Adding a One Health approach to a research framework for minority health and health disparities.

The National Institute on Minority Health and Health Disparities (NIMHD) has developed a framework to guide and orient research into health disparities and minority health. The framework depicts different domains of influence (such as biological and behavioral) and different levels of influence (such as individual and interpersonal). Here, influenced by the "One Health" approach, we propose adding two new levels of influence - interspecies and planetary - to this framework to reflect the interconnected nature of human, animal, and environmental health. Extending the framework in this way will help researchers to create new avenues of inquiry and encourage multidisciplinary collaborations. We then use the One Health approach to discuss how the COVID-19 pandemic has exacerbated health disparities, and show how the expanded framework can be applied to research into health disparities related to antimicrobial resistance and obesity.

Identifying Associations in Minimum Inhibitory Concentration Values of Escherichia coli Samples Obtained From Weaned Dairy Heifers in California Using Bayesian Network Analysis.

Objective: Many antimicrobial resistance (AMR) studies in both human and veterinary medicine use traditional statistical methods that consider one bacteria and one antibiotic match at a time. A more robust analysis of AMR patterns in groups of animals is needed to improve on traditional methods examining antibiotic resistance profiles, the associations between the patterns of resistance or reduced susceptibility for all isolates in an investigation. The use of Bayesian network analysis can identify associations between distributions; this investigation seeks to add to the growing body of AMR pattern research by using Bayesian networks to identify relationships between susceptibility patterns in Escherichia coli (E. coli) isolates obtained from weaned dairy heifers in California. Methods: A retrospective data analysis was performed using data from rectal swab samples collected from 341 weaned dairy heifers on six farms in California and selectively cultured for E. coli. Antibiotic susceptibility tests for 281 isolates against 15 antibiotics were included. Bayesian networks were used to identify joint patterns of reduced susceptibility, defined as an increasing trend in the minimum inhibitory concentration (MIC) values. The analysis involved learning the network structure, identifying the best fitting graphical mode, and learning the parameters in the final model to quantify joint probabilities. Results: The graph identified that as susceptibility to one antibiotic decreases, so does susceptibility to other antibiotics in the same or similar class. The following antibiotics were connected in the final graphical model: ampicillin was connected to ceftiofur; spectinomycin was connected with trimethoprim-sulfamethoxazole, and this association was mediated by farm; florfenicol was connected with tetracycline. Conclusions: Bayesian network analysis can elucidate complex relationships between MIC patterns. MIC values may be associated within and between drug classes, and some associations may be correlated with farm of sample origin. Treating MICs as discretized variables and testing for joint associations in trends may overcome common research problems surrounding the lack of clinical breakpoints.

Interrupted time-series analysis to evaluate the impact of a behavioral change outpatient antibiotic stewardship intervention.

Objective: We evaluated the effect of a behaviorally enhanced quality improvement intervention in reducing the number of antibiotic prescriptions written for antibiotic nonresponsive acute respiratory infections (ARIs). A secondary objective was identifying whether a reduction in inappropriate antibiotic prescriptions, if present, persisted after the immediate implementation of the intervention. Design: Nonrandomized, quasi-experimental study conducted from January 2017 through February 2020. Setting: University of California, Davis Health outpatient clinics. In total, 21 pediatric, family, and internal medicine practices in 10 cities and towns were included. Patients: Patients evaluated by a participating physician at an enrolled practice site during the study period with diagnoses (primary and secondary) from the International Classification of Diseases, Tenth Revision codes consistent with antibiotic nonresponsive ARI diagnoses. Intervention: A behaviorally enhanced quality improvement intervention to reduce inappropriate prescribing for antibiotic nonresponsive ARI. Results: In total, 63,028 eligible patient visits across 21 locations were included in the analysis. The most frequently prescribed antibiotic for antibiotic nonresponsive ARI was azithromycin (n = 3,551), followed by amoxicillin (n = 924). Overall, the intervention was associated with an immediate 46% reduction in antibiotic prescriptions for antibiotic nonresponsive ARI (P = .001) following the intervention. We detected no significant change in the month-to-month trend after the intervention was implemented (P = .87), indicating that the reduction was sustained throughout the postintervention period. Conclusion: Our findings demonstrate that a behaviorally enhanced quality improvement intervention to reduce inappropriate prescribing for antibiotic nonresponsive ARI in ambulatory care encounters was successful in reducing potentially inappropriate prescriptions for presumed antibiotic nonresponsive ARI.

Eph-B2/ephrin-B2 interaction plays a major role in the adhesion and proliferation of Waldenstrom's macroglobulinemia.

PURPOSE: The ephrin receptors (Eph) are found in a wide range of cancers and correlate with metastasis. In this study, we characterized the role of Eph-B2 receptor in the interaction of Waldenstrom's macroglobulinemia (WM) cells with the bone marrow microenvironment. EXPERIMENTAL DESIGN: We screened the activity of different receptor tyrosine kinases in WM patients and found that Eph-B2 was overexpressed compared with control. Also, we tested the expression of ephrin-B2 ligand on endothelial cells and bone marrow stromal cells (BMSC) isolated from WM patients. We then tested the role of Eph-B2/Ephrin-B2 interaction in the adhesion of WM cells to endothelial cells and BMSCs; the cell signaling induced by the coculture in both the WM cells and the endothelial cells; WM cell proliferation, apoptosis, and cell cycle in vitro and tumor progression in vivo; and in angiogenesis. RESULTS: Eph-B2 receptor was found to be activated in WM patients compared with control, with a 5-fold increase in CD19(+) WM cells, and activated cell adhesion signaling, including focal adhesion kinase, Src, P130, paxillin, and cofilin, but decreased WM cell chemotaxis. Ephrin-B2 ligand was highly expressed on endothelial cells and BMSCs isolated from WM patients and on human umbilical vein endothelial cells and induced signaling in the endothelial cells promoting adhesion and angiogenesis. Blocking of ephrin-B2 or Eph-B2 inhibited adhesion, cytoskeletal signaling, proliferation, and cell cycle in WM cells, which was induced by coculture with endothelial cells and decreased WM tumor progression in vivo. CONCLUSION: Ephrin-B2/Eph-B2 axis regulates adhesion, proliferation, cell cycle, and tumor progression in vivo through the interaction of WM with the cells in the bone marrow microenvironment.

FGFR3 is overexpressed waldenstrom macroglobulinemia and its inhibition by Dovitinib induces apoptosis and overcomes stroma-induced proliferation.

PURPOSE: There is no standard of therapy for the treatment of Waldenström macroglobulinemia (WM), therefore there is a need for the development of new agents. Fibroblast growth factor receptor 3 (FGFR3) was shown to play a major role in several types in cancer. Dovitinib, an inhibitor of FGFR3, was effective in hematologic malignancies. In this study, we tested FGFR3 as a therapeutic target in WM and tested the effect of dovitinib on cell proliferation and apoptosis of WM cells in the context of BM microenvironment. METHODS: The expression of FGFR3 in WM cells was tested using immunofluorescence and flow cytometry. Cell signaling in response to stimulation with FGF3 and stromal cells, and its inhibition by dovitinib was performed using immunoblotting. Cell survival and cell proliferation were assessed by MTT and BrdU assays. Apoptosis was measured by detection of APO-2.7 and cleavage of caspase-3 using flow cytometry. Cell cycle was performed by PI staining of cells and flow cytometry. The combinatory effect of dovitinib with other drugs was analyzed using Calcusyn software. The effect of dovitinib was tested in vivo. RESULTS: FGFR3 was overexpressed in WM cells and its activation induced cell proliferation. Inhibition of FGFR3 with dovitinib decreased cell survival, increased apoptosis, and induced cell cycle arrest. Inhibition of FGFR3 by dovitinib reduced the interaction of WM to bone marrow components, and reversed its proliferative effect. Dovitinib had an additive effect with other drugs. Moreover, dovitinib reduced WM tumor progression in vivo. CONCLUSION: We report that FGFR3 is a novel therapeutic target in WM, and suggest dovitinib for future clinical trial the treatment of patients with WM.