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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 examined associations between older drivers' social and environmental characteristics and odds of using non-driving transportation modes. Methods: Using 2015 National Health and Aging Trends Study data for community-dwelling drivers ( n = 5102), we estimated logistic regression models of associations between social characteristics, environmental characteristics, and odds of using non-driving transportation modes three years later. Results: Drivers had 20% increase in odds of getting rides three years later for each additional confidante (adjusted odds ratio [aOR] = 1.20, 95% confidence interval [CI]: 1.11-1.30). Drivers living in more walkable neighborhoods were more likely to walk to get places (National Walkability Index [NWI] score of 18 vs. 2 aOR = 1.71, 95% CI: 1.02-2.90) and take public transit three years later (NWI 18 vs. 2 aOR = 7.47, 95% CI: 1.69-33.0). Discussion: Identifying modifiable social and environmental characteristics can inform future interventions supporting older adults' health during the transition to non-driving., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: To characterize the effect of the actual and potential ability to get rides from others on older adults' driving reduction at 3-year follow-up in the United States., Methods: We analyzed National Health and Aging Trends Study data from community-dwelling drivers in 2015 (unweighted n = 5,102). We used weighted logistic regression models to estimate whether getting rides from others in 2015 was associated with older adults increasing the number of driving behaviors they avoided, decreasing the frequency with which they drove, or not driving at 3-year follow-up after adjusting for biopsychosocial variables. We also measured presence of social network members living nearby including household and non-household members and estimated associated odds of driving reduction at 3-year follow-up., Results: Older adults who got rides from others in 2015 had greater odds of reporting no longer driving at 3-year follow-up compared to those who did not get rides (adjusted odds ratio [aOR] = 1.53, 95% confidence interval [CI]: 1.11-2.11). We found no statistically significant association between older adults living with others or having more nearby confidantes outside their household and their odds of reducing driving at 3-year follow-up., Discussion: These findings suggest that getting rides from others plays an important role in the transition to non-driving for older adults. Future research should examine whether other aspects of social networks (e.g., type, quality, and closer proximity) might also be key modifiable coping factors for older adults transitioning to non-driving., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Infectious diseases can cause steep declines in wildlife populations, leading to changes in genetic diversity that may affect the susceptibility of individuals to infection and the overall resilience of populations to pathogen outbreaks. Here, we examine evidence for a genetic bottleneck in a population of American crows (Corvus brachyrhynchos) before and after the emergence of West Nile virus (WNV). More than 50% of marked birds in this population were lost over the 2-year period of the epizootic, representing a 10-fold increase in adult mortality. Using analyses of single-nucleotide polymorphisms (SNPs) and microsatellite markers, we tested for evidence of a genetic bottleneck and compared levels of inbreeding and immigration in the pre- and post-WNV populations. Counter to expectations, genetic diversity (allelic diversity and the number of new alleles) increased after WNV emergence. This was likely due to increases in immigration, as the estimated membership coefficients were lower in the post-WNV population. Simultaneously, however, the frequency of inbreeding appeared to increase: Mean inbreeding coefficients were higher among SNP markers, and heterozygosity-heterozygosity correlations were stronger among microsatellite markers, in the post-WNV population. These results indicate that loss of genetic diversity at the population level is not an inevitable consequence of a population decline, particularly in the presence of gene flow. The changes observed in post-WNV crows could have very different implications for their response to future pathogen risks, potentially making the population as a whole more resilient to a changing pathogen community, while increasing the frequency of inbred individuals with elevated susceptibility to disease., (© 2023 John Wiley & Sons Ltd.)

Up to 93% of the human immunodeficiency virus (HIV) latent reservoir comprised defective proviruses, suggesting that a functional cure is possible through the elimination of a small population of cells containing intact virus, instead of the entire reservoir. Cyclophosphamide (Cy) is an established chemotherapeutic agent for immune cell cancers. In high doses, Cy is a nonselective cytoreductor, used in allogeneic stem-cell transplantation, while in a low dose, metronomic schedule, Cy selectively depletes regulatory T cells (Tregs). We administered low and high doses to simian immunodeficiency virus (SIV)-infected rhesus macaques (RM) to assess their effects on the SIV reservoirs. As a Treg-depleting agent, Cy unselectively depleted Treg and total lymphocytes, resulting in minimal immune activation and no viral reactivation. As a cytoreductive agent, Cy induced massive viral reactivation in elite controller RMs without ART. However, when administered with antiretroviral therapy (ART), Cy had substantial adverse effects, including mortality. Our study thus dissuades further investigation of Cy as an HIV cure agent.

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.)

The objectives of the study are to understand road safety within the context of regional development processes and to assess how urban-rural categories represent differences in motor vehicle occupant fatality risk. We analysed 2015 motor vehicle occupant deaths in Wisconsin from 2010 to 2014, using three definitions of urban-rural continua and negative binomial regression to adjust for population density, travel exposure and the proportion of teen residents. Rural-Urban Commuting Area codes, Beale codes and the Census definition of urban and rural places do not explain differences in urban and rural transportation fatality rates when controlling for population density. Although it is widely believed that rural places are uniquely dangerous for motorised travel, this understanding may be an artefact of inaccurate constructs. Instead, population density is a more helpful way to represent transportation hazards across different types of settlement patterns, including commuter suburbs and exurbs., Competing Interests: Competing interests: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

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.

Urban and rural places are integrated through economic ties and population flows. Despite their integration, most studies of road safety dichotomize urban and rural places, and studies have consistently demonstrated that rural places are more dangerous for motorists than urban places. Our study investigates whether these findings are sensitive to the definition of urban and rural. We use three different definitions of urban-rural continua to quantify and compare motor vehicle occupant fatality rates per person-trip and person-mile for the state of Wisconsin. The three urban-rural continua are defined by: (1) popular impressions of urban, suburban, and rural places using a system from regional economics; (2) population density; and (3) the intensity of commute flows to core urbanized areas. In this analysis, the three definitions captured different people and places within each continuum level, highlighting rural heterogeneity. Despite this heterogeneity, the three definitions resulted in similar fatality rate gradients, suggesting a potentially latent "rural" characteristic. We then used field observations of urban-rural transects to refine the definitions. When accounting for the presence of higher-density towns and villages in rural places, we found that low-density urban places such as suburbs and exurbs have fatality rates more similar to those in rural places. These findings support the need to understand road safety within the context of regional development processes instead of urban-rural categories., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Comparing the injury risk of different travel modes requires using a travel-based measure of exposure. In this study we quantify injury risk by travel mode, age, race/ethnicity, sex, and injury severity using three different travel-based exposure measures (person-trips, person-minutes of travel, and person-miles of travel) to learn how these metrics affect the characterization of risk across populations. We used a linked database of hospital and police records to identify non-fatal injuries (2001-2009), the Fatality Analysis Reporting System for fatalities (2001-2009), and the 2001 Wisconsin Add-On to the National Household Travel Survey for exposure measures. In Wisconsin, bicyclists and pedestrians have a moderately higher injury risk compared to motor vehicle occupants (adjusting for demographic factors), but the risk is much higher when exposure is measured in distance. Although the analysis did not control for socio-economic status (a likely confounder) it showed that American Indian and Black travelers in Wisconsin face higher transportation injury risk than White travelers (adjusting for sex and travel mode), across all three measures of exposure. Working with multiple metrics to form comprehensive injury risk profiles such as this one can inform decision making about how to prioritize investments in transportation injury prevention., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

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.