Context:The mixed results of success among QI initiatives may be due to differences in the context of these initiatives. Methods:The business and health care literature was systematically reviewed to identify contextual factors that might influence QI success; to categorize, summarize, and synthesize these factors; and to understand the current stage of development of this research field.Findings: Forty-seven articles were included in the final review. Consistent with current theories of implementation and organization change, leadership from top management, organizational culture, data infrastructure and information systems, and years involved in QI were suggested as important to QI success. Other potentially important factors identified in this review included: physician involvement in QI, microsystem motivation to change, resources for QI, and QI team leadership. Key limitations in the existing literature were the lack of a practical conceptual model, the lack of clear definitions of contextual factors, and the lack of well-specified measures. Conclusions:Several contextual factors were shown to be important to QI success, although the current body of literature lacks adequate definitions and is characterized by considerable variability in how contextual factors are measured across studies. Future research should focus on identifying and developing measures of context tied to a conceptual model that examines context across all

All 500 species of cone snails (Conus) are venomous predators. From a biochemical/genetic perspective, differences among Conus species may be based on the 50-200 different peptides in the venom of each species. Venom is used for prey capture as well as for interactions with predators and competitors. The venom of every species has its own distinct complement of peptides. Some of the interspecific divergence observed in venom peptides can be explained by differential expression of venom peptide superfamilies in different species and of peptide superfamily branching in various Conus lineages into pharmacologic groups with different targeting specificity. However, the striking interspecific divergence of peptide sequences is the dominant factor in the differences observed between venoms. The small venom peptides (typically 10-35 amino acids in length) are processed from larger prepropeptide precursors (ca. 100 amino acids). If interspecific comparisons are made between homologous prepropeptides, the three different regions of a Conus peptide precursor (signal sequence, pro-region, mature peptide) are found to have diverged at remarkably different rates. Analysis of synonymous and nonsynonymous substitution rates for the different segments of a prepropeptide suggests that mutation frequency varies by over an order of magnitude across the segments, with the mature toxin region undergoing the highest rate. The three sections of the prepropeptide which exhibit apparently different mutation rates are separated by introns. This striking segment-specific rate of divergence of Conus prepropeptides suggests a role for introns in evolution: exons separated by introns have the potential to evolve very different mutation rates. Plausible mechanisms that could underlie differing mutational frequency in the different exons of a gene are discussed.

We report the discovery and initial characterization of the T-superfamily of conotoxins. Eight different T-superfamily peptides from five Conus species were identified; they share a consensus signal sequence, and a conserved arrangement of cysteine residues (--CC--CC-). T-superfamily peptides were found expressed in venom ducts of all major feeding types of Conus; the results suggest that the T-superfamily will be a large and diverse group of peptides, widely distributed in the 500 different Conus species. These peptides are likely to be functionally diverse; although the peptides are small (11-17 amino acids), their sequences are strikingly divergent, with different peptides of the superfamily exhibiting varying extents of post-translational modification. Of the three peptides tested for in vivo biological activity, only one was active on mice but all three had effects on fish. The peptides that have been extensively characterized are as follows: p5a, GCCP-KQMRCCTL*; tx5a, ␥CC␥DGW ؉ CCT § AAO; and au5a, FC-CPFIRYCCW (where ␥ ‫؍‬ ␥-carboxyglutamate, W ؉ ‫؍‬ bromotryptophan, O ‫؍‬ hydroxyproline, T § ‫؍‬ glycosylated threonine, and * ‫؍‬ COOH-terminal amidation). We also demonstrate that the precursor of tx5a contains a functional ␥-carboxylation recognition signal in the ؊1 to ؊20 propeptide region, consistent with the presence of ␥-carboxyglutamate residues in this peptide.Cone snails (genus Conus) are perhaps the most successful genus of marine invertebrates, with over 500 species, all of which are venomous (1, 2). These predatory marine snails have evolved a highly sophisticated neuropharmacological strategy based on small peptides (10 -35 amino acids) in their venoms (3, 4). Most Conus peptides potently affect ion channel function; these are widely used pharmacological reagents in neuroscience, and several are being directly developed as diagnostic and therapeutic agents. Most Conus peptides are highly disulfide-rich; generically, Conus peptides with multiple disulfide cross-links have been referred to as conotoxins. It has become apparent in recent years that there are tens of thousands of different conotoxins in Conus venoms. Because of the remarkably rapid interspecific divergence of peptide sequences, each Conus species has its own distinct repertoire of between 50 and 200 different venom peptides (5).A major simplification in understanding this complex array of Conus venom peptides is that most of the ϳ50,000 different molecular forms can be grouped into just a few superfamilies. Peptides in the same superfamily share both a conserved pattern of disulfide connectivity and a highly conserved signal sequence (when prepropeptide precursor sequences of the peptides are compared) (5, 6). Three large superfamilies of conotoxins are well characterized: the O-superfamily, comprising several distinct pharmacological families including the -, -, ␦-, and O-conotoxins (7); the A-superfamily, to which the ␣-conotoxins belong (8); and the M-superfamily, to which the -conotoxins belong. In this paper, we describe the ...

Aim The purpose of this study was to develop a population pharmacokinetic and pharmacodynamic (PK−PD) model for mycophenolic acid (MPA) in paediatric renal transplant recipients in the early post‐transplant period. Methods A total of 214 MPA plasma concentrations−time data points from 24 patients were available for PK model development. In 17 out of a total of 24 patients, inosine monophosphate dehydrogenase (IMPDH) enzyme activity measurements (n = 97) in peripheral blood mononuclear cells were available for PK−PD modelling. The PK−PD model was developed using non‐linear mixed effects modelling sequentially by 1) developing a population PK model and 2) incorporating IMPDH activity into a PK−PD model using post hoc Bayesian PK parameter estimates. Covariate analysis included patient demographics, co‐medication and clinical laboratory data. Non‐parametric bootstrapping and prediction‐corrected visual predictive checks were performed to evaluate the final models. Results A two compartment model with a transit compartment absorption best described MPA PK. A non‐linear relationship between dose and MPA exposure was observed and was described by a power function in the model. The final population PK parameter estimates (and their 95% confidence intervals) were CL/F, 22 (14.8, 25.2) l h−1 70 kg−1; Vc/F, 45.4 (29.6, 55.6) l; Vp/F, 411 (152.6, 1472.6)l; Q/F, 22.4 (16.0, 32.5) l h−1; Ka, 2.5 (1.45, 4.93) h−1. Covariate analysis in the PK study identified body weight to be significantly correlated with CL/F. A simplified inhibitory Emax model adequately described the relationship between MPA concentration and IMPDH activity. The final population PK−PD parameter estimates (and their 95% confidence intervals) were: E0, 3.45 (2.61, 4.56) nmol h−1 mg−1 protein and EC50, 1.73 (1.16, 3.01) mg l−1. Emax was fixed to 0. There were two African‐American patients in our study cohorts and both had low IMPDH baseline activities (E0) compared with Caucasian patients (mean value 2.13 mg l−1 vs. 3.86 mg l−1). Conclusion An integrated population PK−PD model of MPA has been developed in paediatric renal transplant recipients. The current model provides information that will facilitate future studies and may be implemented in a Bayesian algorithm to allow a PK−PD guided therapeutic drug monitoring strategy.