Incidence and impact of de novo donor-specific alloantibody in primary renal allografts,”

Background. To date, limited information is available describing the incidence and impact of de novo donor-specific antiYhuman leukocyte antigen (HLA) antibodies (dnDSA) in the primary renal transplant patient. This report details the dnDSA incidence and actual 3-year post-dnDSA graft outcomes. Methods. The study includes 189 consecutive nonsensitized, non-HLA-identical patients who received a primary kidney transplant between March 1999 and March 2006. Protocol testing for DSA via LABScreen single antigen beads (One Lambda) was done before transplantation and at 1, 3, 6, 9, and 12 months after transplantation then annually and when clinically indicated. Results. Of 189 patients, 47 (25%) developed dnDSA within 10 years. The 5-year posttransplantation cumulative incidence was 20%, with the largest proportion of patients developing dnDSA in the first posttransplantation year (11%). Young patients (18Y35 years old at transplantation), deceased-donor transplant recipients, pretransplantation HLA (non-DSA)Ypositive patients, and patients with a DQ mismatch were the most likely to develop dnDSA. From DSA appearance, 9% of patients lost their graft at 1 year. Actual 3-year death-censored post-dnDSA graft loss was 24%. Conclusion. We conclude that 11% of the patients without detectable DSA at transplantation will have detectable DSA at 1 year, and over the next 4 years, the incidence of dnDSA will increase to 20%. After dnDSA development, 24% of the patients will fail within 3 years. Given these findings, future trials are warranted to determine if treatment of dnDSA-positive patients can prevent allograft failure

Understanding context: A concept analysis

Aims To conduct a concept analysis of clinical practice contexts (work environments) in healthcare. Background Context is increasingly recognized as important to the development, delivery and understanding of implementation strategies; however, conceptual clarity about what comprises context is lacking. Design Modified Walker and Avant concept analysis comprised of 5 steps: 1) concept selection; 2) determination of aims; 3) identification of uses of context; 4) determination of its defining attributes; and 5) definition of its empirical referents. Methods A wide range of databases were systematically searched from inception to August 2014. Empirical articles were included if a definition and/or attributes of context were reported. Theoretical articles were included if they reported a model, theory, or framework of context or where context was a component. Double independent screening and data extraction was conducted. Analysis was iterative, involving organizing and reorganizing until a framework of domains, attributes and features of context emerged. Result We identified 15,972 references, of which 70 satisfied our inclusion criteria. In total, 201 unique features of context were identified, of these 89 were shared (reported in 2 or more studies). The 89 shared features were grouped into 21 attributes of context which were further categorized into 6 domains of context. Conclusion This study resulted in a framework of domains, attributes and features of context. These attributes and features, if assessed and used to tailor implementation activities, hold promise for improved research implementation in clinical practice

NMR structure of a minimized human agouti related protein prepared by total chemical synthesis

AbstractThe structure of the chemically synthesized C-terminal region of the human agouti related protein (AGRP) was determined by 2D 1H NMR. Referred to as minimized agouti related protein, MARP is a 46 residue polypeptide containing 10 Cys residues involved in five disulfide bonds that retains the biological activity of full length AGRP. AGRP is a mammalian signaling molecule, involved in weight homeostasis, that causes adult onset obesity when overexpressed in mice. AGRP was originally identified by homology to the agouti protein, another potent signaling molecule involved in obesity disorders in mice. While AGRP’s exact mechanism of action is unknown, it has been identified as a competitive antagonist of melanocortin receptors 3 and 4 (MC3r, MC4r), and MC4r in particular is implicated in the hypothalamic control of feeding behavior. Full length agouti and AGRP are only 25% homologous, however, their active C-terminal regions are ∼40% homologous, with nine out of the 10 Cys residues spatially conserved. Until now, 3D structures have not been available for either agouti, AGRP or their C-terminal regions. The NMR structure of MARP reported here can be characterized as three major loops, with four of the five disulfide bridges at the base of the structure. Though its fold is well defined, no canonical secondary structure is identified. While previously reported structural models of the C-terminal region of AGRP were attempted based on Cys homology between AGRP and certain toxin proteins, we find that Cys spacing is not sufficient to correctly determine the 3D fold of the molecule