ABSTRACT
BACKGROUND: An increasing number of older patients are undergoing emergency laparotomy (EL). Frailty is thought to contribute to adverse outcomes in this group. The best method to assess frailty and impacts on long-term mortality and other important functional outcomes for older EL patients have not been fully explored. METHODS: A prospective multicenter study of older EL patients was conducted across four hospital sites in New Zealand from August 2017 to September 2022. The Clinical Frailty Scale (CFS) was used to measure frailty-defined as a CFS of ≥5. Primary outcomes were 30-day and one-year mortality. Secondary outcomes were postoperative morbidity, admission for rehabilitation, and increased care level on discharge. A multivariate logistic regression analysis was conducted, adjusting for age, sex, and ethnicity. RESULTS: A total of 629 participants were included. Frailty prevalence was 14.6%. Frail participants demonstrated higher 30-day and 1-year mortality-20.7% and 39.1%. Following adjustment, frailty was directly associated with a significantly increased risk of short- and long-term mortality (30-day aRR 2.6, 95% CI 1.5, 4.3, p = <0.001, 1-year aRR 2.0, 95% CI 1.5, 2.8, p < 0.001). Frailty was correlated with a 2-fold increased risk of admission for rehabilitation and propensity of being discharged to an increased level of care, complications, and readmission within 30 days. CONCLUSION: Frailty was associated with increased risk of postoperative mortality up to 1-year and other functional outcomes for older patients undergoing EL. Identification of frailty in older EL patients aids in patient-centered decision-making, which may lead to improvement in outcomes.
Subject(s)
Frailty , Laparotomy , Humans , Female , Male , Aged , Laparotomy/mortality , Prospective Studies , Frailty/mortality , Aged, 80 and over , New Zealand/epidemiology , Postoperative Complications/epidemiology , Postoperative Complications/mortality , Emergencies , Frail Elderly/statistics & numerical data , Geriatric Assessment/methodsABSTRACT
The Notch pathway is an ancient intercellular signaling system with crucial roles in numerous cell-fate decision processes across species. While the canonical pathway is activated by ligand-induced cleavage and nuclear localization of membrane-bound Notch, Notch can also exert its activity in a ligand/transcription-independent fashion, which is conserved in Drosophila, Xenopus, and mammals. However, the noncanonical role remains poorly understood in in vivo processes. Here we show that increased levels of the Notch intracellular domain (NICD) in the early mesoderm inhibit heart development, potentially through impaired induction of the second heart field (SHF), independently of the transcriptional effector RBP-J. Similarly, inhibiting Notch cleavage, shown to increase noncanonical Notch activity, suppressed SHF induction in embryonic stem cell (ESC)-derived mesodermal cells. In contrast, NICD overexpression in late cardiac progenitor cells lacking RBP-J resulted in an increase in heart size. Our study suggests that noncanonical Notch signaling has stage-specific roles during cardiac development.
Subject(s)
Heart/embryology , Myocardium/metabolism , Receptors, Notch/metabolism , Signal Transduction , Animals , Cell Differentiation , Cells, Cultured , GATA4 Transcription Factor/genetics , GATA4 Transcription Factor/metabolism , Homeobox Protein Nkx-2.5/genetics , Homeobox Protein Nkx-2.5/metabolism , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Immunoglobulin J Recombination Signal Sequence-Binding Protein/genetics , Immunoglobulin J Recombination Signal Sequence-Binding Protein/metabolism , Mesoderm/cytology , Mesoderm/embryology , Mesoderm/metabolism , Mice , Mice, Knockout , Mice, Transgenic , Mouse Embryonic Stem Cells/cytology , Mouse Embryonic Stem Cells/metabolism , Myocardium/cytology , T-Box Domain Proteins/genetics , T-Box Domain Proteins/metabolism , Transcription Factors/genetics , Transcription Factors/metabolismABSTRACT
The discovery of the first heart field (FHF) and the second heart field (SHF) led us to understand how cardiac lineages and structures arise during development. However, it remains unknown how they are specified. Here, we generate precardiac spheroids with pluripotent stem cells (PSCs) harboring GFP/RFP reporters under the control of FHF/SHF markers, respectively. GFP+ cells and RFP+ cells appear from two distinct areas and develop in a complementary fashion. Transcriptome analysis shows a high degree of similarities with embryonic FHF/SHF cells. Bmp and Wnt are among the most differentially regulated pathways, and gain- and loss-of-function studies reveal that Bmp specifies GFP+ cells and RFP+ cells via the Bmp/Smad pathway and Wnt signaling, respectively. FHF/SHF cells can be isolated without reporters by the surface protein Cxcr4. This study provides novel insights into understanding the specification of two cardiac origins, which can be leveraged for PSC-based modeling of heart field/chamber-specific disease.
