Involuntary sedation of patients in the emergency department for mental health: A retrospective cohort study.

BACKGROUND: Involuntary sedation of agitated mental health patients in the Emergency Department (ED) is standard practice to obtain accurate medical assessments and maintain safety. However, the rate of this practice and what factors are associated with the use of involuntary sedation is unknown. The purpose of this study was to obtain baseline data on involuntary sedation in our EDs. METHODS: Retrospective chart review of patients with ED visits for mental health care in 2020-2021. Patients >12 years old who received both a psychiatry consultation and involuntary sedation were included. Data variables included demographics, medical and mental health diagnoses, sedatives given, substance use, ED length of stay, and disposition. The primary outcome was repeated involuntary sedation. RESULTS: Involuntary sedation was used in 18.8% of the mental health patients screened for study inclusion. 334 patients were included in the study cohort and 31.6% (n = 106) required repeated involuntary sedation. Their average age was 35.5 ± 13.5 years with 58.4% men, 40.1% women, and 1.2% transgender persons. Most (90.0%, n = 299) had prior mental health diagnoses with the most common being substance use disorder (38.9%, n = 130), bipolar disorder (34.1%, n = 114), depressive disorder (29.0%, n = 97), and schizophrenia (24.3%, n = 81). Two-thirds (65.9%, n = 220) had current substance use and 41.9% (n = 142) reported current use with a chemical associated with aggression. Hospital security was called for 73.1% (n = 244). Current cocaine, methamphetamines, or alcohol use was associated with decreased odds of repeated sedation (0.52 OR, 95% CI 0.32-0.85). Prior mental health diagnosis and non-white race were associated with increased odds of repeated sedation. In the multivariable regression, the effect of race was more significant. CONCLUSIONS: Involuntary sedation was used in 18.8% of ED patients for mental health care and almost a third were repeatedly sedated, with race being a potential risk factor for repeated sedation. ED care could benefit from evidence-based interventions to reduce the need for involuntary sedation.

Conserved oncogenic behavior of the FAM83 family regulates MAPK signaling in human cancer.

UNLABELLED: FAM83B (family with sequence similarity 83, member B) was recently identified as a novel oncogene involved in activating CRAF/MAPK signaling and driving epithelial cell transformation. FAM83B is one of eight members of a protein family (FAM83) characterized by a highly conserved domain of unknown function (DUF1669), which is necessary and sufficient to drive transformation. Here, it is demonstrated that additional FAM83 members also exhibit oncogenic properties and have significantly elevated levels of expression in multiple human tumor types using a TissueScan Cancer Survey Panel PCR array and database mining. Furthermore, modeling the observed tumor expression of FAM83A, FAM83C, FAM83D, or FAM83E promoted human mammary epithelial cell (HMEC) transformation, which correlated with the ability of each FAM83 member to bind CRAF (RAF1) and promote CRAF membrane localization. Conversely, ablation of FAM83A or FAM83D from breast cancer cells resulted in diminished MAPK signaling with marked suppression of growth in vitro and tumorigenicity in vivo. Importantly, each FAM83 member was determined to be elevated in at least one of 17 distinct tumor types examined, with FAM83A, FAM83B, and FAM83D most frequently overexpressed in several diverse tissue types. Finally, evidence suggests that elevated expression of FAM83 members is associated with elevated tumor grade and decreased overall survival. IMPLICATIONS: FAM83 proteins represent a novel family of oncogenes suitable for the development of cancer therapies aimed at suppressing MAPK signaling.

FAM83B-mediated activation of PI3K/AKT and MAPK signaling cooperates to promote epithelial cell transformation and resistance to targeted therapies.

Therapies targeting MAPK and AKT/mTOR signaling are currently being evaluated in clinical trials for several tumor types. However, recent studies suggest that these therapies may be limited due to acquired cancer cell resistance and a small therapeutic index between normal and cancer cells. The identification of novel proteins that are involved in MAPK or AKT/mTOR signaling and differentially expressed between normal and cancer cells will provide mechanistically distinct therapeutic targets with the potential to inhibit these key cancer-associated pathways. We recently identified FAM83B as a novel, previously uncharacterized oncogene capable of hyperactivating MAPK and mTOR signaling and driving the tumorigenicity of immortalized human mammary epithelial cells (HMEC). We show here that elevated FAM83B expression also activates the PI3K/AKT signaling pathway and confers a decreased sensitivity to PI3K, AKT, and mTOR inhibitors. FAM83B co-precipitated with the p85α and p110α subunits of PI3K, as well as AKT, and increased p110α and AKT membrane localization, consistent with elevated PI3K/AKT signaling. In tumor-derived cells harboring elevated FAM83B expression, ablation of FAM83B decreased p110α and AKT membrane localization, suppressed AKT phosphorylation, and diminished proliferation, AIG, and tumorigenicity in vivo. We propose that the level of FAM83B expression may be an important factor to consider when combined therapies targeting MAPK and AKT/mTOR signaling are used. Moreover, the identification of FAM83B as a novel oncogene and its integral involvement in activating PI3K/AKT and MAPK provides a foundation for future therapies aimed at targeting FAM83B in order to suppress the growth of PI3K/AKT- and MAPK-driven cancers.