ABSTRACT
Innate immunity protects us in youth but turns against us as we age. The reason for this tradeoff is unclear. Seeking a thermodynamic basis, we focused on death fold domains (DFDs), whose ordered polymerization has been stoichiometrically linked to innate immune signal amplification. We hypothesized that soluble ensembles of DFDs function as phase change batteries that store energy via supersaturation and subsequently release it through nucleated polymerization. Using imaging and FRET-based cytometry to characterize the phase behaviors of all 109 human DFDs, we found that the hubs of innate immune signaling networks encode large nucleation barriers that are intrinsically insulated from cross-pathway activation. We showed via optogenetics that supersaturation drives signal amplification and that the inflammasome is constitutively supersaturated in vivo. Our findings reveal that the soluble "inactive" states of adaptor DFDs function as essential, yet impermanent, kinetic barriers to inflammatory cell death, suggesting a thermodynamic driving force for aging.
ABSTRACT
PURPOSE: This study aims to quantify the magnitude of missed dispensings in commercial claims databases. METHODS: A retrospective cohort study has been used linking PharMetrics, a commercial claims database, to a prescription database (LRx) that captures pharmacy dispensings independently of payment method, including cash transactions. We included adults with dispensings for opioids, diuretics, antiplatelet medications, or anticoagulants. To determine the degree of capture of dispensings, we calculated the number of subjects with the following: (1) same number of dispensings in both databases; (2) at least one dispensing, but not all dispensings, missed in PharMetrics; and (3) all dispensings missing in PharMetrics. Similar analyses were conducted using dispensings as the unit of analysis. To assess whether a dispensing in LRx was in PharMetrics, the dispensing in PharMetrics had to be for the same medication class and within ±7 days in LRx. RESULTS: A total of 1 426 498 subjects were included. Overall, 68% of subjects had the same number of dispensings in both databases. In 13% of subjects, PharMetrics identified ≥1 dispensing but also missed ≥1 dispensing. In 19% of the subjects, PharMetrics missed all the dispensings. Taking dispensings as the unit of analysis, 25% of the dispensings present in LRx were not captured in PharMetrics. These patterns were similar across all four classes of medications. Of the dispensings missing in PharMetrics, 48% involved a subject who had >1 health insurance plan. CONCLUSIONS: Commercial claims databases provide an incomplete picture of all prescriptions dispensed to patients. The lack of capture goes beyond cash transactions and potentially introduces substantial misclassification bias. © 2017 The Authors. Pharmacoepidemiology & Drug Safety Published by John Wiley & Sons Ltd.
