Maintenance of gene silencing by the coordinate action of the H3K9 methyltransferase G9a/KMT1C and the H3K4 demethylase Jarid1a/KDM5A.

Chromatin remodeling is essential for controlling the expression of genes during development. The histone-modifying enzyme G9a/KMT1C can act both as a coactivator and a corepressor of transcription. Here, we show that the dual function of G9a as a coactivator vs. a corepressor entails its association within two distinct protein complexes, one containing the coactivator Mediator and one containing the corepressor Jarid1a/KDM5A. Functionally, G9a is important in stabilizing the Mediator complex for gene activation, whereas its repressive function entails a coordinate action with the histone H3 lysine 4 (H3K4) demethylase Jarid1a for the maintenance of gene repression. The essential nature of cross-talk between the histone methyltransferase G9a and the demethylase Jarid1a is demonstrated on the embryonic E(y)-globin gene, where the concurrent introduction of repressive histone marks (dimethylated H3K9 and dimethylated H3K27) and removal of activating histone mark (trimethylated H3K4) is required for maintenance of gene silencing. Taken together with our previous demonstration of cross-talk between UTX and MLL2 to mediate activation of the adult ß(maj)-globin gene, these data suggest a model where "active" and "repressive" cross-talk between histone-modifying enzymes coexist on the same multigene locus and play a crucial role in the precise control of developmentally regulated gene expression.

Antecedent treat-and-release diagnoses prior to sepsis hospitalization among adult emergency department patients: a look-back analysis employing insurance claims data using Symptom-Disease Pair Analysis of Diagnostic Error (SPADE) methodology.

OBJECTIVES: The aim of this study was to identify delays in early pre-sepsis diagnosis in emergency departments (ED) using the Symptom-Disease Pair Analysis of Diagnostic Error (SPADE) approach. METHODS: SPADE methodology was employed using electronic health record and claims data from Kaiser Permanente Mid-Atlantic States (KPMAS). Study cohort included KPMAS members ≥18 years with ≥1 sepsis hospitalization 1/1/2013-12/31/2018. A look-back analysis identified treat-and-release ED visits in the month prior to sepsis hospitalizations. Top 20 diagnoses associated with these ED visits were identified; two diagnosis categories were distinguished as being linked to downstream sepsis hospitalizations. Observed-to-expected (O:E) and temporal analyses were performed to validate the symptom selection; results were contrasted to a comparison group. Demographics of patients that did and did not experience sepsis misdiagnosis were compared. RESULTS: There were 3,468 sepsis hospitalizations during the study period and 766 treat-and-release ED visits in the month prior to hospitalization. Patients discharged from the ED with fluid and electrolyte disorders (FED) and altered mental status (AMS) were most likely to have downstream sepsis hospitalizations (O:E ratios of 2.66 and 2.82, respectively). Temporal analyses revealed that these symptoms were overrepresented and temporally clustered close to the hospitalization date. Approximately 2% of sepsis hospitalizations were associated with prior FED or AMS ED visits. CONCLUSIONS: Treat-and-release ED encounters for FED and AMS may represent harbingers for downstream sepsis hospitalizations. The SPADE approach can be used to develop performance measures that identify pre-sepsis.

Feasibility and Assessment of a Cascade Traceback Screening Program (FACTS): Protocol for a Multisite Study to Implement and Assess an Ovarian Cancer Traceback Cascade Testing Program.

Ovarian cancer (OVCA) patients may carry genes conferring cancer risk to biological family; however, fewer than one-quarter of patients receive genetic testing. "Traceback" cascade testing -outreach to potential probands and relatives-is a possible solution. This paper outlines a funded study (U01 CA240747-01A1) seeking to determine a Traceback program's feasibility, acceptability, effectiveness, and costs. This is a multisite prospective observational feasibility study across three integrated health systems. Informed by the Conceptual Model for Implementation Research, we will outline, implement, and evaluate the outcomes of an OVCA Traceback program. We will use standard legal research methodology to review genetic privacy statutes; engage key stakeholders in qualitative interviews to design communication strategies; employ descriptive statistics and regression analyses to evaluate the site differences in genetic testing and the OVCA Traceback testing; and assess program outcomes at the proband, family member, provider, system, and population levels. This study aims to determine a Traceback program's feasibility and acceptability in a real-world context. It will account for the myriad factors affecting implementation, including legal issues, organizational- and individual-level barriers and facilitators, communication issues, and program costs. Project results will inform how health care providers and systems can develop effective, practical, and sustainable Traceback programs.