Understanding the Impact of Trauma Admissions to Nonsurgical Services.

BACKGROUND: The American College of Surgeons Committee on Trauma (ACS COT) delineates trauma center standards, one of which limits the number of injured patients admitted to nonsurgical services. Performance improvement review of nonsurgical admissions (NSAs), particularly those with Injury Severity Score (ISS) > 9, is required. OBJECTIVE: To examine trauma patients with NSA for appropriateness of admission and any potential clinical effect as a result of NSA. METHODS: All trauma patients presenting to our ACS COT-verified level 1 trauma center in Southern California (05/2021-04/2022) were retrospectively screened. Nonsurgical admissions with ISS > 9 were included without exclusions. Appropriateness and clinical impact of NSA were assessed by the Trauma Medical Director (TMD) and Associate TMD. RESULTS: Forty patients met study criteria, with a mean age of 54 years (range 5 d-99 y). The mean ISS was 19 (range 10-30). Nonsurgical admissions most commonly sustained traumatic brain injury (TBI) (n = 27, 68%) after ground level falls (GLF) (n = 32, 80%). All NSAs were evaluated by ≥1 surgical service, commonly neurosurgery (n = 33, 83%) and trauma surgery (n = 13, 33%). Sixteen patients (40%) died, 75% (n = 12) of which were secondary to catastrophic TBI. Upon detailed review, all NSAs were deemed appropriate and without potential clinical impact. CONCLUSIONS: All NSAs in this study were appropriate admissions without clinical effect from lack of surgical admission. Nonsurgical admissions were typically elderly patients with head injuries after GLF. With the anticipated increase in geriatric trauma due to our aging population, NSA with surgical consultation may be an important way to manage trauma admissions without compromising care of injured patients.

Autonomous IL-36R signaling in neutrophils activates potent antitumor effector functions.

While the rapid advancement of immunotherapies has revolutionized cancer treatment, only a small fraction of patients derive clinical benefit. Eradication of large, established tumors appears to depend on engaging and activating both innate and adaptive immune system components to mount a rigorous and comprehensive immune response. Identifying such agents is a high unmet medical need, because they are sparse in the therapeutic landscape of cancer treatment. Here, we report that IL-36 cytokine can engage both innate and adaptive immunity to remodel an immune-suppressive tumor microenvironment (TME) and mediate potent antitumor immune responses via signaling in host hematopoietic cells. Mechanistically, IL-36 signaling modulates neutrophils in a cell-intrinsic manner to greatly enhance not only their ability to directly kill tumor cells but also promote T and NK cell responses. Thus, while poor prognostic outcomes are typically associated with neutrophil enrichment in the TME, our results highlight the pleiotropic effects of IL-36 and its therapeutic potential to modify tumor-infiltrating neutrophils into potent effector cells and engage both the innate and adaptive immune system to achieve durable antitumor responses in solid tumors.

Narrative Review: Is There a Transfusion Cutoff Value After Which Nonsurvivability Is Inevitable in Trauma Patients Receiving Ultramassive Transfusion?

The institution of massive transfusion protocols (MTPs) has improved the timely delivery of large quantities of blood products and improves patient outcomes. In recent years, the cost of blood products has increased, compounded by significant blood product shortages. There is practical need for identification of a transfusion volume in trauma patients that is associated with increased mortality, or a threshold after which additional transfusion is futile and associated with nonsurvivability. This transfusion threshold is often described in the setting of an ultramassive transfusion (UMT). There are few studies defining what constitutes amount or outcomes associated with such large volume transfusion. The purpose of this narrative review is to provide an analysis of existing literature examining the effects of UMT on outcomes including survival in adult trauma patients and to determine whether there is a threshold transfusion limit after which mortality is inevitable. Fourteen studies were included in this review. The data examining the utility of UMT in trauma are of poor quality, and with the variability inherent in trauma patients, and the surgeons caring for them, no universally accepted cutoff for transfusion exists. Not surprisingly, there is a trend toward increasing mortality with increasing transfusions. The decision to continue transfusing is multifactorial and must be individualized, taking into consideration patient characteristics, institution factors, blood bank supply, and most importantly, constant reevaluation of the need for ongoing transfusion rather than blind continuous transfusion until the heart stops.

Brief report: STING expressed in tumor and non-tumor compartments has distinct roles in regulating anti-tumor immunity.

Type I interferon-mediated activation of immune cells can facilitate the generation of productive tumor antigen-specific T cell responses in solid tumors. The cGAS/STING DNA sensing pathway is a critical upstream mediator of type I interferon production and is an important regulator of anti-tumor immunity. Numerous STING pathway agonists are now being tested in clinical trials, but the effectiveness of this approach is not yet clear and a better understanding of the relative importance of this pathway in various tumor settings is needed. We have evaluated syngeneic tumor models with different baseline inflammatory states to determine the contributions of STING activity in both tumor and non-tumor cellular compartments to anti-tumor immune responses. We find that productive anti-tumor immune responses in the poorly immunogenic B16F10 model show a strong dependence on STING expression in non-tumor cells. In the immunogenic MC38 model, constitutive STING activation in tumor cells can partially bypass the requirement for STING-dependent activity from immune cells. Our findings reveal multiple, context-dependent roles for STING activity in the regulation of anti-tumor immunity and the response to immunotherapy. In preclinical models where STING is basally active, checkpoint inhibition is more likely to have a therapeutic effect and removal of STING signaling from either the tumor or the non-tumor compartment has a minimal effect. Removal of STING signaling in both, however, diminishes the efficacy derived from checkpoint therapy. Further work is needed to understand the heterogeneity of STING signaling in patients, both in tumor cells and the tumor microenvironment, and the best means of harnessing this pathway to generate anti-tumor immunity and improve therapeutic outcomes.

Temporary intravascular shunts after civilian arterial injury: A prospective multicenter Eastern Association for the Surgery of Trauma study.

INTRODUCTION: We sought to determine the impact of the indication for shunt placement on shunt-related outcomes after major arterial injuries. We hypothesized that a shunt placed for damage control indications would be associated with an increase in shunt-related complications including shunt dislodgement, thrombosis, or distal ischemia. PATIENTS & METHODS: A prospective, multicenter study (eleven level one US trauma centers) of all adult trauma patients undergoing temporary intravascular shunts (TIVS) after arterial injury was undertaken (January 2017-May 2019). Exclusion criteria included age <15years, shunt placement distal to popliteal/brachial arteries, isolated venous shunts, and death before shunt removal. Clinical variables were compared by indication and shunt-related complications. The primary endpoint was TIVS complications (thrombosis, migration, distal ischemia). RESULTS: The 66 patients who underwent TIVS were primarily young (30years [IQR 22-36]) men (85%), severely injured (ISS 17 [10-25]) by penetrating mechanisms (59%), and had their shunts placed for damage control (41%). After a median SDT of 198min [89-622], 9% experienced shunt-related complications. Compared by shunt placement indication (damage control shunts [n=27] compared to non-damage control shunts [n=39]), there were no differences in gender, mechanism, extremity AIS, MESS score, fractures, or surgeon specialty between the two groups (all p>0.05). Patients with shunts placed for damage control indications had more severe injuries (ISS 23.5 compared to 13; SBP 100 compared to 129; GCS 11 compared to 15; lactate 11.5 compared to 3.6; all p<0.05), and had more frequent shunt complication predictors, but damage control shunts did not have significantly more TIVS complications (11.1% compared to 7.7%, p=0.658). Shunt complication patients were discharged home less often (33% vs 65%; p<0.05) but all survived. CONCLUSION: Shunts placed for damage control indications were not associated with shunt complications in this prospective, multicenter study.

Activity of tumor-associated macrophage depletion by CSF1R blockade is highly dependent on the tumor model and timing of treatment.

Tumor-associated macrophages (TAMs) are abundant in solid tumors where they exhibit immunosuppressive and pro-tumorigenic functions. Inhibition of TAM proliferation and survival through CSF1R blockade has been widely explored as a cancer immunotherapy. To further define mechanisms regulating CSF1R-targeted therapies, we systematically evaluated the effect of anti-CSF1R treatment on tumor growth and tumor microenvironment (TME) inflammation across multiple murine models. Despite substantial macrophage depletion, anti-CSF1R had minimal effects on the anti-tumor immune response in mice bearing established tumors. In contrast, anti-CSF1R treatment concurrent with tumor implantation resulted in more robust tumor growth inhibition and evidence of enhanced anti-tumor immunity. Our findings suggest only minor contributions of CSF1R-dependent TAMs to the inflammatory state of the TME in established tumors, that immune landscape heterogeneity across different tumor models can influence anti-CSF1R activity, and that alternative treatment schedules and/or TAM depletion strategies may be needed to maximize the clinical benefit of this approach.

Correction: Taste loss with obesity in mice and men.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Penetrating injury to the cardiac box.

BACKGROUND: A penetrating injury to the "cardiac box" is thought to be predictive of an injury to the heart; however, there is very little evidence available to support this association. This study aims to evaluate the relationship between penetrating trauma to the cardiac box and a clinically significant injury. METHODS: All patients presenting to a Level I trauma center from January 2009 to June 2015 who sustained a penetrating injury isolated to the thorax were retrospectively identified. Patients were categorized according to the location of injury: within or outside the historical cardiac box. Patients with concurrent injuries both inside and outside the cardiac box were excluded. Clinical demographics, injuries, procedures, and outcomes were compared. RESULTS: During this 7-year period, 330 patients (92% male; median age, 28 years) sustained penetrating injuries isolated to the thorax: 138 (42%) within the cardiac box and 192 (58%) outside the cardiac box. By mechanism, 105 (76%) were stab wounds (SW) and 33 (24%) were gunshot wounds (GSW) inside the cardiac box, and 125 (65%) SW and 67 (35%) GSW outside the cardiac box. The overall rate of thoracotomy or sternotomy (35/138 [25.4%] vs. 15/192 [7.8%], p < 0.001) and the incidence of cardiac injury (18/138 [13%] vs. 5/192 [2.6%], p < 0.001) were significantly higher in patients with penetrating trauma within the cardiac box. This was, however, dependent on mechanism with SW demonstrating a higher incidence of cardiac injury (15/105 [14.3%] vs. 3/125 [2.4%], p = 0.001) and GSW showing no significant difference (3/33 [9.1%] vs. 2/67 [3%], p = 0.328]. There was no difference in overall mortality (9/138 [6.5%] vs. 6/192 [3.1%], p = 0.144). CONCLUSION: The role of the cardiac box in the clinical evaluation of a patient with a penetrating injury to the thorax has remained unclear. In this analysis, mechanism is important. Stab wounds to the cardiac box were associated with a higher risk of cardiac injury. However, for GSW, injury to the cardiac box was not associated with a higher incidence of injury. The diagnostic interaction between clinical examination and ultrasound, for the diagnosis of clinically significant cardiac injuries, warrants further investigation. LEVEL OF EVIDENCE: Prognostic study, Level IV, Therapeutic V.

Taste loss with obesity in mice and men.

BACKGROUND: Our sense of taste is critical in defining our food choices and habits. Located primarily in our tongue, taste buds are small assemblies of constantly renewing sensory cells, tasked with evaluating oral stimuli before the food we eat is consumed. METHODS: Using both mice and a free-living human population, we tracked taste papilla abundancy with weight gain, to test for deficiencies in the taste system of obese mice and humans with increased adiposity. RESULTS: Mice fed a high-fat diet for 8 weeks expressed markers for all subtypes of taste cells at a lower level than chow-fed counterparts. This came alongside the loss of markers for taste cell proliferation (Ki-67) and development (ß-catenin), as well as lower fungiform papillae density, consistent with earlier results showing lower circumvallate taste bud abundance in obese mice. Likewise, in a population of college students tracked through 4 years of college attendance, the change in density of fungiform papillae, which house taste buds in the anterior tongue, was negatively correlated with change in neck circumference, a marker of adiposity. CONCLUSIONS: These results highlight changes in taste during weight gain as a potentially important consideration in the study of obesity.

Calculated Decisions: Focused Assessment With Sonography for Trauma (FAST)

Focused Assessment with Sonography for Trauma (FAST) predicts the presence of pericardial or intra-abdominal injury after penetrating or blunt trauma.

Calculated Decisions: Blast Lung Injury Severity Score

The Blast Lung Injury Severity Score stratifies primary blast lung injuries into 3 categories to guide ventilator treatment.

Calculated Decisions: Bastion Classification of Lower Limb Blast Injuries

The Bastion Classification criteria stratify explosionrelated lower limb injuries into 5 categories to guide treatment.

Calculated Decisions: Wound Closure Classification

The Wound Closure Classification stratifies types of wounds to help guide strategies for closure.

Time to stroke: A Western Trauma Association multicenter study of blunt cerebrovascular injuries.

BACKGROUND: Screening for blunt cerebrovascular injuries (BCVIs) in asymptomatic high-risk patients has become routine. To date, the length of this asymptomatic period has not been defined. Determining the time to stroke could impact therapy including earlier initiation of antithrombotics in multiply injured patients. The purpose of this study was to determine the time to stroke in patients with a BCVI-related stroke. We hypothesized that the majority of patients suffer stroke between 24 hours and 72 hours after injury. METHODS: Patients with a BCVI-related stroke from January 2007 to January 2017 from 37 trauma centers were reviewed. RESULTS: During the 10-year study, 492 patients had a BCVI-related stroke; the majority were men (61%), with a median age of 39 years and ISS of 29. Stroke was present at admission in 182 patients (37%) and occurred during an Interventional Radiology procedure in six patients. In the remaining 304 patients, stroke was identified a median of 48 hours after admission: 53 hours in the 144 patients identified by neurologic symptoms and 42 hours in the 160 patients without a neurologic examination and an incidental stroke identified on imaging. Of those patients with neurologic symptoms, 88 (61%) had a stroke within 72 hours, whereas 56 had a stroke after 72 hours; there was a sequential decline in stroke occurrence over the first week. Of the 304 patients who had a stroke after admission, 64 patients (22%) were being treated with antithrombotics when the stroke occurred. CONCLUSIONS: The majority of patients suffer BCVI-related stroke in the first 72 hours after injury. Time to stroke can help inform clinicians about initiation of treatment in the multiply injured patient. LEVEL OF EVIDENCE: Prognostic/Epidemiologic, level III.

Human Factors Validation of the AeroForm Tissue Expander System for Breast Reconstruction.

The tissue expansion process using traditional saline expanders is lengthy and uncomfortable. A new technology has been developed, providing a needle-free option implanted after a mastectomy, and is activated by a handheld remote control releasing small amounts (10 cc) of carbon dioxide from an internal reservoir. The expander is gradually filled with CO2 resulting in mechanical stretching of the overlying tissue. The AeroForm System has been evaluated in a series of clinical trials including a randomized, controlled U.S. study comparing the AeroForm System with saline expanders. Results demonstrated patients can safely and reliably dose and complete their expansions in half the time compared to saline expanders. A human factors validation study was conducted in 8 patients to evaluate whether patients could correctly use the device to complete their expansion at home. The sessions were recorded and data on performance, behavioral, and subjective measures were collected and analyzed and submitted to the FDA as part of the U.S. marketing approval. All 8 participants were successful in using the controller to deliver a simulated dose. Participants found the device easy to use and the training material provided adequate to understand use of the controller. For women who choose 2-stage breast reconstruction, a new safe and effective option is available for tissue expansion, offering a convenient and empowering alternative. The human factors validation study conducted confirmed the simplicity of the device and further validated that the device can be used safely and effectively for breast tissue expansion.

MICA/B and ULBP1 NKG2D ligands are independent predictors of good prognosis in cervical cancer.

BACKGROUND: NKG2D (natural killer group 2, member D) is thought to play an important role in mediating the activation of anticancer immune response. Expression of NKG2D ligands (NKG2DLs) is pronounced in malignancies and the heterogeneity of NKG2DL expression remains unclear. Here, we investigate the expression and clinical significance of NKG2DLs in cervical cancer. METHODS: Immunohistochemical analyses of MICA/B, ULBP1, ULBP2, ULBP3, RAET1E, and RAET1G were performed using tissue microarray analysis of 200 cervical cancers, 327 high-grade cervical intraepithelial neoplasias (CINs), 99 low-grade CINs, and 541 matched nonadjacent normal cervical epithelial tissues and compared the data with clinicopathologic variables, including the survival of cervical cancer patients. RESULTS: MICA/B, ULBP1, and RAET1E expression was higher in cervical cancer than in low-grade CIN (p<0.001, p=0.012, p=0.013, respectively) and normal cervix (all p<0.001). Among these markers, expression of ULBP1 was significantly different depending on patient tumor stage (p=0.010) and tumor size (p=0.045). ULBP1 expression was correlated with MICA/B (p<0.001) and ULBP2 (p=0.002) expression in cervical cancer. While MICA/B+ or ULBP1+ patients had improved disease-free survival time (p=0.027 and p=0.009, respectively) relative to that of the low expression group, RAET1E+ or RAET1G+ was correlated with shorter survival time (p=0.018 and p=0.029, respectively). However, in terms of overall survival, the ULBP1+ group had significantly longer survival time than the low expression group (p=0.009). Multivariate analysis indicated that MICA/B+/ULBP1+ (HR=0.16, p=0.015) and ULBP1+ (HR=0.31, p=0.024) are independent prognostic factors of disease-free survival in cervical cancer. CONCLUSIONS: High expression of either ULBP1 or MICA/B and ULBP1 combined is an indicator of good prognosis in cervical cancer, suggesting their potential utility as prognostic tests in clinical assessment.

Rapid chemiluminescent sandwich enzyme immunoassay capable of consecutively quantifying multiple tumor markers in a sample.

Using the role of p-iodophenol in enzyme assay, enhanced 1,1'-oxalyldiimidazole chemiluminescent enzyme immunoassays (ODI-CLEIAs) were developed to consecutively quantify trace levels of triple tumor markers, such as alpha fetoprotein (AFP), carcinoembryonic antigen (CEA), and prostate specific antigen (PSA) in a sample. Due to the high sensitivity of enhanced ODI-CLEIAs, it was possible to fix the incubation times (1) to capture a tumor marker with two antibodies, which are primary antibody immobilized on the surface of polystyrene strip-well and detection antibody-conjugated horseradish peroxidase (HRP), and (2) to form resorufin with the addition of substrates (e.g., Amplex Red, H2O2) in order to quantify triple markers in human serum. Enhanced ODI-CLEIAs capable of consecutively and rapidly quantifying triple markers with the same incubation time were more sensitive than conventional enzyme-linked immunosorbent assay (ELISA) capable of separately and slowly quantifying them with different incubation times. In addition, accuracy, precision, and recovery of enhanced ODI CLEIAs in the presence of p-iodophenol were acceptable within statistical error range.

Social Understanding in Israeli-Jewish, Israeli-Palestinian, Palestinian, and Jordanian 5-year-old Children: Moral Judgments and Stereotypes.

An empirical investigation was conducted of young Palestinian, Jordanian, Israeli-Palestinian, and Israeli-Jewish children's (N = 433; M = 5.7 years of age) cultural stereotypes and their evaluations of peer intergroup exclusion based upon a number of different factors, including being from a different country and speaking a different language. Children in this study live in a geographical region that has a history of cultural and religious tension, violence, and extreme intergroup conflict. Our findings revealed that the negative consequences of living with intergroup tension are related to the use of stereotypes. At the same time, the results for moral judgments and evaluations about excluding peers provided positive results about the young children's inclusive views regarding peer interactions.