SUMMARYNotch signaling regulates numerous developmental processes, often acting either to promote one cell fate over another or else to inhibit differentiation altogether. In the embryonic pancreas, Notch and its target gene Hes1 are thought to inhibit endocrine and exocrine specification. Although differentiated cells appear to downregulate Hes1, it is unknown whether Hes1 expression marks multipotent progenitors, or else lineage-restricted precursors. Moreover, although rare cells of the adult pancreas express Hes1, it is unknown whether these represent a specialized progenitor-like population. To address these issues, we developed a mouse Hes1CreERT2 knock-in allele to inducibly mark Hes1 + cells and their descendants. We find that Hes1 expression in the early embryonic pancreas identifies multipotent, Notch-responsive progenitors, differentiation of which is blocked by activated Notch. In later embryogenesis, Hes1 marks exocrine-restricted progenitors, in which activated Notch promotes ductal differentiation. In the adult pancreas, Hes1 expression persists in rare differentiated cells, particularly terminal duct or centroacinar cells. Although we find that Hes1 + cells in the resting or injured pancreas do not behave as adult stem cells for insulin-producing beta ()-cells, Hes1 expression does identify stem cells throughout the small and large intestine. Together, these studies clarify the roles of Notch and Hes1 in the developing and adult pancreas, and open new avenues to study Notch signaling in this and other tissues.

The Notch signaling pathway regulates embryonic development of the pancreas, inhibiting progenitor differentiation into exocrine acinar and endocrine islet cells. The adult pancreas appears to lack progenitor cells, and its mature cell types are maintained by the proliferation of pre-existing differentiated cells. Nonetheless, Notch remains active in adult duct and terminal duct/centroacinar cells (CACs), in which its function is unknown. We previously developed mice in which cells expressing the Notch target gene Hes1 can be labeled and manipulated, by expression of Cre recombinase, and demonstrated that Hes1+ CACs do not behave as acinar or islet progenitors in the uninjured pancreas, or as islet progenitors after pancreatic duct ligation. In the current study, we assessed the function of Notch signaling in the adult pancreas by deleting the transcription factor partner of Notch, Rbpj, specifically in Hes1+ cells. We find that loss of Rbpj depletes the pancreas of Hes1-expressing CACs, abrogating their ongoing contribution to growth and homeostasis of more proximal duct structures. Upon Rbpj deletion, CACs undergo a rapid transformation into acinar cells, suggesting that constitutive Notch activity suppresses the acinar differentiation potential of CACs. Together, our data provide direct evidence of an endogenous genetic program to control interconversion of cell fates in the adult pancreas.

Objective To evaluate the impact of opioid safety edits on opioid utilization. Design Retrospective review. Setting Senior Care Action Network (SCAN) Health Plan, a Medicare Advantage Prescription Drug Plan. Patients, Participants The opioid safety edits reviewed included edits for the following: initial opioid fill more than 7 days’ supply (DS), cumulative opioid doses 90 or greater and 240 or greater morphine milligram equivalent (MME), concurrent opioid and benzodiazepine (COB) use. Members with prescription drug claims meeting these criteria pre- and postedit implementation and those with prescription drug claim rejections resulting from the edits were included in the review. Results 15,232 members experienced claim rejections resulting from the edits. Comparison of utilization pre and postedit implementation revealed the following results (P < 0.001): 41% decrease in the proportion of members with an initial opioid fill for more than 7 DS; 18% decrease in the proportion of members on opioid doses 90 MME or more; 26% decrease in the proportion of members on opioid doses 240 MME or more; 18% decrease in the proportion of members with COB. Conclusion Opioid safety edits are an effective way to combat overuse and misuse. They serve as a means for increasing collaboration between plans, prescribers, pharmacists, and members which improves care coordination, reduces adverse risks, and helps keep members safe.

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