A Diagnostic Stewardship Intervention to Improve Utilization of 1,3 ß-D-Glucan Testing at a Single Academic Center: Five-Year Experience.

Background: (1,3)- ß-D-glucan (BDG) testing is one of the noninvasive tests to aid diagnosis of invasive fungal infections (IFIs). The study results have been heterogenous, and diagnostic performance varies depending on the risks for IFI. Thus, it is important to select appropriate patients for BDG testing to prevent false-positive results. An algorithmic diagnostic stewardship intervention was instituted at a single academic medical center to improve BDG test utilization. Methods: The BDG test order in the electronic health record was replaced with the BDG test request order, which required approval to process the actual test order. The approval criteria were (1) immunocompromised or intensive care unit patient and (2) on empiric antifungal therapy, or inability to undergo invasive diagnostic procedures. A retrospective observational study was conducted to evaluate the efficacy of the intervention by comparing the number of BDG tests performed between 1 year pre- and post-intervention. Safety was assessed by chart review of the patients for whom BDG test requests were deemed inappropriate and rejected. Results: The number of BDG tests performed per year decreased by 85% from 156 in the pre-intervention period to 24 in the post-intervention period. The average monthly number of BDG tests performed was significantly lower between those periods (P = .002). There was no delay in IFI diagnosis or IFI-related deaths in the patients whose BDG test requests were rejected. The sustained effectiveness of the intervention was observed for 5 years. Conclusions: Institution of the diagnostic stewardship intervention successfully and safely improved BDG test utilization.

Activation of retinoid receptor-mediated signaling ameliorates diabetes-induced cardiac dysfunction in Zucker diabetic rats.

Diabetic cardiomyopathy (DCM) is a significant contributor to the morbidity and mortality associated with diabetes and metabolic syndrome. Retinoids, through activation of retinoic acid receptor (RAR) and retinoid x receptor (RXR), have been linked to control glucose and lipid homeostasis, with effects on obesity and diabetes. However, the functional role of RAR and RXR in the development of DCM remains unclear. Zucker diabetic fatty (ZDF) and lean rats were treated with Am580 (RARα agonist) or LGD1069 (RXR agonist) for 16 weeks, and cardiac function and metabolic alterations were determined. Hyperglycemia, hyperlipidemia and insulin resistance were observed in ZDF rats. Diabetic cardiomyopathy was characterized in ZDF rats by increased oxidative stress, apoptosis, fibrosis, inflammation, activation of MAP kinases and NF-κB signaling and diminished Akt phosphorylation, along with decreased glucose transport and increased cardiac lipid accumulation, and ultimately diastolic dysfunction. Am580 and LGD1069 attenuated diabetes-induced cardiac dysfunction and the pathological alterations, by improving glucose tolerance and insulin resistance; facilitating Akt activation and glucose utilization, and attenuating oxidative stress and interrelated MAP kinase and NF-κB signaling pathways. Am580 inhibited body weight gain, attenuated the increased cardiac fatty acid uptake, ß-oxidation and lipid accumulation in the hearts of ZDF rats. However, LGD1069 promoted body weight gain, hyperlipidemia and cardiac lipid accumulation. In conclusion, our data suggest that activation of RAR and RXR may have therapeutic potential in the treatment of diabetic cardiomyopathy. However, further studies are necessary to clarify the role of RAR and RXR in the regulation of lipid metabolism and homeostasis.

Retinoic acid protects cardiomyocytes from high glucose-induced apoptosis through inhibition of NF-κB signaling pathway.

We have previously shown that retinoic acid (RA) has protective effects on high glucose (HG)-induced cardiomyocyte apoptosis. To further elucidate the molecular mechanisms of RA effects, we determined the interaction between nuclear factor (NF)-κB and RA signaling. HG induced a sustained phosphorylation of IKK/IκBα and transcriptional activation of NF-κB in cardiomyocytes. Activated NF-κB signaling has an important role in HG-induced cardiomyocyte apoptosis and gene expression of interleukin-6 (IL-6), tumor necrosis factor (TNF)-α, and monocyte chemoattractant protein-1 (MCP-1). All-trans RA (ATRA) and LGD1069, through activation of RAR/RXR-mediated signaling, inhibited the HG-mediated effects in cardiomyocytes. The inhibitory effect of RA on NF-κB activation was mediated through inhibition of IKK/IκBα phosphorylation. ATRA and LGD1069 treatment promoted protein phosphatase 2A (PP2A) activity, which was significantly suppressed by HG stimulation. The RA effects on IKK and IκBα were blocked by okadaic acid or silencing the expression of PP2Ac-subunit, indicating that the inhibitory effect of RA on NF-κB is regulated through activation of PP2A and subsequent dephosphorylation of IKK/IκBα. Moreover, ATRA and LGD1069 reversed the decreased PP2A activity and inhibited the activation of IKK/IκBα and gene expression of MCP-1, IL-6, and TNF-α in the hearts of Zucker diabetic fatty rats. In summary, our findings suggest that the suppressed activation of PP2A contributed to sustained activation of NF-κB in HG-stimulated cardiomyocytes; and that the protective effect of RA on hyperglycemia-induced cardiomyocyte apoptosis and inflammatory responses is partially regulated through activation of PP2A and suppression of NF-κB-mediated signaling and downstream targets.