SUMMARY Clec16a has been identified as a disease susceptibility gene for type 1 diabetes, multiple sclerosis and adrenal dysfunction, but its function is unknown. Here we report that Clec16a is a membrane-associated endosomal protein that interacts with E3 ubiquitin ligase Nrdp1. Loss of Clec16a leads to an increase in the Nrdp1 target Parkin, a master regulator of mitophagy. Islets from mice with pancreas-specific deletion of Clec16a have abnormal mitochondria with reduced oxygen consumption and ATP concentration, both of which are required for normal β-cell function. Indeed, pancreatic Clec16a is required for normal glucose-stimulated insulin release. Moreover, patients harboring a diabetogenic SNP in the Clec16a gene have reduced islet Clec16a expression and reduced insulin secretion. Thus, Clec16a controls β-cell function and prevents diabetes by controlling mitophagy. This novel pathway could be targeted for prevention and control of diabetes and may extend to the pathogenesis of other Clec16a and Parkin associated diseases.

The calcium-regulated phosphatase calcineurin intersects with both calcium and cAMP-mediated signaling pathways in the pancreatic ␤-cell. Pharmacologic calcineurin inhibition, necessary to prevent rejection in the setting of organ transplantation, is associated with post-transplant ␤-cell failure. We sought to determine the effect of calcineurin inhibition on ␤-cell replication and survival in rodents and in isolated human islets. Further, we assessed whether the GLP-1 receptor agonist and cAMP stimulus, exendin-4 (Ex-4), could rescue ␤-cell replication and survival following calcineurin inhibition. Following treatment with the calcineurin inhibitor tacrolimus, human ␤-cell apoptosis was significantly increased. Although we detected no human ␤-cell replication, tacrolimus significantly decreased rodent ␤-cell replication. Ex-4 nearly normalized both human ␤-cell survival and rodent ␤-cell replication when co-administered with tacrolimus. We found that tacrolimus decreased Akt phosphorylation, suggesting that calcineurin could regulate replication and survival via the PI3K/ Akt pathway. We identify insulin receptor substrate-2 (Irs2), a known cAMP-responsive element-binding protein target and upstream regulator of the PI3K/Akt pathway, as a novel calcineurin target in ␤-cells. Irs2 mRNA and protein are decreased by calcineurin inhibition in both rodent and human islets. The effect of calcineurin on Irs2 expression is mediated at least in part through the nuclear factor of activated T-cells (NFAT), as NFAT occupied the Irs2 promoter in a calcineurinsensitive manner. Ex-4 restored Irs2 expression in tacrolimustreated rodent and human islets nearly to baseline. These findings reveal calcineurin as a regulator of human ␤-cell survival in part through regulation of Irs2, with implications for the pathogenesis and treatment of diabetes following organ transplantation.New onset diabetes mellitus is a major complication following solid organ transplantation, often leading to decreased graft survival and increased mortality (1-3). As with other forms of diabetes, hyperglycemia ensues when there is inadequate pancreatic ␤-cell mass to meet insulin demand (4). Post-transplant diabetes is strongly associated with the use of calcineurin inhibitors, antirejection medications that are widely used in clinical solid organ transplantation (5). This association has prompted long-standing speculation that the calcineurin inhibitors are ␤-cell toxic and pathogenic in transplant-related ␤-cell failure.Calcineurin is a calcium-activated cytosolic phosphatase that is critical for antigen-stimulated T lymphocyte activation (6). Therefore, pharmacologic calcineurin inhibition is highly effective in preventing allograft rejection. However, calcineurin is also expressed in ␤-cells where it has two well described molecular targets, the nuclear factor of activated T cell (NFAT) 2 family of transcription factors (7), and the cAMP-responsive element-binding protein (CREB) transcriptional co-activator, transducer of regulated CREB activity-2 (TO...

Mitophagy is a critical regulator of mitochondrial quality control and is necessary for elimination of dysfunctional mitochondria to maintain cellular respiration. Here, we report that the homeodomain transcription factor Pdx1, a gene associated with both type 2 diabetes and monogenic diabetes of the young, regulates mitophagy in pancreatic β-cells. Loss of Pdx1 leads to abnormal mitochondrial morphology and function as well as impaired mitochondrial turnover. High-throughput expression microarray and chromatin occupancy analyses reveal that Pdx1 regulates the expression of Clec16a, a type 1 diabetes gene and itself a key mediator of mitophagy through regulation of the E3 ubiquitin ligase Nrdp1. Indeed, expression of Clec16a and Nrdp1 are both reduced in Pdx1 haploinsufficient islets, and reduction of Pdx1 impairs fusion of autophagosomes containing mitochondria to lysosomes during mitophagy. Importantly, restoration of Clec16a expression after Pdx1 loss of function restores mitochondrial trafficking during mitophagy and improves mitochondrial respiration and glucose-stimulated insulin release. Thus, Pdx1 orchestrates nuclear control of mitochondrial function in part by controlling mitophagy through Clec16a. The novel Pdx1-Clec16a-Nrdp1 pathway we describe provides a genetic basis for the pathogenesis of mitochondrial dysfunction in multiple forms of diabetes that could be targeted for future therapies to improve β-cell function.

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Precision medicine customizes drug treatment to an individual's disease and genetics in order to optimize therapeutic benefit and minimize risk. Surprisingly, drug dosing is generally not discussed as a component of precision medicine. Because dosing regimens are an independent factor modulating efficacy and toxicity, consideration should be given to the clinical significance of precision drug dosing (PDD) in patient care. Pharmacists routinely face dilemmas when they are asked for dosing recommendations for patients with characteristics that fall outside of those represented in the drug label (eg, morbid obesity, pregnancy, frailty, neonatal patients, or elderly patients). The necessary data and technology now exist to create and implement PDD software for high priority drug‐disease targets in order to assist pharmacists and prescribers in choosing the safest and most effective dose for every patient. Within 5 to 10 years, we believe this software will be available. This study discusses how pharmacists can participate in leading the implementation of these PDD tools to achieve effective and routine clinical use.

257 Background: For patients receiving high dose cytarabine (HiDAC) at University of Virginia (UVA) Health between 10/2019 and 10/2020, median length of stay (LOS) from time of clinic appointment to hospital discharge was 119.35 hours. Standard treatment time should be 112 hours from premedication to end of chemotherapy. There are no national standards for duration of inpatient stay for planned chemotherapy, but only 50% of these patients were discharged after noon (over 3 hours post-chemotherapy completion). LOS that extends beyond the standard treatment time results in increased cost, overutilization of hospital resources, delayed admissions for future patients, and patient dissatisfaction. Methods: A multidisciplinary team comprised of licensed providers, pharmacists, and nurses was formed. The team focused on percentage of patients discharged by noon as a surrogate marker for LOS due to inconsistency of admission times; the aim was to increase patients discharged by noon to 65%. Reviewing the baseline data revealed an unstable process with a 3-sigma X-bar statistical process control chart. The team developed current and ideal process state maps, a Pareto chart, and a priority matrix to determine an action plan. The most common identified causes for delay in discharge included: lack of standardized discharge checklist, discharge order placed after 10 am, medications dispensed from the outpatient pharmacy after 11 am, licensed providers not prioritizing discharge patients, and medication reconciliation not completed prior to day of discharge. Results: From 10/2020 to 5/2021, the first PDSA cycle focused on standardizing the discharge process to correct the instability in the process. A discharge checklist was created based on the ideal process map, which allowed the providers to have a consistent process at discharge. 3-sigma Xbar chart demonstrated a now stable process and an increase of patients discharged by noon to 58%. During the second PDSA cycle starting in 6/2021, providers completed medication reconciliation the day before discharge, prioritized HiDAC discharges first during rounds, and ensured discharge orders were placed by completion of the last chemotherapy bag. Data collection is ongoing, and will be analyzed by August 2021. Future tests of change are planned to focus on the pharmacy medication delivery service. Hospital LOS has also decreased after the first PDSA cycle. Conclusions: Using quality improvement methodology, a multidisciplinary team developed an action plan for patients receiving HiDAC which to date has increased the percentage of patients discharging by noon and decreased length of stay. This outcome may lead to reduce hospitalization costs and increase bed availability for other oncology patients. Further PDSA cycles are scheduled and continuous evaluation of the process is ongoing.

Background For patients receiving high dose cytarabine (HiDAC) at the University of Virginia Health System between 10/2019 and 10/2020, median length of stay (LOS) from time of clinic appointment to hospital discharge exceeded the expected standard treatment time (119.4 hours vs 112 hours). Despite the final dose of chemotherapy being scheduled for completion by 9:00 am on the planned day of discharge, only 50% of patients receiving HiDAC were successfully discharged by 12:00 pm (3 hours post-chemotherapy completion). Though there are no national standards for duration of inpatient stay for planned chemotherapy, LOS that extends beyond the standard treatment time results in increased cost, overutilization of hospital resources, delayed admissions for future patients, and patient dissatisfaction. Methods A multidisciplinary team of licensed providers, pharmacists, and nurses was formed. Due to inconsistency in admission times, the team focused on the percentage of patients discharged by 12:00 pm as a surrogate marker for LOS. The aim was to increase the percentage of patients discharged by 12:00 pm to 65%. Reviewing the baseline data revealed an unstable process with a 3-sigma XmR statistical process control chart. The team developed current and ideal process state maps, a Pareto chart, and a priority matrix to determine an action plan. The most common identified causes for delay in discharge included: lack of standardized discharge checklist, discharge order placed after 10:00 am, medications dispensed from the outpatient pharmacy after 11:00 am, licensed providers not prioritizing patients who were pending discharge, and medication reconciliation not completed prior to day of discharge. Results From 10/2020 to 5/2021, the first PDSA cycle focused on standardizing the discharge process to correct the instability in the process. A discharge checklist was created based on the ideal process map, which allowed providers to have a consistent process at discharge. A 3-sigma XmR chart demonstrated a newly stable process and an increase in percentage of patients discharged by 12:00 pm to 58% (14 of 24). The second PDSA cycle from 6/2021 to 8/2021 addressed the high impact/easy effort interventions identified in the priority matrix: providers completed medication reconciliation the day before discharge, prioritized seeing HiDAC discharge patients first during morning rounds, and ensured discharge orders were placed prior to completion of the last chemotherapy infusion. Following these interventions, the percentage of patients discharged by 12:00 pm increased to 66% (4 of 6). Conclusions Using quality improvement methodology, a multidisciplinary team developed an action plan for patients receiving HiDAC that has increased the percentage of patients discharged by 12:00 pm. This outcome may lead to decreased length of stay, reduced hospitalization costs, and increased bed availability for other hematology/oncology patients. Further PDSA cycles are planned and will focus on the pharmacy medication delivery service, and continuous evaluation of the process is ongoing. Figure 1 Figure 1. Disclosures El Chaer: Amgen: Honoraria, Research Funding.

We wish to report the induced oxidation of cobalt(II) mesoporphyrin IX dimethyl ester, Co(II)MPIXDME, by unsaturated hydrocarbons.