Redox-signaling is implicated in deleterious microglial activation underlying CNS disease, but how ROS program aberrant microglial function is unknown. Here, the oxidation of NF-κB p50 to a free radical intermediate is identified as a marker of dysfunctional M1 (pro-inflammatory) polarization in microglia. Microglia exposed to steady fluxes of H2O2 showed altered NF-κB p50 protein-protein interactions, decreased NF-κB p50 DNA binding, and augmented late-stage TNFα expression, indicating that H2O2 impairs NF-κB p50 function and prolongs amplified M1 activation. NF-κB p50−/− mice and cultures exhibited a disrupted M2 (alternative) response and impaired resolution of the M1 response. Persistent neuroinflammation continued 1 week after LPS (1mg/kg, IP) administration in the NF-κB p50−/− mice. However, peripheral inflammation had already resolved in both strains of mice. Treatment with the spin-trap DMPO mildly reduced LPS-induced 22 h TNFα in the brain in NF-κB p50+/+ mice. Interestingly, DMPO failed to reduce and strongly augmented brain TNFα production in NF-κB p50−/− mice, implicating a fundamental role for NF-κB p50 in the regulation of chronic neuroinflammation by free radicals. These data identify NF-κB p50 as a key redox-signaling mechanism regulating the M1/M2 balance in microglia, where loss of function leads to a CNS-specific vulnerability to chronic inflammation.

Air pollution is implicated in neurodegenerative disease risk and progression and in microglial activation, but the mechanisms are unknown. In this study, microglia remained activated 24 h after ozone (O3) exposure in rats, suggesting a persistent signal from lung to brain. Ex vivo analysis of serum from O3-treated rats revealed an augmented microglial proinflammatory response and β-amyloid 42 (Aβ42) neurotoxicity independent of traditional circulating cytokines, where macrophage-1 antigen-mediated microglia proinflammatory priming. Aged mice exhibited reduced pulmonary immune profiles and the most pronounced neuroinflammation and microglial activation in response to mixed vehicle emissions. Consistent with this premise, cluster of differentiation 36 (CD36)(-/-) mice exhibited impaired pulmonary immune responses concurrent with augmented neuroinflammation and microglial activation in response to O3 Further, aging glia were more sensitive to the proinflammatory effects of O3 serum. Together, these findings outline the lung-brain axis, where air pollutant exposures result in circulating, cytokine-independent signals present in serum that elevate the brain proinflammatory milieu, which is linked to the pulmonary response and is further augmented with age.-Mumaw, C. L., Levesque, S., McGraw, C., Robertson, S., Lucas, S., Stafflinger, J. E., Campen, M. J., Hall, P., Norenberg, J. P., Anderson, T., Lund, A. K., McDonald, J. D., Ottens, A. K., Block, M. L. Microglial priming through the lung-brain axis: the role of air pollution-induced circulating factors.

Increasing reports support that air pollution causes neuroinflammation and is linked to central nervous system (CNS) disease/damage. Diesel exhaust particles (DEP) are a major component of urban air pollution, which has been linked to microglial activation and Parkinson’s disease-like pathology. To begin to address how DEP may exert CNS effects, microglia and neuron-glia cultures were treated with either nanometer-sized DEP (<0.22 µM; 50µg/mL), ultrafine carbon black (ufCB, 50µg/ml), or DEP extracts (eDEP; from 50 µg/ml DEP) and the effect of microglial activation and dopaminergic (DA) neuron function was assessed. All three treatments showed enhanced amoeboid microglia morphology, increased H2O2 production, and decreased DA uptake. Mechanistic inquiry revealed that the scavenger receptor inhibitor fucoidan blocked DEP internalization in microglia, but failed to alter DEP-induced H2O2 production in microglia. However, pretreatment with the MAC1/CD11b inhibitor antibody blocked microglial H2O2 production in response to DEP. MAC1−/− mesencephalic neuron-glia cultures were protected from DEP-induced loss of DA neuron function, as measured by DA uptake. These findings support that DEP may activate microglia through multiple mechanisms, where scavenger receptors regulate internalization of DEP and the MAC1 receptor is mandatory for both DEP-induced microglial H2O2 production and loss of DA neuron function.

Background and purpose Intra-arterial therapy (IAT) is most effective when performed rapidly after ischemic stroke onset. However, there are limited performance benchmarks in IAT and there is a scarcity of information on how to structure an effective IAT protocol and its impact on time to treatment. The objective of our study was to detail a standardized IAT protocol, and to assess its influence on time to treatment in ischemic stroke. Methods This was a retrospective observational study over 4 years at a comprehensive stroke center. A standardized IAT protocol was implemented in June 2013 that included pre-notifying the stroke team before hospital arrival, defining clinician roles, processing tasks in parallel, and standardizing IAT procedures. Three time metrics were examined and reported as median (IQR) minutes: arrival to CT imaging, CT to groin puncture, and puncture to recanalization. We compared these metrics in patients admitted before implementation ( January 2012-May 2013) to patients admitted after ( June 2013-December 2015) using Wilcoxon MannWhitney tests. Results 380 patients were included. After the protocol was implemented, there were significant reductions in time from arrival to CT (17 (14-21) vs 13 (11-19) min, p<0.001), CT to puncture (46 (30-82) vs 31 (23-54) min, p<0.001), and puncture to recanalization (65 (33-90) vs 37 (22-65) min, p<0.001). 60% of time was saved during puncture to recanalization. Significant reductions in time were observed during both normal working hours and off-hours. Conclusions Implementation of a standardized protocol resulted in a significant reduction in time to recanalization for patients with an ischemic stroke. A standardized IAT protocol decreases time to recanalization when team roles are clearly defined, tasks are processed in parallel, and procedures are standardized.

BACKGROUND Patients' trauma burdens are a combination of anatomic damage, physiologic derangement, and the resultant depletion of reserve. Typically, Injury Severity Score (ISS) >15 defines major anatomic injury and Revised Trauma Score (RTS) <7.84 defines major physiologic derangement, but there is no standard definition for reserve. The Need For Trauma Intervention (NFTI) identifies severely depleted reserves (NFTI+) with emergent interventions and/or early mortality. We hypothesized NFTI would have stronger associations with outcomes and better model fit than ISS and RTS. METHODS Thirty-eight adult and pediatric U.S. trauma centers submitted data for 88,488 encounters. Mixed models tested ISS greater than 15, RTS less than 7.84, and NFTI's associations with complications, survivors' discharge to continuing care, and survivors' length of stay (LOS). RESULTS The NFTI had stronger associations with complications and LOS than ISS and RTS (odds ratios [99.5% confidence interval]: NFTI = 9.44 [8.46–10.53]; ISS = 5.94 [5.36–6.60], RTS = 4.79 [4.29–5.34]; LOS incidence rate ratios (99.5% confidence interval): NFTI = 3.15 [3.08–3.22], ISS = 2.87 [2.80–2.94], RTS = 2.37 [2.30–2.45]). NFTI was more strongly associated with continuing care discharge but not significantly more than ISS (relative risk [99.5% confidence interval]: NFTI = 2.59 [2.52–2.66], ISS = 2.51 [2.44–2.59], RTS = 2.37 [2.28–2.46]). Cross-validation revealed that in all cases NFTI's model provided a much better fit than ISS greater than 15 or RTS less than 7.84. CONCLUSION In this multicenter study, NFTI had better model fit and stronger associations with the outcomes than ISS and RTS. By determining depletion of reserve via resource consumption, NFTI+ may be a better definition of major trauma than the standard definitions of ISS greater than 15 and RTS less than 7.84. Using NFTI may improve retrospective triage monitoring and statistical risk adjustments. LEVEL OF EVIDENCE Prognostic, level IV.

Background Since the national stay-at-home order for COVID-19 was implemented, clinicians and public health authorities worldwide have expressed growing concern about the potential repercussions of drug and alcohol use due to social restrictions. We explored the impact of the national stay-at-home orders on alcohol or drug use and screenings among trauma admissions. Methods This was a retrospective cohort study at six Level I trauma centers across four states. Patients admitted during the period after the onset of the COVID-19 restrictions (defined as March 16, 2020-May 31, 2020) were compared with those admitted during the same time period in 2019. We compared 1) rate of urine drug screens and blood alcohol screens; 2) rate of positivity for drugs or alcohol (blood alcohol concentration ≥ 10 mg/dL); 3) characteristics of patients who were positive for drug or alcohol, by period using chi-squared tests or Fisher’s exact tests, as appropriate. Two-tailed tests with an alpha of p < 0.05 was used on all tests. Results There were 4762 trauma admissions across the study period; 2602 (55%) in 2019 and 2160 (45%) in 2020. From 2019 to 2020, there were statistically significant increases in alcohol screens (34% vs. 37%, p = 0.03) and drug screens (21% vs. 26%, p < 0.001). Overall, the rate of alcohol positive patients significantly increased from 2019 to 2020 (32% vs. 39%, p = 0.007), while the rate of drug positive patients was unchanged (57% vs. 52%, p = 0.13). Of the 1025 (22%) patients who were positive for alcohol or drugs, there were significant increases in a history of alcoholism (41% vs. 26%, p < 0.001), and substance abuse (11% vs. 23%, p < 0.001) in the 2020 period. No other statistically significant differences were identified among alcohol or drug positive patients during COVID-19 compared to the same period in 2019. Conclusions Our first wave of COVID-19 data suggests that trauma centers were admitting significantly more patients who were alcohol positive, as well those with substance use disorders, potentially due to the impact of social restrictions and guidelines. Further longitudinal research is warranted to assess the alcohol and drug positive rates of trauma patients over the COVID-19 pandemic.

ObjectiveTo explore satisfaction of care received by older adult patients and their primary caregivers following traumatic injury.DesignProspective, cross-sectional study using the FAMCARE (Family Satisfaction with Advanced Cancer Care Scale) satisfaction surveys prior to discharge.SettingThree level I trauma centres in Colorado from November 2016 to December 2017.ParticipantsTrauma patients ≥55 years old and their primary caregivers.Outcome measuresOverall mean (SD) satisfaction, satisfaction <80% vs ≥80%, and mean satisfaction by survey conceptual structures.ResultsOf the 319 patients and 336 caregivers included, the overall mean (SD) patient satisfaction was 81.7% (15.0%) and for caregivers was 83.6% (13.4%). The area with the highest mean for patient and caregiver satisfaction was psychosocial care (85.4% and 86.9%, respectively). Information giving was the lowest for patients (80.4%) and caregivers (80.9%). When individual items were examined, patients were significantly more satisfied with ‘availability of nurses to answer questions’ (84.5 (15.3) vs 87.4 (14.8), p=0.02) and significantly less satisfied with ‘speed with which symptoms were treated’ (80.6 (17.9) vs 84.0 (17.0), p=0.03) compared with caregivers. Patients with a history of smoking (least squares mean difference: −0.096 (−0.18 to –0.07), p<0.001) and hospital discharge destination to an outside facility of care (adjusted OR: 1.6 (1.0 to 2.4), p=0.048) were identified as independent predictors of lower overall satisfaction in generalised linear and logistic models, respectively.ConclusionsOur data suggest that patients’ medical history was driving both patient and caregiver satisfaction. Patient characteristics and expectations need to be considered when tailoring healthcare interventions.

BACKGROUND Many studies report on the patient-caregiver relationship during palliative care (PC); however, this relationship has yet to be examined following traumatic injury. METHODS This prospective cohort study included trauma patients (≥55 years) and their primary caregivers admitted at two level I trauma centers for 2 years (November 2016 to November 2018), who received PC and who completed satisfaction surveys before discharge; surveys were analyzed by four domains: information giving, availability of care, physical care, and psychosocial care, and by PC assessments: consultations, prognostications, formal family meetings (FFMs), and advanced goals of care discussions. The primary outcome was the percentage of patients and caregivers who were satisfied (defined as ≥80%) and was analyzed using McNemar’s test. Adjusted mixed models identified PC assessments that were associated with satisfaction scores ≥80% for patients and caregivers. RESULTS Of the 441-patient and 441-caregiver pairs, caregivers were significantly less satisfied than patients during prognostications (information giving, physical care), FFMs (information giving, physical care), and consultations (physical care), while caregivers were significantly more satisfied than patients during advanced goals of care discussions (availability of care, psychosocial care). After adjustment, significant predictors of caregiver satisfaction (≥80%) included longer patient hospital length of stay (>4 days), caring for a male patient (physical care, availability of care), higher caregiver age (≥55 years; availability of care), and higher patient age (≥65 years; psychosocial care). Conversely, all PC assessments decreased odds of satisfaction for caregivers in every domain except physical care. Significant predictors of higher patient satisfaction included FFMs (for every domain) and PC consultations (psychosocial care), and decreased odds included advanced goals of care discussions and prognostication assessments (information giving, psychosocial care). CONCLUSIONS Palliative care increased satisfaction of patients, especially family meetings and consultations, while assessments were predictive of lower caregiver satisfaction, suggesting that caregivers may be experiencing some of the patient burden. LEVEL OF EVIDENCE Therapeutic/Care Management, level IV.