Mechanism Matters: Differential benefits of cold-stored whole blood for trauma resuscitation from a prospective multicenter study.

BACKGROUND: Resuscitation with cold-stored low-titre whole blood (LTOWB) has increased despite the paucity of robust civilian data. Most studies are in predominately blunt trauma and lack analysis of specific subgroups or mechanism of injury. We sought to compare outcomes between patients receiving LTOWB vs. balanced component therapy (BCT) after blunt (BL) and penetrating (PN) trauma. METHODS: Secondary analysis of a prospective multicenter study of patients receiving either LTWOB-containing or BCT resuscitation was performed. Patients were grouped by mechanism of injury (BL vs PN). A generalized estimated equations model using inverse probability of treatment weighting was employed. Primary outcome was mortality and secondary outcomes were acute kidney injury, venous thromboembolism, pulmonary complications, and bleeding complications. Additional analyses were performed on non-traumatic brain injury (TBI), severe torso injury, and LTOWB-only resuscitation patients. RESULTS: 1617 patients (BL 47% vs PN 54%) were identified; 1175 (73%) of which received LTOWB. PN trauma patients receiving LTOWB demonstrated improved survival compared to BCT (77% vs. 56%; p<0.01). Interval survival was higher at 6 hrs (95% vs. 88%), 12 hrs (93% vs. 80%) and 24 hrs (88% vs. 57%) (all p<0.05). The survival benefit following LTOWB was also seen across PN non-TBI (83% vs. 52%), and severe torso injuries (75% vs. 43%) (all p <0.05). After controlling for age, sex, injury severity, and trauma center, LTWOB was associated with decreased odds of death (OR .31, p<.05) in PN trauma. However, no difference in overall mortality was seen across the BL groups. Both PN and BL patients receiving LTOWB had more frequent AKI compared to BCT (19% vs. 7% and 12% vs 6%, respectively; p<0.05). CONCLUSIONS: LTOWB resuscitation was independently associated with decreased mortality following PN trauma, but not BL trauma. Further analysis in BL trauma is required to identify subgroups that may demonstrate survival benefit. LEVEL OF EVIDENCE: Therapeutic/Care Management, III.

Deriving acceptable limits for non-mutagenic impurities in medicinal products - Durational adjustments.

ICH Q3A/B guidelines are not intended to be applied to drug substance or product used during the clinical research phase of development and durationally adjusted qualification thresholds are not included. A central tenet of ICH Q3A is that lifetime exposure to 1 mg/day of an unqualified NMI is not a safety concern. An analysis of in vivo toxicology data from 4878 unique chemicals with established NO(A)ELs was conducted to determine whether durationally adjusted qualification limits can be supported. Although not a recommendation of ICH Q3A/B, a conservative approach was taken and allometric scaling was used in the analysis. Following allometric scaling of the 5th percentile of the distribution of NO(A)ELs from available chronic toxicology studies, it was reconfirmed that there is a safety basis for the 1 mg/day qualification threshold in ICH Q3A. Additionally, allometric scaling of the 5th percentile of the distribution of NO(A)ELs from sub-acute and sub-chronic toxicology studies could support acceptable limits of 20 and 5 mg/day for an unqualified NMI for dosing durations of less than or greater than one month, respectively. This analysis supports durationally adjusted NMI qualification thresholds for pharmaceuticals that protect patient safety and contribute to 3Rs efforts for qualifying impurities using NAMs.

Two-center analysis of cannabis on venous thromboembolism risk after traumatic injury: A matched analysis.

BACKGROUND: Conflicting evidence exists evaluating associations between cannabis (THC) and post-traumatic DVT. METHODS: Retrospective analysis (2014-2023) of patients ≥15yrs from two Level I trauma centers with robust VTE surveillance and prophylaxis protocols. Multivariable hierarchical regression assessed the association between THC and DVT risk. THC â€‹+ â€‹patients were direct matched to other drug use categories on VTE risk markers and hospital length of stay. RESULTS: Of 7365 patients, 3719 were drug-, 575 were THC â€‹+ â€‹only, 2583 were other drug+, and 488 were TCH+/other drug+. DVT rates by exposure group did not differ. TCH â€‹+ â€‹only patients had higher GCS scores, shorter hospital length of stay, and the lowest pelvic fracture and mortality rates. A total of 458 drug-, 453 other drug+, and 232 THC+/other drug â€‹+ â€‹patients were matched to 458, 453, and 232 THC â€‹+ â€‹only patients. There were no differences in DVT event rates in any paired sub-cohort set. Additionally, iteratively adjusted paired models did not show an association between THC and DVT. CONCLUSIONS: THC does not appear to be associated with increased DVT risk in patients with strict trauma chemoprophylaxis. Toxicology testing is useful for identifying substance abuse intervention opportunities, but not for DVT risk stratification in THC â€‹+ â€‹patients.

Overcoming osimertinib resistance with AKT inhibition in EGFRm-driven Non-Small-Cell-Lung-Cancer with PIK3CA/PTEN alterations.

PURPOSE: Osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) indicated for the treatment of EGFR mutated (EGFRm)-driven lung adenocarcinomas. Osimertinib significantly improves progression-free survival in first-line treated patients with EGFRm advanced NSCLC. Despite the durable disease control, the majority of patients receiving osimertinib eventually develop disease progression. EXPERIMENTAL DESIGN: ctDNA profiling analysis on-progression plasma samples from patients treated with osimertinib in both first (Phase 3, FLAURA trial) and second-line trials (Phase 3, AURA3 trial) revealed a high prevalence of PIK3CA/AKT/PTEN alterations. In vitro and in vivo evidence using CRISPR engineered NSCLC cell lines and PXD models support a functional role for PIK3CA and PTEN mutations in the development of osimertinib resistance. RESULTS: These alterations are functionally relevant as EGFRm NSCLC cells with engineered PIK3CA/AKT/PTEN alterations develop resistance to osimertinib and can be re-sensitized by treatment with the combination of osimertinib and the AKT inhibitor capivasertib. Moreover, xenograft and PDX in vivo models with PIK3CA/AKT/PTEN alterations display limited sensitivity to osimertinib relative to models without alteration, and in these double mutant models capivasertib and osimertinib combination elicits an improved anti-tumor effect versus osimertinib alone. CONCLUSIONS: Together, this approach offers a potential treatment strategy for patients with EGFRm-driven NSCLC that have a sub-optimal response, or develop resistance, to osimertinib through PIK3CA/AKT/PTEN alterations.

Identifying Pregnant Patients With Suspected Intimate Partner Violence.

INTRODUCTION: Intimate partner violence (IPV) is the leading cause of death in pregnant women. Although it can be difficult to identify patients experiencing IPV, injuries to the head, neck, or face due to an assault are known to correlate with intentional injury. The objective of this study is to assess the contemporary burden of IPV in pregnancy and describe the patient characteristics. METHODS: The National Inpatient Sample was queried for all pregnant women between January 2016 and December 2019. Patients were divided into two groups: suspected IPV (SIPV) and no-SIPV groups. We defined SIPV as any pregnant patient with an identified head, neck, or face injuries categorized as intentional assault. Multivariable logistic regression analysis was performed to assess the association between SIPV and variables of interest. RESULTS: A total of 28,540 pregnant patients presented with traumatic injuries with 530 (.02%) identified as SIPV. Suspected IPV patients were younger (25 vs 27 years, P = .012), more likely to be of Black race (46% vs 28%, P = .002), more likely to be in the lowest income quartile (51% vs 38%, P = .031), less likely to have private insurance (12% vs 34%, P < .001), and have higher rates of substance use disorder (35% vs 18%, P < .001). Black race and history of substance use disorder were associated with increased odds of SIPV-related injuries (odds ratio [OR]: 2.01, interquartile range [IQR]: 1.27-3.16, P = .003 and OR: 2.30, IQR 1.54-3.43, P < .001, respectively). CONCLUSIONS: Our results suggest that there are significant racial and socioeconomic disparities in potential risk for IPV during pregnancy.

Is Barbed Better? Evaluation of Triclosan-Coated Barbed Suture on Wound Complications Following Emergency Laparotomy.

INTRODUCTION: Emergent laparotomy is associated with significant wound complications including surgical site infections (SSI) and fascial dehiscence (FD). Triclosan-coated barbed suture (TCB) for fascial closure has been shown to reduce local complications but primarily in elective settings. We sought to evaluate the effect of TCB emergency laparotomy fascial closure on major wound complications. METHODS: Adult patients undergoing emergency laparotomy were prospectively evaluated over 1-year. Patients were grouped into TCB vs polydioxanone (PDS) for fascial closure. Subanalysis was performed on patients undergoing single-stage laparotomy. Primary outcomes were SSI and FD. Multivariate analysis identified independent factors associated with SSI and FD. RESULTS: Of the 206 laparotomies, 73 (35%) were closed with TCB and 133 (65%) were closed with PDS. Trauma was the reason for laparotomy in 73% of cases; damage control laparotomy (DCL) was performed in 27% of cases. The overall rate of SSI and FD was 18% and 10%, respectively. Operative strategy was similar between groups, including DCL, wound vac use, skin closure, and blood products. SSI events trended lower with TCB vs PDS closure (11% vs. 21%; p = .07), and FD was significantly lower with TCB versus PDS (4% vs. 14%; p < .05, Fig 1). Subanalysis of trauma and non-trauma cases showed no difference in SSI or FD. Multivariable analysis found that TCB decreased the likelihood of FD (OR .07; p < .05, Fig 2) following emergency laparotomy. Increased odds of FD were seen in DCL (OR 3.1; p < 0.05). CONCLUSIONS: Emergency laparotomy fascial closure with TCB showed significantly decreased rates of FD compared to closure with PDS, and a strong trend toward lower SSI events. TCB was independently associated with decreased FD rates after emergency laparotomy.

Bile Duct Injuries During Urgent Cholecystectomy at a Safety Net Teaching Hospital: Attending Experience and Time of Day May Matter.

Background: Bile duct injury (BDI) is one of the most severe complications during cholecystectomy. Early identification of risk factors for BDI may permit risk reduction strategies and inform patient consent.Objective: This study aimed to define patient, provider, and systemic factors associated with BDI; BDI incidence; and short-term outcomes of BDI after urgent cholecystectomy.Methods: Patients who underwent urgent cholecystectomy for acute cholecystitis were retrospectively screened (2020-2022). All patients who sustained BDI were included without exclusions. Demographics, clinical data, and outcomes were collected and compared with descriptive statistics.Results: During the study period, BDI occurred in 4 (0.5%) of 728 patients who underwent urgent cholecystectomy for acute cholecystitis. Most BDI cases (75%) took place overnight or during the weekend. The attending surgeon was almost exclusively (75%) in their first year of practice. BDI was recognized during index operation in 2 cases (50%). Hepatobiliary surgery performed the bile duct repair in all 4 cases. Two complications occurred (50%). All patients were followed by hepatobiliary surgery in the outpatient setting and returned to their baseline level of function within 2 months of hospital discharge.Conclusion: Most BDI occurred in procedures attended by first-year faculty during after hours cholecystectomies, suggesting a role for increased proctorship in early career attendings in addition to in-hours cholecystectomy for acute cholecystitis. The timely return to baseline function experienced by these patients emphasizes the favorable outcomes associated with early recognition of BDI and involvement of hepatobiliary surgery. Further examination with multicenter evaluation would be beneficial to validate these study findings.

Ethics in disaster, mass casualty care, and critical care.

The primary ethical principle guiding general medical practice is autonomy. However, in mass casualty (MASCAL) or disaster scenarios, the principles of beneficence and justice become of foremost concern. Despite multiple reviews, publications, and training courses available to prepare for a MASCAL incident, a minority of physicians and healthcare providers are abreast of these. In this review, we describe several MASCAL scenarios and their associated ethical, moral, and medicolegal quandaries in attempts to curb potential future misadventures.

You've Been Served, Now What? Malpractice tips and prevention for the acute care surgeon.

Trauma and acute care surgeons commonly perform high acuity and emergent interventions on critically ill or injured patients. This often entails making life or death decisions rapidly and with incomplete and imperfect information, and in patients who may have a variety of comorbidities that contribute to the risk of adverse outcomes. In cases where there are real or perceived breaches of care, a medical malpractice claim may result. In the USA, approximately one-third to one-half of all physicians will be named in medical litigation at least once in their career. Among the various specialties, surgery remains among the highest risk for malpractice litigation, at an average of 10.6 defendants per 100 surgeons. These events can be extremely stressful, demoralizing, or even devastating to the career and well-being of the involved physicians. This can be made better or worse by the individual response and actions of the surgeon on notification of a real or potential claim, and the primary goal of this review is to highlight these key areas and optimal strategies in malpractice scenarios. This includes strategies to manage the initial receipt of a malpractice claim, subsequent courses of action, and advice for incorporating preventive measures into everyday practice.

Non-Binary Trauma Patients: Delineating a Vulnerable, At-Risk Population.

INTRODUCTION: An increasing proportion of the population identifies as non-binary. This marginalized group may be at differential risk for trauma compared to those who identify as male or female, but physical trauma among non-binary patients has not yet been examined at a national level. METHODS: All patients aged ≥ 16 years in the National Trauma Data Bank were included (2021-2022). Demographics, injury characteristics, and outcomes after trauma among non-binary patients were compared to males and females. The goal was to delineate differences between groups to inform the care and future study of non-binary trauma patients. RESULTS: In total, 1,012,348 patients were included: 283 (<1%) non-binary, 610,904 (60%) male, and 403,161 (40%) female patients. Non-binary patients were younger than males or females (median age 44 vs 49 vs 67 years, P < .001) and less likely to be White race/ethnicity (58% vs 60% vs 74%, P < .001). Despite non-binary patients having a lower median Injury Severity Score (5 vs 9 vs 9, P < .001), mortality was highest among non-binary and male patients than females (5% vs 5% vs 3%, P < .001). DISCUSSION: In this study, non-binary trauma patients were younger and more likely minority races/ethnicities than males or females. Despite having a lower injury severity, non-binary patient mortality rates were comparable to those of males and greater than for females. These disparities identify non-binary trauma patients as doubly marginalized, by gender and race/ethnicity, who experience worse outcomes after trauma than expected based on injury severity. This vulnerable patient population deserves further study to identify areas for improved trauma delivery care.

The Great Debate: Robotic vs Traditional Surgical Approach in the Acute Care Setting.

Robotic surgery was first introduced in the 1980s as a system to aid patients in the battlefield. Since then, robotic surgery has become an important minimally invasive tool and plays an important role in elective surgery among various surgical specialties. However, the role for robotic surgery in the emergent setting is not well established or studied. Robotic surgery has been shown to be advantageous to both patients and operating surgeons. Though limited, studies have found robotic surgery in the acute setting to be safe for patients. These studies found robotic surgery to have improved perioperative outcomes when compared to an open or laparoscopic approach. Additionally, the robotic platform is thought to be an effective tool to prevent conversion to open procedures in emergent settings. Although some studies demonstrate advantages to robotic acute surgery, others have shown increased complications with robotic acute surgery or no distinct advantage when comparing robotic to laparoscopic surgery. Additionally, some of the published papers supporting the use of robotic surgery in the emergent setting may have a degree of bias favoring the robotic platform. Robotic surgery is a mainstay in minimally invasive elective surgery and gaining popularity among patients and surgeons. There are pros and cons to the adaptation of the robotic platform in the acute care setting. Additional large population studies are indicated to determine the true role of the robotic platform in the emergent setting.

Back on the Streets: Examining Emergency Department Return Rates for Unhoused Patients Discharged After Trauma.

BACKGROUND: The unhoused population is at high risk for traumatic injuries and faces unique challenges in accessing follow-up care. However, there is scarce data regarding differences in Emergency Department (ED) return rates and reasons for return between unhoused and housed patients. METHODS: We conducted a 3-year retrospective cohort study at a level-1 trauma center in a large metropolitan area. All patients who presented to the ED with traumatic injuries and were discharged without hospital admission were included in the study. The primary outcome was ED returns for trauma-related complications or new traumatic events <6 months after discharge. Patient characteristics and study outcomes were compared between housed and unhoused groups. RESULTS: A total of 4184 patients were identified, of which 20.3% were unhoused. Compared to housed, unhoused patients were more likely to return to the ED (18.8% vs 13.9%, P < .001), more likely to return for trauma-related complications (4.6% vs 3.1%, P = .045), more likely to return with new trauma (7.1% vs 2.8%, P < .001), and less likely to return for scheduled wound checks (2.5% vs 4.3%, P = .012). Of the patients who returned with trauma-related complications, unhoused patients had a higher proportion of wound infection (20.5% vs 5.7%, P = .008). In the regression analysis, unhoused status was associated with increased odds of ED return with new trauma and decreased odds of return for scheduled wound checks. CONCLUSIONS: This study observed significant disparities between unhoused and housed patients after trauma. Our results suggest that inadequate follow-up in unhoused patients may contribute to further ED return.

Paradigm Shifts in Vascular Surgery: Analysis of the Top 100 Innovative and Disruptive Academic Publications.

BACKGROUND: Disruption score (DS) is a novel bibliometric created to identify research that shifts paradigms, which may be overlooked by citation count (CC). We analyzed the most disruptive, compared to the most cited, literature in vascular surgery, and hypothesized that DS and CC would not correlate. METHODS: A PubMed search identified vascular surgery publications from 1954 to 2014. The publications were linked to the iCite NIH tool and DS algorithm to identify the top 100 studies by CC and DS, respectively. The publications were reviewed for study focus, design, and contribution, and subsequently compared. RESULTS: A total of 56,640 publications were identified. The top 100 DS papers were frequently published in J Vasc Sur (43%) and Eur J Vasc Endovasc Surg (13%). The top 100 CC papers were frequently published in N Engl J Med (32%) and J Vasc Sur (20%). The most cited article is the fifth most disruptive; the most disruptive article is not in the top 100 cited papers. The DS papers had a higher mean DS than the CC papers (.17 vs .0001, P < .0001). The CC papers had a higher mean CC than the DS papers (866 vs 188, P < .0001). DS and CC are weakly correlated metrics (r = .22, P = .03). DISCUSSION: DS was weakly correlated with CC and captured a unique subset of literature that created paradigm shifts in vascular surgery. DS should be utilized as an adjunct to CC to avoid overlooking impactful research and influential researchers, and to measure true academic productivity.

Genome-wide CRISPR screens identify the YAP/TEAD axis as a driver of persister cells in EGFR mutant lung cancer.

Most lung cancer patients with metastatic cancer eventually relapse with drug-resistant disease following treatment and EGFR mutant lung cancer is no exception. Genome-wide CRISPR screens, to either knock out or overexpress all protein-coding genes in cancer cell lines, revealed the landscape of pathways that cause resistance to the EGFR inhibitors osimertinib or gefitinib in EGFR mutant lung cancer. Among the most recurrent resistance genes were those that regulate the Hippo pathway. Following osimertinib treatment a subpopulation of cancer cells are able to survive and over time develop stable resistance. These 'persister' cells can exploit non-genetic (transcriptional) programs that enable cancer cells to survive drug treatment. Using genetic and pharmacologic tools we identified Hippo signalling as an important non-genetic mechanism of cell survival following osimertinib treatment. Further, we show that combinatorial targeting of the Hippo pathway and EGFR is highly effective in EGFR mutant lung cancer cells and patient-derived organoids, suggesting a new therapeutic strategy for EGFR mutant lung cancer patients.

Clinical factors and outcomes of spleen-conserving surgery versus total splenectomy in splenic injuries: A nationwide database study.

BACKGROUND: The objective of this study was to identify factors associated with the use of spleen-conserving surgeries, as well as patient outcomes, on a national scale. METHODS: This retrospective cohort study (2010-2015) included patients (age≥16 years) with splenic injury in the National Trauma Data Bank. Patients who received a total splenectomy or a spleen-conserving surgery were compared for demographics and clinical outcomes. RESULTS: During the study period, 18,425 received a total splenectomy and 1,825 received a spleen-conserving surgery. Total splenectomy was more likely to be performed for patients with age>65 (odds ratio [OR]: 0.63, p â€‹< â€‹0.001), systolic blood pressure<90 (OR: 0.63, p â€‹< â€‹0.001), heart rate>120 (OR: 0.83, p â€‹= â€‹0.007), and high-grade injuries (OR: 0.18, p â€‹< â€‹0.001). Penetrating trauma patients were more likely to undergo a spleen-conserving surgery (OR: 3.31, p â€‹< â€‹0.001). The use of spleen-conserving surgery was associated with a lower risk of pneumonia (OR: 0.79, p â€‹= â€‹0.009) and venous thromboembolism (OR: 0.72, p â€‹= â€‹0.006). CONCLUSIONS: Spleen-conserving surgeries may be considered for patients with penetrating trauma, age<65, hemodynamic stability, and low-grade injuries. Spleen-conserving surgeries have decreased risk of pneumonia and venous thromboembolism.

Recent Changes in the Management of High-Grade Blunt Pancreatic Injury in Children: A Nationwide Trend Analysis.

BACKGROUND: The optimal management of pediatric patients with high-grade blunt pancreatic injury (BPI) involving the main pancreatic duct remains controversial. This study aimed to assess the nationwide trends in the management of pediatric high-grade BPI at pediatric (PTC), mixed (MTC), and adult trauma centers (ATC). STUDY DESIGN: This is a retrospective observational study of the National Trauma Data Bank. We included pediatric patients (age 16 years or less) sustaining high-grade BPI (Abbreviated Injury Scale 3 or more) from 2011 to 2021. Patients who did not undergo pancreatic operation were categorized into the nonoperative management (NOM) group. Trauma centers were defined as PTC (level I/II pediatric only), MTC (level I/II adult and pediatric), and ATC (level I/II adult only). Primary outcome was the proportion of patients undergoing NOM, and secondary outcomes included the use of ERCP and in-hospital mortality. A Cochran-Armitage test was used to analyze the trend. RESULTS: A total of 811 patients were analyzed. The median age was 9 years (interquartile range 6 to 13), 64% were male patients, and the median injury severity score was 17 (interquartile range 10 to 25). During the study period, there was a significant upward linear trend in the use of NOM and ERCP among the overall cohort (range 48% to 66%; p trend = 0.033, range 6.1% to 19%; p trend = 0.030, respectively). The significant upward trend for NOM was maintained in the subgroup of patients at PTC and MTC (p trend = 0.037), whereas no significant trend was observed at ATC (p trend = 0.61). There was no significant trend in in-hospital mortality (p trend = 0.38). CONCLUSIONS: For the management of pediatric patients with high-grade BPI, this study found a significant trend toward increasing use of NOM and ERCP without mortality deterioration, especially at PTC and MTC.

Nutritional support for the trauma and emergency general surgery patient: What you need to know.

ABSTRACT: Decades of research have provided insight into the benefits of nutritional optimization in the elective surgical patient. Patients who are nutritionally prepared for surgery enjoy reduced length of hospital and intensive care unit stays and suffer fewer complications. In the trauma and emergency general surgery patient populations, we are not afforded the preoperative period of optimization and patients often suffer longer lengths of hospital stay, discharge to nonhome destinations, and higher infectious and mortality rates. Nonetheless, ongoing research in this vulnerable and time critical diagnosis population has revealed significant outcomes benefits with the meticulous nutritional support of these patients. However, it is important to note that optimal nutritional support in this challenging patient population is not simply a matter of "feeding more and feeding earlier." In this review, we will address assessing nutritional needs, the provision of optimal nutrition, the timing and route of nutrition, and monitoring outcomes and discuss the management of nutrition in the complex trauma and emergency general surgery patient. LEVEL OF EVIDENCE: Literature Synthesis and Expert Opinion; Level V.