Development and evaluation of a multidisciplinary controlled substances committee within a patient-centered medical home.

OBJECTIVE: To present the development of a multidisciplinary controlled substances committee and describe its effectiveness in relation to prescribers' acceptance of committee recommendations, the number of premature deaths associated with controlled substances, and prescribers' need for education on controlled substances. SETTING: A patient-centered medical home and accountable care organization in Maine that serves more than 60,000 patients across a large rural area, 70% of whom are classified as lower income. PRACTICE DESCRIPTION: A multidisciplinary group of prescribers and PharmD residents created a committee to influence organizational culture regarding controlled substances. The Controlled Substances Initiative Committee (CSIC) updated institutional policies, developed provider education, and made personalized patient recommendations to prescribers. MAIN OUTCOME MEASURES: The primary outcome was average change in daily morphine equivalent dose (MED) in patients for whom CSIC recommended a dose reduction to the patient's prescriber. Secondary outcomes included the proportion of patients who died of a known overdose or suspected drug-related death during 2012-2013 or 2013-2014. In addition, prescriber beliefs about controlled substances were measured via a needs assessment. RESULTS: The average daily MED for patients whom CSIC recommended dose reduction was lower after 3 months compared with at baseline (175.5 ± 344.3 mg vs. 292.7 ± 466.5 mg; P <0.05). The proportion of patients who died of a known overdose did not differ between 2012-2013 and 2013-2014 (11.8% vs. 11.1%; P = 1.00). However, a greater number of patients had a suspected drug-related death during 2013-2014 compared with during 2012-2013 (0% vs. 27.3%; P = 0.05). CONCLUSION: A multidisciplinary controlled substances committee may improve patient safety and outcomes by offering prescriber support and helping alter prescribing culture.

Alternative splicing controlled by heterogeneous nuclear ribonucleoprotein L regulates development, proliferation, and migration of thymic pre-T cells.

The regulation of posttranscriptional modifications of pre-mRNA by alternative splicing is important for cellular function, development, and immunity. The receptor tyrosine phosphatase CD45, which is expressed on all hematopoietic cells, is known for its role in the development and activation of T cells. CD45 is known to be alternatively spliced, a process that is partially regulated by heterogeneous nuclear ribonucleoprotein (hnRNP) L. To investigate the role of hnRNP L further, we have generated conditional hnRNP L knockout mice and found that LckCre-mediated deletion of hnRNP L results in a decreased thymic cellularity caused by a partial block at the transition stage between double-negative 4 and double-positive cells. In addition, hnRNP L(-/-) thymocytes express aberrant levels of the CD45RA splice isoforms and show high levels of phosphorylated Lck at the activator tyrosine Y394, but lack phosphorylation of the inhibitory tyrosine Y505. This indicated an increased basal Lck activity and correlated with higher proliferation rates of double-negative 4 cells in hnRNP L(-/-) mice. Deletion of hnRNP L also blocked the migration and egress of single-positive thymocytes to peripheral lymphoid organs in response to sphingosine-1-phosphate and the chemokines CCL21 and CXCL12 very likely as a result of aberrant splicing of genes encoding GTPase regulators and proteins affecting cytoskeletal organization. Our results indicate that hnRNP L regulates T cell differentiation and migration by regulating pre-TCR and chemokine receptor signaling.