Efficacy of Osteoporosis Prevention Smartphone App

Background The Striving to be Strong study tested the efficacy of a multifaceted, theory-based, complex osteoporosis prevention smartphone application (app). We hypothesized use of the app would improve bone mineral density and trabecular bone scores. Methods The study was a three-group, prospective, repeated-measure, longitudinal randomized trial. Baseline sample consisted of 290 healthy women between 40 and 60 years of age. Participants were randomly assigned to one of three groups: “Striving,” a dynamically tailored, person-centered app; “Boning Up,” a standardized osteoporosis-education e-book; and “Wait List,” a participant’s choice of intervention in the final 3 months of the 12-month study. Participants had or were provided a smart phone. Bone mineral density and trabecular bone scores were measured using dual-energy X-ray absorptiometry at baseline and 12 months. To assess engagement in health behavior change processes, ecological momentary assessments were administered via text messaging during the 12 months participants actively used the app. Results The final sample reflects an 89.6% retention rate. There were decreases in bone mineral density over time but not among the three groups. The percentage of bone density lost over 12 months was lower than expected. Trabecular bone scores were not different over time or by group but improved across all three groups. Discussion Small but positive results were observed across all groups, suggesting one or more aspects of participation might have affected outcomes, including dissemination of the intervention across groups, retention without participation, ecological momentary assessments functioning as both an intervention and measure, and selective engagement in research-based recommendations

Determinants of low bone mineral density in people with multiple sclerosis: Role of physical activity

Background People with multiple sclerosis (PwMS) have reduced bone mineral density (BMD), but the causes are unclear. Some factors that may cause reduced BMD in PwMS have been understudied, including physical activity, inflammation, cortisol, symptomatic fatigue, and depression. The aim of this study was to investigate factors that may uniquely contribute to reduced BMD in PwMS as compared to people without MS. We hypothesized that physical activity would be the primary determinant of low BMD in PwMS, with additional contributions from inflammation and sympathetic nervous system activation. Methods We tested 23 PwMS (16 women; median EDSS: 2) and 22 control participants (16 women). BMD was measured from the femoral neck and lumbar spine with dual x-ray absorptiometry. Disability was measured with the Expanded Disability Status Scale, and functional capacity was measured with the Multiple Sclerosis Functional Composite. Questionnaires measured symptomatic fatigue and depression. A blood draw was used to measure calcium, phosphate, vitamin D, N-terminal telopeptide, osteopontin, and cytokine markers of inflammation. Physical activity was measured with accelerometry. Salivary cortisol and cardiac heart rate variability also were obtained. All outcome variables were compared between groups with independent samples t-tests. Variables that were different between groups and significantly correlated (Pearson product-moment) with femoral neck BMD, were included in a theoretical model to explain femoral neck BMD. The expected direction of relations in the theoretical model were developed based upon the results of previous research. A Bayesian path analysis was used to test the relations of predictive variables with femoral neck BMD and interrelations among predictive variables, as detailed in the theoretical model. Results PwMS had lower BMD at the femoral neck than controls (p = =0.04; mean difference: -0.09; 95% CI: -0.2, -0.004; Cohen\u27s d = =0.65), and there was a smaller, statistically non-significant difference in BMD at the lumbar spine (p = =0.07; mean difference: -0.08; 95% CI: -0.17, 0.007; Cohen\u27s d = =0.59). PwMS also had lower functional capacity (p ≤ 0.001; Cohen\u27s d = =1.50), greater fatigue (pd = =1.88), greater depression (pd = =1.31), and decreased physical activity (p = =0.03; Cohen\u27s d = =0.62). Using path analysis to test our theoretical model, we found that disability (standardized estimate= -0.17), physical activity (standardized estimate=0.39), symptomatic fatigue (standardized estimate= -0.36), depression (standardized estimate= -0.30), and inflammatory markers (standardized estimate=0.27) explained 51% of the variance in femoral neck BMD. Inflammatory markers were also predictive of disability (standardized estimate=0.44) and physical activity (standardized estimate= -0.40). Symptomatic fatigue and depression were correlated (r = =0.64). Conclusion Physical activity, symptomatic fatigue, depression, disability, and inflammation all contributed independently to decreased femoral neck BMD in PWMS. Bone metabolism in PwMS is complex. Efforts to increase physical activity and address symptomatic fatigue and depression may improve bone mineral density in PwMS. Future research should investigate the mechanisms through which symptomatic fatigue and depression contribute to reduced BMD in PwMS

Background and Method of the Striving to be Strong Study a RCT Testing the Efficacy of a M-health Self-management Intervention

Background Osteoporosis is a prevalent and debilitating condition affecting \u3e50% of post-menopausal women. Yet, a low percentage of women regularly engage in health promoting behaviors associated with osteoporosis prevention. Complex, multidimensional, m-Health interventions hold promise to effect engagement in health behavior change related to calcium and vitamin D intake, balance, core and leg strength, and physical activity. Methods Striving to be Strong study (R01NR013913-01) tests the efficacy of a research and theory based, patient centered, dynamically tailored intervention delivered via smart phone apps. Ecological Momentary Assessments (EMAs) enhance immediate feedback and complement traditional measures. The desired outcomes are the maintenance of osteoporosis self-management behaviors and a decrease in the loss of bone density over time. The Individual and Family Self-management Theory provided the conceptual foundation for the study. The sample consists of 290 healthy women between the ages of 40 and 60 with an anticipated attrition of 33%. This three group repeated measures Randomized Clinical Trial spans a 12-month time period. Data collected occurs via web site, smart-phone app, self-report, observation, and measures. Proximal (engagement in osteoporosis health behaviors) and distal (serum vitamin D, DXA, and body composition) outcomes are collected for testing of the efficacy of the intervention and theory evaluation. Discussion Active and rigorous quality management processes continually evaluate enrollment and retention goals, functionality of the automated intervention delivery and data collection systems, EMAs, and dispersion of incentives

Health Assessment Questionnaire-Disability Index (HAQ-DI) use in modelling disease progression in diffuse cutaneous systemic sclerosis: an analysis from the EUSTAR database

BACKGROUND: Patients with diffuse cutaneous systemic sclerosis (dcSSc) have a poor prognosis. The importance of monitoring subjective measures of functioning and disability, such as the Health Assessment Questionnaire-Disability Index (HAQ-DI), is important as dcSSc is rated by patients as worse than diabetes or hemodialysis for quality of life impairment. This European Scleroderma Trials and Research (EUSTAR) database analysis was undertaken to examine the importance of impaired functionality in dcSSc prognosis. The primary objectives were to identify predictors of death and HAQ-DI score progression over 1 year. HAQ-DI score, major advanced organ involvement, and death rate were also used to develop a comprehensive model to predict lifetime dcSSc progression. METHODS: This was an observational, longitudinal study in patients with dcSSc registered in EUSTAR. Death and HAQ-DI scores were, respectively, analyzed by Cox regression and linear regression analyses in relation to baseline covariates. A microsimulation Markov model was developed to estimate/predict natural progression of dcSSc over a patient's lifetime. RESULTS: The analysis included dcSSc patients with (N = 690) and without (N = 4132) HAQ-DI score assessments from the EUSTAR database. Baseline HAQ-DI score, corticosteroid treatment, and major advanced organ involvement were predictive of death on multivariable analysis; a 1-point increase in baseline HAQ-DI score multiplied the risk of death by 2.7 (p <  0.001) and multiple advanced major organ involvement multiplied the risk of death by 2.8 (p <  0.05). Multivariable analysis showed that baseline modified Rodnan Skin Score (mRSS) and baseline HAQ-DI score were associated with HAQ-DI score progression at 1 year (p <  0.05), but there was no association between baseline organ involvement and HAQ-DI score progression at 1 year. HAQ-DI score, major advanced organ involvement, and death were successfully used to model long-term disease progression in dcSSc. CONCLUSIONS: HAQ-DI score and major advanced organ involvement were comparable predictors of mortality risk in dcSSc. Baseline mRSS and baseline HAQ-DI score were predictive of HAQ-DI score progression at 1 year, indicating a correlation between these endpoints in monitoring disease progression. It is hoped that this EUSTAR analysis may change physician perception about the importance of the HAQ-DI score in dcSSc

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Abnormal fibrillin-1 expression and chronic oxidative stress mediate endothelial mesenchymal transition in a murine model of systemic sclerosis

Systemic sclerosis (SSc) is an autoimmune connective tissue disorder characterized by oxidative stress, impaired vascular function, and attenuated angiogenesis. The tight-skin (Tsk−/+) mouse is a model of SSc that displays many of the cellular features of the clinical disease. We tested the hypotheses that abnormal fibrillin-1 expression and chronic phospholipid oxidation occur in Tsk−/+ mice and, furthermore, that these factors precipitate a prooxidant state, collagen-related protein expression, apoptosis, and mesenchymal transition in endothelial cells cultured on Tsk−/+ extracellular matrix. Human umbilical vein endothelial cells were seeded on microfibrils isolated from skin of C57BL/6J (control) and Tsk−/+ mice in the presence or absence of chronic pretreatment with the apolipoprotein Apo A-I mimetic D-4F (1 mg·kg−1·day−1 ip for 6 to 8 wk). Nitric oxide-to-superoxide anion ratio was assessed 12 h after culture, and cell proliferation, apoptosis, and phenotype were studied 72 h after culture. Tsk−/+ mice demonstrated abnormal “big fibrillin” expression (405 kDa) by Western blot analysis compared with control. Endothelial cells cultured on microfibrils prepared from Tsk−/+ mice demonstrated reduced proliferation, a prooxidant state (reduced nitric oxide-to-superoxide anion ratio), increased apoptosis, and collagen-related protein expression associated with mesenchymal transition. Chronic D-4F pretreatment of Tsk−/+ mice attenuated many of these adverse effects. The findings demonstrate that abnormal fibrillin-1 expression and chronic oxidative stress mediate endothelial mesenchymal transition in Tsk−/+ mice. This mesenchymal transition may contribute to the reduction in angiogenesis that is known to occur in this model of SSc