Telomere shortening is observed in peripheral mononuclear cells from patients with major depressive disorder (MDD). Whether this finding and its biological causes impact the health of the brain in MDD is unknown. Brain cells have differing vulnerabilities to biological mechanisms known to play a role in accelerating telomere shortening. Here, two glia cell populations (oligodendrocytes and astrocytes) known to have different vulnerabilities to a key mediator of telomere shortening, oxidative stress, were studied. The two cell populations were separately collected by laser capture micro-dissection of two white matter regions shown previously to demonstrate pathology in MDD patients. Cells were collected from brain donors with MDD at the time of death and age-matched psychiatrically normal control donors (N = 12 donor pairs). Relative telomere lengths in white matter oligodendrocytes, but not astrocytes, from both brain regions were significantly shorter for MDD donors as compared to matched control donors. Gene expression levels of telomerase reverse transcriptase were significantly lower in white matter oligodendrocytes from MDD as compared to control donors. Likewise, the gene expression of oxidative defence enzymes superoxide dismutases (SOD1 and SOD2), catalase (CAT) and glutathione peroxidase (GPX1) were significantly lower in oligodendrocytes from MDD as compared to control donors. No such gene expression changes were observed in astrocytes from MDD donors. These findings suggest that attenuated oxidative stress defence and deficient telomerase contribute to telomere shortening in oligodendrocytes in MDD, and suggest an aetiological link between telomere shortening and white matter abnormalities previously described in MDD.

Background:Pathology of white matter in brains of patients with major depressive disorder (MDD) is well-documented, but the cellular and molecular basis of this pathology are poorly understood.Methods:Levels of DNA oxidation and gene expression of DNA damage repair enzymes were measured in Brodmann area 10 (BA10) and/or amygdala (uncinate fasciculus) white matter tissue from brains of MDD (n=10) and psychiatrically normal control donors (n=13). DNA oxidation was also measured in BA10 white matter of schizophrenia donors (n=10) and in prefrontal cortical white matter from control rats (n=8) and rats with repeated stress-induced anhedonia (n=8).Results:DNA oxidation in BA10 white matter was robustly elevated in MDD as compared to control donors, with a smaller elevation occurring in schizophrenia donors. DNA oxidation levels in psychiatrically affected donors that died by suicide did not significantly differ from DNA oxidation levels in psychiatrically affected donors dying by other causes (non-suicide). Gene expression levels of two base excision repair enzymes, PARP1 and OGG1, were robustly elevated in oligodendrocytes laser captured from BA10 and amygdala white matter of MDD donors, with smaller but significant elevations of these gene expressions in astrocytes. In rats, repeated stress-induced anhedonia, as measured by a reduction in sucrose preference, was associated with increased DNA oxidation in white, but not gray, matter.Conclusions:Cellular residents of brain white matter demonstrate markers of oxidative damage in MDD. Medications that interfere with oxidative damage or pathways activated by oxidative damage have potential to improve treatment for MDD.

BACKGROUND: Among the goals of prospectively implemented post-hepatectomy care pathways was a focus on patient-centric opioid reduction. We sought to evaluate the impact of pathway implementation on opioid volumes in the last 24-hour period and discharge prescriptions. STUDY DESIGN: This is a retrospective cohort study comparing a prospective cohort (“POST,” September 2019 through February 2020) treated after pathway implementation to a historical cohort of hepatectomy patients (“PRE,” March 2016 through December 2017) before our 2018 departmental opioid reduction efforts. Opioid volumes in the last 24 hours and prescribed at discharge were converted to oral morphine equivalents (OME) and compared between cohorts. RESULTS: There were 276 PRE and 100 POST patients. There was a similar proportion of major (PRE-34.1% vs POST-40%) and minimally invasive hepatectomies (PRE-19.9% vs POST-11%, p = 0.122). Implementation was associated with a shorter length of stay (median 5 d PRE vs 4 d POST, p < 0.001). Standardized opioid weaning was associated with a lower median last 24-hour OME (20 mg PRE vs 10 mg POST, p = 0.001). Using a standardized discharge calculation, median discharge OME were lower (200 mg PRE vs 50 mg POST, p < 0.001). More POST patients were discharged opioid-free (6.9% PRE vs 21% POST, p < 0.001). CONCLUSIONS: Implementation of post-hepatectomy care pathways was associated with a 50% reduction in last 24-hour OME, which, combined with a standardized discharge calculation, was associated with an overall 75% reduction in discharge opioid volumes and tripled opioid-free discharges. These data suggest that no-cost, reproducible pathways can be considered in abdominal operations with similar incisions/length of stay to decrease variation in opioid dosing while prioritizing patient-centric opioid needs.

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BACKGROUND Palliative therapy has been associated with improved overall survival (OS) in several tumor types. Not all patients with metastatic esophageal cancer receive palliative chemotherapy, and the roles of other palliative therapies in these patients are limited. AIM To investigate the impact of other palliative therapies in patients with metastatic esophageal cancer not receiving chemotherapy. METHODS The National Cancer Database was used to identify patients between 2004-2015. Patients with M1 disease who declined chemotherapy and had known palliative therapy status [palliative therapies were defined as surgery, radiotherapy (RT), pain management, or any combination thereof] were included. Cases with unknown chemotherapy, RT, or nonprimary surgery status were excluded. Kaplan-Meier estimates of OS were calculated. Cox proportional hazards regression models were employed to examine factors influencing survival. RESULTS Among 140234 esophageal cancer cases, we identified 1493 patients who did not receive chemotherapy and had complete data. Median age was 70 years, most (66.3%) had a Charlson Comorbidity Index (CCI) of 0, and 37.1% were treated at an academic center. The majority (72.7%) did not receive other palliative therapies. On both univariate and multivariable analyses, there was no difference in OS between those receiving other palliative therapy (median 2.83 mo, 95%CI: 2.53-3.12) vs no palliative therapy (2.37 no, 95%CI: 2.2-2.56; multivariable P = 0.290). On univariate, but not multivariable analysis, treatment at an academic center was predictive of improved OS [Hazard ratio (HR) 0.90, 95%CI: 0.80-1.00; P = 0.047]. On multivariable analysis, female sex (HR 0.81, 95%CI: 0.71-0.92) and non-black, other race compared to white race (HR 0.72, 95%CI: 0.56-0.93) were associated with reduced mortality, while South geographic region relative to West region (HR 1.23, 95%CI: 1.04-1.46) and CCI of 1 relative to CCI of 0 (HR 1.17, 95%CI: 1.03-1.32) were associated with increased mortality. Higher histologic grade and T-stage were also associated with worse OS ( P < 0.05). CONCLUSION Palliative therapies other than chemotherapy conferred a numerically higher, but not statistically significant difference in OS among patients with metastatic esophageal cancer not receiving chemotherapy. Quality of life metrics, inpatient status, and subgroup analyses are important for examining the role of palliative therapies other than chemotherapy in metastatic esophageal cancer and future studies are warranted.

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