A "multi-omics" analysis of blood-brain barrier and synaptic dysfunction in APOE4 mice.

Apolipoprotein E4 (APOE4), the main susceptibility gene for Alzheimer's disease, leads to blood-brain barrier (BBB) breakdown in humans and mice. Remarkably, BBB dysfunction predicts cognitive decline and precedes synaptic deficits in APOE4 human carriers. How APOE4 affects BBB and synaptic function at a molecular level, however, remains elusive. Using single-nucleus RNA-sequencing and phosphoproteome and proteome analysis, we show that APOE4 compared with APOE3 leads to an early disruption of the BBB transcriptome in 2-3-mo-old APOE4 knock-in mice, followed by dysregulation in protein signaling networks controlling cell junctions, cytoskeleton, clathrin-mediated transport, and translation in brain endothelium, as well as transcription and RNA splicing suggestive of DNA damage in pericytes. Changes in BBB signaling mechanisms paralleled an early, progressive BBB breakdown and loss of pericytes, which preceded postsynaptic interactome disruption and behavioral deficits that developed 2-5 mo later. Thus, dysregulated signaling mechanisms in endothelium and pericytes in APOE4 mice reflect a molecular signature of a progressive BBB failure preceding changes in synaptic function and behavior.

Predicting Outcomes for Interhospital Transferred Patients of Emergency General Surgery.

Background: Interhospital transferred (IHT) emergency general surgery (EGS) patients are associated with high care intensity and mortality. However, prior studies do not focus on patient-level data. Our study, using each IHT patient's data, aimed to understand the underlying cause for IHT EGS patients' outcomes. We hypothesized that transfer origin of EGS patients impacts outcomes due to critical illness as indicated by higher Sequential Organ Failure Assessment (SOFA) score and disease severity. Materials and Methods: We conducted a retrospective analysis of all adult patients transferred to our quaternary academic center's EGS service from 01/2014 to 12/2016. Only patients transferred to our hospital with EGS service as the primary service were eligible. We used multivariable logistic regression and probit analysis to measure the association of patients' clinical factors and their outcomes (mortality and survivors' hospital length of stay [HLOS]). Results: We analyzed 708 patients, 280 (39%) from an ICU, 175 (25%) from an ED, and 253 (36%) from a surgical ward. Compared to ED patients, patients transferred from the ICU had higher mean (SD) SOFA score (5.7 (4.5) vs. 2.39 (2), P < 0.001), longer HLOS, and higher mortality. Transferring from ICU (OR 2.95, 95% CI 1.36-6.41, P=0.006), requiring laparotomy (OR 1.96, 95% CI 1.04-3.70, P=0.039), and SOFA score (OR 1.22, 95% CI 1.13-1.32, P < 0.001) were associated with higher mortality. Conclusions: At our academic center, patients transferred from an ICU were more critically ill and had longer HLOS and higher mortality. We identified SOFA score and a few conditions and diagnoses as associated with patients' outcomes. Further studies are needed to confirm our observation.

Factors associated with refractory pain in emergency patients admitted to emergency general surgery.

BACKGROUND: Oligoanalgesia in emergency departments (EDs) is multifactorial. A previous study reported that emergency providers did not adequately manage patients with severe pain despite objective findings for surgical pathologies. Our study aims to investigate clinical and laboratory factors, in addition to providers' interventions, that might have been associated with oligoanalgesia in a group of ED patients with moderate and severe pains due to surgical pathologies. METHODS: We conducted a retrospective study of adult patients who were transferred directly from referring EDs to the emergency general surgery (EGS) service at a quaternary academic center between January 2014 and December 2016. Patients who were intubated, did not have adequate records, or had mild pain were excluded. The primary outcome was refractory pain, which was defined as pain reduction <2 units on the 0-10 pain scale between triage and ED departure. RESULTS: We analyzed 200 patients, and 58 (29%) had refractory pain. Patients with refractory pain had significantly higher disease severity, serum lactate (3.4±2.0 mg/dL vs. 1.4±0.9 mg/dL, P=0.001), and less frequent pain medication administration (median [interquartile range], 3 [3-5] vs. 4 [3-7], P=0.001), when compared to patients with no refractory pain. Multivariable logistic regression showed that the number of pain medication administration (odds ratio [OR] 0.80, 95% confidence interval [95% CI] 0.68-0.98) and ED serum lactate levels (OR 3.80, 95% CI 2.10-6.80) were significantly associated with the likelihood of refractory pain. CONCLUSIONS: In ED patients transferring to EGS service, elevated serum lactate levels were associated with a higher likelihood of refractory pain. Future studies investigating pain management in patients with elevated serum lactate are needed.