Development of depressive symptoms post hip fracture is associated with altered immunosuppressive phenotype in regulatory T and B lymphocytes

Hip fracture is a common physical trauma in older adults that is also associated with a high incidence of new onset depression. The immune system declines with age and is also compromised by physical and psychological stress. This study examined whether hip fracture and depressive symptoms had additive effects upon the aged immune system that might contribute to poor health outcomes after hip fracture. We assessed the frequency of regulatory T cells, Tregs (CD4+ CD25+ Foxp3+) and IL10 production by CD4 T cells, and the frequency and IL10 production by regulatory B cells, Bregs (CD19+ CD24hi CD38hi) in 101 hip fracture patients (81 female) 6 weeks after injury and 43 healthy age-matched controls (28 female). 38 hip fracture patients (37 %) developed depressive symptoms. Hip fracture did not have an effect on circulating Tregs frequency but a significant reduction in the frequency of Bregs was observed in patients who developed depression compared with non-depressed patients (p = 0.001) or healthy controls (p < 0.001). Bregs also showed a significant decline in IL10 production in depressed hip fracture patients compared with controls (p = 0.04) and non-depressed patients (p = 0.01). In contrast, there was an increase in IL10 production by CD4 T cells in hip fracture patients with new onset depression compared to hip fracture patients without depression (p = .04) and healthy controls (p = .02). We conclude that the reduced immunity associated with new onset depression post hip fracture could include a contribution by heightened Tregs function

New-Onset Depression Following Hip Fracture Is Associated With Increased Length of Stay in Hospital and Rehabilitation Centers

This article examines the coincident effects of new-onset depression post hip fracture on length of hospital stay, readmission rates, and incidence of infections in older adults. Participants were 101 hip fracture patients aged 60+ years; 38 developed depressive symptoms following their fracture. Infection rates, readmissions to hospital and rehabilitation units, and length of hospital stay were assessed over the 6 months post hip fracture from hospital and general practitioner notes. Patients who developed depression by Week 6 post fracture were likely to spend more time in hospital/rehabilitation wards (p = .02) and more likely to be discharged to a rehabilitation unit (p < .05). There were no group differences in readmissions or infection rates. New-onset depression coincident with hip fracture in older adults is associated with longer hospital ward stays and greater need for rehabilitation

Depressive symptoms post hip fracture in older adults are associated with phenotypic and functional alterations in T cells

Background Ageing is accompanied by reduced immunity, termed immunesenescence. The immune system does not act in isolation and is sensitive to both psychological and physical stress. Hip fracture is a common physical stressor in older adults with a high incidence of new onset depression, which relates to poorer prognosis. We therefore set out to examine the possible synergistic effects of physical stress (hip fracture) and psychological stress (depressive symptoms) on the aged immune system. Results T cell phenotype and function was assessed in 101 hip fracture patients (81 female) 6 weeks after hip fracture and 43 healthy age-matched controls (26 female). 38 fracture patients had depressive symptoms at 6 weeks. T cell frequency (p = .01) and numbers (p = .003) were both lower in depressed hip fracture patients compared to healthy controls. The frequency of senescent CD28-ve (p = .001), CD57+ve (p = .001), KLRG1+ve (p = .03) CD8 T cells, as well as senescent CD28-ve CD4+ve (p = .01) and CD57+ve CD4+ve (p = .003) T cells were higher in depressed hip fracture patients compared with healthy controls and the frequency of CD28-ve CD8 T cells was also higher when compared to patients with hip fracture alone (p = .01). Additionally, activated CD69+ve (p = .005) and HLADR+ve (p

NK cell immunesenescence is increased by psychological but not physical stress in older adults associated with raised cortisol and reduced perforin expression

NK cell cytotoxicity (NKCC) reduces with age and this has been associated previously with increased mortality. The immune response is also modulated by stress, and here, we assessed the effect of the physical stress of hip fracture and the psychological stress of depression on NKCC in an aged immune system. NKCC was assessed in 101 hip fracture patients (81 female) 6 weeks and 6 months after injury and in 50 healthy age-matched controls (28 female). Thirty-eight patients were depressed at 6 weeks post-injury, and NKCC was reduced in patients who developed depression compared with non-depressed hip fracture patients (p = 0.004) or controls (p

Depressive symptoms in hip fracture patients are associated with reduced monocyte superoxide production

Ageing is accompanied by reduced functioning of the immune system, termed immunesenescence which is associated with increased risk of infection and mortality. However the immune system does not operate in isolation and can be modified by many environmental factors, including stress. In this study we determined whether physical stress (hip fracture) and psychological distress (depressive symptoms) had additive effects upon the aged immune system, specifically on monocyte numbers and function. We assessed immune function in 101 hip fracture patients (81 female) 6 weeks and 6 months after injury and 43 healthy age matched controls (28 females). Thirty-eight of the hip fracture group were found to be depressed at the 6 week sampling. No differences in peripheral monocyte count, distribution of monocyte subsets or TNFα secretion were observed between hip fracture patients and healthy controls. However we observed significantly reduced superoxide production in response to Escherichia coli in the monocytes of hip fracture patients who developed depressive symptoms compared with non-depressed hip fracture patients (p = 0.002) or healthy controls (p = 0.008) 6 weeks after the fracture which remained decreased 6 months following injury. In previous studies we have shown an effect of depression on neutrophil superoxide generation in hip fracture patients, suggesting a particular susceptibility of this aspect of immune cell function to psychological stress

Advancing the Application of Design of Experiments (DOE) to Synthetic Theater Operations Research Model (STORM) Data

NPS NRP Project PosterThe Navy uses simulation-based campaign analysis to help measure risk for investment options for how best to equip, organize, supply, maintain, train, and employ our naval forces. The Synthetic Theater Operations Research Model (STORM) is a stochastic simulation model used to support campaign analysis by the U.S. Navy, Marine Corps, and Air Force. Building, testing, running, and analyzing campaign scenarios in STORM can be a complex, time-consuming process. The goal of this research is to apply Design Of Experiment (DOE) methods in the selection and creation of Design Points (DPs) to minimize the number of modeling runs required for meaningful comparisons. Another objective is to understand how best DOE methods can complement traditional baseline and excursion modeling. In addition to regular reviews, the research deliverables will include: (1) a final brief and/or technical report, in addition to student theses (if applicable); (2) all findings, methods, and data used in the study; and (3) appropriate conference or journal papers related to this research.N8 - Integration of Capabilities & ResourcesThis research is supported by funding from the Naval Postgraduate School, Naval Research Program (PE 0605853N/2098). https://nps.edu/nrpChief of Naval Operations (CNO)Approved for public release. Distribution is unlimited.

Advancing the Application of Design of Experiments (DOE) to Synthetic Theater Operations Research Model (STORM) Data

NPS NRP Technical ReportThe Navy uses simulation-based campaign analysis to help measure risk for investment options for how best to equip, organize, supply, maintain, train, and employ our naval forces. The Synthetic Theater Operations Research Model (STORM) is a stochastic simulation model used to support campaign analysis by the U.S. Navy, Marine Corps, and Air Force. Building, testing, running, and analyzing campaign scenarios in STORM can be a complex, time-consuming process. The goal of this research is to apply Design Of Experiment (DOE) methods in the selection and creation of Design Points (DPs) to minimize the number of modeling runs required for meaningful comparisons. Another objective is to understand how best DOE methods can complement traditional baseline and excursion modeling. In addition to regular reviews, the research deliverables will include: (1) a final brief and/or technical report, in addition to student theses (if applicable); (2) all findings, methods, and data used in the study; and (3) appropriate conference or journal papers related to this research.N8 - Integration of Capabilities & ResourcesThis research is supported by funding from the Naval Postgraduate School, Naval Research Program (PE 0605853N/2098). https://nps.edu/nrpChief of Naval Operations (CNO)Approved for public release. Distribution is unlimited.

Advancing the Application of Design of Experiments (DOE) to Synthetic Theater Operations Research Model (STORM) Data

NPS NRP Executive SummaryThe Navy uses simulation-based campaign analysis to help measure risk for investment options for how best to equip, organize, supply, maintain, train, and employ our naval forces. The Synthetic Theater Operations Research Model (STORM) is a stochastic simulation model used to support campaign analysis by the U.S. Navy, Marine Corps, and Air Force. Building, testing, running, and analyzing campaign scenarios in STORM can be a complex, time-consuming process. The goal of this research is to apply Design Of Experiment (DOE) methods in the selection and creation of Design Points (DPs) to minimize the number of modeling runs required for meaningful comparisons. Another objective is to understand how best DOE methods can complement traditional baseline and excursion modeling. In addition to regular reviews, the research deliverables will include: (1) a final brief and/or technical report, in addition to student theses (if applicable); (2) all findings, methods, and data used in the study; and (3) appropriate conference or journal papers related to this research.N8 - Integration of Capabilities & ResourcesThis research is supported by funding from the Naval Postgraduate School, Naval Research Program (PE 0605853N/2098). https://nps.edu/nrpChief of Naval Operations (CNO)Approved for public release. Distribution is unlimited.

An age-related numerical and functional deficit in CD19+CD24hiCD38hiB cells is associated with an increase in systemic autoimmunity

Autoimmunity increases with aging indicative of reduced immune tolerance, but the mechanisms involved are poorly defined. In recent years, subsets of B cells with immunoregulatory properties have been identified in murine models of autoimmune disorders, and these cells downregulate immune responses via secretion of IL10. In humans, immature transitional B cells with a CD19+CD24hiCD38hi phenotype have been reported to regulate immune responses via IL10 production. We found the frequency and numbers of CD19+CD24hiCD38hi cells were reduced in the PBMC pool with age. IL10 expression and secretion following activation via either CD40, or Toll-like receptors was also impaired in CD19+CD24hiCD38hi B cells from healthy older donors. When investigating the mechanisms involved, we found that CD19+CD24hiCD38hi B-cell function was compromised by age-related effects on both T cells and B cells: specifically, CD40 ligand expression was lower in CD4 T cells from older donors following CD3 stimulation, and signalling through CD40 was impaired in CD19+CD24hiCD38hi B cells from elders as evidenced by reduced phosphorylation (Y705) and activation of STAT3. However, there was no age-associated change in expression of costimulatory molecules CD80 and CD86 on CD19+CD24hiCD38hi cells, suggesting IL10-dependent immune suppression is impaired, but contact-dependent suppressive capacity is intact with age. Finally, we found a negative correlation between CD19+CD24hiCD38hi B-cell IL10 production and autoantibody (Rheumatoid factor) levels in older adults. We therefore propose that an age-related decline in CD19+CD24hiCD38hi B cell number and function may contribute towards the increased autoimmunity and reduced immune tolerance seen with aging

Depression following hip fracture is associated with increased physical frailty in older adults: the role of the cortisol: dehydroepiandrosterone sulphate ratio

Background: Hip fracture in older adults is associated with depression and frailty. This study examined the synergistic effects of depression and hip fracture on physical frailty, and the mediating role of the cortisol: dehydroepiandrosterone sulphate (DHEAS) ratio. Methods This was an observational longitudinal study of patients with a hip fracture carried out in a hospital setting and with follow up in the community. Participants were 101 patients aged 60+ years (81 female) with a fractured neck of femur. Measurements of the ability to carry out activities of daily living (ADL), cognitive function, physical frailty and assays for serum cortisol and DHEAS were performed six weeks and six months post-hip fracture. Depressed and non-depressed groups were compared by ANOVA at each time point. Results Hip fracture patients who developed depression by week six (n = 38) had significantly poorer scores on ADL and walking indices of frailty at both week six and month six, and poorer balance at week six. The association with slower walking speed was mediated by a higher cortisol:DHEAS ratio in the depressed group. Conclusion Depression following hip fracture is associated with greater physical frailty and poorer long term recovery post-injury. Our data indicate that the underlying mechanisms may include an increased cortisol:DHEAS ratio and suggest that correcting this ratio for example with DHEA supplementation could benefit this patient population