sFlt Multivalent Conjugates Inhibit Angiogenesis and Improve Half-Life In Vivo

We would like to thank Jonathan Winger and Xiao Zhu for guidance with the insect cell protein expression system and providing reagents. We would like to acknowledge Ann Fischer for help with expressing the sFlt protein in the Tissue Culture Facility at UC Berkeley and Dawn Spelke and Anusuya Ramasubramanian for help optimizing protein purification from insect cells. We are also grateful for the help from Leah Byrne and John Flannery at in the Helen Wills Neuroscience Institute at UC Berkeley for aiding us in the development of the rat intravitreal residence time model and for allowing us to use their facilities.Current anti-VEGF drugs for patients with diabetic retinopathy suffer from short residence time in the vitreous of the eye. In order to maintain biologically effective doses of drug for inhibiting retinal neovascularization, patients are required to receive regular monthly injections of drug, which often results in low patient compliance and progression of the disease. To improve the intravitreal residence time of anti-VEGF drugs, we have synthesized multivalent bioconjugates of an anti-VEGF protein, soluble fms-like tyrosine kinase-1 (sFlt) that is covalently grafted to chains of hyaluronic acid (HyA), conjugates that are termed mvsFlt. Using a mouse corneal angiogenesis assay, we demonstrate that covalent conjugation to HyA chains does not decrease the bioactivity of sFlt and that mvsFlt is equivalent to sFlt at inhibiting corneal angiogenesis. In a rat vitreous model, we observed that mvsFlt had significantly increased intravitreal residence time compared to the unconjugated sFlt after 2 days. The calculated intravitreal half-lives for sFlt and mvsFlt were 3.3 and 35 hours, respectively. Furthermore, we show that mvsFlt is more effective than the unconjugated form at inhibiting retinal neovascularization in an oxygen-induced retinopathy model, an effect that is most likely due to the longer half-life of mvsFlt in the vitreous. Taken together, our results indicate that conjugation of sFlt to HyA does not affect its affinity for VEGF and this conjugation significantly improves drug half-life. These in vivo results suggest that our strategy of multivalent conjugation could substantially improve upon drug half-life, and thus the efficacy of currently available drugs that are used in diseases such as diabetic retinopathy, thereby improving patient quality of life.Yeshttp://www.plosone.org/static/editorial#pee

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Routing problems, Revenues, Core, C71,

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Evaluation of infectious diseases and clinical microbiology specialists’ preferences for hand hygiene: analysis using the multi-attribute utility theory and the analytic hierarchy process methods

Abstract Background Hand hygiene is one of the most effective attempts to control nosocomial infections, and it is an important measure to avoid the transmission of pathogens. However, the compliance of healthcare workers (HCWs) with hand washing is still poor worldwide. Herein, we aimed to determine the best hand hygiene preference of the infectious diseases and clinical microbiology (IDCM) specialists to prevent transmission of microorganisms from one patient to another. Methods Expert opinions regarding the criteria that influence the best hand hygiene preference were collected through a questionnaire via face-to-face interviews. Afterwards, these opinions were examined with two widely used multi-criteria decision analysis (MCDA) methods, the Multi-Attribute Utility Theory (MAUT) and the Analytic Hierarchy Process (AHP). Results A total of 15 IDCM specialist opinions were collected from diverse private and public hospitals located in İzmir, Turkey. The mean age of the participants was 49.73 ± 8.46, and the mean experience year of the participants in their fields was 17.67 ± 11.98. The findings that we obtained through two distinct decision making methods, the MAUT and the AHP, suggest that alcohol-based antiseptic solution (ABAS) has the highest utility (0.86) and priority (0.69) among the experts’ choices. Conclusion In conclusion, the MAUT and the AHP, decision models developed here indicate that rubbing the hands with ABAS is the most favorable choice for IDCM specialists to prevent nosocomial infection