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Canagliflozin (CANA) is a sodium glucose cotransporter-2 inhibitor that reduces blood glucose levels. Sodium glucose cotransporter-2 is primarily expressed in the kidney, but not in any bone cells, therefore effects on the skeleton are likely to be non-cell autonomous. Originally developed to treat type II diabetes, CANA use has expanded to treat cardiovascular and renovascular disease. Clinical trials examining CANA in diabetic patients have produced contradictory reports on fracture risk, but there are limited data of CANA in nondiabetic conditions. In nondiabetic preclinical models, short-term treatment with CANA negatively affected trabecular bone whereas long-term treatment reduced cortical bone mineralization in male but not female mice. To investigate the skeletal effects of an intermediate period of CANA treatment, we treated male and female C57BL/6 J mice with CANA (180 ppm) for 6 months. Age at treatment initiation was also evaluated, with cohorts starting CANA prior to skeletal maturity (3-months-old) or in adulthood (6-months-old). Longitudinal assessments of bone mineral density revealed early benefits of CANA treatment in female mice. At euthanasia, both trabecular and cortical bone morphology were improved by CANA treatment in males and females. Bone formation was reduced at the endosteal surface. CANA decreased osteoblast number in male mice and bone marrow adiposity in females. Overall, more skeletal benefits were recorded in CANA-treated females than males. Urinary calcium output increased with CANA treatment, but parathyroid hormone was not changed. Despite reduced fasting blood glucose, body composition and whole-body metabolism were minimally changed by CANA treatment. For all outcome measures, limited differences were recorded based on age at treatment initiation. This study demonstrated that in nondiabetic C57BL/6 J mice, an intermediate period of CANA treatment improved bone morphology, but reduced osteoblast and bone marrow adipocyte number as well as serum procollagen type 1 N-terminal pro-peptide in a sex-specific manner., Competing Interests: The authors declare no conflict of interest. All authors have read and agreed to the published version of the manuscript., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Objective: We sought to support public health surveillance and response to coronavirus disease 2019 (COVID-19) through rapid development and implementation of novel visualization applications for data amalgamated across sectors., Materials and Methods: We developed and implemented population-level dashboards that collate information on individuals tested for and infected with COVID-19, in partnership with state and local public health agencies as well as health systems. The dashboards are deployed on top of a statewide health information exchange. One dashboard enables authorized users working in public health agencies to surveil populations in detail, and a public version provides higher-level situational awareness to inform ongoing pandemic response efforts in communities., Results: Both dashboards have proved useful informatics resources. For example, the private dashboard enabled detection of a local community outbreak associated with a meat packing plant. The public dashboard provides recent trend analysis to track disease spread and community-level hospitalizations. Combined, the tools were utilized 133 637 times by 74 317 distinct users between June 21 and August 22, 2020. The tools are frequently cited by journalists and featured on social media., Discussion: Capitalizing on a statewide health information exchange, in partnership with health system and public health leaders, Regenstrief biomedical informatics experts rapidly developed and deployed informatics tools to support surveillance and response to COVID-19., Conclusions: The application of public health informatics methods and tools in Indiana holds promise for other states and nations. Yet, development of infrastructure and partnerships will require effort and investment after the current pandemic in preparation for the next public health emergency., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Arterials are types of roads designed to carry high volumes of motorized traffic. They are an integral part of transportation systems worldwide and exposure to them is ubiquitous, especially in urban areas. Arterials provide access to diverse commercial and cultural resources, which can positively influence community health by supporting social cohesion as well as economic and cultural opportunities. They can negatively influence health via safety issues, noise, air pollution, and lack of economic development. The aims of public health and transportation partially overlap; efforts to improve arterials can meet goals of both professions. Two trends in arterial design show promise. First, transportation professionals increasingly define the performance of arterials via metrics accounting for pedestrians, cyclists, transit riders, and nearby residents in addition to motor vehicle users. Second, applying traffic engineering and design can generate safety, air quality, and livability benefits, but we need evidence to support these interventions. We describe the importance of arterials (including exposures, health behaviors, effects on equity, and resulting health outcomes) and make the case for public health collaborations with the transportation sector.

Ire1 (Ern1) is an unusual transmembrane protein kinase essential for the endoplasmic reticulum (ER) unfolded protein response (UPR). Activation of Ire1 by association of its N-terminal ER luminal domains promotes autophosphorylation by its cytoplasmic kinase domain, leading to activation of the C-terminal ribonuclease domain, which splices Xbp1 mRNA generating an active Xbp1s transcriptional activator. We have determined the crystal structure of the cytoplasmic portion of dephosphorylated human Ire1α bound to ADP, revealing the 'phosphoryl-transfer' competent dimeric face-to-face complex, which precedes and is distinct from the back-to-back RNase 'active' conformation described for yeast Ire1. We show that the Xbp1-specific ribonuclease activity depends on autophosphorylation, and that ATP-competitive inhibitors staurosporin and sunitinib, which inhibit autophosphorylation in vitro, also inhibit Xbp1 splicing in vivo. Furthermore, we demonstrate that activated Ire1α is a competent protein kinase, able to phosphorylate a heterologous peptide substrate. These studies identify human Ire1α as a target for development of ATP-competitive inhibitors that will modulate the UPR in human cells, which has particular relevance for myeloma and other secretory malignancies.