Resolvin D2-G-Protein Coupled Receptor 18 Enhances Bone Marrow Function and Limits Steatosis and Hepatic Collagen Accumulation in Aging.

Aging is associated with nonresolving inflammation and tissue dysfunction. Resolvin D2 (RvD2) is a proresolving ligand that acts through the G-protein-coupled receptor called GPR18. Unbiased RNA sequencing revealed increased Gpr18 expression in macrophages from old mice, and in livers from elderly humans, which was associated with increased steatosis and fibrosis in middle-aged (MA) and old mice. MA mice that lacked GPR18 on myeloid cells had exacerbated steatosis and hepatic fibrosis, which was associated with a decline in Mac2+ macrophages. Treatment of MA mice with RvD2 reduced steatosis and decreased hepatic fibrosis, correlating with increased Mac2+ macrophages, increased monocyte-derived macrophages, and elevated numbers of monocytes in the liver, blood, and bone marrow. RvD2 acted directly on the bone marrow to increase monocyte-macrophage progenitors. A transplantation assay further demonstrated that bone marrow from old mice facilitated hepatic collagen accumulation in young mice. Transient RvD2 treatment to mice transplanted with bone marrow from old mice prevented hepatic collagen accumulation. Together, this study demonstrates that RvD2-GPR18 signaling controls steatosis and fibrosis and provides a mechanistic-based therapy for promoting liver repair in aging.

The Resolvin D2-GPR18 Axis Enhances Bone Marrow Function and Limits Hepatic Fibrosis in Aging.

Aging is associated with non-resolving inflammation and tissue dysfunction. Resolvin D2 (RvD2) is a pro-resolving ligand that acts through the G-protein coupled receptor (GPCR) called GRP18. Using an unbiased screen, we report increased Gpr18 expression in macrophages from old mice and in livers from elderly humans that is associated with increased steatosis and fibrosis in middle-aged (MA) and old mice. MA mice that lack GPR18 on myeloid cells had exacerbated steatosis and hepatic fibrosis, which was associated with a decline in Mac2+ macrophages. Treatment of MA mice with RvD2 reduced steatosis and decreased hepatic fibrosis, correlating with increased Mac2+ macrophages, monocyte-derived macrophages and elevated numbers of monocytes in the liver, blood, and bone marrow. RvD2 acted directly upon the bone marrow to increase monocyte-macrophage progenitors. Using a transplantation assay we further demonstrated that bone marrow from old mice facilitated hepatic collagen accumulation in young mice, and transient RvD2 treatment to mice transplanted with bone marrow from old mice prevented hepatic collagen accumulation. Together, our study demonstrates that RvD2-GPR18 signaling controls steatosis and fibrosis and provides a mechanistic-based therapy for promoting liver repair in aging.

The Use of Salvage Procedures for Wound Complications in Neuromodulation.

OBJECTIVE: Wound complications are a prevalent concern for neuromodulation procedures. While removal of the device was recommended, attempts to salvage expensive hardware have become commonplace. We examine our management in wound issues to aid in providing guidance for these situations. METHODS: We identified 40 patients over an 8-year period in a large neuromodulation practice, who underwent washout or partial salvage of hardware. We examined the efficacy of washout and partial explants on the ability to salvage the implants. Covariates including age, sex, body mass index, smoking status, anticoagulation, and device type were considered. RESULTS: There were 29 washouts and 10 partial hardware removal cases. Washouts were successful in 15/29 cases (51.7%), partial hardware removal was successful in 2/10 cases (20%), and removal with replacement was not successful (0 of 1). Washouts tended to be more successful than partial removal procedures (P = 0.08). In cases of successful washout, the average duration between infectious symptoms and washout was 7.27 ± 2.19 days. None of the demographic variables were associated with increased likelihood of washout failure. CONCLUSIONS: Our results demonstrate a higher rate of washout failure in those who underwent partial device removal and in the presence of purulence at the surgical site. Further investigation must be conducted to determine the instances in which hardware removal is indicated to prevent failure or removal due to infection. Identification of these parameters will optimize therapeutic benefit and long-term financial impact.

Perceptions of pain in aging females undergoing spinal cord stimulation.

Aim: Effects of age and sex on chronic pain outcomes following spinal cord stimulation (SCS) have not yet been assessed. Methods: We retrospectively reviewed 1 year outcomes from a database of patients receiving thoracic SCS. Subjects were divided into four cohorts: pre-menopausal and post-menopausal females, and aged-matched males. Improvement using the numerical rating scale, Oswestry Disability Index (ODI), Beck's Depression Inventory (BDI), McGill Pain Questionnaire and Pain Catastrophizing Scale (PCS) was assessed. Results: Older females were notably different from males and females under 60 as they had greater improvements in ODI, BDI and PCS. Further, females ≥60 had greater improvement in PCS compared with males ≥60. Conclusion: Our findings suggest greater improvement with 1 year SCS treatment in post-menopausal females, compared with age-matched males.

Spinal cord stimulation (SCS) has been shown to be an effective treatment for chronic pain that does not respond to other therapies. It is well recognized that men and women differ in how they perceive pain and how they respond to pain treatments. However, whether women who are over 60 years old and thus presumed to be menopausal respond differently to SCS has not been evaluated. We looked at our database which collected outcomes related to pain, measured before patients had SCS and 1 year after SCS. We found that women over 60 responded better to SCS treatment. They experienced significantly greater improvements in the disability, depression and catastrophizing associated with their pain than did women under 60. Further SCS resulted in more improvements in catastrophizing in women over 60 than in men over 60. Taken together, our hope is that these data help physicians to determine the best patients for SCS and to counsel their patients appropriately. To the best of our knowledge, this study is the first to show the impact of sex-specific aging on response to spinal cord stimulation. While we used age as a surrogate for menopause, menopausal status should be documented in the future to confirm that it effects response.

A Pilot Study Comparing Algorithmic Adaptive Conventional Stimulation with High-Dose Stimulation in Chronic Pain Patients.

INTRODUCTION: Spinal cord stimulation is an effective method of treatment for chronic pain. We previously showed that programming using accelerometry was advantageous for paresthesia-based stimulation. However, programming can be labor intensive. OBJECTIVE: Here we focus on standardized programming for both accelerometer-based paresthesia-induced programming (termed "shuffle") and high-dose (HD) subthreshold programming with stimulation delivered over the T9-10 interspace. METHODS: In this prospective cross-over study, patients received 4 weeks of shuffle programming and 4 weeks of HD programming in a randomized order. In both intervals, contacts overlying T9-10 were programmed. Pain scales with measurements of activity and sleep were collected at the end of each study arm and compared with preoperative baseline scores. RESULTS: Twelve patients were enrolled, with 10 patients completing this study. Compared with baseline, during the HD study period, significant improvements were seen in worst pain of week (P = 0.03) and current pain (P = 0.04) as rated on Numeric Rating Scale scores and walking on the Activity Test (P = 0.012). No difference was seen from baseline compared with shuffle stimulation or in shuffle stimulation compared with HD stimulation. CONCLUSION: In this pilot study, we demonstrated that HD stimulation at T9-10 is superior to algorithmic programming of paresthesia-based stimulation. These results compared with our previous work with shuffle suggest that paresthesia-based stimulation may necessitate stimulation of additional contact locations and additional programming to optimize. This algorithmic programming of paresthesia-based stimulation continues to warrant exploration.

The Impact of Multidisciplinary Conferences on Healthcare Utilization in Chronic Pain Patients.

Approximately 100 million adults in the United States have chronic pain, though only a subset utilizes the vast majority of healthcare resources. Multidisciplinary care has been shown to improve outcomes in a variety of clinical conditions. There is concern that multidisciplinary care of chronic pain patients may overwhelm existing resources and increase healthcare utilization due to the volume of patients and the complexity of care. We report our findings on the use of multidisciplinary conferences (MDC) to facilitate care for the most complex patients seen at our tertiary center. Thirty-two of nearly 2,000 patients seen per year were discussed at the MDC, making up the top 2% of complex patients in our practice. We evaluated patients' numeric rating score (NRS) of pain, medication use, hospitalizations, emergency department visits, and visits to pain specialists prior to their enrollment in MDC and 1 year later. Matched samples were compared using Wilcoxon's signed rank test. Patients' NRS scores significantly decreased from 7.64 to 5.54 after inclusion in MDC (p < 0.001). A significant decrease in clinic visits (p < 0.001) and healthcare utilization (p < 0.05) was also observed. Opioid and non-opioid prescriptions did not change significantly (p = 0.43). 83% of providers agreed that MDC improved patient care. While previous studies have shown the effect of multi-disciplinary care, we show notable improvements with a team established around a once-a-month MDC.