Background
Clinical opioid overdose risk prediction models can be useful tools to reduce the risk of overdose in patients prescribed long-term opioid therapy (LTOT). However, evolving overdose risk ...environments and clinical practices in addition to potential harmful model misapplications require careful assessment prior to widespread implementation into clinical care. Models may need to be tailored to meet local clinical operational needs and intended applications in practice.
Objective
To update and validate an existing opioid overdose risk model, the Kaiser Permanente Colorado Opioid Overdose (KPCOOR) Model, in patients prescribed LTOT for implementation in clinical care.
Design, Setting, and Participants
The retrospective cohort study consisted of 33, 625 patients prescribed LTOT between January 2015 and June 2019 at Kaiser Permanente Colorado, with follow-up through June 2021.
Main Measures
The outcome consisted of fatal opioid overdoses identified from vital records and non-fatal opioid overdoses from emergency department and inpatient settings. Predictors included demographics, medication dispensings, substance use disorder history, mental health history, and medical diagnoses. Cox proportional hazards regressions were used to model 2-year overdose risk.
Key Results
During follow-up, 65 incident opioid overdoses were observed (111.4 overdoses per 100,000 person-years) in the study cohort, of which 11 were fatal. The optimal risk model needed to risk-stratify patients and to be easily interpreted by clinicians. The original 5-variable model re-validated on the new study cohort had a bootstrap-corrected
C
-statistic of 0.73 (95% CI, 0.64–0.85) compared to a
C
-statistic of 0.80 (95% CI, 0.70–0.88) in the updated model and 0.77 (95% CI, 0.66–0.87) in the final adapted 7-variable model, which was also well-calibrated.
Conclusions
Updating and adapting predictors for opioid overdose in the KPCOOR Model with input from clinical partners resulted in a parsimonious and clinically relevant model that was poised for integration in clinical care.
The roles of particular amino acids in substrate and coenzyme binding and catalysis of glucose-6-phosphate dehydrogenase of Leuconostoc mesenteroides have been investigated by site-directed ...mutagenesis, kinetic analysis, and determination of binding constants. The enzyme from this species has functional dual NADP+/NAD+ specificity. Previous investigations in our laboratories determined the three-dimensional structure. Kinetic studies showed an ordered mechanism for the NADP-linked reaction while the NAD-linked reaction is random. His-240 was identified as the catalytic base, and Arg-46 was identified as important for NADP+ but not NAD+ binding. Mutations have been selected on the basis of the three-dimensional structure. Kinetic studies of 14 mutant enzymes are reported and kinetic mechanisms are reported for 5 mutant enzymes. Fourteen substrate or coenzyme dissociation constants have been measured for 11 mutant enzymes. Roles of particular residues are inferred from k cat, K m, k cat/K m, K d, and changes in kinetic mechanism. Results for enzymes K182R, K182Q, K343R, and K343Q establish Lys-182 and Lys-343 as important in binding substrate both to free enzyme and during catalysis. Studies of mutant enzymes Y415F and Y179F showed no significant contribution for Tyr-415 to substrate binding and only a small contribution for Tyr-179. Changes in kinetics for T14A, Q47E, and R46A enzymes implicate these residues, to differing extents, in coenzyme binding and discrimination between NADP+ and NAD+. By the same measure, Lys-343 is also involved in defining coenzyme specificity. Decrease in k cat and k cat/K m for the D374Q mutant enzyme defines the way Asp-374, unique to L. mesenteroides G6PD, modulates stabilization of the enzyme during catalysis by its interaction with Lys-182. The greatly reduced k cat values of enzymes P149V and P149G indicate the importance of the cis conformation of Pro-149 in accessing the correct transition state.
The T&T Clark Companion to Atonement establishes a vision for the doctrine of the atonement as a unified yet extraordinarily rich event calling for the church's full appropriation. Most edited ...volumes on this doctrine focus on one aspect of the work of Christ (for example, Girard, Feminist thought, Penal Substitution or divine violence). The Companion is unique in that every essay seeks to both appropriate and stimulate the church's understanding of the manifold nature of Christ's death and resurrection. The essays are divided into four main sections: 1) dogmatic location, 2) chapters on the Old and New Testaments, 3) major theologians and 4) contemporary developments. The first set of essays explore the inter-relationship between the atonement and other Christian doctrines (for example Trinity, Christology and Pneumatology), opening up yet further avenues of inquiry. Essays on key theologians eschew reductionism, striving to bring out the nuances and breadth of the contribution. The same is true of the biblical essays. The final section explores more recent developments within the doctrine (for example the work of Rene Girard, and the ongoing reflection on "Holy Saturday"). The book is comprised of 18 major essays, and an A-Z section containing shorter dictionary-length entries on a much broader range of topics. The result is a combination of in-depth analysis and breadth of scope, making this a benchmark work for further studies in the doctrine.
