Trauma Incidence During the New Jersey COVID-19 Stay-At-Home Order: A Multicenter Study.

INTRODUCTION: Given the early surge of COVID-19 in New Jersey (NJ), a statewide executive order (EO) to stay-at-home was instituted on March 22, 2020. We hypothesized that the EO would result in a decreased number of trauma admissions, length of stay, and resources utilized in trauma patients at NJ trauma centers. METHODS: In an institutional review board-approved, retrospective, multicenter study, trauma registries at three level one trauma centers in NJ were queried from March 22 to June 14 in 2020 and compared to the same timeframe the year prior. Epidemiological and clinical data were obtained including demographics, select preexisting conditions, mechanism of injury, injury severity score, resources utilized, and outcomes. RESULTS: 1859 trauma patients were evaluated during the EO versus 2201 the year prior. During the EO, trauma patients were less likely to be transferred from another hospital (21% versus 29% P < 0.05), more likely to have a penetrating mechanism (16% versus 12% P < 0.05), were equally likely to require a procedure (P = 0.44) and had similar injury severity score (5 [interquartile range [IQR] 1-9] versus 5 [IQR 1-9], P = 0.73). There was no significant difference in ventilator days (0 [IQR 0-1] versus 0 [IQR 0-2] P = 0.08), intensive care unit days (2 [IQR 0-4] versus 2 [IQR 0-3] P = 0.99), or length of stay (2 [IQR 1-5] versus 2 [IQR 1-6] P = 0.73). Patients were more likely to be sent home than to rehabilitation or long-term acute care hospital during the EO (81% versus 78%, P = 0.02). CONCLUSIONS: The 2020 COVID-19 EO was associated with a significantly different epidemiology with a higher rate of penetrating injury during the EO, and similar volume of injured patients evaluated.

Development of a Model for Abdominal Aortic Aneurysms in Swine.

INTRODUCTION: Producing a reliable large-animal model of AAA has proven challenging. We sought to create a reproducible swine model of AAA using enzymatic degradation of the aortic wall. METHODS: Twelve male Yorkshire swine received periadventitial injections of type 1 collagenase and porcine pancreatic elastase into a 4 cm segment of infrarenal aorta. Nine survived until postoperative day (POD) 21. Aortic growth was monitored at 7 and 14 days using ultrasound. The animals were euthanized on POD 21, and the suprarenal (control) and infrarenal aorta were harvested for analysis, after gross measurement of aortic diameter (AD). Tensile strength was measured and additional segments were collected for histopathological analysis. PCR of matrix metalloproteinases (MMP9) was conducted. Groups were compared with paired t-tests, or ANOVA, where appropriate. RESULTS: Average percent growth of AD at POD 21 for treated segments was 27% versus 4.5% for control tissue. The average difference in AD by subject, was 26.7% (P<0.001). Aortic medial thickness was decreased in treated tissue; 235 µm versus 645 µm (P<0.0001). Quantities of both medial elastin fibers, and smooth muscles cells were decreased in treated tissue; 1.8% compared to 9.9% (P<0.0001), and 24% versus 37.4%, respectively. Tensile strength was also decreased in treated tissue; 16.7 MPa versus 29.5 MPa (P=0.0002). A 12-fold increase in expression of MMP9 mRNA was also demonstrated in aneurysmal tissue (P=0.002) CONCLUSION: A reproducible, large-animal model of AAA, with anatomical, histopathological, and biomechanical properties that are clinically translatable, can be achieved with extraluminal enzymatic degradation.

Role of marijuana components on the regenerative ability of stem cells.

Stem cell therapy promotes tissue regeneration and wound healing. Efforts have been made to prime stem cells to enhance their regenerative abilities. Certain marijuana components, namely the non-psychoactive cannabidiol (CBD) and psychoactive tetrahydrocannabinol (THC), are defined as immunomodulators.9 We test whether two sources of stem cells, primed with CBD or THC, would demonstrate improved regenerative abilities. Human adipose-derived stem cells (ASCs) and bone marrow-derived stem cells (BMDSCs), not obtained from the same individual, were treated with low (300 nM) or high (3 µM) concentration CBD. Porcine ASCs and BMDSCs were isolated from a single pig, and treated with either low or high concentrations of CBD or THC. Transwell migration and MTT proliferation assays were performed on the human ASCs and BMDSCs. Also, transwell migration assay was performed on the porcine ASCs and BMDSCs. Finally, a wound healing scratch assay in porcine primary fibroblasts (PFs) was performed, co-cultured with the cannabinoid-treated ASCs. CBD priming at low concentration induces migration by 180% (P < .01) in porcine ASCs, and by only 93% (P < .02) in porcine BMDSCs. In porcine stem cells, THC priming at low concentration induces migration by 91.6% (P < .01) in ASCs but by only 44.3% (P < .03) in BMDSCs. Compared to PFs co-cultured with untreated ASCs, PFs co-cultured with low CBD-primed ASCs had 75% faster wound closure at 18 hours (P < .01). CBD and THC priming of ASCs and BMDSCs, particularly at lower doses, enhances a number of regenerative parameters, suggesting that these major marijuana components may improve stem cell-based therapies. SIGNIFICANCE OF THE STUDY: Our study demonstrates that cannabinoids can enhance the regenerative capacity of two major sources of stem cells, adipose- and bone marrow-derived, from human and porcine donors. Stem cell isolation and expansion is invasive, costly and time consuming. Stem cells with improved regenerative properties may be effective in the treatment of acute or chronic wounds. This is the first study to compare the priming potential of two sources of stem cells from the same animal, with the same genetic and epigenetic profile, as well as the first to prime with THC.

Determining Trajectory to Predict Injury: The Use of X-Ray During Resuscitation in Gunshot Wounds.

BACKGROUND: The practice of marking gunshot wounds and obtaining X-rays (XRs) has been performed to determine the trajectory of missiles to help identify internal injuries. We hypothesized that surgeons would have poor accuracy in predicting injuries and that X-rays do not alter the clinical decision. METHODS: We developed a 50-patient (89 injury sites) PowerPoint survey based on cases seen at our level 1 trauma center from 2012 to 2014. Images of a silhouetted BodyMan (BM) with wounds marked, XRs, and vital signs (VSs) were shown in series for 20 s each. Surgeons were asked to record which organs they thought could be injured and to document their clinical decision. Data were analyzed to determine the inter-rater reliability (agreement, intraclass correlation coefficient [ICC]) for each mode of clinical information (BM, XR, VS). Predicted versus actual injuries were compared using absolute agreements. RESULTS: Ten surgeons completed the survey. We found that no single piece of information was helpful in allowing the surgeon to accurately predict injuries. Pulmonary injury had the highest agreement among all injuries (ICC = 0.727). VSs had the highest ICC in determining the clinical plan for the patient (ICC = 0.342), whereas both BM and XR had low ICCs (0.162 and 0.183, respectively). CONCLUSIONS: We found that marking wounds and obtaining X-rays, other than a chest X-ray, did not result in accuracy in predicting injury nor alter the clinical decision. VSs were the only piece of information found significant in determining clinical management. We conclude that marking wounds for X-rays is an unnecessary step during the initial resuscitation of patients with gunshot wounds.

Novel treatment strategy of targeting epigenetic dysregulation in pancreatic neuroendocrine tumors.

BACKGROUND: Epigenetic dysregulation is an integral step in the progression of pancreatic neuroendocrine tumors. We hypothesized that tumor suppressor repression by DNA methyltransferase 1 in pancreatic neuroendocrine tumors could be targeted with epigenetic treatment. METHODS: Resected pancreatic neuroendocrine tumors from 32 patients were stained for DNA methyltransferase 1 and scored. Human (BON1) and murine (STC) pancreatic neuroendocrine tumor cells were treated with DNA methyltransferase 1 inhibitor 5-azacytidine and chemotherapeutic agents 5-fluorouracil and temozolomide. Cell proliferation assay and tumor suppressor gene analysis were performed with qRT-PCR and Clarion S microarray. Tumor measurements were compared in a murine treatment model. RESULTS: High DNA methyltransferase scores were associated with high Ki-67 (6.7% vs 70.6% P < .01), mitotic rate (0.0% vs 31.3%), and grade (20.0% vs 80.4%, P < .01). Treatment with 5-azacytidine and chemotherapy resulted in a reduction of cell proliferation compared to chemotherapy alone in BON1 (77.3% vs 53.1%, P < .001) and STC (73.4% vs 34.2%, P < .001). Treatment with 5-azacytidine and chemotherapy resulted in upregulation of tumor suppressors CDKN1A (7.6 rel. fold, P < .001), BRCA2 (4.3 rel. fold, P < .001), and CDH1 (6.0 rel. fold, P = .026) in BON1 and CDKN1a (14.5 rel. fold, P < .001) and CDH (17.5 rel. fold, P < .001) in STC. In microarray, 5-azacytidine drove global genetic changes in combination treatment. In vivo tumors treated with chemotherapy measured 88.6 ± 19.54 mm3 vs 52.89 ± 10.51 mm3 in those treated with combination therapy (P = .009). CONCLUSION: Epigenetic dysregulation with DNA methyltransferase 1 is associated with pancreatic neuroendocrine tumors and is a potential targetable strategy. 5-azacytidine and chemotherapy in combination can reduce cell proliferation, upregulate silenced tumor suppressor genes, and decrease in vivo tumors in pancreatic neuroendocrine tumors.

Epigenetic modulation enhances immunotherapy for pancreatic ductal adenocarcinoma.

Objectives: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a poor prognosis. PDAC has poor response to immunotherapy because of its unique tumour microenvironment (TME). In an attempt to stimulate immunologically silent pancreatic cancer, we investigated the role of epigenetic therapy in modulating the TME to improve immunogenicity. Methods: In vitro human PDAC cell lines MiaPaca2 and S2-013 were treated with 5µ m 3-Deazaneplanocin A (DZNep, an EZH2 inhibitor) and 5 µ m 5-Azacytidine (5-AZA, a DNMT1 inhibitor). In vivo orthotopic murine tumour models using both murine PAN02 cells and KPC cells inoculated in immunocompetent C56/BL7 mice were treated with anti-PD-L1 combined with DZNep and 5-AZA. Short hairpin knockdown (KD) of EZH2 and DNMT1 in PAN02 cells for the orthotopic murine tumour model was established to validate the drug treatment (DZNep and 5-AZA). qRT-PCR and microarray assays were performed for the evaluation of Th1-attracting chemokines and cancer-associated antigen induction. Results: Drug treatments induced significant upregulation of gene expressions of Th1-attracting chemokines, CXCL9 and CXCL10, and the cancer-testis antigens, NY-ESO-1, LAGE and SSX-4 (P < 0.05). In orthotopic tumour models, inoculation of PAN02 cells or KPC cells demonstrated significant tumour regression with corresponding increased apoptosis and infiltration of cytotoxic T lymphocytes in the combination treatment group. In the orthotopic Pan02-KD model, the anti-PD-L1 treatment also caused significant tumour regression. Conclusion: We demonstrate that immunotherapy for PDAC can be potentiated with epigenetic therapy by increasing cancer-associated antigen expression and increased T-cell trafficking across the immunosuppressive tumour microenvironment via upregulation of the repressed chemokines and increased apoptosis with subsequent tumour regression.

Omental patch versus gastric resection for perforated gastric ulcer: Systematic review and meta-analysis for an unresolved debate.

BACKGROUND: Perforated gastric ulcers are surgical emergencies with paucity of data on the preferred treatment modality of resection versus omental patch. We aim to compare outcomes with ulcer repair and gastric resection surgeries in perforated gastric ulcers after systematic review of literature. METHODS: A systematic literature search was performed for publications in PubMed Medline, Embase, and Cochrane Central Register of Controlled Trials. We included all studies which compared ulcer repair vesus gastric resection surgeries for perforated gastric ulcers. We excluded studies which did not separate outcomes gastric and duodenal ulcer perforations. RESULTS: The search included nine single-institution retrospective reviews comparing ulcer repair (449 patients) versus gastric resection surgeries (212 patients). Meta-analysis was restricted to perforated gastric ulcers and excluded perforated duodenal ulcers. The majority of these studies did not control for baseline characteristics, and surgical strategies were often chosen in a non-randomized manner. All of the studies included were at high risk of bias. The overall odds ratio of mortality in ulcer repair surgery compared to gastric resection surgery was 1.79, with 95% CI 0.72 to 4.43 and p-value 0.209. CONCLUSION: In this meta-analysis, there was no difference in mortality between the two surgical groups. The overall equivalence of clinical outcomes suggests that gastric resection is a potentially viable alternative to ulcer repair surgery and should not be considered a secondary strategy. We would recommend a multicenter randomized control trial to evaluate the surgical approach that yields superior outcomes. LEVEL OF EVIDENCE: Systematic review and meta-analysis, level III.

The emergency surgery score (ESS) and outcomes in elderly patients undergoing emergency laparotomy: A post-hoc analysis of an EAST multicenter study.

INTRODUCTION: We sought to evaluate whether the Emergency Surgery Score (ESS) can accurately predict outcomes in elderly patients undergoing emergent laparotomy (EL). METHODS: This is a post-hoc analysis of an EAST multicenter study. Between April 2018 and June 2019, all adult patients undergoing EL in 19 participating hospitals were prospectively enrolled, and ESS was calculated for each patient. Using the c-statistic, the correlation between ESS and mortality, morbidity, and need for ICU admission was assessed in three patient age cohorts (65-74, 75-84, ≥85 years old). RESULTS: 715 patients were included, of which 52% were 65-74, 34% were 75-84, and 14% were ≥85 years old; 51% were female, and 77% were white. ESS strongly correlated with postoperative mortality (c-statistic:0.81). Mortality gradually increased from 0% to 20%-60% at ESS of 2, 10 and 16 points, respectively. ESS predicted mortality, morbidity, and need for ICU best in patients 65-74 years old (c-statistic:0.81, 0.75, 0.83 respectively), but its performance significantly decreased in patients ≥85 years (c-statistic:0.72, 0.64, 0.67 respectively). CONCLUSION: ESS is an accurate predictor of outcome in the elderly EL patient 65-85 years old, but its performance decreases for patients ≥85. Consideration should be given to modify ESS to better predict outcomes in the very elderly patient population.

The Emergency Surgery Score accurately predicts the need for postdischarge respiratory and renal support after emergent laparotomies: A prospective EAST multicenter study.

BACKGROUND: The Emergency Surgery Score (ESS) was recently validated as an accurate mortality risk calculator for emergency general surgery. We sought to prospectively evaluate whether ESS can predict the need for respiratory and/or renal support (RRS) at discharge after emergent laparotomies (EL). METHODS: This is a post hoc analysis of a 19-center prospective observational study. Between April 2018 and June 2019, all adult patients undergoing EL were enrolled. Preoperative, intraoperative, and postoperative variables were systematically collected. In this analysis, patients were excluded if they died during the index hospitalization, were discharged to hospice, or transferred to other hospitals. A composite variable, the need for RRS, was defined as the need for one or more of the following at hospital discharge: tracheostomy, ventilator dependence, or dialysis. Emergency Surgery Score was calculated for all patients, and the correlation between ESS and RRS was examined using the c-statistics method. RESULTS: From a total of 1,649 patients, 1,347 were included. Median age was 60 years, 49.4% were men, and 70.9% were White. The most common diagnoses were hollow viscus organ perforation (28.1%) and small bowel obstruction (24.5%); 87 patients (6.5%) had a need for RRS (4.7% tracheostomy, 2.7% dialysis, and 1.3% ventilator dependence). Emergency Surgery Score predicted the need for RRS in a stepwise fashion; for example, 0.7%, 26.2%, and 85.7% of patients required RRS at an ESS of 2, 12, and 16, respectively. The c-statistics for the need for RRS, the need for tracheostomy, ventilator dependence, or dialysis at discharge were 0.84, 0.82, 0.79, and 0.88, respectively. CONCLUSION: Emergency Surgery Score accurately predicts the need for RRS at discharge in EL patients and could be used for preoperative patient counseling and for quality of care benchmarking. LEVEL OF EVIDENCE: Prognostic and epidemiological, level III.

Prospective validation of the Emergency Surgery Score in emergency general surgery: An Eastern Association for the Surgery of Trauma multicenter study.

BACKGROUND: The Emergency Surgery Score (ESS) was recently developed and retrospectively validated as an accurate mortality risk calculator for emergency general surgery. We sought to prospectively validate ESS, specifically in the high-risk nontrauma emergency laparotomy (EL) patient. METHODS: This is an Eastern Association for the Surgery of Trauma multicenter prospective observational study. Between April 2018 and June 2019, 19 centers enrolled all adults (aged >18 years) undergoing EL. Preoperative, intraoperative, and postoperative variables were prospectively and systematically collected. Emergency Surgery Score was calculated for each patient and validated using c-statistic methodology by correlating it with three postoperative outcomes: (1) 30-day mortality, (2) 30-day complications (e.g., respiratory/renal failure, infection), and (3) postoperative intensive care unit (ICU) admission. RESULTS: A total of 1,649 patients were included. The mean age was 60.5 years, 50.3% were female, and 71.4% were white. The mean ESS was 6, and the most common indication for EL was hollow viscus perforation. The 30-day mortality and complication rates were 14.8% and 53.3%; 57.0% of patients required ICU admission. Emergency Surgery Score gradually and accurately predicted 30-day mortality; 3.5%, 50.0%, and 85.7% of patients with ESS of 3, 12, and 17 died after surgery, respectively, with a c-statistic of 0.84. Similarly, ESS gradually and accurately predicted complications; 21.0%, 57.1%, and 88.9% of patients with ESS of 1, 6, and 13 developed postoperative complications, with a c-statistic of 0.74. Emergency Surgery Score also accurately predicted which patients required intensive care unit admission (c-statistic, 0.80). CONCLUSION: This is the first prospective multicenter study to validate ESS as an accurate predictor of outcome in the EL patient. Emergency Surgery Score can prove useful for (1) perioperative patient and family counseling, (2) triaging patients to the intensive care unit, and (3) benchmarking the quality of emergency general surgery care. LEVEL OF EVIDENCE: Prognostic study, level III.