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Abstract Background Limited research has explored the effect of Circle of Willis (CoW) anatomy among blunt cerebrovascular injuries (BCVI) on outcomes. It remains unclear if current BCVI screening and scanning practices are sufficient in identification of concomitant COW anomalies and how they affect outcomes. Methods This retrospective cohort study included adult traumatic BCVIs at 17 level I-IV trauma centers (08/01/2017-07/31/2021). The objectives were to compare screening criteria, scanning practices, and outcomes among those with and without COW anomalies. Results Of 561 BCVIs, 65% were male and the median age was 48 y/o. 17% (n = 93) had a CoW anomaly. Compared to those with normal CoW anatomy, those with CoW anomalies had significantly higher rates of any strokes (10% vs. 4%, p = 0.04), ICHs (38% vs. 21%, p = 0.001), and clinically significant bleed (CSB) before antithrombotic initiation (14% vs. 3%, p

Abstract Background There is an epidemic of firearm injuries in the United States since the mid-2000s. Thus, we sought to examine whether hospitalization from firearm injuries have increased over time, and to examine temporal changes in patient demographics, firearm injury intent, and injury severity. Methods This was a multicenter, retrospective, observational cohort study of patients hospitalized with a traumatic injury to six US level I trauma centers between 1/1/2016 and 6/30/2022. ICD-10-CM cause codes were used to identify and describe firearm injuries. Temporal trends were compared for demographics (age, sex, race, insured status), intent (assault, unintentional, self-harm, legal intervention, and undetermined), and severity (death, ICU admission, severe injury (injury severity score ≥ 16), receipt of blood transfusion, mechanical ventilation, and hospital and ICU LOS (days). Temporal trends were examined over 13 six-month intervals (H1, January–June; H2, July–December) using joinpoint regression and reported as semi-annual percent change (SPC); significance was p

Introduction The surgical approach of hemiarthroplasty for displaced femoral neck fractures remains debated. The study objective was to compare in-hospital outcomes for geriatric displaced femoral neck fractures treated with hemiarthroplasty based on surgical approach (direct lateral vs. posterior approach). Materials and Methods This retrospective cohort study included geriatric patients (≥60 y/o) admitted 7/1/2016-3/31/2020 treated with hemiarthroplasty. Outcomes included: operative time (incision to closure), length of stay (HLOS), and blood loss volume (mL). The Harding direct lateral approach was compared to the posterior approach; P < .05. Results There were 164 patients (59% direct lateral, 41% posterior). Patients treated with the direct lateral approach had an advanced directive ( P = .03), dementia, ( P = .03), or were functionally dependent ( P = .03) more often than patients treated with the posterior approach. Time to surgery was comparable between groups ( P = .52). The direct lateral approach was associated with a shorter operative time (2.3 vs. 2.8 h, P = .03), a longer HLOS (5.0 vs. 4.0 days, P < .01), and a lower median volume of blood loss (50 vs. 100 mL, P = .01), than the posterior approach, respectively. In a stratified analysis, for those who were not functionally dependent, did not have dementia or an advanced directive, the direct lateral approach led to a longer HLOS ( P = .03) and shorter operative time ( P = .04) than the posterior approach. Whereas among those who were functionally dependent, had dementia or had an advanced directive, the direct lateral approach led to less blood loss ( P = .02) than the posterior approach. Discussion While those treated with the direct lateral approach lost significantly less blood, they had a significantly longer HLOS than those treated with the posterior approach. Comorbidities significantly modified outcomes, which may suggest their presence could assist with treatment decisions. Conclusions This study found neither approach, the direct lateral nor posterior, to be superior. Surgical approach could remain physician preference.

Background Stress ulcers in patients with traumatic brain injury (TBI) and spinal cord injury (SCI) present significant morbidity and mortality risks. Despite the low reported stress ulcer rates, stress ulcer prophylaxis (SUP) is widely administered in neurocritical care. It was hypothesized that universal SUP administration may not be associated with reduced rates of complications across all neurocritical care patients.Methods This retrospective study encompassed neurocritical care patients aged ≥18 with moderate or severe TBI or SCI, admitted to the intensive care unit (ICU) between October 2020 and September 2021, across six level I trauma centers. Exclusions included patients with an ICU stay

Objective The perioperative management of patients on antiplatelet drugs is a rising challenge in orthopedic trauma because antiplatelet drugs are frequently encountered and carry an increased risk of hemorrhagic consequences. The study objective was to examine the effect of aspirin on bleeding outcomes for patients with lower extremity fractures.Methods This retrospective study included patients requiring surgical fixation of traumatic hip, femur, and tibia fractures from January 1, 2018, to March 1, 2020. Patients were excluded if they had a significant head injury, were on chronic anticoagulant therapy, or they did not receive venous thromboembolism chemoprophylaxis. Comparisons between aspirin users (patients on aspirin therapy preinjury) and non-aspirin users were examined using χ2 tests, Cochran-Mantel-Haenszel tests, and multivariate logistic regression. The primary outcome was an overt, actionable bleed (eg, blood transfusion for surgical site hemorrhage) within 24 hours postoperative.Results There were 864 patients with lower extremity long bone fractures and 24% were aspirin users. The incidence of postoperative bleeding was 8.8% and significantly differed for patients taking aspirin versus not (13.6% vs 7.3%, p=0.01). However, biological sex at birth (M/F) was a significant effect modifier (interaction p=0.04). Among women, there were significantly more postoperative bleeds for aspirin users (17.8% aspirin vs 7.4% no aspirin, adjusted OR (AOR): 2.48 (1.28–4.81), p=0.01). Among men, there were similar postoperative bleeding events by aspirin use (5.6% aspirin vs 7.2% no aspirin, AOR: 0.50 (0.14–1.82), p=0.30). Postoperative hemoglobin values

Abstract Background Reversal of direct oral anticoagulants (DOACs) is currently recommended prior to emergent surgery, such as surgical intervention for traumatic geriatric hip fractures. However, reversal methods are expensive and timely, often delaying surgical intervention, which is a predictor of outcomes. The study objective was to examine the effect of DOAC reversal on blood loss and transfusions among geriatric patients with hip fractures. Methods This retrospective propensity-matched study across six level I trauma centers included geriatric patients on DOACs with isolated fragility hip fractures requiring surgical intervention (2014–2017). Outcomes included: intraoperative blood loss, intraoperative pRBCs, and hospital length of stay (HLOS). Results After matching there were 62 patients (31 reversed, 31 not reversed), 29 patients were not matched. The only reversal method utilized was passive reversal (waiting ≥ 24 hours for elimination). Passively reversed patients had a longer time to surgery (mean, 43 vs. 18 hours, p

ObjectiveThere are no studies to date that examine the association between anti-factor-Xa (AFXa)-based heparin monitoring and clinical outcomes in the setting of cerebral venous thrombosis (CVT).MethodsThis pilot study included adults aged ≥18 admitted with CVT between 1 January 2018 and 1 January 2021, who were treated with unfractionated heparin (UFH) and were monitored via AFXa-based nomogram within 24 h of arrival. Comparisons were made between patients with AFXa levels within the target therapeutic range (0.25–0.5 IU/mL) and patients whose levels were not within the therapeutic range within 24 h of arrival; the time (hours) from arrival to reach the therapeutic range was also examined. Outcomes were length of stay (LOS) in the hospital, major (actionable) bleeding events, and discharge home (vs. higher acuity location). Continuous data are reported in the form of the median (interquartile range).ResultsAmong 45 patients, treatment with UFH was initiated 2 (1–11) h after arrival, and the majority (84%) of UFH infusions did not need dose adjustment. AFXa assays were conducted every 6 (5.5–7) h. Thirty patients (67%) fell within the therapeutic range. Outcomes were similar for patients with levels within the therapeutic range vs. not: major bleeding events, 10% vs. 0% (p = 0.54); discharge home, 77% vs. 80% (p = 1.0); LOS, 5 days in each group (p = 0.95). There was also no association between outcomes and time to reach the therapeutic range.ConclusionOur findings demonstrate the practicability of monitoring UFH based on AFXa values in this population of patients with CVT, but reaching target AFXa levels within 24 h of arrival may not necessarily be prognostic.

The objective of this study was to quantify nation-wide interhospital variation in neurosurgical intervention risk by intracranial hemorrhage (ICH) type in the setting of mild traumatic brain injury (mTBI). This was a retrospective cohort study of adult (?18 years) trauma patients included in the National Trauma Data Bank from 2007 to 2019 with an emergency department Glasgow Coma Scale score 13?15, diagnosed ICH, no skull fracture. The primary outcome was neurosurgical intervention. Interhospital variation was assessed by examining the best linear unbiased predictors (BLUPs) obtained from mixed-effects logistic regression with random slopes and intercepts for hospitals and covariates for time and 14 demographic, injury, and hospital characteristics; one model per ICH type. Intercept BLUPs are estimates of how different each hospital is from the average hospital (after covariate adjustment). The study population included 49,220 (7%) neurosurgical interventions among 666,842 patients in 1060 hospitals. In 2019, after adjusting for patient case-mix and hospital characteristics, the percentage of hospitals with hemorrhage-specific neurosurgical intervention risk significantly different from the average hospital was as follows: isolated unspecified hemorrhage (0% of 995 hospitals); isolated contusion/laceration (0.54% of 929); isolated epidural hemorrhage (0.39% of 778); isolated subarachnoid hemorrhage (0.10% of 1002); multiple hemorrhages (2.49% of 963); and isolated subdural hemorrhage (16.25% of 1028). In the setting of mTBI, isolated subdural hemorrhages were the only ICH type to have considerable interhospital variability. Causes for this significant variation should be elucidated and might include changing hemorrhage characteristics and practice patterns over time.

There have been large changes over the past several decades to patient demographics in those presenting with mild traumatic brain injury (mTBI) with intracranial hemorrhage (ICH; complicated mTBI) with the potential to affect the use of neurosurgical interventions. The objective of this study was to characterize long-term trends of neurosurgical interventions in patients with complicated mTBI using 13 years of the National Trauma Data Bank (NTDB). This was a retrospective cohort study of adult (?18 years) trauma patients included in the NTDB from 2007 to 2019 who had an emergency department Glasgow Coma Scale score 13?15, an intracranial hemorrhage (ICH), and no skull fracture. Neurosurgical intervention time trends were quantified for each ICH type using mixed-effects logistic regression with random slopes and intercepts for hospitals, as well as covariates for time and 14 demographic, injury, and hospital characteristics. In total, 666,842 ICH patients across 1060 hospitals were included. The four most common hemorrhages were isolated subdural hemorrhage (36%), isolated subarachnoid hemorrhage (24%), multiple hemorrhage types (24%), and isolated unspecified hemorrhages (9%). Overall, 49,220 (7%) patients received a neurosurgical intervention. After adjustment, the odds of neurosurgical intervention significantly decreased every 10 years by the following odds ratios (odds ratio [95% confidence interval]): 0.85 [0.78, 0.93] for isolated subdural, 0.63 [0.51, 0.77] for isolated subarachnoid, 0.50 [0.41, 0.62] for isolated unspecified, and 0.79 [0.73, 0.86] for multiple hemorrhages. There were no significant temporal trends in neurosurgical intervention odds for isolated epidural hemorrhages (0.87 [0.68, 1.12]) or isolated contusions/lacerations (1.03 [0.75, 1.41]). In the setting of complicated mTBI, the four most common ICH types were associated with significant declines in the odds of neurosurgical intervention over the past decade. It remains unclear whether changing hemorrhage characteristics or practice patterns drove these trends.

Objective:. Restrictive fluid management (RFM) for hemodynamically unstable trauma patients has reduced mortality rates. The objective was to determine whether RFM benefits geriatric hip fracture patients, who are usually hemodynamically stable. Design:. Retrospective propensity-matched study. Setting:. Five Level I trauma centers (January 1, 2018–December 12, 2018). Patients:. Geriatric patients (65 years or older) with hip fractures were included in this study. Patients with multiple injuries, nonoperative management, and preoperative blood products were excluded. Intervention:. Patients were grouped by fluid volume (normal saline, lactated Ringer, dextrose, electrolytes, and medications) received preoperatively or ≤24 hours of arrival; patients with standard fluid management (SFM) received ≥150 mL and RFM 2 days postoperatively), and mortality. Paired Student t-tests, Wilcoxon paired rank sum tests, and McNemar tests were used; an α value of < 0.05 was considered statistically significant. Results:. There were 523 patients (40% RFM, 60% SFM); after matching, there were 95 patients per arm. The matched patients were well-balanced, including no difference in time from arrival to surgery. RFM and SFM patients received a median of 80 mL and 1250 mL of preoperative fluids, respectively (P < 0.001). Postoperative fluid volumes were 1550 versus 2000 mL, respectively, (P = 0.73), and LOSs were similar between the two groups (5 versus 5 days, P = 0.83). Mortality and complications, including acute kidney injuries, were similar. Delayed ambulation rates were similar overall. When stratified by preinjury ambulation status, SFM was associated with delayed ambulation for patients not walking independently before injury (P = 0.01), but RFM was not (P = 0.09). Conclusions:. RFM seems to be safe in terms of laboratory results, complications, and disposition. SFM may lead to delayed ambulation for patients who are not walking independently before injury.

Introduction Controversary exists around the best surgical management for traumatic geriatric displaced femoral neck fractures. The study objective was to compare outcomes among those managed with a total hip arthroplasty (THA) to those managed with a hemiarthroplasty (HA). Methods This retrospective matched cohort study included geriatric hip fractures (≥65 y/o) admitted 7/1/16-3/31/20. Patients were matched on having an advanced directive, pre-existing dementia, and age. Outcomes included: time to surgery, length of stay (LOS), blood loss volume, and discharge destination. THAs were compared to HAs; an alpha of

Abstract Objectives Intracranial pressure (ICP) monitoring is recommended for severe traumatic brain injuries (TBI) but some data suggests it may not improve outcomes. The objective was to investigate the effect of ICP monitoring among TBI. Methods This retrospective observational cohort study (1/1/2015–6/1/2020) included severe TBI patients. Outcomes [discharge destination, length of stay (LOS)] were compared by ICP monitoring and were stratified by GCS (3 vs. 4–8), α

From asymptomatic to severe, SARS-CoV-2, causative agent of COVID-19, elicits varying disease severities. Moreover, understanding innate and adaptive immune responses to SARS-CoV-2 is imperative since variants such as Omicron negatively impact adaptive antibody neutralization. Severe COVID-19 is, in part, associated with aberrant activation of complement and Factor XII (FXIIa), initiator of contact system activation. Paradoxically, a protein that inhibits the three known pathways of complement activation and FXIIa, C1 esterase inhibitor (C1-INH), is increased in COVID-19 patient plasma and is associated with disease severity. Here we review the role of C1-INH in the regulation of innate and adaptive immune responses. Additionally, we contextualize regulation of C1-INH and SERPING1, the gene encoding C1-INH, by other pathogens and SARS viruses and propose that viral proteins bind to C1-INH to inhibit its function in severe COVID-19. Finally, we review the current clinical trials and published results of exogenous C1-INH treatment in COVID-19 patients.

Abstract Background Traumatic aortic injuries (TAIs) are rare but are associated with a high mortality. Prior studies have shown skiers and pilots, whose injuries occur at high altitudes, are at an increased risk for a TAI. The purpose of this study was to examine the effect of altitude on the incidence of TAIs across all causes of injury. Methods This retrospective cohort study at six Level I trauma centers (8/1/2016–1/1/2020) included adult blunt trauma patients with a chest or abdomen injury. High altitude injuries (> 5000 ft.) were compared to low altitude injuries (≤ 5000 ft.). The primary outcome was incidence of TAI. Results There were 8562 patients, 37% were at high altitude and 63% at low altitude. High altitude patients were older (p

Abstract Background The decision-making for admission versus emergent transfer of patients with blunt splenic injuries presenting to remote trauma centers with limited resources remains a challenge. Although splenectomy is standard for hemodynamically unstable patients, the specific criterion for non-operative management continues to be debated. Often, lower-level trauma centers do not have interventional radiology capabilities for splenic artery embolization, leading to transfer to a higher level of a care. Thus, the aim of this study was to identify specific characteristics of patients with blunt splenic injuries used for admittance or transfer at a remote trauma center. Methods A retrospective observational study was performed to examine the management of splenic injuries at a mountainous and remote Level III trauma center. Trauma patients ≥ 18 years who had a blunt splenic injury and initially received care at a Level III trauma center prior to admittance or transfer were included. Data were collected over 4.5 years (January 1, 2016 – June 1, 2020). Patients who were transferred out in > 24 h were excluded. Patient demographics, injury severity, spleen radiology findings, and clinical characteristics were compared by decision to admit or transfer to a higher level of care ≤ 24 h of injury. Results were analyzed using chi-square, Fisher’s exact, or Wilcoxon tests. Multivariable logistic models were used to identify predictors of transfer. Results Of the 73 patients included with a blunt splenic injury, 48% were admitted and 52% were transferred to a Level I facility. Most patients were male (n = 58), were a median age of 26 (21–42) years old, most (n = 62) had no comorbidities, and 47 had been injured from a ski/snowboarding accident. Compared to admitted patients, transferred patients were significantly more likely to be female (13/38 vs. 3/36, p = 0.007), to have an abbreviated injury scale score ≥ 3 of the chest (31/38 vs. 7/35, p = 0.002), have a higher injury severity score (16 (16–22) vs. 13 (9–16), p = 0.008), and a splenic injury grade ≥ 3 (32/38 vs. 12/35, p

Myoendothelial junctions (MEJs) are structures that allow chemical signals to be transmitted between endothelial cells (ECs) and vascular smooth muscle cells, which control vascular tone. MEJs contain hemoglobin alpha (Hbα) and endothelial nitric oxide synthase (eNOS) complexes that appear to control the production and scavenging of nitric oxide (NO) along with the activity of cytochrome b5 reductase 3 (CYB5R3). The aim of this study was to examine how hypoxia affected the regulation of proteins involved in the production of NO in brain ECs. In brief, human brain microvascular endothelial cells (HBMEC) were exposed to cobalt chloride (CoCl2), a hypoxia mimetic, and a transcriptional analysis was performed using primers for eNOS, CYB5R3, and Hbα2 with ΔΔCt relative gene expression normalized to GAPDH. NO production was also measured after treatment using 4,5-diaminofluorescein diacetate (DAF-DA), a fluorescent NO indicator. When HBMEC were exposed to CoCl2 for 48 h, eNOS and CYB5R3 messenger RNA significantly decreased (up to −17.8 ± 4.30-fold and −10.4 ± 2.8, respectively) while Hbα2 increased to detectable levels. Furthermore, CoCl2 treatment caused a redistribution of peripheral membrane-generated NO production to a perinuclear region. To the best of our knowledge, this is the first time this axis has been studied in brain ECs and these findings imply that hypoxia may cause dysregulation of proteins that regulate NO production in brain MEJs.

Abstract Background The relationship between drug use and traumatic injury is well documented, yet only a small proportion of patients are biochemically tested for cannabis and other substances. The study objective was to determine whether patient self-report can be used as a proxy for biochemical drug testing following traumatic injury. Methods This study was a secondary analysis that included 320 patients admitted to four level I trauma centers in Colorado and Texas, primarily involved in motor vehicle crash (89%). If performed, biochemical testing was collected via urine toxicology screen (“tox screen”) for cannabis, amphetamines, barbiturates, cocaine, opiates, PCP, and benzodiazepines. All patients were screened for self-reported current drug use, which was evaluated for any drug and specifically for cannabis use. Analyses used to compare results of self-reported drug use and tox screen included sensitivity, specificity, positive, and negative predictive values, and percent agreement. Results Among 320 patients, 23% (n = 75) self-reported drug use; cannabis was the most frequently reported drug (n = 63). A tox screen was performed in 59% of patients (n = 190); the proportion of patients who had a tox screen was similar for those self-reporting drug use (60.0%) to those who denied using drugs (59.2%), p = 0.90. Among patients who had a tox screen performed, 18% (n = 35) tested positive for any drug, 12% (n = 22) tested positive for THC, and 7% (n = 13) tested positive for opiates. The percent agreement was 80% for any drug and 81% for cannabis. The specificity was 84–85%, indicating a high likelihood that a patient will not have a positive tox screen if they do not report using drugs. Negative predictive values were 90–95%, indicating a negative self-report correctly identified nearly all patients testing negative on tox screen. Sensitivity was only 60% and positive predictive values were 30–47% for cannabis and drugs, respectively. Conclusion These findings may negate the need for biochemical drug testing in this population, particularly as a “rule out” based on self-reporting. Future studies are needed to confirm these findings and should address risk of selection bias.

Metabolic causes such as altered bioenergetics and amino acid metabolism may play a major role in Long COVID. Renal-metabolic regulation is an integral part of these pathways but has not been systematically or routinely investigated in Long COVID. Here we discuss the biochemistry of renal tubular injury as it may contribute to Long COVID symptoms. We propose three potential mechanisms that could be involved in Long COVID namely creatine phosphate metabolism, un-reclaimed glomerular filtrate and COVID specific proximal tubule cells (PTC) injury-a tryptophan paradigm. This approach is intended to allow for improved diagnostics and therapy for the long-haul sufferers.

Abstract Background Dysregulation of antiviral immunity has been implicated in the progression of acute respiratory syndrome coronavirus 2 infection into severe cases of coronavirus disease of 2019 (COVID-19). Imbalances in the inflammatory response drive the overabundant production of pro-inflammatory cytokines and chemokines. The low molecular weight fraction of 5% human serum albumin commercial preparation (AMP5A) is a novel biologic drug currently under clinical investigation for the treatment of osteoarthritis and the hyperinflammatory response associated with COVID-19. This study aims to elucidate AMP5A effects following the activation of immune cells with agonists of Toll-like receptor (TLR) 7 and/or 8, which detect ssRNA viral sequences. Methods CXCL10 ELISAs were used to evaluate the dynamics of myeloid cells activated with CL075 and CL307, agonists of TLR7/8 and TLR7, respectively. In addition, enrichment analysis of gene sets generated by ELISA arrays was utilized to gain insight into the biologic processes underlying the identified differentially expressed cytokine profiles. Finally, relative potency (REP) was employed to confirm the involvement of mechanisms of action paramount to AMP5A activity. Results AMP5A inhibits the release of CXCL10 from both CL075- and CL307-activated PMA-differentiated THP-1 and peripheral blood mononuclear cells. Furthermore, AMP5A suppresses a distinct set of pro-inflammatory cytokines (including IL-1β, IL-6, IL-12, and CXCL10) associated with COVID-19 and pro-inflammatory NF-κB activation. REP experiments using antagonists specific for the immunomodulatory transcription factors, peroxisome proliferator-activated receptor γ, and aryl hydrocarbon receptor, also indicate that these pathways are involved in the ability of AMP5A to inhibit CXCL10 release. Conclusion Due to the biphasic course of COVID-19, therapeutic approaches that augment antiviral immunity may be more beneficial early in infection, whereas later interventions should focus on inflammation suppression. In this study, we show that AMP5A inhibits TLR 7/8 signaling in myeloid cells, resulting in a decrease in inflammatory mediators associated with hyperinflammation and autoimmunity. Furthermore, data demonstrating that AMP5A activates immunomodulatory transcription factors found to be protective in lung disease is provided. These findings suggest that the modes and mechanisms of action of AMP5A are well suited to treat conditions involving dysregulated TLR 7/8 activation. Graphical Abstract

Abstract Background American College of Surgeons level I trauma center verification requires an active research program. This study investigated differences in the research programs of academic and non-academic trauma centers. Methods A 28-question survey was administered to ACS-verified level I trauma centers in 11/12/2020–1/7/2021. The survey included questions on center characteristics (patient volume, staff size), peer-reviewed publications, staff and resources dedicated to research, and funding sources. Results The survey had a 31% response rate: 137 invitations were successfully delivered via email, and 42 centers completed at least part of the survey. Responding level I trauma centers included 36 (86%) self-identified academic and 6 (14%) self-identified non-academic centers. Academic and non-academic centers reported similar annual trauma patient volume (2190 vs. 2450), number of beds (545 vs. 440), and years of ACS verification (20 vs. 14), respectively. Academic centers had more full-time trauma surgeons (median 8 vs 6 for non-academic centers) and general surgery residents (median 30 vs 7) than non-academic centers. Non-academic centers more frequently ranked trauma surgery (100% vs. 36% academic), basic science (50% vs. 6% academic), neurosurgery (50% vs. 14% academic), and nursing (33% vs. 0% academic) in the top three types of studies conducted. Academic centers were more likely to report non-profit status (86% academic, 50% non-academic) and utilized research funding from external governmental or non-profit grants more often (76% vs 17%). Conclusions Survey results suggest that academic centers may have more physician, resident, and financial resources available to dedicate to trauma research, which may make fulfillment of ACS level I research requirements easier. Structural and institutional changes at non-academic centers, such as expansion of general surgery resident programs and increased pursuit of external grant funding, may help ensure that academic and non-academic sites are equally equipped to fulfill ACS research criteria.

Objectives Open fractures are at risk of infection because of exposure of bone and tissue to the environment. Facial fractures are often accompanied by other severe injuries, and therefore fracture management may be delayed until after stabilization. Previous studies in this area have examined timing of multiple facets of care but have tended to report on each in isolation (eg, antibiotic initiation).Methods This was a retrospective study of adult patients admitted to five trauma centers from January 1, 2017 to March 31, 2021 with open facial fractures. Variables collected included demographics, injury mechanism, details on facial and non-facial injuries, facial fracture management (irrigation and debridement (I&D), irrigation without debridement, open reduction internal fixation (ORIF), antibiotics), and other hospital events. The study hypothesized that the presence of serious non-facial injuries would be associated with delays in facial fracture management. The primary aims were to describe open facial fracture management practices and examine factors associated with early versus delayed fracture management. A secondary aim was to describe infection rates. Early treatment was defined as within 24 hours of arrival for I&D, irrigation without debridement, and ORIF and within 1 hour for antibiotics.Results A total of 256 patients were included. Twenty-seven percent had major trauma (Injury Severity Score ≥16). The presence of serious head injury/traumatic brain injury was associated with delayed I&D (ORearly=0.04, p

Abstract Background Concerns of contracting the highly contagious disease COVID-19 have led to a reluctance in seeking medical attention, which may contribute to delayed hospital arrival among traumatic patients. The study objective was to describe differences in time from injury to arrival for patients with traumatic hip fractures admitted during the pandemic to pre-pandemic patients. Materials and methods This retrospective cohort study at six level I trauma centers included patients with traumatic hip fractures. Patients with a non-fall mechanism and those who were transferred in were excluded. Patients admitted 16 March 2019–30 June 2019 were in the “pre-pandemic” group, patients were admitted 16 March 2020–30 June 2020 were in the “pandemic” group. The primary outcome was time from injury to arrival. Secondary outcomes were time from arrival to surgical intervention, hospital length of stay (HLOS), and mortality. Results There were 703 patients, 352 (50.1%) pre-pandemic and 351 (49.9%) during the pandemic. Overall, 66.5% were female and the median age was 82 years old. Patients were similar in age, race, gender, and injury severity score. The median time from injury to hospital arrival was statistically shorter for pre-pandemic patients when compared to pandemic patients, 79.5 (56, 194.5) min vs. 91 (59, 420), p = 0.04. The time from arrival to surgical intervention (p = 0.64) was statistically similar between groups. For both groups, the median HLOS was 5 days, p = 0.45. In-hospital mortality was significantly higher during the pandemic, 1.1% vs 3.4%, p = 0.04. Conclusions While time from injury to hospital arrival was statistically longer during the pandemic, the difference may not be clinically important. Time from arrival to surgical intervention remained similar, despite changes made to prevent COVID-19 transmission.

Abstract 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

Abstract Background Recommendations are for nearly universal venous thromboembolism (VTE) prophylaxis in critically ill hospitalized patients because of their well-recognized risks. In those intensive care units (ICUs) where patient care is more uniformly directed, it may be expected that VTE prophylaxis would more closely follow this standard over units that are less uniform, such as open-model ICUs. Methods This was a retrospective cohort study on all patients aged 18+ admitted to an open ICU between 6/1/2017 and 5/31/2018. Patients were excluded if they had instructions to receive comfort measures only or required therapeutic anticoagulant administration. Prophylaxis administration practices, including administration of mechanical and/or pharmacologic prophylaxis and delayed (≥48 h post-ICU admission) initiation of pharmacologic prophylaxis, were compared between patients admitted to the ICU by the trauma service versus other departments. Root causes for opting out of pharmacological prophylaxis were documented and compared between the two study groups. Results One-hundred two study participants were admitted by the trauma service, and 98 were from a non-trauma service. Mechanical (98% trauma vs. 99% non-trauma, P = 0.99) and pharmacologic (54% vs. 44%, P = 0.16) prophylaxis rates were similar between the two admission groups. The median time from ICU admission to pharmacologic prophylaxis initiation was 53 h for the trauma service and 10 h for the non–trauma services (P ≤ 0.01). In regression analyses, trauma-service admission (odds ratio (OR) = 2.88, 95% confidence interval (CI) 1.21–6.83) and increasing ICU length of stay (OR = 1.13, 95% CI 1.05–1.21) were independently associated with pharmacologic prophylaxis use. Trauma-service admission (OR = 8.30, 95% CI 2.18–31.56) and increasing hospital length of stay (OR = 1.15, 95% CI 1.03–1.28) were independently associated with delayed prophylaxis initiation. Conclusions Overall, the receipt of VTE prophylaxis of any type was close to 100%, due to the nearly universal use of mechanical compression devices among ICU patients in this study. However, when examining pharmacologic prophylaxis specifically, the rate was considerably lower than is currently recommended: 54% among the trauma services and 44% among non-trauma services.

Abstract Background The purpose of this study was to examine if satisfaction with care differs among older trauma patients with and without preexisting mental illness (PMI+/PMI-). Methods Data from two level I trauma centers were examined from 11/2016 through 12/2017. Trauma patients ≥55 years were included and satisfaction of those who had a diagnosis of mental illness prior to the trauma admission (PMI+) to those without a diagnosis (PMI-) (n = 299; 62 PMI+ and 237 PMI-) were compared. Enrolled patients completed the Family Satisfaction with Advanced Care Cancer Scale Patient Survey (FAMCARE-P13) prior to discharge. Associations between mental illness status and patient baseline characteristics, overall mean satisfaction, and mean satisfaction by question were compared. Generalized linear models adjusted for differences in patient satisfaction by mental illness status. Analyses were stratified by hospital to account for the interaction between hospital and mental illness status. Results Compared to PMI- patients, PMI+ patients were more likely to be younger, female, have multiple comorbidities, and to report lower overall satisfaction with care. Among PMI+ patients, the most common diagnoses were depression and anxiety. After adjustment, PMI+ was associated with lower patient satisfaction at hospital 1; after examining individual questions lower satisfaction was associated with information provided on procedures and questions surrounding “Physical care.” Conversely, PMI+ did not affect satisfaction at hospital 2 after adjustment. Conclusions At hospital 1, room for improvement was identified in providing information about prognosis and procedures, symptom management, and continuity of care. Reexamining practices for older PMI+ trauma patients is warranted.

Abstract Background Dysregulation of transcription and cytokine expression has been implicated in the pathogenesis of a variety inflammatory diseases. The resulting imbalance between inflammatory and resolving transcriptional programs can cause an overabundance of pro-inflammatory, classically activated macrophage type 1 (M1) and/or helper T cell type 1 (Th1) products, such as IFNγ, TNFα, IL1-β, and IL12, that prevent immune switching to resolution and healing. The low molecular weight fraction of human serum albumin (LMWF5A) is a novel biologic drug that is currently under clinical investigation for the treatment of osteoarthritis and the hyper-inflammatory response associated with COVID-19. This study aims to elucidate transcriptional mechanisms of action involved with the ability of LMWF5A to reduce pro-inflammatory cytokine release. Methods ELISA arrays were used to identify cytokines and chemokines influenced by LMWF5A treatment of LPS-stimulated peripheral blood mononuclear cells (PBMC). The resulting profiles were analyzed by gene enrichment to gain mechanistic insight into the biologic processes and transcription factors (TFs) underlying the identified differentially expressed cytokines. DNA-binding ELISAs, luciferase reporter assays, and TNFα or IL-1β relative potency were then employed to confirm the involvement of enriched pathways and TFs. Results LMWF5A was found to significantly inhibit a distinct set of pro-inflammatory cytokines (TNFα, IL-1β, IL-12, CXCL9, CXCL10, and CXCL11) associated with pro-inflammatory M1/Th1 immune profiles. Gene enrichment analysis also suggests these cytokines are, in part, regulated by NF-κB and STAT transcription factors. Data from DNA-binding and reporter assays support this with LMWF5A inhibition of STAT1α DNA-binding activity as well as a reduction in overall NF-κB-driven luciferase expression. Experiments using antagonists specific for the immunomodulatory and NF-κB/STAT-repressing transcription factors, peroxisome proliferator-activated receptor (PPAR)γ and aryl hydrocarbon receptor (AhR), indicate these pathways are involved in the LMWF5A mechanisms of action by reducing LMWF5A drug potency as measured by TNFα and IL-1β release. Conclusion In this report, we provide evidence that LMWF5A reduces pro-inflammatory cytokine release by activating the immunoregulatory transcription factors PPARγ and AhR. In addition, our data indicate that LMWF5A suppresses NF-κB and STAT1α pro-inflammatory pathways. This suggests that LMWF5A acts through these mechanisms to decrease pro-inflammatory transcription factor activity and subsequent inflammatory cytokine production.

Objectives Outcomes after traumatic hip fracture have shown to be significantly improved with timely surgical management. This study determined whether there were differences in efficacy of fascia iliaca compartment block (FICB) on pain outcomes in patients with hip fracture, once stratified by time to surgery.Methods Trauma patients (55–90 years) admitted to five Level I/II trauma centers within 12 hours of hip fracture were included. Patients with coagulopathy, significant multi-trauma (injury severity score >16), bilateral hip fractures, and postoperative FICBs were excluded. The primary exposure was analgesia modality: adjunctive FICB or systemic analgesics (no FICB). Study endpoints were incidence of delirium through 48 hours postoperatively (%), preoperative and postoperative oral morphine equivalents (OMEs), and preoperative and postoperative pain (0–10 scale). Adjusted regression models were used to examine the effect of FICB on outcomes; all models were stratified by time from arrival to surgery, ≤24 hours (earlier surgery; n=413) and >24 hours (later surgery; n=143).Results FICB use was similar with earlier and later surgery (70.2% vs 76.2%), and there were no demographic differences by utilization of FICB, by time to surgery. In the earlier surgery group, preoperative pain was lower for patients with FICB versus no FICB (3.6 vs 4.5, p0.99) or OMEs (p=0.75 preoperative, p=0.91 postoperative). In the later surgery group, there was a nearly twofold reduction in preoperative OMEs with FICB than no FICB (25.5 mg vs 45.2 mg, p=0.04), with no differences for delirium (OR 4.21, p=0.18), pain scores (p=0.25 preoperative, p=0.27 postoperative), and postoperative OMEs (p=0.34).Conclusions Compared with systemic analgesia, FICB resulted in improved pain scores at the preoperative assessment among patients with earlier surgery, whereas FICB reduced opioid consumption over the preoperative period only when surgery was later than 24 hours from arrival.Level of evidence II, prospective, therapeutic.

Objectives Until recently, systemic opioids have been standard care for acute pain management of geriatric hip fracture; however, opioids increase risk for delirium. Fascia Iliaca compartment blocks (FICB) may be favored to systemic analgesia for reducing delirium, but this has not been well demonstrated. We evaluated the efficacy of adjunctive FICB versus systemic analgesia on delirium incidence, opioid consumption, and pain scores.Methods This prospective, observational cohort study was performed in patients (55–90 years) with traumatic hip fracture admitted to five trauma centers within 12 hours of injury, enrolled between January 2019 and November 2020. The primary end point was development of delirium, defined by the Confusion Assessment Method tool, from arrival through 48 hours postoperatively, and analyzed with multivariate Firth logistic regression. Secondary end points were analyzed with analysis of covariance models and included preoperative and postoperative oral morphine equivalents and pain numeric rating scale scores.Results There were 517 patients enrolled, 381 (74%) received FICB and 136 (26%) did not. Delirium incidence was 5.4% (n=28) and was similar for patients receiving FICB versus no FICB (FICB, 5.8% and no FICB, 4.4%; adjusted OR: 1.2 (95% CI 0.5 to 3.0), p=0.65). Opioid requirements were similar for patients receiving FICB and no FICB, preoperatively (p=0.75) and postoperatively (p=0.51). Pain scores were significantly lower with FICB than no FICB, preoperatively (4.2 vs 5.1, p=0.002) and postoperatively (2.9 vs 3.5, p=0.04).Conclusions FICB demonstrated significant benefit on self-reported pain but without a concomitant reduction in opioid consumption. Regarding delirium incidence, these findings suggest clinical equipoise and the need for a randomized trial.Level of evidence II—prospective, therapeutic.

Abstract Background A common complication of viral pulmonary infections, such as in the ongoing COVID-19 pandemic, is a phenomenon described as a “cytokine storm”. While poorly defined, this hyperinflammatory response results in diffuse alveolar damage. The low molecular weight fraction of commercial human serum albumin (LMWF5A), a novel biologic in development for osteoarthritis, demonstrates beneficial in vitro immunomodulatory effects complimentary to addressing inflammation, thus, we hypothesize that LMWF5A could improve the clinical outcomes of COVID-19 by attenuating hyperinflammation and the potential development of a cytokine storm. Presentation of the hypothesis A variety of human in vitro immune models indicate that LMWF5A reduces the production of pro-inflammatory cytokines implicated in cytokine storm associated with COVID-19. Furthermore, evidence suggests LMWF5A also promotes the production of mediators required for resolving inflammation and enhances the barrier function of endothelial cultures. Testing the hypothesis A randomized controlled trial, to evaluate the safety and efficacy of nebulized LMWF5A in adults with Acute Respiratory Distress Syndrome (ARDS) secondary to COVID-19 infection, was developed and is currently under review by the Food and Drug Administration. Implications of hypothesis If successful, this therapy may attenuate the cytokine storm observed in these patients and potentially reduce mortality, increase ventilation free days, improve oxygenation parameters and consequently lessen the burden on patients and the intensive care unit. Conclusions In conclusion, in vitro findings suggest that the immunomodulatory effects of LMWF5A make it a viable candidate for treating cytokine storm and restoring homeostasis to the immune response in COVID-19.

Abstract Introduction There is a lack of data on the use and effectiveness of pre-hospital pelvic circumferential compression devices (PCCD) as a temporary intervention for pelvic fracture management; they are thought to decrease pelvic volume and hemorrhage but are not without risks. The purpose of this study is to examine pre-hospital PCCD practices at US Level I trauma centers. Methods This was a prospective cross-sectional survey of trauma medical directors at US Level I trauma centers. The aim of this study was to describe patterns of pre-hospital PCCD utilization for pelvic fractures. Responses were compared by region, length in time the center was designated Level I, trauma patient volume, pelvic management guideline followed and blood product guidelines. Data were compared using Fisher’s exact and chi-squared tests. Results Of the 158 Level I trauma centers invited, 25% responded. All Level I trauma centers use in-hospital PCCDs, whereas 71% of participant’s paramedic agencies trained on pre-hospital PCCD application. Of those, 44% trained to apply pre-hospital PCCDs to all suspected pelvic fractures. A higher proportion of high-volume centers (77%) than low-volume centers (25%) trained on pre-hospital PCCD placement, p = 0.06. PCCD practices were not dependent on the trauma center’s region, trauma volume, length in time as a Level I trauma center, or pelvic fracture guideline followed. Conclusions There is widespread application of in-hospital and pre-hospital PCCD at US Level I trauma centers, however pre-hospital PCCDs are not applied to all suspected pelvic fractures. Future studies should focus on efficacy, safety, and contraindications for pre-hospital PCCDs.

Abstract Background Hospital length of stay (HLOS) is a commonly used measure of hospital quality and is influenced by clinical and non-clinical factors. To reduce HLOS, it is key to identify factors placing patients at increased risk of lengthy HLOS and discharge delays. Methods This was a retrospective cohort study of patients age ≥ 18 admitted to four level 1 trauma centers between 1/1/2015 and 3/31/2018 with traumatic brain injury (TBI). The primary outcome was discharge delay, defined as discharge ≥24 h after case management notes indicated the patient was ready for discharge. The independent variables of interest were primary insurance provider and discharge destination. Chi-square, Fisher exact, and unadjusted and adjusted logistic regression analyses were used to assess associations between discharge delay and the two primary independent variables, as well as other patient demographic and clinical characteristics. Complications developing during the delay period were also examined. Results A total of 1543 patients with TBI were included. The median age was 61 years, and the median HLOS was 5 days. Approximately half of patients were discharged home (54%). The most common insurance providers were Medicare (35%) and commercial/private (35%). Two-hundred ten (14%) patients experienced a discharge delay. The median delay period was 3 days, and the most common reasons for delay were insurance authorization (52%) and lack of accepting bed (41%). Compared to being discharged home, patients discharged to a skilled nursing facility (adjusted odds ratio (AOR) = 10.35) or intermediate care facility (AOR = 10.64) had the highest odds of discharge delay. Compared to Medicare patients, uninsured/self-pay patients (AOR = 2.98) and those with Medicaid (AOR = 2.83) or commercial/private insurance (AOR = 2.22) had higher odds of delay. Thirty-two patients (15% of those delayed) experienced at least one complication during the delay, some of which were clinically severe. Conclusions A substantial portion of TBI patients in this study experienced discharge delays, and discharge destination and primary insurance provider were significant drivers of these delays. Evaluation of a facility’s quality of care should consider the specific causes of these delays.

Abstract Background Resuscitative endovascular balloon occlusion of the aorta (REBOA) is not widely adopted for pelvic fracture management. Western Trauma Association recommends REBOA for hemodynamically unstable pelvic fractures, whereas Eastern Association for the Surgery of Trauma and Advanced Trauma Life Support do not. Method Utilizing a prospective cross-sectional survey, all 158 trauma medical directors at American College of Surgeons-verified Level I trauma centers were emailed survey invitations. The study aimed to determine the rate of REBOA use, REBOA indicators, and the treatment sequence of REBOA for hemodynamically unstable pelvic fractures. Results Of those invited, 25% (40/158) participated and 90% (36/40) completed the survey. Nearly half of trauma centers [42% (15/36)] use REBOA for pelvic fracture management. All participants included hemodynamic instability as an indicator for REBOA placement in pelvic fractures. In addition to hemodynamic instability, 29% (4/14) stated REBOA is used for patients who are ineligible for angioembolization, 14% (2/14) use REBOA when interventional radiology is unavailable, 7% (1/14) use REBOA for patients with a negative FAST. Fifty percent (7/14) responded that hemodynamically unstable pelvic fractures exclusively indicates REBOA placement. Hemodynamic instability for pelvic fractures was most commonly defined as systolic blood pressure of

Background Damage control laparotomy (DCL) is a life-saving procedure in patients with abdominal hemorrhage. After DCL, patients are sometimes left with an open abdomen (OA) so they may undergo multiple exploratory laparotomies (EXLAP), or re-explorations. Patients with OA are at increased risk of infectious complications (ICs). The association between number of re-explorations after DCL and the number of ICs is not clear. We hypothesized that each additional re-exploration increases the risk of developing IC.Methods This 6-year retrospective cohort study included patients aged ≥16 years from the NTDB who had DCL defined as EXLAP within 2 hours of arrival (ICD-9: 54.11, 54.12, 54.19) with at least one re-exploration. The primary outcome was IC (ie, superficial surgical site infection (SSI), organ space SSI, deep SSI, sepsis, pneumonia, or catheter-related bloodstream infection), examined dichotomously (present/absent) and ordinally as the number of ICs. Multivariate Poisson regression was used to assess the association between number of re-explorations and number of ICs. Significance was assigned at p

Abstract Background Patients with hemodynamically unstable pelvic fractures have high mortality due to delayed hemorrhage control. We hypothesized that the availability of interventional radiology (IR) for angioembolization may vary in spite of the mandated coverage at US Level I trauma centers, and that the priority treatment sequence would depend on IR availability. Methods This survey was designed to investigate IR availability and pelvic fracture management practices. Six email invitations were sent to 158 trauma medical directors at Level I trauma centers. Participants were allowed to skip questions and irrelevant questions were skipped; therefore, not all questions were answered by all participants. The primary outcome was the priority treatment sequence for hemodynamically unstable pelvic fractures. Predictor variables were arrival times for IR when working off-site and intervention preparation times. Kruskal-Wallis and ordinal logistic regression were used; alpha = 0.05. Results Forty of the 158 trauma medical directors responded to the survey (response rate: 25.3%). Roughly half of participants had 24-h on-site IR coverage, 24% (4/17) of participants reported an arrival time ≥ 31 min when IR was on-call. 46% (17/37) of participants reported an IR procedure setup time of 31–120 min. Arrival time when IR was working off-site, and intervention preparation time did not significantly affect the sequence priority of angioembolization for hemodynamically unstable pelvic fractures. Conclusions Trauma medical directors should review literature and guidelines on time to angioembolization, their arrival times for IR, and their procedural setup times for angioembolization to ensure utilization of angioembolization in an optimal sequence for patient survival.

Abstract Background The medical legalization of marijuana has been shown to result in an increased risk of motor vehicle injuries. In Colorado, commercialization of recreational marijuana (initiation of retail sales) occurred on January 1, 2014, resulting in the rapid proliferation of its availability. The objective of this study was to determine whether the proportion of injured patients testing positive for marijuana and other drugs changed two years before and two years after commercialization of recreational marijuana in Colorado. Methods This retrospective multi-institutional cohort study included all patients admitted with a traumatic injury to six trauma centers (three centers in Colorado and three centers in states without permissive marijuana laws) from 2012 to 2015. The primary outcome was the rate (%) of a positive urine drug screen (UDS) for marijuana. Generalized linear regression models were used to examine the rate of change over time in the pre-commercialization period relative to the post- commercialization period (via an interaction effect), separately for states with and without recreational marijuana legalization. Results There were 40,591 trauma admissions. In Colorado, the rate of marijuana detected with UDS decreased over time pre-commercialization; this trend reversed post-commercialization, when marijuana detection rates increased significantly over time (interaction p = 0.004). At non-Colorado hospitals, the rate over time of marijuana detection was significantly reduced post-commercialization relative to the pre-commercialization period (p

Abstract Background Mortality from hemodynamically unstable pelvic fractures remains high. Guidelines offer varying care approaches including the use of pelvic packing (PP), which was recently adopted for potential control of bleeding for this condition. However, the implementation of PP is uncertain as the debate on the optimal resuscitation strategy, angioembolization or PP continues. The study was designed to assess current practices among level 1 trauma centers in the US in regard to PP treatment for hemodynamically unstable pelvic fractures. Methods A cross-sectional survey was created to assess when to apply PP, application approach, and the respondent’s anecdotal perception on safety and effectiveness. Trauma Medical Directors at 158 US level 1 trauma centers were sent biweekly email invitations for 3 months. Participants were allowed to skip questions for any reason. The study hypothesis was that PP practices vary by US census bureau region, annual trauma admissions, and length of time in years since each trauma center received their respective level 1 trauma center designation. Results Twenty-five percent (40/158) of trauma medical directors participated and 75% (118/158) of the trauma medical directors did not participate. Of those who took the survey, 36/40 (90%) completed the survey and 4/40 (10%) partially completed the survey. Only 36 trauma medical directors responded on their perception of safety and effectiveness; 72% (26/36) of participants perceived PP as safe, whereas only a third (12/36) of participants perceived PP as effective. There were 25 trauma medical directors who provided the sequence of treatment modalities utilized at their level 1 trauma center, 76% (19/25) of participants reported that PP is utilized as the third or fourth priority. None of the participating level 1 trauma centers reported a preference towards utilization of PP as the first priority treatment. Half of the participants reported a preference towards applying PP only as a last resort to control hemorrhage. Northeastern and Western level 1 trauma centers were significantly more likely than Midwestern and Southern level 1 trauma centers to have reported application of PP to all hemodynamically unstable patients (p = 0.05). Midwestern, Southern, and Western level 1 trauma centers were significantly more likely to have perceived PP as safe than Northeastern level 1 trauma centers (p = 0.04). All low-volume and 38% high-volume level 1 trauma centers perceived PP to increase infection risks, (p = 0.03). We observed no association between the length of time each trauma center was designated a level 1 trauma center, and all participant responses. Conclusion Controversy and varying anecdotal perception regarding safety and effectiveness of PP prevails among trauma medical directors at level 1 trauma centers in the US.

Inflammatory responses to the novel coronavirus SARS-CoV-2, which causes COVID-19, range from asymptomatic to severe. Here we present a follow-up analysis of a longitudinal study characterizing COVID-19 immune responses from a father and son with distinctly different clinical courses. The father required a lengthy hospital stay for severe symptoms, whereas his son had mild symptoms and no fever yet tested positive for SARS-CoV-2 for 29 days. Father and son, as well as another unrelated COVID-19 patient, displayed a robust increase of SERPING1, the transcript encoding C1 esterase inhibitor (C1–INH). We further bolstered this finding by incorporating a serum proteomics dataset and found that serum C1–INH was consistently increased in COVID-19 patients. C1–INH is a central regulator of the contact and complement systems, potentially linking COVID-19 to complement hyperactivation, fibrin clot formation, and immune depression. Furthermore, despite distinct clinical cases, significant parallels were observed in transcripts involved in interferon and B cell signaling. As symptoms were resolving, widespread decreases were seen in immune-related transcripts to levels below those of healthy controls. Our study provides insight into the immune responses of likely millions of people with extremely mild symptoms who may not be aware of their infection with SARS-CoV-2 and implies a potential for long-lasting consequences that could contribute to reinfection risk.

BackgroundTo determine whether adjunctive dronabinol, a licensed form of delta-9-tetrahydrocannabinol, reduces opioid consumption when used off-label for managing acute pain following traumatic injury.MethodsThis matched cohort study included patients who were admitted with a traumatic injury between 1 March 2017 and 30 October 2017. The hospital pharmacy database was used to identify patients who received dronabinol (cases), and they were matched 1:1 to patients who did not receive dronabinol (controls) using age, cause of injury and hospital length of stay. The primary outcome, change in opioid consumption, was calculated using morphine milligram equivalents (MME). The change in MME was calculated for cases as total MME over 48 hours with adjunctive dronabinol minus 48 hours prior to dronabinol, and for controls as total MME 48–96 hours from admission minus 0–48 hours from admission. Data are presented as mean and SE or median and IQR. Statistical analysis was performed using paired t-tests and McNemar’s tests.ResultsThere were 66 patients included: 33 cases and 33 matched controls. Dronabinol was initiated 55 (28–107) hours from admission. Cases and controls were well matched. Cases had a significant reduction in opioid consumption with adjunctive dronabinol (−79 (20) MME, p

BackgroundIn patients with hemodynamically stable blunt splenic injury (BSI), there is no consensus on whether quantity of hemoperitoneum (HP) is a predictor for intervention with splenic artery embolization (SAE) or failing nonoperative management (fNOM). We sought to analyze whether the quantity of HP was associated with need for intervention.MethodsThis retrospective cohort study included adult trauma patients with hemodynamically stable BSI admitted to six trauma centers between 2014 and 2016. Quantity of HP was defined as small (perisplenic blood or blood in Morrison’s pouch), moderate (blood in one or both pericolic gutters), or large (additional finding of free blood in the pelvis). Multivariate logistic regression was performed to identify predictors of intervention with SAE or fNOM versus successful observation.ResultsThere were 360 patients: hemoperitoneum was noted in 214 (59%) patients, of which the quantity was small in 92 (43%), moderate in 76 (35.5%), and large in 46 (21.5%). Definitive management was as follows: 272 (76%) were observed and 88 (24%) had intervention (83 SAE, 5 fNOM). The rate of intervention was univariately associated with quantity of HP, even after stratification by American Association for the Surgery of Trauma (AAST) grade. After adjustment, larger quantities of HP significantly increased odds of intervention (p=0.01). Compared with no HP, the odds of intervention were significantly increased for moderate HP (OR=3.51 (1.49 to 8.26)) and large HP (OR=2.89 (1.03 to 8.06)), with similar odds for small HP (OR=1.21 (0.46 to 2.76)). Other independent predictors of intervention were higher AAST grade, older age, and presence of splenic vascular injury.ConclusionGreater quantity of HP was associated with increased odds of intervention, with no difference in risk for moderate versus large HP. These findings suggest quantity of HP should be incorporated in the management algorithm of BSI as a consideration for angiography and/or embolization to maximize splenic preservation and reduce the risk of splenic rupture.Level of evidenceIII, retrospective epidemiological study.

Background: Advanced aged adults have the highest rate of traumatic brain injury (TBI) related hospital admissions, compared to younger age groups. Data were published in 2014 indicating differential injury and neurological responses to a TBI by age categories. In a recent article examining patients with mTBI and isolated subdural hematoma, it was found that older patients had a decreased risk of documented loss of consciousness (LOC). The primary objective was to determine the extent to which the odds of documented LOC changes with increasing age in a population of older adults suffering an isolated concussion and uncomplicated mTBI.Methods: This was a retrospective study utilizing 6 years (2010–2015) of National Trauma Data Bank data. This study included patients with (1) diagnosis of concussion; (2) positive or negative loss of consciousness; (3) loss of consciousness durations no longer than 59 min or undefined; (4) age ≥50 years; (5) had a “fall” mechanism of injury; and (6) a valid emergency department Glasgow coma scale 13–15. We excluded patients (1) with any intracranial hemorrhage or intracranial injury of other and unspecified nature; (2) skull fracture; (3) an injury severity scale score >17; (4) a concussion with “unspecified” LOC (ICD-9: 850.9).Results: There were 7,466 patients included in the study; the median (IQR) age was 70 (60–80) years. The risk of documented LOC was 71% (n = 5,319). An 80-year-old had 72% decreased odds of having a documented LOC, compared to a 50-year-old (OR = 0.28, 99.5%CI [0.23–0.34], P < 0.001). This association held when controlling for multiple demographic, comorbid, and clinical variables, and in sensitivity analyses.Conclusion: These nationwide data suggest that in patients aged ≥50 years, a significant inverse association exists between age and odds of documented LOC after sustaining a fall-related concussion. Additional studies are needed to validate these findings and to investigate the triad of age, documented LOC, and intracranial hemorrhage. Clinical diagnostic criteria relying on LOC might be at risk of being modified by the association between increasing age and decreasing odds of LOC.

After a traumatic insult, macrophages can become activated leading to general inflammation at the site of injury. Activated macrophages are partially regulated by the aryl hydrocarbon receptor (AhR) which when activated suppresses inflammation by limiting the secretion of pro-inflammatory cytokines and promoting the over expression of immuno-modulatory mediators. This study aims to determine whether the low molecular weight fraction of 5% human serum albumin (LMWF5A) and N-acetyl kynurenine (NAK), an N-acetyl tryptophan (NAT) breakdown product in LMWF5A, can regulate inflammation by inhibiting macrophage activation through the AhR since kynurenine is a known AhR agonist. Using LCMS, we demonstrate that NAT is non-enzymatically degraded during accelerated aging of LMWF5A with high heat accelerating degradation. More importantly, NAK is a major degradation product found in LMWF5A. THP-1 monocytes were differentiated into macrophages using phorbol 12-myristate 13-acetate (PMA) and pre-treated with 2-fold dilutions of LMWF5A or synthetic NAK with or without an AhR antagonist (CH223191) prior to overnight stimulation with lipopolysaccharide (LPS). Treatment with LMWF5A caused a 50–70% decrease in IL-6 release throughout the dilution series. A dose-response inhibition of IL-6 release was observed for NAK with maximal inhibition (50%) seen at the highest NAK concentration. Finally, an AhR antagonist partially blocked the anti-inflammatory effect of LMWF5A while completely blocking the effect of NAK. A similar inhibitory effect was observed for CXCL-10, but the AhR antagonist was not effective suggesting additional mechanisms for CXCL-10 release. These preliminary findings suggest that LMWF5A and NAK partially promote the suppression of activated macrophages via the AhR receptor. Therefore, LMWF5A, which contains NAK, is potentially a useful therapeutic in medical conditions where inflammation is prevalent such as trauma, sepsis, and wound healing. Keywords: Tryptophan, Inflammation, Macrophages, Aryl hydrocarbon receptor, Kynurenine, Human serum albumin

Abstract Background There are limited efficacious treatment options for severe osteoarthritis of the knee (OAK). The Low Molecular Weight Fraction of 5% human serum Albumin (LMWF-5A) is in development to treat severe OAK. This study evaluated the safety and efficacy of LMWF-5A for the signs and symptoms of OAK. Methods This 12-week randomized, double-blind, controlled clinical trial was conducted at thirteen sites across the United States. Patients with symptomatic, severe OAK (Kellgren-Lawrence grade 4 disease) who were fully ambulatory and had no other conditions interfering with the study knee were randomized to a single 4 ml intra-articular injection of LMWF-5A or saline, randomized 6:1. The primary endpoint was Outcome Measures in Rheumatology-Osteoarthritis Research Society International (OMERACT-OARSI) responder rate (%), examined with a one-sided exact binomial test compared to a clinically meaningful response rate of 30%. Efficacy of LMWF-5A was also evaluated as controlled responder (%), defined as 20% improvements in both pain and function, compared to historical saline control from three previous trials. Safety was examined as the incidence and severity of adverse events (AEs). This trial was registered (clinicaltrials.gov identifier: NCT03182686). Results In total, 168 patients were randomized; 144 subjects treated with LMWF-5A were analysed. Overall, 71% (95% CI: 63.4%–78.3%) of subjects treated with LMWF-5A met the OMERACT-OARSI responder criteria, exceeding the 30% threshold (p

Abstract Background The disease modifying potential of osteoarthritis therapies are of increasing interest, including their effects on delaying total knee replacement (TKR). To date, there have been no studies to determine the effect of LMWF-5A, a novel anti-inflammatory compound derived from human serum albumin, on delaying TKR. Methods We evaluated time to TKR three years after patients participated in a randomized trial of three intra-articular injections of LMWF-5A or saline. Patients were contacted via last known phone number and were asked to participate in a short nine item telephone questionnaire; verbal consent was obtained. The primary endpoint was incidence of TKR (%). Results In total, 39 of 45 patients responded (87% response rate). The overall incidence of TKR was 38.5% (15/39). TKR rates were higher in patients with more severe osteoarthritis defined by Kellgren-Lawrence grade 4, compared to patients with moderate osteoarthritis defined by Kellgren-Lawrence grade 3 (56% vs. 26%, p = 0.06). Overall, there were no differences in TKR rates by treatment arm (39% LMWF-5A vs. 38% saline, p = 0.92). In the severe osteoarthritis subset (n = 16), treatment with LMWF-5A resulted in a lower incidence of TKR compared to saline vehicle arm (40% vs. 83%, p = 0.15). TKR rates were significantly lower with LMWF-5A in patients who responded to treatment (14% with LMWF-5A, vs. 100% with saline, p = 0.03). Conclusion This study demonstrates significant delays in TKR for patients with severe osteoarthritis treated with LMWF-5A, suggesting that LMWF-5A has the potential to provide structure modifying/preserving therapy in this population.

Abstract Background Widespread legislative efforts to legalize marijuana have increased the prevalence of marijuana use and abuse. The effects of marijuana on pain tolerance and analgesic pain management in the acute pain setting have not been reported. Although marijuana has been shown to have antinociceptive effects and is approved for medical use to treat chronic pain, anecdotal evidence suggests marijuana users admitted with traumatic injuries experience poorer pain control than patients who do not use marijuana. We hypothesized that marijuana users would report higher pain scores and require more opioid analgesia following traumatic injury. Methods This retrospective pilot study included all patients involved in motor vehicle crashes, consecutively admitted to four trauma centers from 1/1/2016–4/30/2016. Marijuana status was examined as non-use and use, and was further categorized as chronic and episodic use. We performed a repeated measures mixed model to examine the association between marijuana use and a) average daily opioid consumption and b) average daily pain scores (scale 0–10). Opioid analgesics were converted to be equianalgesic to 1 mg IV hydromorphone. Results Marijuana use was reported in 21% (54/261), of which 30% reported chronic use (16/54). Marijuana use was reported more frequently in Colorado hospitals (23–29%) compared to the hospital in Texas (6%). Drug use with other prescription/street drugs was reported in 9% of patients. Other drug use was a significant effect modifier and results were presented after stratification by drug use. After adjustment, marijuana users who did not use other drugs consumed significantly more opioids (7.6 mg vs. 5.6 mg, p

Introduction: Plasma oxidized human serum albumin (OxHSA) is evidence of an active antioxidant mechanism as measured by oxidized species of HSA. CXCL-10 is a pro-inflammatory chemokine associated with ischemic conditions. Accordingly, we examined the relationship of admission OxHSA and CXCL-10 with discharge mRS in acute ischemic stroke (AIS).Methods: Plasma samples and clinical data were collected prospectively at a Comprehensive Stroke Center. Admission biomarkers of oxidative stress, CXCL-10 and %OxHSA, were measured. We examined if CXCL-10 or %OxHSA correlated with age, admission NIHSS score, and discharge mRS score using Spearman's Rank correlation. Logistic regression was performed to identify independent predictors of a favorable discharge mRS (≤2).Results: In 106 consecutive AIS patients, the median age was 73 (IQR 61–84), 47% were male, and the median admission NIHSS score was 11 (IQR 5–19). %OxHSA and CXCL-10 were significantly correlated (r = 0.23, p = 0.02). Both biomarkers were significantly correlated with age: %OxHSA (r = 0.44, p < 0.001) and CXCL-10 (r = 0.32, p = 0.001). Neither biomarker was correlated with admission NIHSS. There was a borderline significant correlation with discharge mRS and %OxHSA (r = −0.17, p = 0.08), where higher %OxHSA correlated with lower discharge mRS scores. For every 1% increase in %OxHSA, the odds of a favorable discharge mRS increased 11%. The odds of a favorable discharge mRS decreased 18% for every 1-point increase in the initial NIHSS.Conclusions: OxHSA, the result of an oxidative environment and evidence of the strong antioxidant buffering capacity of HSA, correlated with CXCL-10 and discharge mRS, implying that strong antioxidant activity of albumin may confer better outcomes.

Severe sepsis, systemic inflammatory response syndrome (SIRS), and traumatic brain injury are frequently associated with hyperglycemia in non-diabetic patients. In patients suffering from any of these conditions, hyperglycemia at admission to an intensive care unit (ICU) is directly correlated with increased mortality or morbidity. Although there was initial enthusiasm for insulin treatment to blood glucose levels below 110 mg/dL in these patients, recent understanding suggests that the potential for hypoglycemic complications make this approach potentially dangerous. More moderate glucose control seems to be more beneficial than the aggressive glucose lowering initially suggested. An important publication has shown that hyperlactatemia accompanying hyperglycemia could be the real culprit in bad outcomes. This suggests that coupling moderate glucose lowering with therapeutic agents which might treat the underlying metabolic disturbances in these conditions may be a better strategy. The key metabolic disturbance in these three conditions seems to be persistent glycolysis as an energy source even in the presence of adequate tissue oxygenation (the Warburg Effect). We look at recent advances in understanding aerobic glycolysis and possibly the action of DPP4 on incretins resulting in insulin dysregulation and suggest key metabolic pathways involved in hyperglycemia regulation.

Delta-9-tetrahydrocannabinol (Δ9-THC) and other cannabinoids present in cannabis (marijuana) have been shown to affect the normal inhibitory pathways that influence nociception in humans. The potential benefits of cannabinoids as an analgesic are likely greatest in hyperalgesic and inflammatory states, suggesting a role as a therapeutic agent for treating acute pain following injury. Dronabinol is a licensed form of Δ9-THC. The primary objective of this single center randomized controlled trial is to evaluate the efficacy of adjunctive dronabinol versus control (systemic analgesics only, no dronabinol) for reducing opioid consumption in adults with traumatic injury. Study inclusion is based on high baseline utilization of opioids ≥50 morphine equivalents (mg) within 24 h of admission for adults aged 18–65 years with traumatic injury. There is a 48-hour screening period followed by a 48-hour treatment period after randomization. A total of 122 patients will be randomized 1:1 across 2 study arms: adjunctive dronabinol versus control (standard of care using systemic analgesics, no adjunctive dronabinol). Patients randomized to the dronabinol arm should receive their first dose within 12 h of randomization, with a dose range of 5 mg up to 30 mg daily in divided doses, in addition to systemic analgesics as needed for pain. The primary efficacy endpoint is a change in opioid consumption (morphine equivalents), assessed post-randomization (48 h after randomization) minus pre-randomization (24 h prior to randomization). This is the first randomized trial to investigate whether adjunctive dronabinol is effective in reducing opioid consumption in acute pain management of traumatic injury. Trial Registration: ClinicalTrials.gov Identifier: NCT03928015.

BackgroundCerebral venous thrombosis is a rare cause of stroke that poses diagnostic, therapeutic, and prognostic challenges. Mainstay treatment is systemic anticoagulation, but endovascular treatment is increasingly advocated. Our objectives were to describe the epidemiology, treatment, and prognosis of 152 patients with cerebral venous thrombosis. Methods and ResultsThis was a retrospective study of consecutive cerebral venous thrombosis cases from 2006 to 2013 at a comprehensive stroke center through hospital discharge. Predictors of full recovery (modified Rankin Scale scores 0–1) were analyzed with multiple logistic regression and presented as adjusted odds ratios (AORs) with 95% confidence intervals (CIs). The population was young (average age: 42 years), majority female (69%), and commonly presenting with cerebral edema (63%), and 72% were transferred in. All patients received systemic anticoagulation; 49% (n=73) required endovascular treatment. Reasons for requiring endovascular treatment included cerebral edema, herniation, or hemorrhagic infarct (n=38); neurologic decline (n=17); rethrombosis, persistent occlusion, or clot propagation (n=10); extensive clot burden (n=7); and persistent headache despite anticoagulation (n=1). There were 7 (10%) procedural complications. Recanalization was successful (61%), partial (30%), and unsuccessful (9%). Overall, 60% fully recovered. Positive predictors of full recovery included hormonal etiology, particularly for patients who were transferred in (AOR: 7.06 [95% CI, 2.27–21.96], interaction P=0.03) and who had migraine history (AOR: 4.87 [95% CI, 1.01–23.50], P=0.05), whereas negative predictors of full recovery were cerebral edema (AOR: 0.11 [95% CI, 0.04–0.34], P

The overall redox potential of a cell is primarily determined by oxidizable/reducible chemical pairs, including glutathione–glutathione disulfide, reduced thioredoxin–oxidized thioredoxin, and NAD+–NADH (and NADP–NADPH). Current methods for evaluating oxidative stress rely on detecting levels of individual byproducts of oxidative damage or by determining the total levels or activity of individual antioxidant enzymes. Oxidation–reduction potential (ORP), on the other hand, is an integrated, comprehensive measure of the balance between total (known and unknown) pro-oxidant and antioxidant components in a biological system. Much emphasis has been placed on the role of oxidative stress in chronic diseases, such as Alzheimer's disease and atherosclerosis. The role of oxidative stress in acute diseases often seen in the emergency room and intensive care unit is considerable. New tools for the rapid, inexpensive measurement of both redox potential and total redox capacity should aid in introducing a new body of literature on the role of oxidative stress in acute illness and how to screen and monitor for potentially beneficial pharmacologic agents.