Cell Type-Specific Whole-Genome Landscape of ΔFOSB Binding in the Nucleus Accumbens After Chronic Cocaine Exposure.

BACKGROUND: The ability of neurons to respond to external stimuli involves adaptations of gene expression. Induction of the transcription factor ΔFOSB in the nucleus accumbens, a key brain reward region, is important for the development of drug addiction. However, a comprehensive map of ΔFOSB's gene targets has not yet been generated. METHODS: We used CUT&RUN (cleavage under targets and release using nuclease) to map the genome-wide changes in ΔFOSB binding in the 2 main types of nucleus accumbens neurons-D1 or D2 medium spiny neurons-after chronic cocaine exposure. To annotate genomic regions of ΔFOSB binding sites, we also examined the distributions of several histone modifications. Resulting datasets were leveraged for multiple bioinformatic analyses. RESULTS: The majority of ΔFOSB peaks occur outside promoter regions, including intergenic regions, and are surrounded by epigenetic marks indicative of active enhancers. BRG1, the core subunit of the SWI/SNF chromatin remodeling complex, overlaps with ΔFOSB peaks, a finding consistent with earlier studies of ΔFOSB's interacting proteins. Chronic cocaine use induces broad changes in ΔFOSB binding in both D1 and D2 nucleus accumbens medium spiny neurons of male and female mice. In addition, in silico analyses predict that ΔFOSB cooperatively regulates gene expression with homeobox and T-box transcription factors. CONCLUSIONS: These novel findings uncover key elements of ΔFOSB's molecular mechanisms in transcriptional regulation at baseline and in response to chronic cocaine exposure. Further characterization of ΔFOSB's collaborative transcriptional and chromatin partners specifically in D1 and D2 medium spiny neurons will reveal a broader picture of the function of ΔFOSB and the molecular basis of drug addiction.

Estradiol withdrawal following a hormone simulated pregnancy induces deficits in affective behaviors and increases ∆FosB in D1 and D2 neurons in the nucleus accumbens core in mice.

In placental mammals, estradiol levels are chronically elevated during pregnancy, but quickly drop to prepartum levels following birth. This may produce an "estrogen withdrawal" state that has been linked to changes in affective states in humans and rodents during the postpartum period. The neural mechanisms underlying these affective changes, however, are understudied. We used a hormone-simulated pseudopregnancy (HSP), a model of postpartum estrogen withdrawal, in adult female C57BL/6 mice to test the impact of postpartum estradiol withdrawal on several behavioral measures of anxiety and motivation. We found that estradiol withdrawal following HSP increased anxiety-like behavior in the elevated plus maze, but not in the open field or marble burying tests. Although hormone treatment during HSP consistently increased sucrose consumption, sucrose preference was generally not impacted by hormone treatment or subsequent estradiol withdrawal. In the social motivation test, estradiol withdrawal decreased the amount of time spent in proximity to a social stimulus animal. These behavioral changes were accompanied by changes in the expression of ∆FosB, a transcription factor correlated with stable long-term plasticity, in the nucleus accumbens (NAc). Specifically, estrogen-withdrawn females had higher ∆FosB expression in the nucleus accumbens core, but ∆FosB expression did not vary across hormone conditions in the nucleus accumbens shell. Using transgenic reporter mice, we found that this increase in ∆FosB occurred in both D1- and D2-expressing cells in the NAc core. Together, these results suggest that postpartum estrogen withdrawal impacts anxiety and motivation and increases ∆FosB in the NAc core.

Accuracy of a modified 4Ts score in predicting heparin-induced thrombocytopenia in critically ill patients: A pilot study.

PURPOSE: Thrombocytopenia is common among critically ill patients and heparin-induced thrombocytopenia (HIT) is often on the differential. Professional guidelines recommend calculating a pre-test probability score before performing HIT testing. The 4Ts score is widely utilized but accuracy has been questioned in critically ill patients. The HIT Expert Probability (HEP) score is available, but complexity limits use. Our objective was to compare a modified intensive care unit (ICU)-4Ts score to available scoring tools. MATERIALS AND METHODS: This was a single-center retrospective pilot study. Adult ICU patients that were tested for HIT and had a documented 4Ts score were included. A blinded investigator retrospectively calculated the HEP and ICU-4Ts score. Receiver operating characteristics (ROC) area under the curve (AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were compared. RESULTS: In 194 included patients, ROC AUC was significantly higher for the ICU-4Ts compared to the 4Ts score (0.80 versus 0.66, respectively; p = 0.044). The ICU-4Ts score had the highest specificity, PPV, and NPV. The sensitivity was similar between the HEP and ICU-4Ts score. CONCLUSIONS: The ICU-4Ts score better predicted the diagnosis of HIT compared to the 4Ts score. Prospective validation studies are needed to confirm these results.

Improving medication information transfer between hospitals, skilled-nursing facilities, and long-term-care pharmacies for hospital discharge transitions of care: A targeted needs assessment using the Intervention Mapping framework.

INTRODUCTION: Patients transitioning from the hospital to a skilled nursing home (SNF) are susceptible to medication-related errors resulting from fragmented communication between facilities. Through continuous process improvement efforts at the hospital, a targeted needs assessment was performed to understand the extent of medication-related issues when patients transition from the hospital into a SNF, and the gaps between the hospital's discharge process, and the needs of the SNF and long-term care (LTC) pharmacy. We report on the development of a logic model that will be used to explore methods for minimizing patient care medication delays and errors while further improving handoff communication to SNF and LTC pharmacy staff. METHODS: Applying the Intervention Mapping (IM) framework, a targeted needs assessment was performed using quantitative and qualitative methods. Using the hospital discharge medication list as reference, medication discrepancies in the SNF and LTC pharmacy lists were identified. SNF and LTC pharmacy staffs were also interviewed regarding the continuity of medication information post-discharge from the hospital. RESULTS: At least one medication discrepancy was discovered in 77.6% (n = 45/58) of SNF and 76.0% (n = 19/25) of LTC pharmacy medication lists. A total of 191 medication discrepancies were identified across all SNF and LTC pharmacy records. Of the 69 SNF staff interviewed, 20.3% (n = 14) reported patient care delays due to omitted documents during the hospital-to-SNF transition. During interviews, communication between the SNF/LTC pharmacy and the discharging hospital was described by facility staff as unidirectional with little opportunity for feedback on patient care concerns. CONCLUSIONS: The targeted needs assessment guided by the IM framework has lent to several planned process improvements initiatives to help reduce medication discrepancies during the hospital-to-SNF transition as well as improve communication between healthcare entities. Opening lines of communication along with aligning healthcare entity goals may help prevent medication-related errors.