Barriers and Facilitators to End-of-Life Care Delivery in ICUs: A Qualitative Study.

OBJECTIVES: To understand frontline ICU clinician's perceptions of end-of-life care delivery in the ICU. DESIGN: Qualitative observational cross-sectional study. SETTING: Seven ICUs across three hospitals in an integrated academic health system. SUBJECTS: ICU clinicians (physicians [critical care, palliative care], advanced practice providers, nurses, social workers, chaplains). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In total, 27 semi-structured interviews were conducted, recorded, and transcribed. The research team reviewed all transcripts inductively to develop a codebook. Thematic analysis was conducted through coding, category formulation, and sorting for data reduction to identify central themes. Deductive reasoning facilitated data category formulation and thematic structuring anchored on the Systems Engineering Initiative for Patient Safety model identified that work systems (people, environment, tools, tasks) lead to processes and outcomes. Four themes were barriers or facilitators to end-of-life care. First, work system barriers delayed end-of-life care communication among clinicians as well as between clinicians and families. For example, over-reliance on palliative care people in handling end-of-life discussions prevented timely end-of-life care discussions with families. Second, clinician-level variability existed in end-of-life communication tasks. For example, end-of-life care discussions varied greatly in process and outcomes depending on the clinician leading the conversation. Third, clinician-family-patient priorities or treatment goals were misaligned. Conversely, regular discussion and joint decisions facilitated higher familial confidence in end-of-life care delivery process. These detailed discussions between care teams aligned priorities and led to fewer situations where patients/families received conflicting information. Fourth, clinician moral distress occurred from providing nonbeneficial care. Interviewees reported standardized end-of-life care discussion process incorporated by the people in the work system including patient, family, and clinicians were foundational to delivering end-of-life care that reduced both patient and family suffering, as well as clinician moral distress. CONCLUSIONS: Standardized work system communication tasks may improve end-of life discussion processes between clinicians and families.

Association of ataxia telangiectasia mutated (ATM) gene mutation/deletion with rhabdomyosarcoma.

Rhabdomyosarcoma is a common malignancy in children. There are two major types of rhabdomyosarcomas, the embryonal and the alveolar, differing in cytogenetic and morphologic features. The alveolar type of rhabdomyosarcoma is frequently associated with chromosome translocation t(2; 13) and poor clinical prognosis. Pathogenesis of rhabdomyosarcoma remains obscure, and especially it occurs in the location where skeletal muscle is absent. We report here that there is a high frequency of association of rhabdomyosarcoma with ataxia telangiectasia mutated (ATM) gene mutation/deletion. Totally 17 cases of rhabdomyosarcoma specimens were studied by immunohistochemical or immunofluorescent staining with ATM antibody and revealed that 7 of the 17 cases were negative for ATM expression (41%). Further analyses of rhabdomyosarcoma cell lines with RT-PCR revealed that in Rh30 cells, an alveolar rhabdomyosarcoma cell line, there are three separate deletions/mutations of the ATM mRNA. Western blotting analysis of the Rh30 cellular extract with anti-ATM antibody showed that there is an aberrant form of ATM protein within the Rh30 cells that are smaller than normal control. These results suggest, for the first time, a link of ATM gene deletion/mutation with rhabdomyosarcoma, and since ATM kinase is a crucial regulatory protein in DMA damage repair signaling pathway, and ATM deletion/mutation may contribute to pathogenesis of rhabdomyosarcoma.

A myogenic differentiation checkpoint activated by genotoxic stress.

Cell-cycle checkpoints help to protect the genomes of proliferating cells under genotoxic stress. In multicellular organisms, cell proliferation is often directed toward differentiation during development and throughout adult homeostasis. To prevent the formation of differentiated cells with genetic instability, we hypothesized that genotoxic stress may trigger a differentiation checkpoint. Here we show that exposure to genotoxic agents causes a reversible inhibition of myogenic differentiation. Muscle-specific gene expression is suppressed by DNA-damaging agents if applied prior to differentiation induction but not after the differentiation program is established. The myogenic determination factor, MyoD (encoded by Myod1), is a target of the differentiation checkpoint in myoblasts. The inhibition of MyoD by DNA damage requires a functional c-Abl tyrosine kinase (encoded by Abl1), but occurs in cells deficient for p53 (transformation-related protein 53, encoded by Trp53) or c-Jun (encoded by the oncogene Jun). These results support the idea that genotoxic stress can regulate differentiation, and identify a new biological function for DNA damage-activated signaling network.