or younger, patients with cognitive impairments, and patients who entered the unit in an ambulance or with the need for immediate care were excluded. Patients completed the CDSS web-based form and usability questionnaire when waiting for the triage nurse's evaluation. The CDSS data were anonymized and did not affect the patients' usual evaluation or treatment. Retrospectively, 2 medical doctors evaluated the urgency of each patient's condition by using the triage nurse's information, and urgent and nonurgent groups were created. The International Statistical Classification of Diseases, Tenth Revision diagnoses were collected from the electronic health records. Usability was assessed by using a positive version of the System Usability Scale questionnaire. Results: In total, our analyses included 248 patients. Regarding urgency, the mean sensitivities were 85% and 19%, respectively, for urgent and nonurgent cases when assessing the performance of CDSS evaluations in comparison to that of physicians. The mean sensitivities were 85% and 35%, respectively, when comparing the evaluations between the two physicians. Our CDSS did not miss any cases that were evaluated to be emergencies by physicians; thus, all emergency cases evaluated by physicians were evaluated as either urgent cases or emergency cases by the CDSS. In differential diagnosis, the CDSS had an exact match accuracy of 45.5% (97/213). The usability was good, with a mean System Usability Scale score of 78.2 (SD 16.8). Conclusions: In a university hospital emergency department setting with a large real-world population, our CDSS was found to be equally as sensitive in urgent patient cases as physicians and was found to have an acceptable differential diagnosis accuracy, with good usability. These results suggest that this CDSS can be safely assessed further in a real-world setting. A CDSS could accelerate triage by providing patient-provided data in advance of patients' initial consultations and categorize patient cases as urgent and nonurgent cases upon patients' arrival to the emergency department.

The absence of macrophage Nrf2 promotes early atherogenesis.

AIMS: The loss of nuclear factor E2-related factor 2 (Nrf2) has been shown to protect against atherogenesis in apoE-deficient mice. The mechanism by which Nrf2 deficiency affords atheroprotection in this model is currently unknown, but combined systemic and local vascular effects on lesion macrophages have been proposed. We investigated the effect of bone marrow-specific loss of Nrf2 on early atherogenesis in low-density lipoprotein (LDL) receptor-deficient (LDLR(-/-)) mice, and assessed the effect of Nrf2 on cellular accumulation of modified LDLs and the expression of inflammatory markers in macrophages. METHODS AND RESULTS: The effect of bone marrow-specific loss of Nrf2 on atherogenesis was studied using bone marrow transplantation of wild-type (WT) or Nrf2(-/-) bone marrow to LDLR(-/-) mice. Mice transplanted with Nrf2(-/-) bone marrow and fed a high-fat diet for 6 weeks exhibited significantly larger atherosclerotic lesions than WT bone marrow transplanted mice. Moreover, in thioglycollate-elicited Nrf2(-/-) macrophages, the uptake of acetylated and malondialdehyde-modified LDLs was increased in comparison with WT controls, with the concomitant increase in the expression of scavenger receptor A and toll-like receptor 4. In addition, the expression of pro-inflammatory monocyte chemoattractant protein-1 and interleukin-6 were increased in Nrf2(-/-) vs. WT macrophages. CONCLUSION: Nrf2 deficiency specific to bone marrow-derived cells aggravates atherosclerosis in LDLR(-/-) mice. Furthermore, the loss of Nrf2 in macrophages enhances foam cell formation and promotes the pro-inflammatory phenotype.

Nrf2 regulates antioxidant gene expression evoked by oxidized phospholipids in endothelial cells and murine arteries in vivo.

Besides their well-characterized proinflammatory and proatherogenic effects, oxidized phospholipids, such as oxPAPC (oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-phosphocholine) have been shown to have beneficial responses in vascular cells via induction of antioxidant enzymes such as heme oxygenase-1. We therefore hypothesized that oxPAPC could evoke a general cytoprotective response via activation of antioxidative transcription factor Nrf2. Here, we show that oxPAPC increases nuclear accumulation of Nrf2. Using the small interfering RNA approach, we demonstrate that Nrf2 is critical in mediating the induction of glutamate-cysteine ligase modifier subunit (GCLM) and NAD(P)H quinone oxidoreductase-1 (NQO1) by oxPAPC in human endothelial cells, whereas the contribution to the induction of heme oxygenase-1 was less significant. The induction of GCLM and NQO1 was attenuated by reduction of electrophilic groups with sodium borohydrate, as well as treatment with thiol antioxidant N-acetylcysteine, suggesting that the thiol reactivity of oxPAPC is largely mediating its effect on Nrf2-responsive genes. Moreover, we show that oxidized phospholipid having a highly electrophilic isoprostane ring in its sn-2 position is a potent inducer of Nrf2 target genes. Finally, we demonstrate that the oxPAPC-inducible expression of heme oxygenase-1, GCLM, and NQO1 is lower in Nrf2-null than wild-type mouse carotid arteries in vivo. We suggest that the activation of Nrf2 by oxidized phospholipids provides a mechanism by which their deleterious effects are limited in the vasculature.

Extracellular superoxide dismutase accelerates endothelial recovery and inhibits in-stent restenosis in stented atherosclerotic Watanabe heritable hyperlipidemic rabbit aorta.

OBJECTIVES: This study examined whether local gene therapy with extracellular superoxide dismutase (EC-SOD) could inhibit in-stent restenosis in atherosclerotic Watanabe heritable hyperlipidemic rabbits. BACKGROUND: Stenting causes an acute increase in superoxide anion production and oxidative stress; EC-SOD is a major component of antioxidative defense in blood vessels and has powerful cardioprotective effects in ischemic myocardium. METHODS: Endothelial denudation and stenting were done in 36 adult (15 to 18 months old) rabbits. Catheter-mediated intramural delivery of clinical good manufacturing practice-grade adenoviruses encoding rabbit EC-SOD were done simultaneously with stenting. Control animals received adenovirus-encoding nuclear-targeted beta-galactosidase (AdLacZ). Circulating markers for oxidative stress (nonesterified 8-iso-prostaglandin F2 alpha) were measured. Analysis of 6-day, 28-day, and 90-day vessel histology, radical production, oxidation-specific epitopes, and expression studies were performed. RESULTS: The EC-SOD treatment reduced oxidant production in stented vessels compared with control vessels. Early systemic recovery of total SOD activity was observed in the treated rabbits. The EC-SOD significantly accelerated endothelial recovery (67.4% +/- 10.8% vs. 24.2.1% +/- 4.6% at 6 days, p < 0.05; 89.3% +/- 3.7% vs. 45.1% +/- 9.6% at 28 days, p < 0.05), and the beneficial effect involved increased proliferation of regenerating endothelium. The EC-SOD group showed a 61.3% lower (p < 0.05) neointimal formation at 28 days, with a similar, albeit nonsignificant trend at 90 days (1.20 +/- 0.32 mm2 vs. 1.88 +/- 0.24 mm2, p = 0.06). CONCLUSIONS: The results suggest a central pathogenetic role of oxidation sensitive signaling processes in endothelial recovery and developing in-stent restenosis in atherosclerotic vessels. Local therapy against oxidative stress represents a promising therapeutic strategy in stent-induced vascular injury.

Nrf2 gene transfer induces antioxidant enzymes and suppresses smooth muscle cell growth in vitro and reduces oxidative stress in rabbit aorta in vivo.

BACKGROUND: Reactive oxygen species (ROS) play a major role in vascular inflammation and pathophysiology of many vascular diseases such as atherosclerosis and injury-induced neointima formation after balloon angioplasty. Nuclear factor E2-related factor-2 (Nrf2) is a transcription factor orchestrating antioxidant and cytoprotective responses on oxidative and electrophilic stress, and it has been shown to have antiinflammatory effects in vascular cells in vitro. We therefore postulated that Nrf2 gene transfer would have salutary effects on vascular inflammation after angioplasty. METHODS AND RESULTS: Transduction of vascular smooth muscle cells (VSMCs) with Nrf2-expressing adenovirus increased the expression of several antioxidant enzymes including heme oxygenase-1 (HO-1) compared with beta-galactosidase (AdLacZ)-transduced controls. Moreover, Nrf2 gene transfer also inhibited vascular smooth muscle cell (VSMC) proliferation, and the effect was partially reversed by the HO inhibitor Sn(IV) protoporphyrin. In vivo, adenoviral gene transfer effectively reduced oxidative stress determined by antibody staining against oxidized epitopes of LDL, as well as inhibited vascular inflammation assessed by the macrophage cell count and monocyte chemoattractant protein-1 (MCP-1) staining. However, the antiproliferative effects of Nrf2 in vivo were counterbalanced with diminished apoptosis in neointimal VSMCs, resulting in no change in neointimal hyperplasia. CONCLUSIONS: Nrf2 gene transfer or Nrf2-inducing drugs may have therapeutic applications in vascular diseases in which inflammation and oxidative stress play a role. However, the contrasting growth inhibitory and antiapoptotic effects of Nrf2 need to be considered in pathological conditions in which SMC proliferation plays a critical role.

Extracellular superoxide dismutase with vaccinia virus anti-inflammatory protein 35K or tissue inhibitor of metalloproteinase-1: Combination gene therapy in the treatment of vein graft stenosis in rabbits.

Bypass graft surgery is limited by stenosis of vein grafts. Neointimal formation in vein graft stenosis is affected by oxidative stress, acute inflammatory response, and proliferation. Gene therapy offers a novel treatment strategy for vein graft stenosis because gene transfer can be done ex vivo during the graft operation. In this study we used adenovirus-mediated ex vivo gene transfer of extracellular superoxide dismutase (EC-SOD) alone or in combination with tissue inhibitor of metalloproteinase-1 (TIMP-1) or vaccinia virus antiinflammatory protein 35K to prevent vein graft stenosis in a jugular vein graft model in normocholesterolemic New Zealand White rabbits. Vein grafts were analyzed 14 and 28 days after the gene transfer, using histological methods. It was found that at the 2-week time point EC-SOD + 35K and EC-SOD + TIMP-1 combinations delivered by gene transfer were the most efficient treatments in decreasing neointimal formation. At the 4-week time point the effect was seen only in the EC-SOD + TIMP-1 combination group. The combination of antiinflammatory proteins (EC-SOD + 35K) was the most effective in reducing macrophage accumulation, which was still significant at the 4-week time point, but this did not prevent vein graft thickening. In conclusion, oxidative, inflammatory, and proliferative processes are important for neointimal formation in vein graft stenosis. In the rabbit model of vein graft disease, combination gene therapy with antioxidative, antiinflammatory, and antiproliferative genes was effective in decreasing neointimal formation. This may be because two different genes may more efficiently affect different pathogenetic pathways at the early stage of the disease process than gene transfer approaches based on single genes.