Association between frailty, long-term mortality and functional outcomes for older adults undergoing emergency laparotomy.

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.

Noncanonical Notch signals have opposing roles during cardiac development.

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.

Frailty using the Clinical Frailty Scale to predict short- and long-term adverse outcomes following emergency laparotomy: meta-analysis.

BACKGROUND: Emergency laparotomy has high morbidity and mortality rates. Frailty assessment remains underutilized in this setting, in part due to time constraints and feasibility. The Clinical Frailty Scale has been identified as the most appropriate tool for frailty assessment in emergency laparotomy patients and is recommended for all older patients undergoing emergency laparotomy. The prognostic impact of measured frailty using the Clinical Frailty Scale on short- and long-term mortality and morbidity rates remains to be determined. METHODS: Observational cohort studies were identified by systematically searching Medline, Embase, Scopus and CENTRAL databases up to February 2024, comparing outcomes following emergency laparotomy for frail and non-frail participants defined according to the Clinical Frailty Scale. The primary outcomes were short- and long-term mortality rates. A random-effects model was created with pooling of effect estimates and a separate narrative synthesis was created. Risk of bias was assessed. RESULTS: Twelve articles comprising 5704 patients were included. Frailty prevalence was 25% in all patients and 32% in older adults (age ≥55 years). Older patients with frailty had a significantly greater risk of postoperative death (30-day mortality rate OR 3.84, 95% c.i. 2.90 to 5.09, 1-year mortality rate OR 3.03, 95% c.i. 2.17 to 4.23). Meta-regression revealed that variations in cut-off values to define frailty did not significantly affect the association with frailty and 30-day mortality rate. Frailty was associated with higher rates of major complications (OR 1.93, 95% c.i. 1.27 to 2.93) and discharge to an increased level of care. CONCLUSION: Frailty is significantly correlated with short- and long-term mortality rates following emergency laparotomy, as well as an adverse morbidity rate and functional outcomes. Identifying frailty using the Clinical Frailty Scale may aid in patient-centred decision-making and implementation of tailored care strategies for these 'high-risk' patients, with the aim of reducing adverse outcomes following emergency laparotomy.

Precardiac organoids form two heart fields via Bmp/Wnt signaling.

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.