Modeling and targeting of erythroleukemia by hematopoietic genome editing.

Acute erythroid leukemia (AEL) is characterized by a distinct morphology, mutational spectrum, lack of preclinical models, and poor prognosis. Here, using multiplexed genome editing of mouse hematopoietic stem and progenitor cells and transplant assays, we developed preclinical models of AEL and non-erythroid acute leukemia and describe the central role of mutational cooperativity in determining leukemia lineage. Different combination of mutations in Trp53, Bcor, Dnmt3a, Rb1, and Nfix resulted in the development of leukemia with an erythroid phenotype, accompanied by the acquisition of alterations in signaling and transcription factor genes that recapitulate human AEL by cross-species genomic analysis. Clonal expansion during tumor evolution was driven by mutational cooccurrence, with clones harboring a higher number of founder and secondary lesions (eg, mutations in signaling genes) showing greater evolutionary fitness. Mouse and human AEL exhibited deregulation of genes regulating erythroid development, notably Gata1, Klf1, and Nfe2, driven by the interaction of mutations of the epigenetic modifiers Dnmt3a and Tet2 that perturbed methylation and thus expression of lineage-specific transcription factors. The established mouse leukemias were used as a platform for drug screening. Drug sensitivity was associated with the leukemia genotype, with the poly (ADP-ribose) polymerase inhibitor talazoparib and the demethylating agent decitabine efficacious in Trp53/Bcor-mutant AEL, CDK7/9 inhibitors in Trp53/Bcor/Dnmt3a-mutant AEL, and gemcitabine and bromodomain inhibitors in NUP98-KDM5A leukemia. In conclusion, combinatorial genome editing has shown the interplay of founding and secondary genetic alterations in phenotype and clonal evolution, epigenetic regulation of lineage-specific transcription factors, and therapeutic tractability in erythroid leukemogenesis.

Implementation of the Helping Babies Breathe Training Program: A Systematic Review.

CONTEXT: Helping Babies Breathe (HBB) is a well-established neonatal resuscitation program designed to reduce newborn mortality in low-resource settings. OBJECTIVES: In this literature review, we aim to identify challenges, knowledge gaps, and successes associated with each stage of HBB programming. DATA SOURCES: Databases used in the systematic search included Medline, POPLINE, Cumulative Index to Nursing and Allied Health Literature, Latin American and Caribbean Health Sciences Literature, African Index Medicus, Cochrane, and Index Medicus. STUDY SELECTION: All articles related to HBB, in any language, were included. Article quality was assessed by using the Grading of Recommendations Assessment, Development, and Evaluation framework. DATA EXTRACTION: Data were extracted if related to HBB, including its implementation, acquisition and retention of HBB knowledge and skills, changes in provider behavior and clinical care, or the impact on newborn outcomes. RESULTS: Ninety-four articles met inclusion criteria. Barriers to HBB implementation include staff turnover and limited time or focus on training and practice. Researchers of several studies found HBB cost-effective. Posttraining decline in knowledge and skills can be prevented with low-dose high-frequency refresher trainings, on-the-job practice, or similar interventions. Impact of HBB training on provider clinical practices varies. Although not universal, researchers in multiple studies have shown a significant association of decreased perinatal mortality with HBB implementation. LIMITATIONS: In addition to not conducting a gray literature search, articles relating only to Essential Care for Every Baby or Essential Care for Small Babies were not included in this review. CONCLUSIONS: Key challenges and requirements for success associated with each stage of HBB programming were identified. Despite challenges in obtaining neonatal mortality data, the program is widely believed to improve neonatal outcomes in resource-limited settings.

Genomic subtyping and therapeutic targeting of acute erythroleukemia.

Acute erythroid leukemia (AEL) is a high-risk leukemia of poorly understood genetic basis, with controversy regarding diagnosis in the spectrum of myelodysplasia and myeloid leukemia. We compared genomic features of 159 childhood and adult AEL cases with non-AEL myeloid disorders and defined five age-related subgroups with distinct transcriptional profiles: adult, TP53 mutated; NPM1 mutated; KMT2A mutated/rearranged; adult, DDX41 mutated; and pediatric, NUP98 rearranged. Genomic features influenced outcome, with NPM1 mutations and HOXB9 overexpression being associated with a favorable prognosis and TP53, FLT3 or RB1 alterations associated with poor survival. Targetable signaling mutations were present in 45% of cases and included recurrent mutations of ALK and NTRK1, the latter of which drives erythroid leukemogenesis sensitive to TRK inhibition. This genomic landscape of AEL provides the framework for accurate diagnosis and risk stratification of this disease, and the rationale for testing targeted therapies in this high-risk leukemia.

A new method for the characterization of the degree of fire damage to gypsum wallboard for use in fire investigations.

A new method to characterize the degree of fire damage to gypsum wallboard is introduced, implemented, and tested to determine the efficacy of its application among novices. The method was evaluated by comparing degree of fire damage assessments of novices with and without the method. Thirty-nine "novice" raters assessed damage to a gypsum wallboard surface, completing 66 ratings, first without the method, and then again using the method. The inter-rater reliability was evaluated for ratings of damage without and with the method. For novice fire investigators rating degree of damage without the aid of the method, ICC(1,2) = 0.277 with 95% CI (0.211, 0.365), and with the method, ICC(2,1) = 0.593 with 95% CI (0.509, 0.684). Results indicate that the raters were more reliable in their analysis of the degree of fire damage when using the method, which support the use of standardized processes to decrease the variability in data collection and interpretation.

Use of the Braden Scale for pressure ulcer risk assessment in a community hospital setting: the role of total score and individual subscale scores in triggering preventive interventions.

PURPOSE: To determine whether pressure ulcer preventive interventions are implemented when a total Braden Scale score reflects that the patient is at risk. DESIGN: A retrospective chart review was completed for 20 patients with confirmed hospital-acquired pressure ulcers (HAPUs). SUBJECTS AND SETTING: A convenience sample of 20 patients with HAPUs confirmed by a certified wound nurse was systematically selected from 63 charts. The study setting was a 200-bed acute care facility in the Midwestern United States. METHODS: A retrospective review of 20 patient charts was conducted. Data collected included daily Braden Scale scores and subscale scores, along with pressure ulcer preventive intervention implementation for at-risk (cumulative Braden Scale scores ≤ 18) and not-at-risk (cumulative Braden Scale scores > 18) days. Data were collected both before and after pressure ulcer occurrence. The occurrence of preventive interventions was compared between at-risk and not-at-risk patient days. RESULTS: Nineteen percent of not-at-risk patient days were found to have lower subscale scores, indicating a need for focused preventive interventions. The day before an HAPU occurred, the mean Braden Scale score was 13.7 ± 2.8 (mean ± SD) for those who were provided an intervention and 18.5 ± 2.3 for those not provided an intervention (t = 3.89, P = .001). Sixty-three percent of at-risk patients received some intervention the day before an HAPU occurred, while 20% of not-at-risk patients received some intervention. CONCLUSIONS: Routine use of a pressure ulcer risk assessment tool is considered necessary for a comprehensive pressure ulcer prevention program. Planning preventive care according to the subscale scores of the Braden Scale may be more effective for prevention of HAPUs in some cases.