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Small extracellular vesicles (EVs) are released by cells and deliver biologically active payloads to coordinate the response of multiple cell types in cutaneous wound healing. Here we used a cutaneous injury model as a donor of pro-reparative EVs to treat recipient diabetic obese mice, a model of impaired wound healing. We established a functional screen for microRNAs (miRNAs) that increased the pro-reparative activity of EVs and identified a down-regulation of miR-425-5p in EVs in vivo and in vitro associated with the regulation of adiponectin. We tested a cell type-specific reporter of a tetraspanin CD9 fusion with GFP to lineage map the release of EVs from macrophages in the wound bed, based on the expression of miR-425-5p in macrophage-derived EVs and the abundance of macrophages in EV donor sites. Analysis of different promoters demonstrated that EV release under the control of a macrophage-specific promoter was most abundant and that these EVs were internalized by dermal fibroblasts. These findings suggested that pro-reparative EVs deliver miRNAs, such as miR-425-5p, that stimulate the expression of adiponectin that has insulin-sensitizing properties. We propose that EVs promote intercellular signaling between cell layers in the skin to resolve inflammation, induce proliferation of basal keratinocytes, and accelerate wound closure., Competing Interests: Declaration of interests The laboratory receives funding support for EV tropism screening research that is unrelated to the studies described herein from Ionis Pharmaceuticals (B.P.E., P.M., and J.P.N.). J.P.N. is the CEO of Cellarcus Biosciences., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: The COVID pandemic has necessitated mask-wearing by inpatient providers; however, the impact of masks on the acute care surgeon-patient relationship is unknown. We hypothesized that mask-wearing, while necessary, has a negative impact by acting as a barrier to communication, empathy, and trust between patients and surgeons., Methods: A cross-sectional study was performed by administering a written survey in English or Spanish to trauma, emergency general surgery, burn, and surgical critical care inpatients aged ≥18 y at a University Level 1 Trauma Center between January 2023 and June 2023. Patients were asked seven questions about their perception of mask effect on interactions with their surgery providers. Responses were scored on a five-point Likert scale and binarized for multivariable logistic regression., Results: There were 188 patients who completed the survey. The patients were 68% male, 44% Hispanic, and 17% Spanish speaking, with a median age of 45-54 y. A third of patients agreed that surgeon mask-wearing made it harder to understand the details of their surgical procedure and made them less comfortable in giving consent. Twenty three percent agreed that it was harder to trust their provider; increasing age was associated with lower levels of trust, odds ratio 1.36 (confidence interval 1.10-1.71, P = 0.006). Findings were consistent among patients of different sex, race/ethnicity, language, and pre-COVID hospital experience., Conclusions: Mask-wearing, while important, has a negative impact on the patient-surgeon relationship in trauma and acute care surgery. Providers must be conscious of this effect while wearing masks and strive to optimize communication with patients to ensure high-quality trauma-informed care., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Tranexamic Acid (TXA) is an antifibrinolytic drug that is used in traumatic hemorrhage and TBI. Although TXA is considered relatively safe, inexpensive and is widely available, data regarding its mechanisms, optimal dosing, and timing, as well as relative risks and benefits for different patient populations, are inconsistent. In this study we aim to identify and summarize consensus research questions related to TXA across all NTRAP Delphi expert panels to identify priorities for future research on TXA in trauma., Methods: A secondary analysis was performed using consensus-based research priorities collected by 11 NTRAP topic panels using a Delphi methodology. The database of questions was queried for the keywords "tranexamic" and "TXA". The identified questions were sorted by subject matter and summarized., Results: 7 panels included a total of 73 TXA-related questions. 46 questions reached consensus. The most addressed topic was outcomes (discussed in 64% of questions) followed by indications (49%) and specific patient populations (38%). Due to overlap across panels, questions were summarized and sorted by topic resulting in 21 priority research questions., Conclusions: 73 total questions and 46 questions reaching consensus were identified by NTRAP panelists. The key topics identified in these questions should be prioritized in future funded research on TXA in trauma., Level of Evidence: Original Research, IV., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Failure-to-rescue (FTR), defined as death following a major complication, is a metric of trauma quality. The impact of patient frailty on FTR has not been fully investigated, especially in geriatric trauma patients. This study hypothesized that frailty increased the risk of FTR in geriatric patients with severe injury., Methods: A retrospective cohort study was conducted using the TQIP database between 2015 and 2019, including geriatric patients with trauma (age ≥65 years) and an Injury Severity Score (ISS) > 15, who survived ≥48 hours postadmission. Frailty was assessed using the modified 5-item frailty index (mFI). Patients were categorized into frail (mFI ≥ 2) and nonfrail (mFI < 2) groups. Logistic regression analysis and a generalized additive model (GAM) were used to examine the association between FTR and patient frailty after controlling for age, sex, type of injury, trauma center level, ISS, and vital signs on admission., Results: Among 52,312 geriatric trauma patients, 34.6% were frail (mean mFI: frail: 2.3 vs. nonfrail: 0.9, p < 0.001). Frail patients were older (age, 77 vs. 74 years, p < 0.001), had a lower ISS (19 vs. 21, p < 0.001), and had a higher incidence of FTR compared with nonfrail patients (8.7% vs. 8.0%, p = 0.006). Logistic regression analysis revealed that frailty was an independent predictor of FTR (odds ratio, 1.32; confidence interval, 1.23-1.44; p < 0.001). The GAM plots showed a linear increase in FTR incidence with increasing mFI after adjusting for confounders., Conclusion: This study demonstrated that frailty independently contributes to an increased risk of FTR in geriatric trauma patients. The impact of patient frailty should be considered when using FTR to measure the quality of trauma care., Level of Evidence: Therapeutic/Care Management; Level IV., (Copyright © 2024 American Association for the Surgery of Trauma.)

Major floods pose a severe threat to coastal receiving environments, negatively impacting environmental health and ecosystem services through direct smothering with sediment and nutrient loading. This study examined the short and long-term impacts of the February 2022 major flood event on mud extent and sediment nitrogen flux in Moreton Bay (the Bay), a large, sub-tropical embayment in Southeast Queensland, Australia. Short-term impacts were assessed three days after the flood peak by sampling surface water at 47 sites in the direction of the predominant circulation pattern. Longer-term impacts were assessed by undertaking an intensive sediment survey of 223 sites and a nutrient flux experiment using sediment core incubations to simulate calm and resuspension conditions for the four key sediment classes. Short-term impacts revealed elevated turbidity levels extended across the Bay but were highest at the Brisbane River mouth, ammonium concentrations varied inversely with surface turbidity, whereas nitrate concentrates closely tracked surface turbidity. The sediment survey confirmed fine sediment deposition across 98 % of the Bay. Porewater within the upper 10 cm contained a standing pool of 280 t of ammonium, with concentrations more than three orders of magnitude higher than overlying surface waters. The nutrient flux experiment revealed an order of magnitude higher sediment ammonium flux rate in the sandy mud sediment class compared to the other sediment classes; and for simulated resuspension conditions compared to calm conditions for sand, muddy sand, and mud sediment classes. Scaling across the whole Bay, we estimated a mean annual sediment flux of 17,700 t/year ammonium, with a range of 13,500 to 21,900 t/year. Delivery of fine sediments by major floods over the last 50 years now impact >98 % of the benthic zone and provide a major loading pathway of available nitrogen to surface waters of Moreton Bay; representing a significant threat to ecosystem health., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: California issued stay-at-home (SAH) orders to mitigate COVID-19 spread. Previous studies demonstrated a shift in mechanisms of injuries (MOIs) and decreased length of stay (LOS) for the general trauma population after SAH orders. This study aimed to evaluate the effects of SAH orders on geriatric trauma patients (GTPs), hypothesizing decreased motor vehicle collisions (MVCs) and LOS., Methods: A post-hoc analysis of GTPs (≥65 years old) from 11 level-I/II trauma centers was performed, stratifying patients into 3 groups: before SAH (1/1/2020-3/18/2020) (PRE), after SAH (3/19/2020-6/30/2020) (POST), and a historical control (3/19/2019-6/30/2019) (CONTROL). Bivariate comparisons were performed., Results: 5486 GTPs were included (PRE-1756; POST-1706; CONTROL-2024). POST had a decreased rate of MVCs (7.6% vs 10.6%, P = .001; vs 11.9%, P < .001) and pedestrian struck (3.4% vs 5.8%, P = .001; vs 5.2%, P = .006) compared with PRE and CONTROL. Other mechanisms of injury, LOS, mortality, and operations performed were similar between cohorts. However, POST had a lower rate of discharge to skilled nursing facility (SNF) (20% vs 24.5%, P = .001; and 20% vs 24.4%, P = .001)., Conclusion: This retrospective multicenter study demonstrated lower rates of MVCs and pedestrian struck for GTPs, which may be explained by decreased population movement as a result of SAH orders. Contrary to previous studies on the generalized adult population, no differences in other MOIs and LOS were observed after SAH orders. However, there was a lower rate of discharge to SNF, which may be related to a lack of resources due to the COVID-19 pandemic, and thus potentially negatively impacted recovery of GTPs.Keywords., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Prognostic significance of different anticoagulants in TBI patients remains unanswered. We aimed to compare effects of different anticoagulants on outcomes of TBI patients., Methods: A secondary analysis of AAST BIG MIT. Blunt TBI patients ≥50 years using anticoagulants presenting ICH were identified. Outcomes were progression of ICH and need for neurosurgical intervention (NSI)., Results: 393 patients were identified. Mean age was 74 and most common anticoagulant was aspirin (30%), followed by Plavix (28%), and coumadin (20%). 20% had progression of ICH and 10% underwent NSI. On multivariate regression for ICH progression, warfarin, SDH, IPH, SAH, alcohol intoxication and neurologic exam deterioration were associated with increased odds. Warfarin, abnormal neurologic exam on presentation, and SDH were independent predictors of NSI., Conclusions: Our findings reflect a dynamic interaction between type of anticoagulants, bleeding pattern & outcomes. Future modifications of BIG may need to take the type of anticoagulant into consideration., Competing Interests: Declaration of competing interest There are no identifiable conflicts of interest to report., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Abstract: Venous thromboembolism (VTE) is a major issue in trauma patients. Without prophylaxis, the rate of deep venous thrombosis approaches 60% and even with chemoprophylaxis may be nearly 30%. Advances in VTE reduction are imperative to reduce the burden of this issue in the trauma population. Novel approaches in VTE prevention may include new medications, dosing regimens, and extending prophylaxis to the postdischarge phase of care. Standard dosing regimens of low-molecular-weight heparin are insufficient in trauma, shifting our focus toward alternative dosing strategies to improve prophylaxis. Mixed data suggest that anti-Xa-guided dosage, weight-based dosing, and thromboelastography are among these potential strategies. The concern for VTE in trauma does not end upon discharge, however. The risk for VTE in this population extends well beyond hospitalization. Variable extended thromboprophylaxis regimens using aspirin, low-molecular-weight heparin, and direct oral anticoagulants have been suggested to mitigate this prolonged VTE risk, but the ideal approach for outpatient VTE prevention is still unclear. As part of the 2022 Consensus Conference to Implement Optimal Venous Thromboembolism Prophylaxis in Trauma, a multidisciplinary array of participants, including physicians from multiple specialties, pharmacists, nurses, advanced practice providers, and patients met to attack these issues. This paper aims to review the current literature on novel approaches for optimizing VTE prevention in injured patients and identify research gaps that should be investigated to improve VTE rates in trauma., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Disease burden of venous thromboembolism (VTE) without pharmacologic prophylaxis is high in trauma patients. Although VTE prophylaxis guidelines exist, studies on real-world use of VTE prophylaxis in trauma shows limited uptake of guideline recommendations. Despite existing guidelines, reports indicate that VTE prophylaxis implementation across trauma centers is lagging. Implementation barriers of VTE prophylaxis in trauma are multifactorial, and VTE prescribing practices require further optimization. Implementation science methods can help standardize and improve care; well-established approaches in medical and surgical hospitalized patients and their effects on clinical outcomes such as VTE and bleeding complications must be investigated because they apply to trauma patients. Nonadministration of VTE prophylaxis medications in hospitalized patients is associated with VTE events and remains a barrier to providing optimal defect-free care. Further investigations are required for VTE prophylaxis implementation across all trauma populations., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Optimizing prophylaxis against venous thromboembolic events (VTEs) is a critical issue in the care of injured patients. Although these patients are at significant risk of developing VTE, they also present competing concerns related to exacerbation of bleeding from existing injuries. Especially after high-risk trauma, including injuries to the abdominal solid organs, brain, and spine, trauma providers must delineate the time period in which VTE prophylaxis successfully reduces VTE rates without encouraging bleeding. Although existing data are primarily retrospective in nature and further study is required, literature supports early VTE chemoprophylaxis initiation even for severely injured patients. Early initiation is most frequently defined as <48 hours from admission but varies from <24 hours to 72 hours and occasionally refers to time from initial trauma. Prior to chemical VTE prophylaxis initiation in patients at risk for bleeding, an observation period is necessary during which injuries must show themselves to be hemostatic, either clinically or radiographically. In the future, prospective examination of optimal timing of VTE prophylaxis is necessary. Further study of specific subsets of trauma patients will allow for development of effective VTE mitigation strategies based upon collective risks of VTE and hemorrhage progression., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

COVID-19 stay-at-home (SAH) orders were impactful on adolescence, when social interactions affect development. This has the potential to change adolescent trauma. A post-hoc multicenter retrospective analysis of adolescent (13-17 years-old) trauma patients (ATPs) at 11 trauma centers was performed. Patients were divided into 3 groups based on injury date: historical control (CONTROL:3/19/2019-6/30/2019, before SAH (PRE:1/1/2020-3/18/2020), and after SAH (POST:3/19/2020-6/30/2020). The POST group was compared to both PRE and CONTROL groups in separate analyses . 726 ATPs were identified across the 3 time periods. POST had a similar penetrating trauma rate compared to both PRE (15.8% vs 13.8%, P = .56) and CONTROL (15.8% vs 14.5%, P = .69). POST also had a similar rate of suicide attempts compared to both PRE (1.2% vs 1.5%, P = .83) and CONTROL (1.2% vs 2.1%, P = .43). However, POST had a higher rate of drug positivity compared to CONTROL (28.6% vs 20.6%, P = .032), but was similar in all other comparisons of alcohol and drugs to PRE and POST periods (all P > .05). Hence ATPs were affected differently than adults and children, as they had a similar rate of penetrating trauma, suicide attempts, and alcohol positivity after SAH orders. However, they had increased drug positivity compared to the CONTROL, but not PRE group.

Introduction: Brain Injury Guidelines (BIG) was developed to effectively use health care resources including repeat head computed tomography (RHCT) scan and neurosurgical consultation in traumatic brain injury (TBI) patients. The aim of this study was to prospectively validate BIG at a multi-institutional level., Methods: This is a prospective, observational, multi-institutional trial across nine Levels I and II trauma centers. Adult (16 years or older) blunt TBI patients with a positive initial head computed tomography (CT) scan were identified and categorized into BIG 1, 2, and 3 based on their neurologic examination, alcohol intoxication, antiplatelet/anticoagulant use, and head CT scan findings. The primary outcome was neurosurgical intervention. The secondary outcomes were neurologic worsening, RHCT progression, postdischarge emergency department visit, and 30-day readmission., Results: A total of 2,432 patients met the inclusion criteria, of which 2,033 had no missing information and were categorized into BIG 1 (301 [14.8%]), BIG 2 (295 [14.5%]), and BIG 3 (1,437 [70.7%]). In BIG 1, no patient worsened clinically, 4 of 301 patients (1.3%) had progression on RHCT with no change in management, and none required neurosurgical intervention. In BIG 2, 2 of 295 patients (0.7%) worsened clinically, and 21 of 295 patients (7.1%) had progression on RHCT. Overall, 7 of 295 patients (2.4%) would have required upgrade from BIG 2 to 3 because of neurologic examination worsening or progression on RHCT, but no patient required neurosurgical intervention. There were no TBI-related postdischarge emergency department visits or 30-day readmissions in BIG 1 and 2 patients. All patients who required neurosurgical intervention were BIG 3 (280 of 1,437 patients [19.5%]). Agreement between assigned and final BIG categories was excellent ( κ = 99%). In this cohort, implementing BIG would have decreased CT scan utilization and neurosurgical consultation by 29% overall, with a 100% reduction in BIG 1 patients and a 98% reduction in BIG 2 patients., Conclusion: Brain Injury Guidelines is safe and defines the management of TBI patients by trauma and acute care surgeons without the routine need for RHCT and neurosurgical consultation., Level of Evidence: Therapeutic/Care Management; Level III., (Copyright © 2022 American Association for the Surgery of Trauma.)

Many workers are exposed to the effects of heat and often to extreme temperatures. Heat stress has been further aggravated during the COVID-19 pandemic by the use of personal protective equipment to prevent SARS-CoV-2 infection. However, workers' risk perception of heat stress is often low, with negative effects on their health and productivity. The study aims to identify workers' needs and gaps in knowledge, suggesting the adaptation of measures that best comply with the needs of both workers and employers. A cross-sectional online questionnaire survey was conducted in Italy in the hottest months of 2020 (June-October) through different multimedia channels. The data collected were analyzed using descriptive statistics; analytical tests and analysis of variance were used to evaluate differences between groups of workers. In total, 345 questionnaires were collected and analyzed. The whole sample of respondents declared that heat is an important contributor to productivity loss and 83% of workers did not receive heat warnings from their employer. In this context, the internet is considered as the main source of information about heat-related illness in the workplace. Results highlight the need to increase workers' perception of heat stress in the workplace to safeguard their health and productivity. About two-thirds of the sample stated that working in the sun without access to shaded areas, working indoors without adequate ventilation, and nearby fire, steam, and hot surfaces, represent the main injuries' risk factors.

Background: The COVID-19 pandemic overwhelmed hospitals, forcing adjustments including discharging patients earlier and limiting intensive care unit (ICU) utilization. This study aimed to evaluate ICU admissions and length of stay (LOS) for blunt trauma patients (BTPs)., Methods: A retrospective review of COVID (3/19/20-6/30/20) versus pre-COVID (3/19/19-6/30/19) BTPs at eleven trauma centers was performed. Multivariable analysis was used to identify risk factors for ICU admission., Results: 12,744 BTPs were included (6942 pre-COVID vs. 5802 COVID). The COVID cohort had decreased mean LOS (3.9 vs. 4.4 days, p = 0.029), ICU LOS (0.9 vs. 1.1 days, p < 0.001), and rate of ICU admission (22.3% vs. 24.9%, p = 0.001) with no increase in complications or mortality compared to the pre-COVID cohort (all p > 0.05). On multivariable analysis, the COVID period was associated with decreased risk of ICU admission (OR = 0.82, CI 0.75-0.90, p < 0.001)., Conclusions: BTPs had decreased LOS and associated risk of ICU admission during COVID, with no corresponding increase in complications or mortality., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Death from noncompressible torso hemorrhage (NCTH) may be preventable with improved prehospital care and shorter in-hospital times to hemorrhage control. We hypothesized that shorter times to surgical intervention for hemorrhage control would decrease mortality in hypotensive patients with NCTH., Methods: This was an AAST-sponsored multicenter, prospective analysis of hypotensive patients aged 15+ years who presented with NCTH from May 2018 to December 2020. Hypotension was defined as an initial systolic blood pressure (SBP) ≤ 90 mm Hg. Primary outcomes of interest were time to surgical intervention and in-hospital mortality., Results: There were 242 hypotensive patients, of which 48 died (19.8%). Nonsurvivors had higher mean age (47.3 vs. 38.8; p = 0.02), higher mean New Injury Severity Score (38 vs. 29; p < 0.001), lower admit systolic blood pressure (68 vs. 79 mm Hg; p < 0.01), higher incidence of vascular injury (41.7% vs. 21.1%; p = 0.02), and shorter median (interquartile range, 25-75) time from injury to operating room start (74 minutes [48-98 minutes] vs. 88 minutes [61-128 minutes]; p = 0.03) than did survivors. Multivariable Cox regression showed shorter time from emergency department arrival to operating room start was not associated with improved survival (p = 0.04)., Conclusion: Patients who died arrived to a trauma center in a similar time frame as did survivors but presented in greater physiological distress and had significantly shorter times to surgical hemorrhage intervention than did survivors. This suggests that even expediting a critically ill patient through the current trauma system is not sufficient time to save lives from NCTH. Civilian prehospital advance resuscitative care starting from the patient first contact needs special consideration., Level of Evidence: Prognostic/Epidemiologic, Level III., (Copyright © 2022 American Association for the Surgery of Trauma.)

Background: Viscoelastic tests including thromboelastography (TEG) and rotational thromboelastometry (ROTEM) are being used in patients with severe hemorrhage at trauma centers to guide resuscitation. Several recent studies demonstrated hypercoagulability in female trauma patients that was associated with a survival advantage. The objective of our study was to elucidate the effects of gender differences in TEG/ROTEM values on survival in trauma patients with severe hemorrhage., Methods: A retrospective review of consecutive adult patients receiving massive transfusion protocol (MTP) at 7 Level I trauma centers was performed from 2013 to 2018. Data were stratified by gender and then further examined by TEG or ROTEM parameters. Results were analyzed using univariate and multi-variate analyses., Results: A total of 1565 patients were included with 70.9% male gender (n = 1110/1565). Female trauma patients were older than male patients (43.5 ± .9 vs 41.1 ± .6 years, P = .01). On TEG, females had longer reaction times (6.1 ± .9 min vs 4.8 ± .2 min, P = .03), increased alpha angle (68.6 ± .8 vs 65.7 ± .4, P < .001), and higher maximum amplitude (59.8 ± .8 vs 56.3 ± .4, P < .001). On ROTEM, females had significantly longer clot time (99.2 ± 13.7 vs 75.1 ± 2.6 sec, P = .09) and clot formation time (153.6 ± 10.6 sec vs 106.9 ± 3.8 sec, P < .001). When comparing by gender, no difference for in-hospital mortality was found for patients in the TEG or ROTEM group ( P > .05). Multivariate analysis showed no survival difference for female patients (OR 1.11, 95% CI .83-1.50, P = .48)., Conclusions: Although a difference between male and females was found on TEG/ROTEM for certain clotting parameters, no difference in mortality was observed. Prospective multi-institutional studies are needed.

Purpose: The COVID-19 pandemic resulted in increased penetrating trauma and decreased length of stay (LOS) amongst the adult trauma population, findings important for resource allocation. Studies regarding the pediatric trauma population are sparse and mostly single-center. This multicenter study examined pediatric trauma patients, hypothesizing increased penetrating trauma and decreased LOS after the 3/19/2020 stay-at-home (SAH) orders., Methods: A multicenter retrospective analysis of trauma patients ≤ 17 years old presenting to 11 centers in California was performed. Demographic data, injury characteristics, and outcomes were collected. Patients were divided into three groups based on injury date: 3/19/2019-6/30/2019 (CONTROL), 1/1/2020-3/18/2020 (PRE), 3/19/2020-6/30/2020 (POST). POST was compared to PRE and CONTROL in separate analyses., Results: 1677 patients were identified across all time periods (CONTROL: 631, PRE: 479, POST: 567). POST penetrating trauma rates were not significantly different compared to both PRE (11.3 vs. 9.0%, p = 0.219) and CONTROL (11.3 vs. 8.2%, p = 0.075), respectively. POST had a shorter mean LOS compared to PRE (2.4 vs. 3.3 days, p = 0.002) and CONTROL (2.4 vs. 3.4 days, p = 0.002). POST was also not significantly different than either group regarding intensive care unit (ICU) LOS, ventilator days, and mortality (all p > 0.05)., Conclusions: This multicenter retrospective study demonstrated no difference in penetrating trauma rates among pediatric patients after SAH orders but did identify a shorter LOS., (© 2021. The Author(s).)

Purpose: There is mounting evidence that surgical patients with COVID-19 have higher morbidity and mortality than patients without COVID-19. Infection is prevalent amongst the trauma population, but any effect of COVID-19 on trauma patients is unknown. We aimed to evaluate the effect of COVID-19 on a trauma population, hypothesizing increased mortality and pulmonary complications for COVID-19-positive (COVID) trauma patients compared to propensity-matched COVID-19-negative (non-COVID) patients., Methods: A retrospective analysis of trauma patients presenting to 11 Level-I and II trauma centers in California between 1/1/2019-6/30/2019 and 1/1/2020-6/30/2020 was performed. A 1:2 propensity score model was used to match COVID to non-COVID trauma patients using age, blunt/penetrating mechanism, injury severity score, Glasgow Coma Scale score, systolic blood pressure, respiratory rate, and heart rate. Outcomes were compared between the two groups., Results: A total of 20,448 trauma patients were identified during the study period. 53 COVID trauma patients were matched with 106 non-COVID trauma patients. COVID patients had higher rates of mortality (9.4% vs 1.9%, p = 0.029) and pneumonia (7.5% vs. 0.0%, p = 0.011), as well as a longer mean length of stay (LOS) (7.47 vs 3.28 days, p < 0.001) and intensive care unit LOS (1.40 vs 0.80 days, p = 0.008), compared to non-COVID patients., Conclusion: This multicenter retrospective study found increased rates of mortality and pneumonia, as well as a longer LOS, for COVID trauma patients compared to a propensity-matched cohort of non-COVID patients. Further studies are warranted to validate these findings and to elucidate the underlying pathways responsible for higher mortality in COVID trauma patients., (© 2021. The Author(s).)

Abstract: Major pelvic hemorrhage remains a considerable challenge of modern trauma care associated with mortality in over a third of patients. Efforts to improve outcomes demand continued research into the optimal employment of both traditional and newer hemostatic adjuncts across the full spectrum of emergent care environments. The purpose of this review is to provide a concise description of the rationale for and effective use of currently available adjuncts for the control of pelvic hemorrhage. In addition, the challenges of defining the optimal order and algorithm for employment of these adjuncts will be outlined., Level of Evidence: Review, level IV., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background : COVID-19 related stay-at-home (SAH) orders created many economic and social stressors, possibly increasing the risk of drug/alcohol abuse in the community and trauma population. Objectives : Describe changes in alcohol/drug use in traumatically injured patients after SAH orders in California and evaluate demographic or injury pattern changes in alcohol or drug-positive patients. Methods : A retrospective analysis of 11 trauma centers in Southern California (1/1/2020-6/30/2020) was performed. Blood alcohol concentration, urine toxicology results, demographics, and injury characteristics were collected. Patients were grouped based on injury date - before SAH (PRE-SAH), immediately after SAH (POST-SAH), and a historical comparison (3/19/2019-6/30/2019) (CONTROL) - and compared in separate analyses. Groups were compared using chi-square tests for categorical variables and Mann-Whitney U tests for continuous variables. Results : 20,448 trauma patients (13,634 male, 6,814 female) were identified across three time-periods. The POST-SAH group had higher rates of any drug (26.2% vs. 21.6% and 24.7%, OR = 1.26 and 1.08, p < .001 and p = .035), amphetamine (10.4% vs. 7.5% and 9.3%, OR = 1.43 and 1.14, p < .001 and p = .023), tetrahydrocannabinol (THC) (13.8% vs. 11.0% and 11.4%, OR = 1.30 and 1.25, p < .001 and p < .001), and 3,4-methylenedioxy methamphetamine (MDMA) (0.8% vs. 0.4% and 0.2%, OR = 2.02 and 4.97, p = .003 and p < .001) positivity compared to PRE-SAH and CONTROL groups. Alcohol concentration and positivity were similar between groups ( p > .05). Conclusion : This Southern California multicenter study demonstrated increased amphetamine, MDMA, and THC positivity in trauma patients after SAH, but no difference in alcohol positivity or blood concentration. Drug prevention strategies should continue to be adapted within and outside of hospitals during a pandemic.

Background: The rapid spread of coronavirus disease 2019 in the United States led to a variety of mandates intended to decrease population movement and "flatten the curve." However, there is evidence some are not able to stay-at-home due to certain disadvantages, thus remaining exposed to both coronavirus disease 2019 and trauma. We therefore sought to identify any unequal effects of the California stay-at-home orders between races and insurance statuses in a multicenter study utilizing trauma volume data., Methods: A posthoc multicenter retrospective analysis of trauma patients presenting to 11 centers in Southern California between the dates of January 1, 2020, and June 30, 2020, and January 1, 2019, and June 30, 2019, was performed. The number of trauma patients of each race/insurance status was tabulated per day. We then calculated the changes in trauma volume related to stay-at-home orders for each race/insurance status and compared the magnitude of these changes using statistical resampling., Results: Compared to baseline, there was a 40.1% drop in total trauma volume, which occurred 20 days after stay-at-home orders. During stay-at-home orders, the average daily trauma volume of patients with Medicaid increased by 13.7 ± 5.3%, whereas the volume of those with Medicare, private insurance, and no insurance decreased. The average daily trauma volume decreased for White, Black, Asian, and Latino patients with the volume of Black and Latino patients dropping to a similar degree compared to White patients., Conclusion: This retrospective multicenter study demonstrated that patients with Medicaid had a paradoxical increase in trauma volume during stay-at-home orders, suggesting that the most impoverished groups remain disproportionately exposed to trauma during a pandemic, further exacerbating existing health disparities., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Anticoagulants prevent thrombosis and death in patients with atrial fibrillation and venous thromboembolism (VTE) but also increase bleeding risk. The benefit/risk ratio favors anticoagulation in most of these patients. However, some will have a bleeding complication, such as the common trip-and-fall brain injury in elderly patients that results in traumatic intracranial hemorrhage. Clinicians must then make the difficult decision about when to restart the anticoagulant. Restarting too early risks making the bleeding worse. Restarting too late risks thrombotic events such as ischemic stroke and VTE, the indications for anticoagulation in the first place. There are more data on restarting patients with spontaneous intracranial hemorrhage, which is very different than traumatic intracranial hemorrhage. Spontaneous intracranial hemorrhage increases the risk of rebleeding because intrinsic vascular changes are widespread and irreversible. In contrast, traumatic cases are caused by a blow to the head, usually an isolated event portending less future risk. Clinicians generally agree that anticoagulation should be restarted but disagree about when. This uncertainty leads to long restart delays causing a large, potentially preventable burden of strokes and VTE, which has been unaddressed because of the absence of high quality evidence. Restart Traumatic Intracranial Hemorrhage (the "r" distinguished intracranial from intracerebral) (TICrH) is a prospective randomized open label blinded end-point response-adaptive clinical trial that will evaluate the impact of delays to restarting direct oral anticoagulation (1, 2, or 4 weeks) on the composite of thrombotic events and bleeding in patients presenting after traumatic intracranial hemorrhage.

Background: The COVID-19 pandemic resulted in a statewide stay-at-home (SAH) order in California beginning March 19, 2020, forcing large-scale behavioral changes and taking an emotional and economic toll. The effects of SAH orders on the trauma population remain unknown. We hypothesized an increase in rates of penetrating trauma, gunshot wounds, suicide attempts, and domestic violence in the Southern California trauma population after the SAH order., Methods: A multicenter retrospective analysis of all trauma patients presenting to 11 American College of Surgeons levels I and II trauma centers spanning seven counties in California was performed. Demographic data, injury characteristics, clinical data, and outcomes were collected. Patients were divided into three groups based on injury date: before SAH from January 1, 2020, to March 18, 2020 (PRE), after SAH from March 19, 2020, to June 30, 2020 (POST), and a historical control from March 19, 2019, to June 30, 2019 (CONTROL). POST was compared with both PRE and CONTROL in two separate analyses., Results: Across all periods, 20,448 trauma patients were identified (CONTROL, 7,707; PRE, 6,022; POST, 6,719). POST had a significantly increased rate of penetrating trauma (13.0% vs. 10.3%, p < 0.001 and 13.0% vs. 9.9%, p < 0.001) and gunshot wounds (4.5% vs. 2.4%, p = 0.002 and 4.5% vs. 3.7%, p = 0.025) compared with PRE and CONTROL, respectively. POST had a suicide attempt rate of 1.9% and a domestic violence rate of 0.7%, which were similar to PRE (p = 0.478, p = 0.514) and CONTROL (p = 0.160, p = 0.618)., Conclusion: This multicenter Southern California study demonstrated an increased rate of penetrating trauma and gunshot wounds after the COVID-19 SAH orders but no difference in attempted suicide or domestic violence rates. These findings may provide useful information regarding resource utilization and a target for societal intervention during the current or future pandemic(s)., Level of Evidence: Epidemiological, level IV., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Trauma registries are used to identify modifiable injury risk factors for trauma prevention efforts. However, these may miss factors useful for prevention of bicycle-automobile collisions, such as vehicle speeds, driver intoxication, street conditions, and neighborhood characteristics. We hypothesize that (GIS) analysis of trauma registry data matched with a traffic accident database could identify risk factors for bicycle-automobile injuries and better inform injury prevention efforts., Methods: The trauma registry of a US Level I trauma center was used retrospectively to identify bicycle-motor vehicle collision admissions from January 1, 2010, to December 31, 2018. Data collected included demographics, vitals, injury severity scores, toxicology, helmet use, and mortality.Matching with the Statewide Integrated Traffic Records System was done to provide collision, victim and GIS information. The GIS mapping of collisions was done with census tract data including poverty level scoring. Incident hot spot analysis to identify statistically significant incident clusters was done using the Getis Ord Gi* statistic., Results: Of 25,535 registry admissions, 531 (2.1%) were bicyclists struck by automobiles, 425 (80.0%) were matched to Statewide Integrated Traffic Records System. Younger age (odds ratio [OR], 1.026; 95% confidence interval [CI], 1.013-1.040, p < 0.001), higher census tract poverty level percentage (OR, 0.976; 95% CI, 0.959-0.993, p = 0.007), and high school or less education (OR, 0.60; 95 CI, 0.381-0.968; p = 0.036) were predictive of not wearing a helmet. Higher census tract poverty level percentage (OR, 1.019; 95% CI, 1.004-1.034; p = 0.012) but not educational level was predictive of toxicology positive-bicyclists in automobile collisions. Geographic information systems analysis identified hot spots in the catchment area for toxicology-positive bicyclists and lack of helmet use., Conclusion: Combining trauma registry data and matched traffic accident records data with GIS analysis identifies additional risk factors for bicyclist injury. Trauma centers should champion efforts to prospectively link public traffic accident data to their trauma registries., Level of Evidence: Prognostic and Epidemiological, level III., (Copyright © 2021 American Association for the Surgery of Trauma.)

Microbial communities drive diverse processes that impact nearly everything on this planet, from global biogeochemical cycles to human health. Harnessing the power of these microorganisms could provide solutions to many of the challenges that face society. However, naturally occurring microbial communities are not optimized for anthropogenic use. An emerging area of research is focusing on engineering synthetic microbial communities to carry out predefined functions. Microbial community engineers are applying design principles like top-down and bottom-up approaches to create synthetic microbial communities having a myriad of real-life applications in health care, disease prevention, and environmental remediation. Multiple genetic engineering tools and delivery approaches can be used to 'knock-in' new gene functions into microbial communities. A systematic study of the microbial interactions, community assembling principles, and engineering tools are necessary for us to understand the microbial community and to better utilize them. Continued analysis and effort are required to further the current and potential applications of synthetic microbial communities., (© 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

The complex molecular microenvironment of the wound bed regulates the duration and degree of inflammation in the wound repair process, while its dysregulation leads to impaired healing. Understanding factors controlling this response provides therapeutic targets for inflammatory disease. Esophageal cancer-related gene 4 (ECRG4) is a candidate chemokine that is highly expressed on leukocytes. We used ECRG4 knockout (KO) mice to establish that the absence of ECRG4 leads to defective neutrophil recruitment with a delay in wound healing. An in vitro human promyelocyte model identified an ECRG4-mediated suppression of the hyaluronic acid receptor, CD44, a key receptor mediating inflammation resolution. In ECRG4 KO mouse leukocytes, there was an increase in CD44 expression, consistent with a model in which ECRG4 negatively regulates CD44 levels. Therefore, we propose a previously unidentified mechanism in which ECRG4 regulates early neutrophil recruitment and subsequent CD44-mediated resolution of inflammation., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Background: Gut damage after trauma/hemorrhagic shock contributes to multiple organ dysfunction syndrome. Electrical vagal nerve stimulation is known to prevent gut damage in animal models of trauma/hemorrhagic shock by altering the gut inflammatory response; however, the effect of vagal nerve stimulation on intestinal blood flow, which is an essential function of the vagus nerve, is unknown. This study aimed to determine whether vagal nerve stimulation influences the abdominal vagus nerve activity, intestinal blood flow, gut injury, and the levels of autonomic neuropeptides., Methods: Male Sprague Dawley rats were anesthetized, and the cervical and abdominal vagus nerves were exposed. One pair of bipolar electrodes was attached to the cervical vagus nerve to stimulate it; another pair of bipolar electrodes were attached to the abdominal vagus nerve to measure action potentials. The rats underwent trauma/hemorrhagic shock (with maintenance of mean arterial pressure of 25 mmHg for 30 min) without fluid resuscitation and received cervical vagal nerve stimulation post-injury. A separate cohort of animals were subjected to transection of the abdominal vagus nerve (vagotomy) just before the start of cervical vagal nerve stimulation. Intestinal blood flow was measured by laser Doppler flowmetry. Gut injury and noradrenaline level in the portal venous plasma were also assessed., Results: Vagal nerve stimulation evoked action potentials in the abdominal vagus nerve and caused a 2-fold increase in intestinal blood flow compared to the shock phase (P < .05). Abdominal vagotomy eliminated the effect of vagal nerve stimulation on intestinal blood flow (P < .05). Vagal nerve stimulation protected against trauma/hemorrhagic shock -induced gut injury (P < .05), and circulating noradrenaline levels were decreased after vagal nerve stimulation (P < .05)., Conclusion: Cervical vagal nerve stimulation evoked abdominal vagal nerve activity and relieved the trauma/hemorrhagic shock-induced impairment in intestinal blood flow by modulating the vasoconstriction effect of noradrenaline, which provides new insight into the protective effect of vagal nerve stimulation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Wound healing is a complex process involving diverse changes in multiple cell types where the application of electric fields has been shown to accelerate wound closure. To define the efficacy of therapies based on electric fields, it would be valuable to have a platform to systematically study the effects of electrical stimulation (ES) upon the inflammation phase and the activation of signaling mediators. Here, an in vivo ES model in which flexible electrodes are applied to an animal model for monitoring inflammation in a wound is reported on. Subcutaneous implants of polyvinyl alcohol sponges elicit inflammation response as defined by the infiltration of leukocytes. The wound site is subjected to electric fields using two types of additively fabricated flexible electrode arrays. The sponges are then harvested for flow cytometry analysis to identify changes in the phosphorylation state of intracellular targets. This platform enables studies of molecular mechanisms, as it shows that an application of low-frequency ES ≤0.5 Hz increases phosphorylation of Erk proteins in recruited leukocytes, identifying a signaling pathway that is activated during the healing process., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background and Purpose: Surfing is a rapidly growing major worldwide sport; however, little is understood regarding severe injuries and resulting hospital admissions. This study explores surfing-related injuries in the major surfing hub of San Diego presenting in the acute trauma setting. The purpose of this study is to address the void of information regarding severe surfing injuries in the trauma setting, including injury patterns, associated hospitalization course, and risk factors. Understanding the injury patterns in surfing accidents is crucial for proper management of surfing injuries., Methods: A retrospective analysis was performed of all surfing-related injuries in a Level 1 trauma center between 2000 and 2016., Results: A total of 93 patients were identified. Body parts most commonly affected include the head (42, 46%), face (21, 22%), and spine (47, 51%). Twenty-eight (30%) patients required surgical intervention, including 19 for spinal injuries, 3 for facial injuries, 4 for upper extremity injuries, and 2 for lower extremity injuries. The distribution for most presentations (55, 59%) occurred in the summer months between July and September. The Injury Severity Score demonstrated strong positive correlation with the length of hospital stay, with a Pearson coefficient of 0.52 (P < 0.01). The average length of hospitalization was 5.8 days, with intensive care unit level care required in 49% (46) patients and average length of intensive care unit stay of 5.5 days. Alcohol content was tested in 84% (78) of patients and found positive in 10% (8) of tested patients. Drug screening was performed in 70% (64) patients and found positive in 38% (24) of tested patients., Conclusions: Surfing, although a relatively safe sport, is not without major risks. In contrast with other studies, we found a high proportion of head, face, and spine injuries in patients presenting with surfing injuries in the trauma setting, consistent with its presentation as a high velocity and high impact injury. With plastic surgeons often treating severe head and facial injuries, understanding the injury patterns in severe surfing accidents is crucial for proper management. High rates of positive alcohol and drug screening signal the importance to bring awareness to the dangers of surfing under the influence.

In light of the central role of inflammation in normal wound repair and regeneration, we hypothesize that the preponderance of human-specific genes expressed in human inflammatory cells is commensurate with the genetic versatility of inflammatory response and the emergence of injuries associated with uniquely hominid behaviors, like a bipedal posture and the use of tools, weapons and fire. The hypothesis underscores the need to study human-specific signaling pathways in experimental models of injury and infers that a selection of human-specific genes, driven in part by the response to injury, may have facilitated the emergence of multifunctional genes expressed in other tissues., (© 2016 The Authors Wound Repair and Regeneration published by Wiley Periodicals, Inc. on behalf of The Wound Healing Society.)

Objective and Design: The human c2orf40 gene encodes a tumor suppressor gene called esophageal cancer-related gene-4 (ECRG4) with pro- and anti-inflammatory activities that depend on cell surface processing. Here, we investigated its physical and functional association with the innate immunity receptor complex., Methods: Interactions between ECRG4 and the innate immunity receptor complex were assessed by flow cytometry, immunohistochemistry, confocal microscopy, and co-immunoprecipitation. Phage display was used for ligand targeting to cells that overexpress the TLR4-MD2-CD14., Results: Immunoprecipitation and immunohistochemical studies demonstrate a physical interaction between ECRG4 and TLR4-MD2-CD14 on human granulocytes. Flow cytometry shows ECRG4 on the cell surface of a subset of CD14(+) and CD16(+) leukocytes. In a cohort of trauma patients, the C-terminal 16 amino acid domain of ECRG4 (ECRG4(133-148)) appears to be processed and shed, presumably at a thrombin-like consensus sequence. Phage targeting this putative ligand shows that this peptide sequence internalizes into cells through the TLR4/CD14/MD2 complex, but modulates inflammation through non-canonical, NFκB signal transduction., Conclusions: ECRG4 is present on the surface of human monocytes and granulocytes. Its interaction with the human innate immunity receptor complex supports a role for cell surface activation of ECRG4 during inflammation and implicates this receptor in its mechanism of action.

In humans, esophageal cancer-related gene 4 (ECRG4) is encoded by four exons in the c2orf40 locus of chromosome 2. Translation of ECRG4 messenger ribonucleic acid produces a 148 amino acid-secreted 17 KDa protein that is then processed to 14, ten, eight, six, four, and two KDa peptides, depending on the cell in which the gene is expressed. As hypermethylation at the c2orf40 locus inhibits ECRG4 gene expression in many epithelial cancers, several investigators have speculated that ECRG4 is a candidate tumor suppressor. Indeed, overexpression of ECRG4 inhibits cell proliferation in vitro, but it also has a wide range of effects in vivo beyond its antitumor activity. ECRG4 overexpression affects apoptosis, senescence, cell migration, inflammation, injury, and infection responsiveness. ECRG4 activities also depend on its cellular localization, secretion, and post-translational processing. These cytokine/chemokine-like characteristics argue that ECRG4 is not a traditional candidate tumor suppressor gene, as originally predicted by its downregulation in cancer. We review how insights into the regulation of ECRG4 gene expression, knowledge of its primary structure, and the study of its emerging physiological functions come together to support a much more complex role for ECRG4 at the interface of inflammation, infection, and malignancy.

Damage control laparotomy was first described by Dr. Harlan Stone in 1983 when he suggested that patients with severe trauma should have their primary procedures abbreviated when coagulopathy was encountered. He recommended temporizing patients with abdominal packing and temporary closure to allow restoration of normal physiology prior to returning to the operating room for definitive repair. The term damage control in the trauma setting was coined by Rotondo et al., in 1993. Studies in subsequent years have validated this technique by demonstrating decreased mortality and immediate post-operative complications. The indications for damage control laparotomy have evolved to encompass abdominal compartment syndrome, abdominal sepsis, vascular and acute care surgery cases. The perioperative critical care provided to these patients, including sedation, paralysis, nutrition, and fluid management strategies may improve closure rates and recovery. In the rare cases of inability to primarily close the abdomen, there are a number of reconstructive strategies that may be used in the acute and chronic phases of abdominal closure.

Mitochondria play a central role in the integration and execution of a wide variety of apoptotic signals. In the present study, we examined the deleterious effects of burn injury on heart tissue. We explored the effects of vagal nerve stimulation (VNS) on cardiac injury in a murine burn injury model, with a focus on the protective effect of VNS on mitochondrial dysfunction in heart tissue. Mice were subjected to a 30% total body surface area, full-thickness steam burn followed by right cervical VNS for 10 min. and compared to burn alone. A separate group of mice were treated with the M3-muscarinic acetylcholine receptor (M3-AchR) antagonist 4-DAMP or phosphatidylinositol 3 Kinase (PI3K) inhibitor LY294002 prior to burn and VNS. Heart tissue samples were collected at 6 and 24 hrs after injury to measure changes in apoptotic signalling pathways. Burn injury caused significant cardiac pathological changes, cardiomyocyte apoptosis, mitochondrial swelling and decrease in myocardial ATP content at 6 and 24 hrs after injury. These changes were significantly attenuated by VNS. VNS inhibited release of pro-apoptotic protein cytochrome C and apoptosis-inducing factor from mitochondria to cytosol by increasing the expression of Bcl-2, and the phosphorylation level of Bad (pBad(136)) and Akt (pAkt(308)). These protective changes were blocked by 4-DAMP or LY294002. We demonstrated that VNS protected against burn injury-induced cardiac injury by attenuating mitochondria dysfunction, likely through the M3-AchR and the PI3K/Akt signalling pathways., (© 2013 The Authors. Published by Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.)

Background: It has been well established that laparoscopic surgery presents several clinical benefits, including reduced pain and a shorter hospital stay. These effects have been associated with a decrease in the inflammatory response. Previous studies have demonstrated that reduced inflammation after laparoscopic surgery is the product of carbon dioxide insufflation, which decreases peritoneal pH. The objective of this study was to investigate the cellular and molecular mechanisms responsible for the reduced response after exposure to acidic environments., Materials and Methods: A murine macrophage line (J744) was incubated in culture medium at pH 6.0 or pH 7.4 for 3 h at 37°C. Then, cells were stimulated with lipopolysaccharide (LPS) at pH 7.4, the expression of TNF-α (qRT-PCR or enzyme-linked immunosorbent assay (ELISA) and intracellular pH were measured. In addition, CD14 and Toll-like receptor 4 expression and NF-κB nuclear translocation were analyzed., Results: A significant decrease in LPS-induced TNF-α expression levels was observed in cells pre-incubated at pH 6.0 in comparison with cells at neutral pH conditions. This decrease in TNF-α levels was not associated with a reduction in cell surface expression of CD14 and Toll-like receptor 4. Exposure to an extracellular acidic environment resulted in a reduction of IκB phosphorylation and NF-κB nuclear translocation, secondary to a significant drop in cytosolic pH., Conclusions: These observations provide a potential mechanism for the reduced expression of TNF-α after exposure to low extracellular pH, which may be related to acidification after CO(2) insufflation during laparoscopic surgery. In addition, extracellular acidic pH environments could emerge as an important regulator of macrophage function., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Intestinal barrier breakdown following traumatic brain injury (TBI) is characterized by increased intestinal permeability, leading to bacterial translocation, and inflammation. The hormone ghrelin may prevent intestinal injury and have anti-inflammatory properties. We hypothesized that exogenous ghrelin prevents intestinal injury following TBI. A weight-drop model created severe TBI in three groups of anesthetized Balb/c mice. Group TBI: animals underwent TBI only; Group TBI/ghrelin: animals were given 10 μg of ghrelin intraperitoneally prior and 1 h following TBI; Group sham: no TBI or ghrelin injection. Intestinal permeability was measured 6 h following TBI by detecting serum levels of FITC-Dextran after injection into the intact ileum. The terminal ileum was harvested for histology, expression of the tight junction protein MLCK and inflammatory cytokine TNF-α. Permeability increased in the TBI group compared to the sham group (109.7 ± 21.8 μg/mL vs. 32.2 ± 10.1 μg/mL; p < 0.002). Ghrelin prevented TBI-induced permeability (28.3 ± 4.2 μg/mL vs. 109.7 ± 21.8 μg/mL; p < 0.001). The intestines of the TBI group showed blunting and necrosis of villi compared to the sham group, while ghrelin injection preserved intestinal architecture. Intestinal MLCK increased 73% compared to the sham group (p < 0.03). Ghrelin prevented TBI-induced MLCK expression to sham levels. Intestinal TNF-α increased following TBI compared to the sham group (46.2 ± 7.1 pg/mL vs. 24.4 ± 2.2 pg/mL p < 0.001). Ghrelin reduced TNF-α to sham levels (29.2 ± 5.0 pg/mL; p = NS). We therefore conclude that ghrelin prevents TBI-induced injury, as determined by intestinal permeability, histology, and intestinal levels of TNF-α. The mechanism for ghrelin mediating intestinal protection is likely multifactorial, and further studies are needed to delineate these possibilities.

Background: Hypertonic saline (HS) restores prostaglandin E(2) (PGE(2))-induced T-cell suppression in the presence of 1100 microM arginine. However, under arginine-free culture conditions, HS dose not restore T-cell proliferation. Therefore, we wanted to determine if HS can restore PGE(2)-induced T-cell suppression in the presence of 80 microM of arginine, the physiologically relevant arginine concentration. We also wanted to determine the concentration of arginine that induces HS restoration of PGE(2)-suppressed T-cell proliferation and whether HS restoration of T-cell dysfunction is dependent on the injection time of HS., Materials and Methods: Jurkat cells were cultured in media containing 0, 40, 80, 400, 800, or 1100 microM arginine. In both the PGE(2)-stimulated and HS-treated group, we measured cell proliferation using MTT assay and arginase activity. We also measured cell proliferation relative to HS injection time., Results: In 80 microM arginine, HS did not restore Jurkat cell proliferation that had been suppressed by PGE(2). Increased concentrations of arginine in the media increased MTT cell proliferation. In 800 microM arginine media, HS restored PGE(2)-suppressed Jurkat cell proliferation to normal. HS restored PGE(2)-suppressed Jurkat cell proliferation when it was added at 2 h, similar to at same time and 1 h after PGE(2) stimulation., Conclusions: In order to restore PGE(2)-suppressed Jurkat cell proliferation, HS requires at least 800 microM arginine. HS restored PGE(2)-suppressed Jurkat cell proliferation even though HS was added at 2 h after PGE(2) stimulation., (Copyright 2010 Elsevier Inc. All rights reserved.)