Boundary spanning at the science-policy interface: the practitioners' perspectives.

Cultivating a more dynamic relationship between science and policy is essential for responding to complex social challenges such as sustainability. One approach to doing so is to "span the boundaries" between science and decision making and create a more comprehensive and inclusive knowledge exchange process. The exact definition and role of boundary spanning, however, can be nebulous. Indeed, boundary spanning often gets conflated and confused with other approaches to connecting science and policy, such as science communication, applied science, and advocacy, which can hinder progress in the field of boundary spanning. To help overcome this, in this perspective, we present the outcomes from a recent workshop of boundary-spanning practitioners gathered to (1) articulate a definition of what it means to work at this interface ("boundary spanning") and the types of activities it encompasses; (2) present a value proposition of these efforts to build better relationships between science and policy; and (3) identify opportunities to more effectively mainstream boundary-spanning activities. Drawing on our collective experiences, we suggest that boundary spanning has the potential to increase the efficiency by which useful research is produced, foster the capacity to absorb new evidence and perspectives into sustainability decision-making, enhance research relevance for societal challenges, and open new policy windows. We provide examples from our work that illustrate this potential. By offering these propositions for the value of boundary spanning, we hope to encourage a more robust discussion of how to achieve evidence-informed decision-making for sustainability.

Beyond single-marker analyses: mining whole genome scans for insights into treatment responses in severe sepsis.

Management of severe sepsis, an acute illness with high morbidity and mortality, suffers from the lack of effective biomarkers and largely empirical predictions of disease progression and therapeutic responses. We conducted a genome-wide association study using a large randomized clinical trial cohort to discover genetic biomarkers of response to therapy and prognosis utilizing novel approaches, including combination markers, to overcome limitations of single-marker analyses. Sepsis prognostic models were dominated by clinical variables with genetic markers less informative. In contrast, evidence for gene-gene interactions were identified for sepsis treatment responses with genetic biomarkers dominating models for predicting therapeutic responses, yielding candidates for replication in other cohorts.

Genomewide association for schizophrenia in the CATIE study: results of stage 1.

Little is known for certain about the genetics of schizophrenia. The advent of genomewide association has been widely anticipated as a promising means to identify reproducible DNA sequence variation associated with this important and debilitating disorder. A total of 738 cases with DSM-IV schizophrenia (all participants in the CATIE study) and 733 group-matched controls were genotyped for 492,900 single-nucleotide polymorphisms (SNPs) using the Affymetrix 500K two-chip genotyping platform plus a custom 164K fill-in chip. Following multiple quality control steps for both subjects and SNPs, logistic regression analyses were used to assess the evidence for association of all SNPs with schizophrenia. We identified a number of promising SNPs for follow-up studies, although no SNP or multimarker combination of SNPs achieved genomewide statistical significance. Although a few signals coincided with genomic regions previously implicated in schizophrenia, chance could not be excluded. These data do not provide evidence for the involvement of any genomic region with schizophrenia detectable with moderate sample size. However, a planned genomewide association study for response phenotypes and inclusion of individual phenotype and genotype data from this study in meta-analyses hold promise for eventual identification of susceptibility and protective variants.

Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel.

BACKGROUND: Thienopyridines are metabolized to active metabolites that irreversibly inhibit the platelet P2Y(12) adenosine diphosphate receptor. The pharmacodynamic response to clopidogrel is more variable than the response to prasugrel, but the reasons for variation in response to clopidogrel are not well characterized. OBJECTIVE: To determine the relationship between genetic variation in cytochrome P450 (CYP) isoenzymes and the pharmacokinetic/pharmacodynamic response to prasugrel and clopidogrel. METHODS: Genotyping was performed for CYP1A2, CYP2B6, CYP2C19, CYP2C9, CYP3A4 and CYP3A5 on samples from healthy subjects participating in studies evaluating pharmacokinetic and pharmacodynamic responses to prasugrel (60 mg, n = 71) or clopidogrel (300 mg, n = 74). RESULTS: In subjects receiving clopidogrel, the presence of the CYP2C19*2 loss of function variant was significantly associated with lower exposure to clopidogrel active metabolite, as measured by the area under the concentration curve (AUC(0-24); P = 0.004) and maximal plasma concentration (C(max); P = 0.020), lower inhibition of platelet aggregation at 4 h (P = 0.003) and poor-responder status (P = 0.030). Similarly, CYP2C9 loss of function variants were significantly associated with lower AUC(0-24) (P = 0.043), lower C(max) (P = 0.006), lower IPA (P = 0.046) and poor-responder status (P = 0.024). For prasugrel, there was no relationship observed between CYP2C19 or CYP2C9 loss of function genotypes and exposure to the active metabolite of prasugrel or pharmacodynamic response. CONCLUSIONS: The common loss of function polymorphisms of CYP2C19 and CYP2C9 are associated with decreased exposure to the active metabolite of clopidogrel but not prasugrel. Decreased exposure to its active metabolite is associated with a diminished pharmacodynamic response to clopidogrel.

Audit of opioid prescribing: the effect of hospital guidelines.

The effects of prescribing guidelines for analgesia were assessed by auditing prescriptions for opioids before and after the introduction of hospital prescribing guidelines. Opioid prescriptions were collected by the pharmacy department over a 2-week period in November 1994 and repeated in November 1995. Following the initial audit, analgesic prescribing guidelines were introduced. A statistically significant increase was achieved in the number of prescriptions that were correct for both dose and frequency according to both the British National Formulary recommendations (40-61%; p < 0.001) and our Acute Pain Service guidelines (16-26%; p < 0.05). There was a statistically significant decrease in the number of prescriptions that were inadequate for both dose and frequency according to both the British National Formulary recommendations (18-3%; p < 0.001) and our Acute Pain Service guidelines (36-17%; p = 0.001). The use of accessible prescribing guidelines promotes demonstrable improvements in opioid prescribing.