Organotins are members of the environmental obesogen class of contaminants because they activate peroxisome proliferator-activated receptor γ (PPARγ), the essential regulator of adipogenesis. Exposure to thiazolidinediones, PPARγ ligands used to treat type 2 diabetes, is associated with increased fractures. Diminished bone quality likely results from PPARγ’s role in promoting adipogenesis while suppressing osteogenesis of bone marrow multipotent mesenchymal stromal cells (BM-MSC). We hypothesized that tributyltin (TBT) would be a potent modifier of BM-MSC differentiation and a negative regulator of bone formation. Organotins interact with both PPARγ and retinoid X receptors (RXR) suggesting that they activate multiple nuclear receptor pathways. To investigate the role of RXR in the actions of TBT, the effects of PPARγ (rosiglitazone) and RXR (bexarotene, LG100268) agonists were compared to the effects of TBT in BMS2 cells and primary mouse BM-MSC cultures. In BMS2 cells, TBT induced the expression of Fabp4, Abca1 and Tgm2 in an RXR-dependent manner. All agonists suppressed osteogenesis in primary mouse BM-MSC cultures, based on decreased alkaline phosphatase activity, mineralization and expression of osteoblast-related genes. While rosiglitazone and TBT strongly activated adipogenesis, based on lipid accumulation and expression of adipocyte-related genes, the RXR agonists did not. Extending these analyses to other RXR-heterodimers showed that TBT and the RXR agonists activated the liver X receptor pathway, while rosiglitazone did not. Application of either a PPARγ antagonist (T0070907) or an RXR antagonist (HX531) significantly reduced rosiglitazone-induced suppression of bone nodule formation. Only the RXR antagonist significantly reduced LG100268- and TBT-induced bone suppression. The RXR antagonist also inhibited LG100268- and TBT-induced expression of Abca1, an LXR target gene, in primary BM-MSC cultures. These results provide novel evidence that TBT activates multiple nuclear receptor pathways in BM-MSCs, activation of RXR is sufficient to suppress osteogenesis, and TBT suppresses osteogenesis largely through its direct interaction with RXR.

Introduction Norovirus, a contagious disease that spreads rapidly in close-quartered communities, has a debilitating effect in military settings, affecting troops’ health, productivity, and mission-readiness. This research presents a model of norovirus transmission, testing the vaccination’s effectiveness in military training centers. Methods Transmission was modeled using structured ordinary differential equations, including symptomatic and asymptomatic infection, genetic resistance, vaccination, and herd-immunity effects, within a hypothetical cohort of trainees and support staff. The modeled vaccine had an efficacy of 72%, 4 weeks after a single dose in phase 2 clinical trials. The transmission model was calibrated against data from a norovirus outbreak in a university setting. Sensitivity and uncertainty analyses were performed on 22 parameters. Results The greatest reduction in norovirus cases resulted from prophylactic environmental decontamination and vaccination of trainee and staff populations. These combined interventions prevented more than 6,800 cases of norovirus over the 10-year simulated period—a 15% reduction over the baseline scenario of no interventions. Implementing vaccination and environmental decontamination with an outbreak response threshold of 0.1%, prevented more than 5,300 infections; raising the threshold to 0.2% to 0.5% significantly reduced effectiveness. Environmental decontamination and contact reduction alone had little impact on overall norovirus cases. Conclusions Given vaccine characteristics, the model predicted that up to 15% of norovirus cases occurring in training settings over a 10-year period could be prevented by vaccinating all trainees and staff members immediately upon arrival on-base combined with continuous environmental decontamination. There was an impact on morbidity from implementing vaccination of trainees, alone and in combination with staff members. However, vaccinating staff alone prevented few cases over the simulation period, indicating the importance of trainees in norovirus transmission. Likewise, the negligible impact of environmental decontamination or contact reduction alone highlights the importance of addressing both person-to-person and environmental transmission together to minimize illnesses and training downtime.

Introduction Zika virus (ZIKV) is a mild febrile illness generally transmitted via the bite of infected Aedes species mosquitoes, including Aedes aegypti, with the potential to cause neurological complications. Nearly 200 U.S. military installations are located within areas where Aedes mosquitos are found, putting thousands of personnel at risk for infection with ZIKV. This analysis aims to quantify the benefits of interventions, including vaccination, to decrease the risk of ZIKV on U.S. military installations. Methods The authors developed a dynamic transmission model to test the “effectiveness” of vaccination, personal protective measures (PPM), and mosquito control at reducing morbidity within U.S. military populations. ZIKV transmission was modeled as a compartmental susceptible-exposed-infected-recovered model tracking interactions between humans and mosquitos and incorporating seasonality of mosquito populations and the potential for herd immunity. The model included two-dose vaccination as well as symptomatic and asymptomatic infection. The model was calibrated against 2016 public health data in Puerto Rico; sensitivity analyses were performed on model parameters and interventions. Results The greatest reduction in total modeled ZIKV cases resulted from vaccination combined with mosquito control and PPM. All three interventions at their highest estimated level of efficiency reduced ZIKV cases by 99.9% over the baseline case of low-level adherence to PPM. The addition of vaccination had limited additional benefit over effective vector control and PPM since the significant lag to vaccine-induced protection limited effectiveness of vaccination. Conclusions Given the current vaccine, the model predicted that up to 92.8% of Zika cases occurring in deployment settings over a 10-year period could be prevented by adding vaccination to current low-level PPM. Combining vaccination with other interventions can reduce cases further. A location-specific cost-benefit analysis would be a valuable contribution to outbreak control policy as it could evaluate the economic impact of the interventions versus the reduced level of illness and downtime in this setting.