ABSTRACT
The genomics era has facilitated discovery of new genes predisposing to bone marrow failure (BMF) and hematological malignancy (HM). We report the discovery of ERG as a novel autosomal dominant BMF/HM predisposition gene. ERG is a highly constrained transcription factor critical for definitive hematopoiesis, stem cell function and platelet maintenance. ERG colocalizes with other transcription factors including RUNX1 and GATA2 on promoters/enhancers of genes orchestrating hematopoiesis. We identified a rare heterozygous ERG missense variant in 3 thrombocytopenic individuals from one family and 14 additional ERG variants in unrelated individuals with BMF/HM including 2 de novo cases and 3 truncating variants. Phenotypes associated with pathogenic germline ERG variants included cytopenias (thrombocytopenia, neutropenia, pancytopenia) and HMs (acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia) with onset before 40 years. Twenty ERG variants (19 missense, 1 truncating) including 3 missense population variants were functionally characterized. Thirteen potentially pathogenic ETS domain missense variants displayed loss-of-function characteristics disrupting transcriptional transactivation, DNA-binding and/or nuclear localization. Selected variants overexpressed in mouse fetal liver cells failed to drive myeloid differentiation and cytokine-independent growth in culture, and to promote acute erythroleukemia when transplanted into mice, concordant with these variants being loss-of-function. Four individuals displayed somatic genetic rescue by copy neutral loss of heterozygosity. Identification of predisposing germline ERG variants has clinical implications for patient/family diagnosis, counselling, surveillance, and treatment strategies including selection of bone marrow donors or cell/gene therapy.
ABSTRACT
BACKGROUND: Early interventions are needed to support the behavioral health of healthcare staff in the context of the COVID-19 pandemic. Stress First Aid (SFA) is a self-care and peer support model for reducing burnout and stress that is designed for use in high-stress occupations. METHODS: We conducted a mixed-methods evaluation of an SFA program in the Veterans Health Administration (VHA). This brief, multi-session, didactic program was adapted for hospital workgroups. Program attendees completed a survey assessing implementation outcomes, burnout, stress, mood, and SFA skills at the beginning (N = 246) and end (n = 94) of the SFA program and a subgroup (n = 11) completed qualitative feedback interviews. FINDINGS: Program acceptability, appropriateness, and feasibility were rated highly. From pre- to post-SFA, the impact of the pandemic on stress and anxiety, as well as proficiency in supporting peers increased. Qualitative findings suggest the program provided a shared language to discuss stress, normalized stress reactions, met a need for stress management tools, and helped staff feel valued, empowered, connected with each other. Staff reported being more aware of their stress, but SFA was insufficient to address many of the systemic sources of burnout and stress. CONCLUSIONS AND APPLICATIONS TO PRACTICE: While the SFA program was well received, the impact of brief programs is likely to be modest when implemented in the middle of an ongoing pandemic and when burnout arises from chiefly from systemic sources. Lessons learned during the program implementation that may guide future efforts are discussed.
