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The current study was designed to determine whether vascular endothelial-derived endothelin-1 (ET-1) is important for skin Na+ buffering. In control mice (C57BL/6J), plasma Na+ and osmolarity were significantly elevated in animals on high- vs. low-salt (HS and LS, respectively) intake. The increased plasma Na+ and osmolarity were associated with increased ET-1 mRNA in vascular tissue. There was no detectable difference in skin Na+:H2O in HS fed mice (0.119 ± 0.005 mM vs. 0.127 ± 0.007 mM; LS vs. HS); however, skin Na+:H2O was significantly increased by blockade of the endothelin type A receptor with ABT-627 (0.116 ± 0.006 mM vs. 0.137 ± 0.007 mM; LS vs. HS; half-maximal inhibitory concentration, 0.055 nM). ET-1 peptide content in skin tissue was increased in floxed control animals on HS (85.9 ± 0.9 pg/mg vs. 106.4 ± 6.8 pg/mg; P < 0.05), but not in vascular endothelial cell endothelin-1 knockout (VEET KO) mice (76.4 ± 5.7 pg/mg vs. 65.7 ± 7.9 pg/mg; LS vs. HS). VEET KO mice also had a significantly elevated skin Na+:H2O (0.113 ± 0.007 mM vs. 0.137 ± 0.005 mM; LS vs. HS; P < 0.05). Finally, ET-1 production was elevated in response to increasing extracellular osmolarity in cultured human endothelial cells. These data support the hypothesis that increased extrarenal vascular ET-1 production in response to HS intake is mediated by increased extracellular osmolarity and plays a critical role in regulating skin storage of Na+. [ABSTRACT FROM AUTHOR]

Summary The age‐associated mutational state of clonal haematopoiesis (CH) is linked to multiple adverse health outcomes. As higher risk CH can lead to progressive neoplastic or vascular disease, there is interest in developing clinical trials to mitigate risk associated with CH. Given the high prevalence of CH, data from clinical trials could have broad public health implications for screening and therapy. Thoughtful consideration is needed to design trials that are both clinically relevant and avoid overmedicalization. Here, we summarize clinical studies of CH to date and provide suggestions and guidance on how to approach designing CH‐focused therapeutic clinical trials. These recommendations are derived from discussions among clinical researchers and scientists emanating from the Inaugural Meeting on Somatic Mutations and Predisease in October 2021. [ABSTRACT FROM AUTHOR]

Background: Clonal hematopoiesis of indeterminate potential (CHIP) occurs due to acquired mutations in bone marrow progenitor cells. CHIP confers a 2-fold risk of atherosclerotic cardiovascular disease. However, there are limited data regarding specific cardiovascular phenotypes. The purpose of this study was to define the coronary artery disease phenotype of the CHIP population-based on coronary angiography., Methods: We recruited 1142 patients from the Vanderbilt University Medical Center cardiac catheterization laboratory and performed DNA sequencing to determine CHIP status. Multivariable logistic regression models and proportional odds models were used to assess the association between CHIP status and angiography phenotypes., Results: We found that 18.4% of patients undergoing coronary angiography had a CHIP mutation. Those with CHIP had a higher risk of having obstructive left main (odds ratio, 2.44 [95% CI, 1.40-4.27]; P =0.0018) and left anterior descending (odds ratio, 1.59 [1.12-2.24]; P =0.0092) coronary artery disease compared with non-CHIP carriers. We additionally found that a specific CHIP mutation, ten eleven translocase 2 (TET2 ), has a larger effect size on left main stenosis compared with other CHIP mutations., Conclusions: This is the first invasive assessment of coronary artery disease in CHIP and offers a description of a specific atherosclerotic phenotype in CHIP wherein there is an increased risk of obstructive left main and left anterior descending artery stenosis, especially among TET2 mutation carriers. This serves as a basis for understanding enhanced morbidity and mortality in CHIP., Competing Interests: Dr Bick reports personal fees and serves on the scientific advisory board of TenSixteen Bio unrelated to the present work. The other authors report no conflicts.

Clonal hematopoiesis of indeterminate potential (CHIP) is a common age-related phenomenon that occurs when hematopoietic stem cells acquire mutations in a select set of genes commonly mutated in myeloid neoplasia which then expand clonally. Current sequencing assays to detect CHIP are not optimized for the detection of these variants and can be cost-prohibitive when applied to large cohorts or serial sequencing. Here, we present and validate a CHIP targeted sequencing assay that is affordable (∼$8/sample), accurate and highly scalable. To demonstrate the utility of this assay, we detected CHIP in a cohort of 456 individuals with DNA collected at multiple timepoints in the Vanderbilt BioVU biobank and quantified clonal expansion rates over time. A total of 101 individuals with CHIP were identified, and individual-level clonal expansion rate was calculated using the variant allele fraction (VAF) at both timepoints. Differences in clonal expansion rate by driver gene were observed, but there was also significant individual-level heterogeneity, emphasizing the multifactorial nature of clonal expansion. We further describe the mutation co-occurrence and clonal competition between multiple driver mutations.

Designed and implemented in 2006, the Academy for Conservation Training (ACT) is a conservation education academy modeled after the Association for Zoos and Aquariums' (AZA) professional conservation education course. ACT incorporates conservation education best practices utilized by AZA-accredited institutions to provide zoo and wildlife park professionals in China with the skills, knowledge, and tools needed to design, implement, and evaluate effective conservation education programs at their facilities. Initial findings indicate that the ACT model is an effective approach to connect these emerging educators with conservation education best practices. The strongest satisfaction responses in this study were in perceptions of the program preparing the individual for work and in personal development. In terms of the longitudinal survey conducted with ACT graduates after the training, the lowest scoring items were the opportunities to meet other zoo educators in China and the quantity of information provided. The most revealing trend in regards to preparedness in becoming zoo educators was that specific pedagogical skills were those where perceived gain was consistent and strong across all three academies.

Interagency collaboration is used to coordinate services and programs, pool resources, or achieve goals. This study utilizes the Interagency Collaboration Model to assess interagency relationships of Early Intervention (EI) collaboratives in three rural Ohio counties. The model includes five constructs: environmental factors (broader community environment), situational factors (organizational factors), task characteristics (project's scope and complexity), interagency processes (between agency processes), and outcomes (end products). Respondents from 42 agencies completed the 18-item Interagency Collaboration Assessment Tool (ICAT) and demographic questions. The ICAT uses a 5-point Likert-type scale to assess the five domains of the model. Respondents included public health nurses, representatives from schools, social service agencies, and hospitals. State policies were perceived as encouraging local interagency collaboration; respondents knew staff and goals of other agencies, but agencies did not share funding sources or provide similar services. Diverse specialists were needed to accomplish goals. Some information was exchanged between agencies. Interagency activities were not perceived to be well coordinated and outcomes were only moderately positive. Path analysis revealed that interagency processes were directly affected by environmental and situational factors, but not task characteristics (R2 = 0.42). Situational factors, and interagency processes predicted outcomes (R2 = 0.60). Awareness of personnel, goals and services of other agencies were key to positive interagency process and perceived outcomes.