Ceramide levels in blood plasma correlate with major depressive disorder severity and its neutralization abrogates depressive behavior in mice.

Major depressive disorder (MDD) is a severe disease of unknown pathogenesis that will affect ∼10% of people during their lifetime. Therapy for MDD requires prolonged treatment and often fails, predicating a need for novel treatment strategies. Here, we report increased ceramide levels in the blood plasma of MDD patients and in murine stress-induced models of MDD. These blood plasma ceramide levels correlated with the severity of MDD in human patients and were independent of age, sex, or body mass index. In addition, intravenous injection of anti-ceramide antibodies or neutral ceramidase rapidly abrogated stress-induced MDD, and intravenous injection of blood plasma from mice with MDD induced depression-like behavior in untreated mice, which was abrogated by ex vivo preincubation of the plasma with anti-ceramide antibodies or ceramidase. Mechanistically, we demonstrate that ceramide accumulated in endothelial cells of the hippocampus of stressed mice, evidenced by the quantitative measurement of ceramide in purified hippocampus endothelial cells. We found ceramide inhibited the activity of phospholipase D (PLD) in endothelial cells in vitro and in the hippocampus in vivo and thereby decreased phosphatidic acid in the hippocampus. Finally, we show intravenous injection of PLD or phosphatidic acid abrogated MDD, indicating the significance of this pathway in MDD pathogenesis. Our data indicate that ceramide controls PLD activity and phosphatidic acid formation in hippocampal endothelial cells and thereby mediates MDD. We propose that neutralization of plasma ceramide could represent a rapid-acting targeted treatment for MDD.

Robotic approach mitigates the effect of major complications on survival after pancreaticoduodenectomy for periampullary cancer.

BACKGROUND: Major complications (MCs) after pancreaticoduodenectomy (PD) are a known independent predictor of worse oncologic outcomes. There are limited data on the effect of major complications on long-term outcomes after robotic PD (RPD). The aim of this study is to compare the effect of MC on overall (OS) and disease-free survival (DFS) after RPD and open PD (OPD). METHODS: This is a single-center, retrospective review of a prospectively maintained database of all patients undergoing PD for periampullary cancer including ampullary adenocarcinoma, distal cholangiocarcinoma, and duodenal carcinoma. Univariate analysis was performed on all clinical, pathologic, and treatment factors. MCs were defined as Clavien-Dindo ≥ grade 3. Kaplan-Maier survival analysis was performed with log-rank test for group comparison. Multivariable Cox regression analysis was used to identify factors associated with overall survival (OS) in both the OPD and RPD groups. RESULTS: A total of 190 patients with ampullary carcinoma (n = 98), cholangiocarcinoma (n = 55), and duodenal adenocarcinoma (n = 37) were examined over the study period with 61.1% (n = 116) undergoing RPD and 38.9% (n = 74) undergoing OPD. There was no significant difference in patient demographics between the RPD and OPD cohorts. Furthermore, R0 resection rates, tumor size, and lymph node involvement were similar between the RPD and OPD cohorts. OPD had higher rate of MC (40.5% vs 28.3% in RPD, p = 0.011) including clinically relevant pancreatic fistula (25.7% vs 8.6%, p = 0.001) and wound infection (34.5% vs 13.8%, p < 0.001). MCs were associated with a lower OS in the OPD cohort (HR = 2.18, 95%CI 1.0-4.55, p = 0.038). MCs were not associated with OS in the RPD cohort (HR = 1.55, 95%CI 0.87-2.76, p = 0.14). CONCLUSION: MCs are associated with worse patient outcomes after OPD but not after RPD. Robotic approach mitigates and possibly abrogates the negative effects of MCs on patient outcomes after PD for malignancy and is associated with improved adjuvant chemotherapy completion rates.

The volume-outcomes relationship in donation after circulatory death liver transplantation.

BACKGROUND: Donation after circulatory death (DCD) liver transplantation (LT) has become an effective mechanism for expanding the donor pool and decreasing waitlist mortality. However, it is unclear if low-volume DCD centers can achieve comparable outcomes to high-volume centers. METHODS: From 2011 to 2019 utilizing the United Network for Organ Sharing (UNOS) database, liver transplant centers were categorized into tertiles based on their annual volume of DCD LTs. Donor selection, recipient selection, and survival outcomes were compared between very-low volume (VLV, n = 1-2 DCD LTs per year), low-volume (LV, n = 3-5), and high-volume (HV, n > 5) centers. RESULTS: One hundred and ten centers performed 3273 DCD LTs. VLV-centers performed 339 (10.4%), LV-centers performed 627 (19.2%), and HV-centers performed 2307 (70.4%) LTs. 30-day, 90-day, and 1-year patient and graft survival were significantly increased at HV-centers (all P < .05). Recipients at HV-centers had shorter waitlist durations (P < .01) and shorter hospital lengths of stay (P < .01). On multivariable regression, undergoing DCD LT at a VLV-center or LV-center was associated with increased 1-year patient mortality (VLV-OR:1.73, 1.12-2.69) (LV-OR: 1.42, 1.01-2.00) and 1-year graft failure (VLV-OR: 1.79, 1.24-2.58) (LV-OR: 1.28, .95-1.72). DISCUSSION: Increased annual DCD liver transplant volume is associated with improved patient and graft survival.