BACKGROUND: The Brain Trauma Foundation recommends intracranial pressure (ICP) monitor placement for patients with severe traumatic brain injury (TBI). Adherence with these guidelines in elderly patients is unknown. We hypothesized that disparities in ICP monitor placement would exist based on patient age. METHODS: Using the National Trauma Data Bank (2010-2014), we identified patients admitted for blunt TBI with admission Glasgow Coma Scale (GCS) scores of 3-8. Patients were excluded if they had a non-Head Abbreviated Injury Scale (AIS) score ≥3, hospital length of stay <24 hours or were discharged from the emergency department. Demographic data, ICP monitor placement, GCS, AIS-Head, Injury Severity Score, and outcome measures were collected. Propensity score matching between ICP monitor and non-ICP monitor patients was used for logistic regression and Cox multivariate regression analyses. RESULTS: Of the 30 710 patients with blunt TBI with GCS scores of 3-8 included in our study, 4093 were treated with an ICP monitor. ICP monitor placement rates significantly decreased with increasing age. Multivariable analysis demonstrated that patients treated with an ICP monitor were more likely to be younger, male, have private/commercial insurance, and receive care at an institution with three or more neurosurgeons. CONCLUSION: Patients ≥65 years of age with severe blunt TBI are less likely to be treated with an ICP monitor than younger patients. Age disparities in adherence to Brain Trauma Foundation guidelines may alter the outcomes for patients with severe TBI. LEVEL OF EVIDENCE: Level IV.

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

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

INTRODUCTION: The CHRNA7 gene encodes the α-7 nicotinic acetylcholine receptor (α7nAchR) that regulates anti-inflammatory responses to injury; however, only humans express a variant gene called CHRFAM7A that alters the function of α7nAChR; CHRFAM7A expression predominates in bone marrow and monocytes/macrophages where the CHRFAM7A/CHRNA7 ratio is highly variable between individuals. We have previously shown in transgenic mice that CHRFAM7A increased emergency myelopoiesis from the bone marrow and monocyte/macrophage expression in lungs. MATERIALS AND METHODS: CHRFAM7A transgenic mice are compared to age- and gender-matched wild-type (WT) siblings. We utilized a model of sepsis using LPS injection to measure survival. Lung vascular permeability was measured after severe burn injury in WT vs. CHRFAM7A transgenic mice. Bone marrow CHRFAM7A expression was evaluated using adoptive transfer of CHRFAM7A transgenic bone marrow into WT mice. RESULTS: Here, we demonstrate that CHRFAM7A expression results in an anti-inflammatory phenotype with an improved survival to LPS and decreased acute lung injury in a severe cutaneous burn model compared to WT. CONCLUSIONS: These data suggest that the relative expression of CHRFAM7A may alter resiliency to injury and contribute to individual variability in the human systemic inflammatory response (SIRS) to injury.

Introduction

Trauma/hemorrhagic shock (T/HS) causes the release of pro-inflammatory mediators into the mesenteric lymph (ML), triggering a systemic inflammatory response and acute lung injury (ALI). Direct and pharmacologic vagal nerve stimulation prevents gut barrier failure and alters the biologic activity of ML after injury. We hypothesize that treatment with a pharmacologic vagal agonist after T/HS would attenuate the biologic activity of ML and prevent ALI.

Methods

ML was collected from male Sprague-Dawley rats after T/HS, trauma-sham shock (T/SS) or T/HS with administration of the pharmacologic vagal agonist CPSI-121. ML samples from each experimental group were injected into naïve mice to assess biologic activity. Blood samples were analyzed for changes in STAT3 phosphorylation (pSTAT3). Lung injury was characterized by histology, permeability and immune cell recruitment.

Results

T/HS lymph injected in naïve mice caused a systemic inflammatory response characterized by hypotension and increased circulating monocyte pSTAT3 activity. Injection of T/HS lymph also resulted in ALI, confirmed by histology, lung permeability and increased recruitment of pulmonary macrophages and neutrophils to lung parenchyma. CPSI-121 attenuated T/HS lymph-induced systemic inflammatory response and ALI with stable hemodynamics and similar monocyte pSTAT3 levels, lung histology, lung permeability and lung immune cell recruitment compared to animals injected with lymph from T/SS.

Conclusion

Treatment with CPSI-121 after T/HS attenuated the biologic activity of the ML and decreased ALI. Given the superior clinical feasibility of utilizing a pharmacologic approach to vagal nerve stimulation, CPSI-121 is a potential treatment strategy to limit end organ dysfunction after injury.

Background

The α7-subunit of the α7-nicotinic acetylcholine receptor (α7-nAChR) is an obligatory intermediate for the anti-inflammatory effects of the vagus nerve. But in humans, there exists a second gene called CHRFAM7A that encodes a dominant negative α7-nAChR inhibitor. Here, we investigated whether their expression was altered in inflammatory bowel disease (IBD) and colon cancer.

Methods

Quantitative RT-PCR measured gene expression of human α7-nAChR gene (CHRNA7), CHRFAM7A, TBC3D1, and actin in biopsies of normal large and small intestine, and compared to their expression in biopsies of ulcerative colitis, Crohn's disease, and colon cancer.

Results

qRT-PCR showed that CHRFAM7A and CHRNA7 gene expression was significantly (p < .02) up-regulated in IBD (N = 64). Gene expression was unchanged in colon cancer. Further analyses revealed that there were differences in ulcerative colitis and Crohn's Disease. Colon biopsies of ulcerative colitis (N = 33) confirmed increased expression of CHRFAM7A and decreased in CHRNA7 expression (p < 0.001). Biopsies of Crohn's disease (N = 31), however, showed only small changes in CHRFAM7A expression (p < 0.04) and no change in CHRNA7. When segregated by tissue source, both CHRFAM7A up-regulation (p < 0.02) and CHRNA7 down-regulation (p < 0.001) were measured in colon, but not in small intestine.

Conclusion

The human-specific CHRFAM7A gene is up-regulated, and its target, CHRNA7, down-regulated, in IBD. Differences between ulcerative colitis and Crohn's disease tie to location of disease.

Significance

The appearance of IBD in modern humans may be consequent to the emergence of CHRFAM7A, a human-specific α7-nAChR antagonist. CHRFAM7A could present a new, unrecognized target for development of IBD therapeutics.

External causes of death are important in the pediatric population worldwide. We performed an analysis of all injury-fatalities in children between ages zero and 17 years, between January 2000 and December 2006, in San Diego County, California, United States of America. Information was obtained from the County of San Diego Medical Examiner’s database. External causes were selected and grouped by intent and mechanism. Demographics, location of death and relation between the injury mechanism and time of death were described. There were 884 medico-legal examinations, of which 480 deaths were due to external causes. There majority were males (328, 68.3%) and whites (190, 39.6%). The most prevalent mechanism of injury leading to death was road traffic accidents (40.2%), followed by asphyxia (22.7%) and penetrating trauma (17.7%). Unintentional injuries occurred in 65.8% and intentional injuries, including homicide and suicide, occurred in 24.2 and 9.4%, respectively. Death occurred at the scene in 196 cases (40.9%). Most deaths occurred in highways (35.3%) and at home (28%). One hundred forty-six patients (30.4%) died in the first 24 h. Seven percent died 1 week after the initial injury. Among the cases that died at the scene, 48.3% were motor vehicle accidents, 20.9% were victims of firearms, 6.5% died from poisoning, 5% from hanging, and 4% from drowning. External causes remain an important cause of death in children in San Diego County. Specific strategies to decrease road-traffic accidents and homicides must be developed and implemented to reduce the burden of injury-related deaths in children.

Introduction

CHRFAM7A is a uniquely-human gene that encodes a human-specific variant of the alpha-7 nicotinic acetylcholine receptor (α7nAchR). While the homopentameric α7nAChR consists of 5 equal subunits, previous studies demonstrated that CHRFAM7A expression disrupts the formation of α7nAChR homopentamers. Here we use a rat neuronal cell line expressing CHRFAM7A and a transgenic mouse expressing CHRFAM7A to define the alpha-bungarotoxin (α-BTX) binding in vitro and in vivo.

Methods

Rat PC12 cells were stably transfected with human CHRFAM7A. α-BTX, a protein that irreversibly binds the α7nAchR, was utilized to assess the capacity for CHRFAM7A to interfere with α 7AchR subunits using immunohistochemistry and flow cytometry. To evaluate the effects of CHRFAM7A on α7nAchR at the neuromuscular junction in vivo, transgenic mice were engineered to express the uniquely human gene CHRFAM7A under the control of the EF1-α promoter. Using this model, muscle was harvested and CHRFAM7A and CHRNA7 gene expression evaluated by PCR. Binding of α-BTX to the α7nAchR in muscle was compared in sibling-matched wild-type C57 mice by immunostaining the neuromuscular junction using α-BTX and neurofilament antibodies.

Results

Expression of CHRFAM7A in transfected, but not vector cells, was confirmed by PCR and by immunoblotting using an antibody we raised to a peptide sequence unique to CHRFAM7A. CHRFAM7A decreased α-BTX binding as detected by immunohistochemistry and flow cytometry. In vivo, α-BTX co-stained with neurofilament at the neuromuscular junction in wild-type mice, however, α-BTX staining was decreased at the neuromuscular junction of CHRFAM7A transgenic mice.

Conclusion

CHRFAM7A expression interferes with the binding of α7nAchR to α-BTX. Understanding the contribution of this uniquely human gene to human disease will be important in the identification of potential therapeutic targets.

Background

The Affordable Care Act (ACA) increased Medicaid coverage of Emergency General Surgery (EGS). We hypothesized that despite the ACA, racial and geographic disparities persisted for EGS admissions.

Methods

The Nationwide Inpatient Sample was queried from 2012 through Q3 of 2015 for Non-Medicare patient EGS admissions. Difference-in-Differences analyses (DID) compared payors, complications, mortality and costs in pre-ACA years (2012-2013) and post-ACA years (2014-2015Q3).

Results

EGS cases fell 9.1% from 1,711,940 to 1,555,033 NIS-weighted cases. Hispanics were still most likely to be uninsured but had improved coverage (OR 0.92, 95% CI: 0.88-0.96, p < 0.001). Risk of uninsured EGS admissions from the South region persisted (OR 1.52, 95% CI: 1.46-1.58, p < 0.001). Uninsured EGS patients had higher DID increased mortality than insured patients (0.31% higher, P = 0.003). Insured group DID costs increased more rapidly than in self-pay Patients (6.0% higher, P = 0.008) CONCLUSIONS: Post ACA, risk of uninsured EGS admissions remained highest in the South, in males, and Hispanics.

Background

The systemic inflammatory response (SIRS) drives late morbidity and mortality after injury. The α7 nicotinic acetylcholine receptor (α7nAchR) expressed on immune cells regulates the vagal anti-inflammatory pathway that prevents an overwhelming SIRS response to injury. Nonspecific pharmacologic stimulation of the vagus nerve has been evaluated as a potential therapeutic to limit SIRS. Unfortunately, the results of clinical trials have been underwhelming. We hypothesized that directly targeting the α7nAchR would more precisely stimulate the vagal anti-inflammatory pathway on immune cells and decrease gut and lung injury after severe burn.

Methods

C57BL/6 mice underwent 30% total body surface area steam burn. Mice were treated with an intraperitoneal injection of a selective agonist of the α7nAchR (AR-R17779) at 30 minutes postburn. Intestinal permeability to 4 kDa FITC-dextran was measured at multiple time points postinjury. Lung vascular permeability was measured 6 hours after burn injury. Serial behavioral assessments were performed to quantify activity levels.

Results

Intestinal permeability peaked at 6 hours postburn. AR-R17779 decreased burn-induced intestinal permeability in a dose-dependent fashion (p < 0.001). There was no difference in gut permeability to 4 kDa FITC-dextran between sham and burn-injured animals treated with 5 mg/kg of AR-R17779. While burn injury increased lung permeability 10-fold, AR-R17779 prevented burn-induced lung permeability with no difference compared with sham (p < 0.01). Postinjury activity levels were significantly improved in burned animals treated with AR-R17779.

Conclusion

Directly stimulating the α7nAchR prevents burn-induced gut and lung injury. Directly targeting the α7nAChR that mediates the cholinergic anti-inflammatory response may be an improved strategy compared with nonspecific vagal agonists.