Guidance on noncorticosteroid systemic immunomodulatory therapy in noninfectious uveitis: fundamentals of care for uveitis (focus) initiative

Topic: An international, expert-led consensus initiative to develop systematic, evidence-based recommendations for the treatment of noninfectious uveitis in the era of biologics. Clinical Relevance: The availability of biologic agents for the treatment of human eye disease has altered practice patterns for the management of noninfectious uveitis. Current guidelines are insufficient to assure optimal use of noncorticosteroid systemic immunomodulatory agents. Methods: An international expert steering committee comprising 9 uveitis specialists (including both ophthalmologists and rheumatologists) identified clinical questions and, together with 6 bibliographic fellows trained in uveitis, conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol systematic reviewof the literature (English language studies from January 1996 through June 2016; Medline [OVID], the Central Cochrane library, EMBASE,CINAHL,SCOPUS,BIOSIS, andWeb of Science). Publications included randomized controlled trials, prospective and retrospective studies with sufficient follow-up, case series with 15 cases or more, peer-reviewed articles, and hand-searched conference abstracts from key conferences. The proposed statements were circulated among 130 international uveitis experts for review.Atotal of 44 globally representativegroupmembersmet in late 2016 to refine these guidelines using a modified Delphi technique and assigned Oxford levels of evidence. Results: In total, 10 questions were addressed resulting in 21 evidence-based guidance statements covering the following topics: when to start noncorticosteroid immunomodulatory therapy, including both biologic and nonbiologic agents; what data to collect before treatment; when to modify or withdraw treatment; how to select agents based on individual efficacy and safety profiles; and evidence in specific uveitic conditions. Shared decision-making, communication among providers and safety monitoring also were addressed as part of the recommendations. Pharmacoeconomic considerations were not addressed. Conclusions: Consensus guidelines were developed based on published literature, expert opinion, and practical experience to bridge the gap between clinical needs and medical evidence to support the treatment of patients with noninfectious uveitis with noncorticosteroid immunomodulatory agents

Competitive Benchmarking: An IS Research Approach to Address Wicked Problems with Big Data and Analytics

Wicked problems like sustainable energy and financial market stability are societal challenges that arise from complex socio-technical systems in which numerous social, economic, political, and technical factors interact. Understanding and mitigating them requires research methods that scale beyond the traditional areas of inquiry of Information Systems (IS) “individuals, organizations, and markets” and that deliver solutions in addition to insights. We describe an approach to address these challenges through Competitive Benchmarking (CB), a novel research method that helps interdisciplinary research communities to tackle complex challenges of societal scale by using different types of data from a variety of sources such as usage data from customers, production patterns from producers, public policy and regulatory constraints, etc. for a given instantiation. Further, the CB platform generates data that can be used to improve operational strategies and judge the effectiveness of regulatory regimes and policies. We describe our experience applying CB to the sustainable energy challenge in the Power Trading Agent Competition (Power TAC) in which more than a dozen research groups from around the world jointly devise, benchmark, and improve IS-based solutions

On finite element variational multiscale methods for incompressible turbulent flows

Two realizations of finite element variational multiscale (VMS) methods for the simulation of incompressible turbulent flows are studied. The difference between the two approaches consists in the way the spaces for the large scales and the resolved small scales are chosen. The paper addresses issues of the implementation of these methods, the treatment of the additional terms and equations in the temporal discretization, and the additional costs of these methods

Oxidation inhibits substrate proteolysis by calpain I but not autolysis

In this study, the effects of oxidation on calpain I autolysis and calpain-mediated proteolysis were examined. Calpain I was incubated with increasing concentrations of free calcium in the presence or absence of oxidant, and autolytic conversion of both the 80- and 30-kDa subunits was measured by immunoblotting utilizing monoclonal antibodies which recognize both autolyzed and non-autolyzed forms of each subunit, respectively. Autolytic conversion of the 80-kDa subunit of calpain I was not detected until free calcium concentration was greater than 40 μM, whereas autolysis of the 30-kDa subunit did not occur until the free calcium concentration was greater than 100 μM. In addition, autolytic conversion of either the 80- or 30-kDa subunit was not inhibited by the presence of oxidant. Calpain I activity was measured using the fluorescent peptide N-succinyl-L-leucyl-L-leucyl-L-valyl-L-tyrosine-7-amido-4-methylcoumarin or the microtubule-associated protein tau as substrate. Calpain I was found to have proteolytic activity at free calcium concentrations below that required for autolysis. Calpain I activity was strongly inhibited by oxidant at all calcium concentrations studied, suggesting that proteolytic activity of both the non-autolyzed 80-kDa and autolyzed 76-kDa forms was susceptible to oxidation. Interestingly, whereas oxidation did not inhibit autolytic conversion, the presence of high substrate concentrations did result in a significant reduction of autolysis without altering calpain proteolytic activity. Calpain I activity that had been inhibited by the presence of oxidant was recovered immediately by addition of the reducing agent dithiothreitol.Journal ArticleFinal article publishe