RESUMO
Bone non-unions resulting from severe traumatic injuries pose significant clinical challenges, and the biological factors that drive progression towards and healing from these injuries are still not well understood. Recently, a dysregulated systemic immune response following musculoskeletal trauma has been identified as a contributing factor for poor outcomes and complications such as infections. In particular, myeloid-derived suppressor cells (MDSCs), immunosuppressive myeloid-lineage cells that expand in response to traumatic injury, have been highlighted as a potential therapeutic target to restore systemic immune homeostasis and ultimately improve functional bone regeneration. Previously, we have developed a novel immunomodulatory therapeutic strategy to deplete MDSCs using Janus gold nanoparticles that mimic the structure and function of antibodies. Here, in a preclinical delayed treatment composite injury model of bone and muscle trauma, we investigate the effects of these nanoparticles on circulating MDSCs, systemic immune profiles, and functional bone regeneration. Unexpectedly, treatment with the nanoparticles resulted in depletion of the high side scatter subset of MDSCs and an increase in the low side scatter subset of MDSCs, resulting in an overall increase in total MDSCs. This overall increase correlated with a decrease in bone volume (P = 0.057) at 6 weeks post-treatment and a significant decrease in mechanical strength at 12 weeks post-treatment compared to untreated rats. Furthermore, MDSCs correlated negatively with endpoint bone healing at multiple timepoints. Single cell RNA sequencing of circulating immune cells revealed differing gene expression of the SNAb target molecule S100A8/A9 in MDSC sub-populations, highlighting a potential need for more targeted approaches to MDSC immunomodulatory treatment following trauma. These results provide further insights on the role of systemic immune dysregulation for severe trauma outcomes in the case of non-unions and composite injuries and suggest the need for additional studies on targeted immunomodulatory interventions to enhance healing.
RESUMO
Background: Within many public health settings, there remain large challenges to sustaining evidence-based practices. The Program Sustainability Assessment Tool has been developed and validated to measure sustainability capacity of public health, social service, and educational programs. This paper describes how this tool was utilized between January 2014 and January 2019. We describe characteristics of programs that are associated with increased capacity for sustainability and ultimately describe the utility of the PSAT in sustainability research and practice. Methods: The PSAT is comprised of 8 subscales, measuring sustainability capacity in eight distinct conceptual domains. Each subscale is made up of five items, all assessed on a 7-point Likert scale. Data were obtained from persons who used the PSAT on the online website (https://sustaintool.org/), from 2014 to 2019. In addition to the PSAT scale, participants were asked about four program-level characteristics. The resulting dataset includes 5,706 individual assessments reporting on 2,892 programs. Results: The mean overall PSAT score was 4.73, with the lowest and highest scoring subscales being funding stability and program adaptation, respectively. Internal consistency for each subscale was excellent (average Cronbach's alpha = 0.90, ranging from 0.85 to 0.94). Confirmatory factor analysis highlighted good to excellent fit of the PSAT measurement model (eight distinct conceptual domains) to the observed data, with a comparative fit index of 0.902, root mean square error of approximation equal to 0.054, and standardized root mean square residual of 0.054. Overall sustainability capacity was significantly related to program size (F = 25.6; p < 0.001). Specifically, smaller programs (with staff sizes of ten or below) consistently reported lower program sustainability capacity. Capacity was not associated with program age and did not vary significantly by program level. Discussion: The PSAT maintained its excellent reliability when tested with a large and diverse sample over time. Initial criterion validity was explored through the assessment of program characteristics, including program type and program size. The data collected reinforces the ability of the PSAT to assess sustainability capacity for a wide variety of public health and social programs.