Association of sex and aspirin use with postoperative bleeding in patients with lower extremity long bone fractures.

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 <8 g/dL were more frequent among female aspirin users (21.5% aspirin vs 12.5% no aspirin, p=0.01), but this association was not observed in men (p=0.43). Conclusion: Women taking aspirin who suffer lower extremity fractures have greater than twofold greater odds of a postoperative bleeding event. These findings suggest adequate perioperative planning to ensure blood availability, and increased awareness to monitor closely for hemorrhage in the 24-hour postoperative window for women taking aspirin preinjury. Level of evidence: IV.

Epidemiology of C2 fractures and determinants of surgical management: analysis of a national registry.

Objective: Operative management of axis fractures (C2) usually depend on the stability and location of the break and individual patient characteristics. We sought to describe the epidemiology of C2 fractures and hypothesized that determinants for surgery would differ by fracture diagnosis. Methods: Patients with C2 fractures were identified from the US National Trauma Data Bank from January 1, 2017, to January 1, 2020. Patients were classified by C2 fracture diagnosis: odontoid type II, odontoid types I and III, and non-odontoid fracture (hangman's fracture or fractures through base of the axis). The primary comparison was C2 fracture surgery versus non-operative management. Multivariate logistic regression was used to identify independent associations with surgery. Decision tree-based models were developed to identify determinants for surgery. Results: There were 38 080 patients; 42.7% had an odontoid type II fracture; 16.5% had an odontoid type I/III fracture; and 40.8% had a non-odontoid fracture. All examined patient demographics, clinical characteristics, outcomes, and interventions differed by C2 fracture diagnosis. Overall, 5292 (13.9%) were surgically managed (17.5% odontoid type II, 11.0% odontoid type I/III, and 11.2% non-odontoid; p<0.001). The following covariates increased odds of surgery for all three fracture diagnoses: younger age, treatment at a level I trauma center, fracture displacement, cervical ligament sprain, and cervical subluxation. Determinants of surgery differed by fracture diagnosis: for odontoid type II, age ≤80 years, a displaced fracture, and cervical ligament sprain were determinants; for odontoid type I/III, age ≤85 years, a displaced fracture, and cervical subluxation were determinants; for non-odontoid fractures, cervical subluxation and cervical ligament sprain were the strongest determinants for surgery, by hierarchy. Conclusions: This is the largest published study of C2 fractures and current surgical management in the USA. Odontoid fractures, regardless of type, had age and fracture displacement as the strongest determinants for surgical management, whereas associated injuries were determinants of surgery for non-odontoid fractures. Level of evidence: III.

Low Prevalence but High Impact of COVID-19 Positive Status in Adult Trauma Patients: A Multi-institutional Analysis of 28 904 Patients.

BACKGROUND: Few large investigations have addressed the prevalence of COVID-19 infection among trauma patients and impact on providers. The purpose of this study was to quantify the prevalence of COVID-19 infection among trauma patients by timing of diagnosis, assess nosocomial exposure risk, and evaluate the impact of COVID-19 positive status on morbidity and mortality. METHODS: Registry data from adults admitted 4/1/2020-10/31/2020 from 46 level I/II trauma centers were grouped by: timing of first positive status (Day 1, Day 2-6, or Day ≥ 7); overall Positive/Negative status; or Unknown if test results were unavailable. Groups were compared on outcomes (Trauma Quality Improvement Program complications) and mortality using univariate analysis and adjusted logistic regression. RESULTS: There were 28 904 patients (60.7% male, mean age: 56.4, mean injury severity score: 10.5). Of 13 274 (46%) patients with known COVID-19 status, 266 (2%) were Positive Day 1, 119 (1%) Days 2-6, 33 (.2%) Day ≥ 7, and 12 856 (97%) tested Negative. COVID-19 Positive patients had significantly worse outcomes compared to Negative; unadjusted comparisons showed longer hospital length of stay (10.98 vs 7.47;P < .05), higher rates of intensive care unit (57.7% vs 45.7%; P < .05) and ventilation use (22.5% vs 16.9%; P < .05). Adjusted comparisons showed higher rates of acute respiratory distress syndrome (1.7% vs .4%; P < .05) and death (8.1% vs 3.4%; P < .05). CONCLUSIONS: This multicenter study conducted during the early pandemic period revealed few trauma patients tested COVID-19 positive, suggesting relatively low exposure risk to care providers. COVID-19 positive status was associated with significantly higher mortality and specific morbidity. Further analysis is needed with consideration for care guidelines specific to COVID-19 positive trauma patients as the pandemic continues.

Adherence to Antibiotic Recommendations and Infection Among Patients With Open Long-Bone Fractures: An Examination of Antibiotic Prioritization in Fracture Management.

Open fractures are at high risk of infection because of exposure of bone and tissue to the environment. Initiation of intravenous antibiotics is recommended within 1 hour of hospital arrival, although the presence of other severe injuries may lead to delays in fracture management. This retrospective study of adult patients with open long-bone fractures admitted to six level 1 trauma centers between January 1, 2018, and December 31, 2019, aimed to examine adherence to antibiotic recommendations. Associations between receiving recommendation-adherent antibiotics and patient and injury characteristics were investigated univariately and in adjusted regression analyses. The most common fracture locations among the 404 patients included were the tibia (43%) and fibula (26%). Fifty-eight percent of patients received recommendation-adherent antibiotics. After adjustment, patient demographics, comorbidities, cause of injury, and overall injury severity did not show significant associations with adherence to recommendations. Concomitant serious abdominal (adjusted odds ratio [AOR]=0.44) and spinal injuries (AOR=0.23) were associated with lower odds of receiving recommendation-adherent antibiotics. Additionally, fractures of certain locations were associated with increased odds of adherence (humerus: AOR=2.78; fibula: AOR=1.64), as were type 3 fractures (AOR=1.55). The overall infection rate was 4%, and adherence to antibiotic recommendations was not associated with infection (3% vs 5% for nonadherent, P=.34). Results suggest that although full recommendation adherence was somewhat low among this patient population, certain injury characteristics were predictive of adherence rates. Current antibiotic recommendations may benefit from consideration of how antibiotic initiation may fit into the prioritization of injury management, especially in patients with polytrauma with other severe injuries. [Orthopedics. 2023;46(1):54-58.].

Hypoxia Dysregulates the Transcription of Myoendothelial Junction Proteins Involved with Nitric Oxide Production in Brain Endothelial Cells.

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.

Factors associated with delays in medical and surgical open facial fracture management.

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<0.01), irrigation without debridement (ORearly=0.09, p<0.01), and ORIF (ORearly=0.10, p<0.01). Going to the OR within 24 hours was associated with early I&D (ORearly=377.26, p<0.01), irrigation without debridement (ORearly=13.54, p<0.01), and ORIF (ORearly=154.92, p<0.01). The infection rate was 4%. Conclusions: In this examination of multiple aspects of open facial fracture management, serious injuries to non-facial regions led to delays in surgical fracture management, consistent with the study hypothesis. Level of evidence: Level III, prognostic/epidemiological.

Hyperglycemia in nondiabetic adult trauma patients is associated with worse outcomes than diabetic patients: An analysis of 95,764 patients.

BACKGROUND: The adverse impact of acute hyperglycemia is well documented but its specific effects on nondiabetic trauma patients are unclear. The purpose of this study was to analyze the differential impact of hyperglycemia on outcomes between diabetic and nondiabetic trauma inpatients. METHODS: Adults admitted 2018 to 2019 to 46 Level I/II trauma centers with two or more blood glucose tests were analyzed. Diabetes status was determined from International Classification of Diseases-10th Rev.-Clinical Modification, trauma registry, and/or hemoglobin A1c greater than 6.5. Patients with and without one or more hyperglycemic result >180 mg/dL were compared. Logistic regression examined the effects of hyperglycemia and diabetes on outcomes, adjusting for age, sex, Injury Severity Score, and body mass index. RESULTS: There were 95,764 patients: 54% male; mean age, 61 years; mean Injury Severity Score, 10; diabetic, 21%. Patients with hyperglycemia had higher mortality and worse outcomes compared with those without hyperglycemia. Nondiabetic hyperglycemic patients had the highest odds of mortality (diabetic: adjusted odds ratio, 3.11; 95% confidence interval, 2.8-3.5; nondiabetics: adjusted odds ratio, 7.5; 95% confidence interval, 6.8-8.4). Hyperglycemic nondiabetics experienced worse outcomes on every measure when compared with nonhyperglycemic nondiabetics, with higher rates of sepsis (1.1 vs. 0.1%, p < 0.001), more SSIs (1.0 vs. 0.1%, p < 0.001), longer mean hospital length of stay (11.4 vs. 5.0, p < 0.001), longer mean intensive care unit length of stay (8.5 vs. 4.0, p < 0.001), higher rates of intensive care unit use (68.6% vs. 35.1), and more ventilator use (42.4% vs. 7.3%). CONCLUSION: Hyperglycemia is associated with increased odds of mortality in both diabetic and nondiabetic patients. Hyperglycemia during hospitalization in nondiabetics was associated with the worst outcomes and represents a potential opportunity for intervention in this high-risk group. LEVEL OF EVIDENCE: Therapeutic/care management; Level III.

Characterization of peritoneal reactive ascites collected from acute appendicitis and small bowel obstruction patients.

BACKGROUND: Pathological abdominal adhesions can cause bowel obstructions. A history of appendectomy (appy) increases patient rehospitalization risk directly related to adhesions. To potentially identify strategies for adhesion treatment, we characterized reactive ascites (rA) collected during appy or adhesiolysis for small bowel obstruction (SBO). METHODS: This is a non-randomized, prospective observational study recruiting patients with non-perforated appendicitis or SBO from three Level 1 trauma centers in the United States. rA were analyzed via liquid chromatography-mass spectrometry (LC-MS) (n = 31), bead-based quantification cytokines and chemokines (n = 32) and soluble receptors (n = 30), and LC-MS metabolomics (n = 18). RESULTS: LC-MS showed that samples contained albumin, apolipoprotein A1, and transthyretin and that metabolites increased in SBO vs appy rA were biomarkers of oxidative stress. Multi-plex analyses showed levels of 17 cytokines/chemokines and 6 soluble receptors were significantly different in appy vs SBO rA. Top increased proteins in appy compared to SBO rA by 20.14-, 11.53-, and 8.18-fold were granulocyte-colony stimulating factor, C-X-C motif chemokine ligand 10, and interleukin-10, respectively. CONCLUSIONS: These data further define pro- and anti-inflammatory mediators and metabolites that may drive formation or perpetuate chronic abdominal adhesions. Future research is to further explore whether attenuation of these factors may decrease pathologic adhesion formation.

The public health burden of geriatric trauma: Analysis of 2,688,008 hospitalizations from Centers for Medicare and Medicaid Services inpatient claims.

BACKGROUND: Geriatric trauma care (GTC) represents an increasing proportion of injury care, but associated public health research on outcomes and expenditures is limited. The purpose of this study was to describe GTC characteristics, location, diagnoses, and expenditures. METHODS: Patients at short-term nonfederal hospitals, 65 years or older, with ≥1 injury International Classification of Diseases, Tenth Revision, were selected from 2016 to 2019 Centers for Medicare and Medicaid Services Inpatient Standard Analytical Files. Trauma center levels were linked to Inpatient Standard Analytical Files data via American Hospital Association Hospital ID and fuzzy string matching. Demographics, care location, diagnoses, and expenditures were compared across groups. RESULTS: A total of 2,688,008 hospitalizations (62% female; 90% White; 71% falls; mean Injury Severity Score, 6.5) from 3,286 hospitals were included, comprising 8.5% of all Medicare inpatient hospitalizations. Level I centers encompassed 7.2% of the institutions (n = 236) but 21.2% of hospitalizations, while nontrauma centers represented 58.5% of institutions (n = 1,923) and 37.7% of hospitalizations. Compared with nontrauma centers, patients at Level I centers had higher Elixhauser scores (9.0 vs. 8.8) and Injury Severity Score (7.4 vs. 6.0; p < 0.0001). The most frequent primary diagnosis at all centers was hip/femur fracture (28.3%), followed by traumatic brain injury (10.1%). Expenditures totaled $32.9 billion for trauma-related hospitalizations, or 9.1% of total Medicare hospitalization expenditures and approximately 1.1% of the annual Medicare budget. The overall mortality rate was 3.5%. CONCLUSION: Geriatric trauma care accounts for 8.5% of all inpatient GTC and a similar percentage of expenditures, the most common injury being hip/femur fractures. The largest proportion of GTC occurs at nontrauma centers, emphasizing their vital role in trauma care. Public health prevention programs and GTC guidelines should be implemented by all hospitals, not just trauma centers. Further research is required to determine the optimal role of trauma systems in GTC, establish data-driven triage guidelines, and define the impact of trauma centers and nontrauma centers on GTC mortality. LEVEL OF EVIDENCE: Therapeutic/care management, Level III.

Examining trends in gun violence injuries before and during the COVID-19 pandemic across six trauma centers.

OBJECTIVES: The onset of the national stay-at-home orders accompanied by a surge in firearm sales has elevated the concerns of clinicians and public health authorities. The purpose of this study was to examine the impact of the stay-at-home orders among gunshot wound (GSW) trauma admissions. METHODS: This was a retrospective cohort study at six level I trauma centers across four states. Patients admitted after the onset of COVID-19 restrictions (March 16, 2020-June 30, 2020) were compared with those admitted during the same period in 2019. We compared (1) rate of patients with GSW and (2) characteristics of patients with GSW, by period using Χ2 tests or Fisher's exact tests, as appropriate. RESULTS: There were 6996 trauma admissions across the study period; 3707 (53%) in 2019 and 3289 (47%) in 2020. From 2019 to 2020, there was a significant increase in GSW admissions (4% vs. 6%, p=0.001); 4 weeks specifically had significant increases (March 16-March 23: 4%, April 1-April 8: 5%, April 9-April 16: 6%, and May 11-May 18: 5%). Of the 334 GSWs, there were significant increases in patients with mental illness (5% vs. 11%, p=0.03), alcohol use disorder (2% vs. 10%, p=0.003), substance use disorder (11% vs. 25%, p=0.001), and a significant decrease in mortality (14% vs. 7%, p=0.03) in 2020. No other significant differences between time periods were identified. CONCLUSION: Our data suggest that trauma centers admitted significantly more patients with GSW following the national guidelines, including an increase in those with mental illness and substance use-related disorders. This could be attributable to the stay-at-home orders. LEVEL OF EVIDENCE: Level III, retrospective study.

C1 esterase inhibitor-mediated immunosuppression in COVID-19: Friend or foe?

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.

Are trauma research programs in academic and non-academic centers measured by equal standards? A survey of 137 level I trauma centers in the United States.

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.

Effect of the COVID-19 pandemic on the ability of level 1 trauma centers to meet American College of Surgeons research requirements.

INTRODUCTION: The COVID-19 pandemic has had major effects on hospitals' ability to perform scientific research while providing patient care and minimizing virus exposure and spread. Many non-COVID-19 research has been halted, and funding has been diverted to COVID-19 research and away from other areas. METHODS: A 28-question survey was administered to all level 1 trauma centers in the USA that included questions about how the pandemic affected the trauma centers' ability to fulfill the volume and research requirements of level 1 verification by the American College of Surgeons (ACS). RESULTS: The survey had a 29% response rate (40/137 successful invitations). Over half of respondents (52%) reported reduced trauma admissions during the pandemic, and 7% reported that their admissions dropped below the volume required for level 1 verification. Many centers diverted resources from research during the pandemic (44%), halted ongoing consenting studies (33%), and had difficulty fulfilling research requirements because of competing clinical priorities (40%). DISCUSSION: Results of this study show a need for flexibility in the ACS verification process during the COVID-19 pandemic, potentially including reduction of the required admissions and/or research publication volumes. LEVEL OF EVIDENCE: Level IV, cross-sectional study.

Effect of the COVID-19 pandemic on health insurance coverage among trauma patients: a study of six level I trauma centers.

BACKGROUND: Increased unemployment during the COVID-19 pandemic has likely led to widespread loss of employer-provided health insurance. This study examined trends in health insurance coverage among trauma patients during the COVID-19 pandemic, including differences in demographics and clinical characteristics by insurance type. METHODS: This was a retrospective study on adult patients admitted to six level 1 trauma centers between January 1, 2018 and June 30, 2020. The primary exposure was hospital admission date: January 1, 2018 to December 31, 2018 (Period 1), January 1, 2019 to March 15, 2020 (Period 2), and March 16, 2020 to June 30, 2020 (Period 3). Covariates included demographic and clinical variables. χ² tests examined whether the rates of patients covered by each insurance type differed between the pandemic and earlier periods. Mann-Whiney U and χ² tests investigated whether patient demographics or clinical characteristics differed within each insurance type across the study periods. RESULTS: A total of 31 225 trauma patients admitted between January 1, 2018 and June 30, 2019 were included. Forty-one per cent (n=12 651) were admitted in Period 1, 49% (n=15 258) were from Period 2, and 11% (n=3288) were from Period 3. Percentages of uninsured patients increased significantly across the three periods (Periods 1 to 3: 15%, 16%, 21%) (ptrend=0.02); however, there was no accompanying decrease in the percentages of commercial/privately insured patients (Periods 1 to 3: 40%, 39%, 39%) (ptrend=0.27). There was a significant decrease in the percentage of patients on Medicare during the pandemic period (Periods 1 to 3: 39%, 39%, 34%) (p<0.01). DISCUSSION: This study found that job loss during the COVID-19 pandemic resulted in increases of uninsured trauma patients. However, there was not a corresponding decrease in commercial/privately insured patients, as may have been expected; rather, a decrease in Medicare patients was observed. These findings may be attributable to a growing workforce during the study period, in combination with a younger overall patient population during the pandemic. LEVEL OF EVIDENCE: Retrospective, level III study.

Incorporating age improves the Glasgow Coma Scale score for predicting mortality from traumatic brain injury.

BACKGROUND: The Glasgow Coma Scale (GCS) score has been adapted into categories of severity (mild, moderate, and severe) and are ubiquitous in the trauma setting. This study sought to revise the GCS categories to account for an interaction by age and to determine the discrimination of the revised categories compared with the standard GCS categories. METHODS: The American College of Surgeons National Trauma Data Bank registry was used to identify patients with traumatic brain injury (TBI; ICD-9 codes 850-854.19) who were admitted to participating trauma centers from 2010 to 2015. The primary exposure variables were GCS score and age, categorized by decade (teens, 20s, 30s…, 80s). In-hospital mortality was the primary outcome for examining TBI severity/prognostication. Logistic regression was used to calculate the conditional probability of death by age decade and GCS in a development dataset (75% of patients). These probabilities were used to create a points-based revision of the GCS, categorized as low (mild), moderate, and high (severe). Performance of the revised versus standard GCS categories was compared in the validation dataset using area under the receiver operating characteristic (AUC) curves. RESULTS: The final population included 539,032 patients with TBI. Age modified the performance of the GCS, resulting in a novel categorization schema for each age decile. For patients in their 50s, performance of the revised GCS categories mirrored the standard GCS categorization (3-8, 9-12, 13-15); all other revised GCS categories were heavily modified by age. Model validation demonstrated the revised GCS categories statistically significantly outperformed the standard GCS categories at predicting mortality (AUC: 0.800 vs 0.755, p<0.001). The revised GCS categorization also outperformed the standard GCS categories for mortality within pre-specified subpopulations: blunt mechanism, isolated TBI, falls, non-transferred patients. DISCUSSION: We propose the revised age-adjusted GCS categories will improve severity assessment and provide a more uniform early prognostic indicator of mortality following traumatic brain injury. LEVEL OF EVIDENCE: III epidemiologic/prognostic.

Clinically distinct COVID-19 cases share notably similar immune response progression: A follow-up analysis.

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.

Effects of propofol on ischemia-reperfusion and traumatic brain injury.

Oxidative stress exacerbates brain damage following ischemia-reperfusion and traumatic brain injury (TBI). Management of TBI and critically ill patients commonly involves use of propofol, a sedation medication that acts as a general anesthetic with inherent antioxidant properties. Here we review available evidence from animal model systems and clinical studies that propofol protects against ischemia-reperfusion injury. However, evidence of propofol toxicity in humans exists and manifests as a rare complication, "propofol infusion syndrome" (PRIS). Evidence in animal models suggests that brain injury induces expression of the p75 neurotrophin receptor (p75NTR), which is associated with proapoptotic signaling. p75NTR-mediated apoptosis of neurons is further exacerbated by propofol's superinduction of p75NTR and concomitant inhibition of neurotrophin processing. Propofol is toxic to neurons but not astrocytes, a type of glial cell. Evidence suggests that propofol protects astrocytes from oxidative stress and stimulates astroglial-mediated protection of neurons. One may speculate that in brain injury patients under sedation/anesthesia, propofol provides brain tissue protection or aids in recovery by enhancing astrocyte function. Nevertheless, our understanding of neurologic recovery versus long-term neurological sequelae leading to neurodegeneration is poor, and it is also conceivable that propofol plays a partial as yet unrecognized role in long-term impairment of the injured brain.

The presence of S-sulfonated transthyretin in commercial human serum albumin solutions: Potential contribution to neuropathy.

BACKGROUND: Commercial solutions of human serum albumin (HSA) are administered to critically ill patients for the treatment of shock, restoration of blood volume, and the acute management of burns. Previously, conflicting results on the effects of HSA administration have been reported varying from a favorable increase in total plasma antioxidant capacity to a higher mortality rate in traumatic brain injury (TBI) patients. These results could be partially explained due to the known heterogeneity of HSA solutions. We report the discovery of S-sulfonated human transthyretin (hTTR) in HSA solutions. METHODS: Proteomics was performed on commercially available solutions of 5% HSA by LC-MS analysis. The MS charge envelope for hTTR was deconvolved to the uncharged native hTTR parent mass (13,762 Da). The parent mass was then integrated, and relative proportions of the 2 major species of hTTR, native and S-sulfonated hTTR (13,842 Da), were calculated. RESULTS: The majority of hTTR found in 5% commercial HSA solutions is in the S-sulfonated form regardless of the age of the HSA solution. S-sulfonation of hTTR at the free cysteine residue in position 10 appears to be the result of a mixed disulfide exchange possibly with S-cysteinylated hTTR or S-cysteinylated HSA. hTTR is a tetramer composed of four identical monomers each containing a reduced cysteine residue in position 10. S-sulfonation of hTTR at this cysteine residue can destabilize the hTTR tetramer, an important step in the formation of TTR-related amyloid fibrils. CONCLUSIONS: Administration of a commercial HSA solution that already contains S-sulfonated hTTR could potentially contribute to the development of amyloid-related/polyneuropathy in the critically ill.

Stress Hyperglycemia in Critically Ill Patients: Insight Into Possible Molecular Pathways.

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.

Clinically relevant redifferentiation of fibroblast-like chondrocytes into functional chondrocytes by the low molecular weight fraction of human serum albumin.

OBJECTIVES: Traumatic joint injury induces chondrocyte dysfunction and progressive breakdown of articular cartilage, leading to post-traumatic osteoarthritis (PTOA). In this condition, dysfunctional fibroblast-like chondrocytes (FLCs) no longer express proteins required for cartilage maintenance, such as SOX9 and collagen-type II (COL2). Interleukin-6 (IL-6) has been demonstrated to downregulate expression of these two critical proteins in chondrocytes, and increased IL-6 levels have been measured in patients with PTOA. The <5kDa fraction of human serum albumin (LMWF5A) has been suggested to modulate this pathway, as decreased levels of IL-6 are secreted by immunostimulated LMWF5A-treated macrophages. Our objective was to determine whether LMWF5A induces an in vitro model of FLCs to redifferentiate into functional chondrocytes. METHODS: SOX9 and COL2 were monitored via western blot, and COL2 was detected with immunofluorescence. Aggrecan and IL-6 were quantified by ELISA. Glycosaminoglycan (GAG) levels were quantified with alcian blue. RESULTS: We found that LMWF5A significantly increases the principal cartilage transcription factor SOX9 and the SOX9 target protein COL2 in monolayer-cultured FLCs. Multiple LMWF5A treatments of 3-D pellet FLC cultures over 2wks resulted in a significant decrease in IL-6 and significant increases in the major players of articular cartilage mechanics, aggrecan and highly-sulfated GAGs. CONCLUSIONS: These data support the hypothesis and clinical outcomes of two phase III clinical trials that LMWF5A-treatment induces chondrogenesis and supports functional cartilage. We propose that LMWF5A could maintain articular cartilage integrity in all joints following traumatic injury.