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Rapid source control is recommended to improve patient outcomes in sepsis. Yet there are few data to guide how rapidly source control is required.To determine the association between time to source control and patient outcomes in community-acquired sepsis.Multihospital integrated health care system cohort study of hospitalized adults (January 1, 2013, to December 31, 2017) with community-acquired sepsis as defined by Sepsis-3 who underwent source control procedures. Follow-up continued through January 1, 2019, and data analyses were completed March 17, 2022.Early (6 hours) compared with late (6-36 hours) source control as well as each hour of source control delay (1-36 hours) from sepsis onset.Multivariable models were clustered at the level of hospital with adjustment for patient factors, sepsis severity, resource availability, and the physiologic stress of procedures generating adjusted odds ratios (aOR) and 95% CI.Of 4962 patients with sepsis (mean [SD] age, 62 [16] years; 52% male; 85% White; mean [SD] Sequential Organ Failure Assessment score, 3.8 [2.5]), source control occurred at a median (IQR) of 15.4 hours (5.5-21.7) after sepsis onset, with 1315 patients (27%) undergoing source control within 6 hours. The crude 90-day mortality was similar for early and late source control (n = 177 [14%] vs n = 529 [15%]; P = .35). In multivariable models, early source control was associated with decreased risk-adjusted odds of 90-day mortality (aOR, 0.71; 95% CI, 0.63-0.80). This association was greater among gastrointestinal and abdominal (aOR, 0.56; 95% CI, 0.43-0.80) and soft tissue interventions (aOR, 0.72; 95% CI, 0.55-0.95) compared with orthopedic and cranial interventions (aOR, 1.33; 95% CI, 0.96-1.83; P .001 for interaction).Source control within 6 hours of community-acquired sepsis onset was associated with a reduced risk-adjusted odds of 90-day mortality. Prioritizing the rapid identification of septic foci and initiation of source control interventions can reduce the number of avoidable deaths among patients with sepsis.

Trauma-induced coagulopathy (TIC) is provoked by multiple mechanisms and is perceived to be one driver of massive transfusions (MT). Single laboratory values using prothrombin time (INR) or thrombelastography (TEG) are used to clinically define this complex process. We used a proteomics approach to test whether current definitions of TIC (INR, TEG, or clinical judgement) are sufficient to capture the majority of protein changes associated with MT.Eight level-I trauma centers contributed blood samples from patients available early after injury. TIC was defined as INR1.5 (INR-TIC), TEG maximum amplitude50mm (TEG-TIC), or clinical judgement (Clin-TIC) by the trauma surgeon. MT was defined as10 units of red blood cells in 24 hours or4 units RBC/hour during the first 4 hr. SomaLogic proteomic analysis of 1,305 proteins was performed. Pathways associated with proteins dysregulated in patients with each TIC definition and MT were identified.Patients (n=211) had a mean injury severity score of 24, with a MT and mortality rate of 22% and 12%, respectively. We identified 578 SOMAscan analytes dysregulated among MT patients, of which INR-TIC, TEG-TIC, and Clin-TIC patients showed dysregulation only in 25%, 3%, and 4% of these, respectively. TIC definitions jointly failed to show changes in 73% of the protein levels associated with MT, and failed to identify 26% of patients that received a massive transfusion. INR-TIC and TEG-TIC patients showed dysregulation of proteins significantly associated with complement activity. Proteins dysregulated in Clin-TIC or massive transfusion patients were not significantly associated with any pathway.These data indicate there are unexplored opportunities to identify patients at risk for massive bleeding. Only a small subset of proteins that are dysregulated in patients receiving MT are statistically significantly dysregulated among patients whose TIC is defined based solely on laboratory measurements or clinical assessment.

This Guide to Statistics and Methods discusses adjunct outcome parameters that optimize patient-centered, timely, efficient, and equitable components in randomized clinical trials.

OBJECTIVE We sought to characterize the timing of administration of prehospital tranexamic acid (TXA) and associated outcome benefits. BACKGROUND TXA has been shown to be safe in the prehospital setting post-injury. METHODS We performed a secondary analysis of a recent prehospital randomized TXA clinical trial in injured patients. Those who received prehospital TXA within 1 hour (EARLY) from time of injury were compared to those who received prehospital TXA beyond 1 hour (DELAYED). We included patients with a shock index of >0.9. Primary outcome was 30-day mortality. Kaplan-Meier and Cox Hazard regression were utilized to characterize mortality relationships. RESULTS EARLY and DELAYED patients had similar demographics, injury characteristics, and shock severity but DELAYED patients had greater prehospital resuscitation requirements and longer prehospital times. Stratified Kaplan-Meier analysis demonstrated significant separation for EARLY patients (N = 238, log-rank chi-square test, 4.99; P = 0.03) with no separation for DELAYED patients (N = 238, log-rank chi-square test, 0.04; P = 0.83). Stratified Cox Hazard regression verified, after controlling for confounders, that EARLY TXA was associated with a 65% lower independent hazard for 30-day mortality [hazard ratio (HR) 0.35, 95% confidence interval (CI) 0.19-0.65, P = 0.001] with no independent survival benefit found in DELAYED patients (HR 1.00, 95% CI 0.63-1.60, P = 0.999). EARLY TXA patients had lower incidence of multiple organ failure and 6-hour and 24-hour transfusion requirements compared to placebo. CONCLUSIONS Administration of prehospital TXA within 1 hour from injury in patients at risk of hemorrhage is associated with 30-day survival benefit, lower incidence of multiple organ failure, and lower transfusion requirements.

BACKGROUND Prehospital plasma improves survival for severely injured trauma patients transported by air ambulance. We sought to characterize the unexpected survivors, patients who survived despite having high predicted mortality after traumatic injury. METHODS The Prehospital Air Medical Plasma trial randomized severely injured patients (n = 501) to receive either standard care (crystalloid) or two units of prehospital plasma followed by standard care fluid resuscitation. We built a generalized linear model to estimate patient mortality. Area under the receiver operating characteristic curve was used to evaluate model performance. We defined unexpected survivors as patients who had a predicted mortality greater than 50% and survived to 30 days. We characterized patient demographics, clinical features, and outcomes of the unexpected survivors. Observed to expected (O/E) ratios and Z-statistics were calculated using model-estimated mortality for each cohort. RESULTS Our model predicted mortality better than Injury Severity Score or Revised Trauma Score parameters and identified 36 unexpected survivors. Compared with expected survivors, unexpected survivors were younger (33 years [24, 52 years] vs. 47 years [32, 59 years], p = 0.013), were more severely injured (Injury Severity Score 34 [22, 50] vs. 18 [10, 27], p < 0.001), had worse organ dysfunction and hospital resource outcomes (multiple organ failure, intensive care unit, hospital length of stay, and ventilator days), and were more likely to receive prehospital plasma (67 vs. 46%, p = 0.031). Nonsurvivors with high predicted mortality were more likely to receive standard care resuscitation (p < 0.001). Unexpected survivors who received prehospital plasma had a lower observed to expected mortality than those that received standard care resuscitation (O/E 0.56 [0.33-0.84] vs. 1.0 [0.73-1.32]). The number of prehospital plasma survivors (24) exceeded the number of predicted survivors (n = 10) estimated by our model (p < 0.001). CONCLUSION Prehospital plasma is associated with an increase in the number of unexpected survivors following severe traumatic injury. Prehospital interventions may improve the probability of survival for injured patients with high predicted mortality based on early injury characteristics, vital signs, and resuscitation measures. LEVEL OF EVIDENCE Therapeutic Level III.

Background Increases in plasma von Willebrand Factor (VWF) levels, accompanied by decreases in the metalloprotease ADAMTS13, have been demonstrated soon after traumatic injury while downstream effects remain unclear. Study design and methods A cohort of 37 injured trauma patients from a randomized control trial investigating the use of prehospital plasma transfusion were analyzed for activity and antigen levels of ADAMTS13 and VWF at 0 and 24 hours after admission. Relevant clinical data were abstracted from the medical records. Trauma patient plasma was analyzed via agarose gel electrophoresis to evaluate the effects of injury on VWF multimer composition compared to healthy controls. Results von Willebrand factor levels were elevated at presentation (189% [110%-263%] vs. 95% [74%-120%]), persisting through 24 hours (213% [146%-257%] vs. 132% [57%-160%]), compared to healthy controls. Ultralarge VWF (UL-VWF) forms were elevated in trauma patients at both 0 and 24 hours, when compared to pooled normal plasma (10.0% [8.9%-14.3%] and 11.3% [9.1%-21.2%], respectively, vs. 0.6%). Circulating plasma ADAMTS13 activity was decreased at 0 hours (66% [47%-86%] vs. 100% [98%-100%]) and at 24 hours (72.5% [56%-87.3%] vs. 103% [103%-103%]) in trauma patients. ADAMTS13 activity independently predicted the development of coagulopathy and correlated with international normalized ratio, thromboelastography values, injury severity, and blood product transfusion. Conclusion Traumatic injury is associated with acute coagulopathy that is characterized by increased UL-VWF multimers and reduction in ADAMTS13, which correlates with blood loss, transfusion requirement, and injury severity. These findings suggest the potential for future trials targeting ADAMTS13 repletion to enhance clearance of VWF multimers.

The purpose was to determine the role of AMPK activation in the renal metabolic response to sepsis, the development of sepsis-induced acute kidney injury (AKI) and on survival. In a prospective experimental study, 167 10- to 12-week-old C57BL/6 mice underwent cecal ligation and puncture (CLP) and human proximal tubule epithelial cells (TEC; HK2) were exposed to inflammatory mix (IM), a combination of lipopolysaccharide (LPS) and high mobility group box 1 (HMGB1). Renal/TEC metabolic fitness was assessed by monitoring the expression of drivers of oxidative phosphorylation (OXPHOS), the rates of utilization of OXPHOS/glycolysis in response to metabolic stress, and mitochondrial function by measuring O2 consumption rates (OCR) and the membrane potential (Δψm ). Sepsis/IM resulted in AKI, increased mortality, and in renal AMPK activation 6-24 hours after CLP/IM. Pharmacologic activation of AMPK with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) or metformin during sepsis improved the survival, while AMPK inhibition with Compound C increased mortality, impaired mitochondrial respiration, decreased OCR, and disrupted TEC metabolic fitness. AMPK-driven protection was associated with increased Sirt 3 expression and restoration of metabolic fitness. Renal AMPK activation in response to sepsis/IM is an adaptive mechanism that protects TEC, organs, and the host by preserving mitochondrial function and metabolic fitness likely through Sirt3 signaling.

Nitric oxide is a strong vasodilatory and anti-inflammatory signaling molecule that plays diverse roles in maintaining vascular homeostasis. Nitric oxide produced by endothelial cells is a critical regulator of this balance, such that endothelial dysfunction is defined as a reduced capacity for nitric oxide production and decreased nitric oxide sensitivity. This ultimately results in an imbalance in vascular homeostasis leading to a prothrombotic, proinflammatory, and less compliant blood vessel wall. Endothelial dysfunction is central in numerous pathophysiologic processes. This article reviews mechanisms governing nitric oxide production and downstream effects, highlighting the role of nitric oxide signaling in organ system pathologies.

Whether metformin exposure is associated with improved outcomes in patients with type 2 diabetes mellitus and sepsis.Retrospective cohort study.Patients admitted to ICUs in 16 hospitals in Pennsylvania from October 2008 to December 2014.Adult critical ill patients with type 2 diabetes mellitus and sepsis.None.We conducted a retrospective cohort study to compare 90-day mortality in diabetic patients with sepsis with and without exposure to metformin during hospitalization. Data were obtained from the electronic health record of a large healthcare system in Pennsylvania from October 2008 to December 2014, on patients admitted to the ICU at any of the 16 hospitals within the system. The primary outcome was mortality at 90 days. The absolute and adjusted odds ratio (OR) with 95% CI were calculated in a propensity score-matched cohort. Among 14,847 patients with type 2 diabetes mellitus and sepsis, 682 patients (4.6%) were exposed to metformin during hospitalization and 14,165 (95.4%) were not. Within a total of 2,691 patients subjected to propensity score-matching at a 1:4 ratio, exposure to metformin (n = 599) was associated with decreased 90-day mortality (71/599, 11.9% vs 475/2,092, 22.7%; OR, 0.46; 95% CI, 0.35-0.60), reduced severe acute kidney injury (50% vs 57%; OR, 0.75; 95% CI, 0.62-0.90), less Major Adverse Kidney Events at 1 year (OR, 0.27; 95% CI, 0.22-0.68), and increased renal recovery (95% vs 86%; OR, 6.43; 95% CI, 3.42-12.1).Metformin exposure during hospitalization is associated with a decrease in 90-day mortality in patients with type 2 diabetes mellitus and sepsis.

Acute kidney injury (AKI) is common after trauma, but contributory factors are incompletely understood. Increases in plasma von Willebrand Factor (vWF) with concurrent decreases in ADAMTS13 are associated with renal microvascular thrombosis in other disease states, but similar findings have not been shown in trauma. We hypothesized that molecular changes in circulating vWF and ADAMTS13 promote AKI following traumatic injury. VWF antigen, vWF multimer composition and ADAMTS13 levels were compared in plasma samples from 16 trauma patients with and without trauma-induced AKI, obtained from the Prehospital Air Medical Plasma (PAMPer) biorepository. Renal histopathology and function, vWF and ADAMTS13 levels were assessed in parallel in a murine model of polytrauma and haemorrhage. VWF antigen was higher in trauma patients when compared with healthy controls [314% (253–349) vs. 100% (87–117)] [median (IQR)], while ADAMTS13 activity was lower [36.0% (30.1–44.7) vs. 100.0% (83.1–121.0)]. Patients who developed AKI showed significantly higher levels of high molecular weight multimeric vWF at 72-h when compared with non-AKI counterparts [32.9% (30.4–35.3) vs. 27.8% (24.6–30.8)]. Murine plasma cystatin C and vWF were elevated postpolytrauma model in mice, with associated decreases in ADAMTS13, and immunohistologic analysis demonstrated renal injury with small vessel plugs positive for fibrinogen and vWF. Following traumatic injury, the vWF-ADAMTS13 axis shifted towards a prothrombotic state in both trauma patients and a murine model. We further demonstrated that vWF-containing, microangiopathic deposits were concurrently produced as the prothrombotic changes were sustained during the days following trauma, potentially contributing to AKI development.

This Guide to Statistics and Methods outlines the considerations when determining a budget for a clinical trial in preparation for submitting applications to various funding agencies.

Aims: We sought to investigate the relationship between macrohemodynamic resuscitation and microcirculatory parameters with the response of microcirculatory flow, tissue-specific parameters of metabolic stress and injury. We hypothesized that early resuscitation based on macrohemodynamic parameters does not prevent the development of organ dysfunction in a porcine model of endotoxemic shock, and that sublingual microcirculatory parameters are associated with markers of tissue metabolic stress and injury. Results: Both resuscitation groups had significant increases in creatinine and neutrophil gelatinase-associated lipocalin as compared with baseline. Neither the macrovascular response to endotoxemia or resuscitation, nor group allocation predicted the development of acute kidney injury (AKI). Only a microvascular flow index (MFI) 6 and P(a-v)CO(2)/C(v-a)O(2) >1.8 were associated with increased organ L/P ratio and AKI. Innovation and Conclusion: Our findings demonstrate that targeting macrohemodynamics to guide resuscitation during endotoxemic shock failed to predict tissue metabolic stress and the response of the microvasculature to resuscitation, and was unsuccessful in preventing tubular injury and AKI. Mechanistically, our data suggest that loss of hemodynamic coherence and decoupling of microvascular flow from tissue metabolic demand during endotoxemia may explain the lack of association between macrohemodynamics and perfusion goals. Finally, we demonstrate that MFI, PCO(2) gap, and P(v-a)CO(2)/C(a-v)O(2) ratio outperformed macrohemodynamic parameters at predicting the development of renal metabolic stress and tubular injury, and therefore, that these indices merit further validation as promising resuscitation targets. Antioxid. Redox Signal. 35, 1407–1425.

Importance Prehospital plasma transfusion is lifesaving for trauma patients in hemorrhagic shock but is not commonly used owing to cost and feasibility concerns. Objective To evaluate the cost-effectiveness of prehospital thawed plasma transfusion in trauma patients with hemorrhagic shock during air medical transport. Design, setting, and participants A decision tree and Markov model were created to compare standard care and prehospital thawed plasma transfusion using published and unpublished patient-level data from the Prehospital Plasma in Air Medical Transport in Trauma Patients at Risk for Hemorrhagic Shock (PAMPer) trial conducted from May 2014 to October 2017, health care and trauma-specific databases, and the published literature. Prehospital transfusion, short-term inpatient care, and lifetime health care costs and quality of life outcomes were included. One-way, 2-way, and Monte Carlo probabilistic sensitivity analyses were performed across clinically plausible ranges. Data were analyzed in December 2019. Main outcomes and measures Relative costs and health-related quality of life were evaluated by an incremental cost-effectiveness ratio at a standard willingness-to-pay threshold of $100 000 per quality-adjusted life-year (QALY). Results The trial included 501 patients in the modified intention-to-treat cohort. Median (interquartile range) age for patients in the thawed plasma and standard care cohorts were 44 (31-59) and 46 (28-60) years, respectively. Overall, 364 patients (72.7%) were male. Thawed plasma transfusion was cost-effective with an incremental cost-effectiveness ratio of $50 467.44 per QALY compared with standard care. The preference for thawed plasma was robust across all 1- and 2-way sensitivity analyses. When considering only patients injured by a blunt mechanism, the incremental cost-effectiveness ratio decreased to $37 735.19 per QALY. Thawed plasma was preferred in 8140 of 10 000 iterations (81.4%) on probabilistic sensitivity analysis. A detailed analysis of incremental costs between strategies revealed most were attributable to the in-hospital and postdischarge lifetime care of critically ill patients surviving severe trauma. Conclusions and relevance In this study, prehospital thawed plasma transfusion during air medical transport for trauma patients in hemorrhagic shock was lifesaving and cost-effective compared with standard care and should become commonplace.

Background A recent analysis derived from the Prehospital Air Medical Plasma trial data set demonstrated no significant independent plasma survival benefit in those who required massive transfusion (≥10 units of red cells in 24 hours). The definition of massive transfusion has evolved over time to minimize bias and predict those at highest risk of death. We sought to characterize the definition of massive transfusion, their associated mortality risks and the survival benefit associated with prehospital plasma. Methods A secondary analysis was performed using data from a recent prehospital plasma trial. Patients transferred directly from the scene were characterized. We defined historic massive transfusion using ≥10 units red cells in 24 hours and critical administration threshold (CAT) as ≥3 units per hour in the first hour (CAT1hr) or in any of the first 4 hours (CAT4hr) from arrival. The primary outcome was 30-day mortality. Kaplan-Meier analysis and Cox hazard regression were used to characterize the survival benefit of prehospital plasma. Results There were a total of 390 enrolled patients who were transferred from the scene and represent the study cohort. Overall, 126 patients were positive for the CAT1hr metric, 183 patients were positive for the CAT4hr metric and 84 patients were positive for historic massive transfusion metric. The overall study mortality rate for those patients who met each transfusion definition was 13.1%, 17.4% and 10.0%, respectively. The CAT4hr metric had the lowest potential for survival bias. Kaplan-Meier survival analysis demonstrated a prehospital plasma survival benefit in the patients who were CAT4hr positive. Conclusion The current analysis demonstrates the superior utility of the CAT4hr definition with optimization of survival bias while conserving mortality risk prediction. This transfusion definition was associated with a prehospital plasma survival benefit and may be the most appropriate definition of massive transfusion for pragmatic studies which focus on hemorrhagic shock. Level of evidence Epidemiologic, Level II.

Background Recent randomized clinical trial evidence demonstrated a survival benefit with the use of prehospital plasma in patients at risk of hemorrhagic shock. We sought to characterize the survival benefit associated with prehospital plasma relative to the blood transfusion volume over the initial 24 hours. We hypothesized that the beneficial effects of prehospital plasma would be most robust in those with higher severity of hemorrhage. Methods We performed a prespecified secondary analysis using data derived from a prospective randomized prehospital plasma trial. Blood component transfusion volumes were recorded over the initial 24 hours. Massive transfusion (MT) was defined a priori as receiving ≥10 units of red cells in 24 hours. We characterized the 30-day survival benefit of prehospital plasma and the need for MT and overall 24-hour red cell transfusion volume utilizing Kaplan-Meier survival analysis and Cox proportional hazard regression. Results There were 501 patients included in this analysis with 230 randomized to prehospital plasma with 104 patients requiring MT. Mortality in patients who received MT were higher compared with those that did not (MT vs. NO-MT, 42% vs. 26%, p = 0.001). Kaplan-Meier survival curves demonstrated early separation in the NO-MT subgroup (log rank p = 0.008) with no survival benefit found in the MT group (log rank p = 0.949). Cox regression analysis verified these findings. When 24-hour red cell transfusion was divided into quartiles, there was a significant independent association with 30-day survival in patients who received 4 to 7 units (hazard ratio, 0.33, 95% confidence interval, 0.14-0.80, p = 0.013). Conclusion The survival benefits of prehospital plasma was demonstrated only in patients with red cell requirements below the transfusion level of MT. Patients who received 4 to 7 units of red cells demonstrated the most robust independent survival benefit attributable to prehospital plasma transfusion. Prehospital plasma may be most beneficial in those patients with moderate transfusion requirements and mortality risk. Level of evidence Therapeutic, Level I.

The Prehospital Air Medical Plasma (PAMPer) trial demonstrated a 30-day survival benefit among hypotensive trauma patients treated with prehospital plasma during air medical transport. We characterized resources, costs and feasibility of air medical prehospital plasma program implementation.We performed a secondary analysis using data derived from the recent PAMPer trial. Intervention patients received thawed plasma (5-day shelf life). Unused plasma units were recycled back to blood bank affiliates, when possible. Distribution method and capability of recycling varied across sites. We determined the status of plasma units deployed, utilized, wasted, and returned. We inventoried thawed plasma use and annualized costs for distribution and recovery.The PAMPer trial screened 7,275 patients and 5,103 plasma units were deployed across 22 air medical bases during a 42-month period. Only 368 (7.2%) units of this total thawed plasma pool were provided to plasma randomized PAMPer patients. Of the total plasma pool, 3,716 (72.8%) units of plasma were returned to the blood bank with the potential for transfusion prior to expiration and 1,019 (20.0%) thawed plasma units were deemed wasted for this analysis. The estimated average annual cost of implementation of a thawed plasma program per air medical base at an average courier distance would be between US $24,343 and US $30,077, depending on the ability to recycle plasma and distance of courier delivery required.A prehospital plasma program utilizing thawed plasma is resource intensive. Plasma waste can be minimized depending on trauma center and blood bank specific logistics. Implementation of a thawed plasma program can occur with financial cost. Products with a longer shelf life, such as liquid plasma or freeze-dried plasma, may provide a more cost-effective prehospital product relative to thawed plasma.Therapeutic, level III.

Hemolysis is a pathological component of many diseases and is associated with thrombosis and vascular dysfunction. Hemolytic products, including cell-free hemoglobin and free heme directly activate platelets. However, the effect of hemolysis on platelet degranulation, a central process in not only thrombosis, but also inflammatory and mitogenic signaling, remains less clear. Our group showed that hemoglobin-induced platelet activation involved the production of mitochondrial reactive oxygen species (mtROS). However, the molecular mechanism by which extracellular hemolysis induces platelet mtROS production, and whether the mtROS regulate platelet degranulation remains unknown. Here, we demonstrate using isolated human platelets that cell free heme is a more potent agonist for platelet activation than hemoglobin, and stimulates the release of a specific set of molecules from the α-granule of platelets, including the glycoprotein thrombospondin-1 (TSP-1). We uncover the mechanism of heme-mediated platelet mtROS production which is dependent on the activation of platelet TLR4 signaling and leads to the downstream phosphorylation of complex-V by the serine kinase Akt. Notably, inhibition of platelet TLR4 or Akt, or scavenging mtROS prevents heme-induced granule release in vitro. Further, heme-dependent granule release is significantly attenuated in vivo in mice lacking TLR4 or those treated with the mtROS scavenger MitoTEMPO. These data elucidate a novel mechanism of TLR4-mediated mitochondrial regulation, establish the mechanistic link between hemolysis and platelet degranulation, and begin to define the heme and mtROS-dependent platelet secretome. These data have implications for hemolysis-induced thrombo-inflammatory signaling and for the consideration of platelet mitochondria as a therapeutic target in hemolytic disorders.Key pointsHeme induces platelet mtROS production by inhibiting complex-V activity via TLR4 signaling.Heme stimulated platelet granule secretion is regulated by mtROS.

Introduction. Aged individuals are at higher risk for morbidity and mortality following acute stressors than similarly stressed young people. Evaluation of age-associated metabolic changes could lead to the identification of specific therapeutic targets to improve outcomes from acute stressors, such as infections, in the elderly. We thus compared the plasma metabolomes of both young and old mice following cecal ligation and puncture (CLP), an accepted model of acute infection and stress. Methods. Young (9-17 wks) and aged (78-96 wks) male C57bl/6 mice were subjected to a retro-orbital bleed and two-week recovery prior to sham surgery (laparotomy alone) or CLP. Animals were sacrificed at 4 h, 8 h, or 12 h following intervention, and plasma was isolated from blood for subsequent analysis. Metabolomic analysis of samples were performed (Metabolon; Durham, NC). Results. Aged animals demonstrated greater intraprocedural mortality than young (30.2% vs. 17.4%, χ 2 p = 0.0004 ), confirming enhanced frailty. Principal component analysis and partial-least squares discriminant analysis of 566 metabolites demonstrated distinct metabolomic shifts following sham surgery or CLP in both young and aged animals. Identification of metabolites of interest using a consensus statistical approach revealed that both the histidine/histamine pathway and the nicotinamide pathway have significant age-associated alterations following CLP. Conclusions. The application of untargeted plasma metabolomics identified key pathways underpinning metabolomic responses to CLP in both young and aged animals. Ultimately, these data provide a robust foundation for future mechanistic studies that may assist in improving outcomes in frail patients in response to acute stressors such as infection, trauma, or surgery.

Surgeon-scientists provide critical perspectives to academic medicine, both as lead scientists and as collaborators. Successfully applying for and obtaining funding is critical to sustain a research program; however, significant challenges exist. It is imperative to be aware of and consider all funding sources available to surgeons during the evolution of one's career. Additionally, a deep understanding of intramural and extramural nonfinancial resources, such as mentorship relationships, grant writing, and career development courses, and research infrastructure are required. In this article, we present a set of recommendations and guidelines for surgeon-scientists to leverage funding resources with active planning longitudinally during their careers to sustain their research programs and provide their unique perspectives on surgical disease to the scientific community.

Background The current COVID-19 pandemic has had an unprecedented impact on all physicians and has resulted in dramatic changes to clinical and research operations. No study has yet looked at the impact of COVID-19 on the surgical research community. In this study, we sought to understand the impact of the pandemic and its associated restrictions on academic surgeons. Methods We surveyed members of the Association for Academic Surgery (AAS) and Society of University Surgeons (SUS). Survey questions included demographics, current challenges to basic and clinical research activities, attitudes towards remote work and productivity maintenance, and the solutions implemented to maintain productivity. Results Of 301 respondents, 70% cited a negative impact on research productivity due to mandatory building shutdowns, minimized personnel due to social distancing, and suspensions of animal work and clinical trials, with senior faculty and division chiefs/chairs more likely to report a negative impact (p=0.001). Only 11% of respondents are documenting their financial losses, and only 19% indicated they received appropriate guidance regarding why and how to monitor the financial impact of the pandemic. Researchers have attempted to maintain research productivity through a focus on remote work, including manuscript writing, grant writing and data analysis. Some participants have found silver linings, including more time to dedicate to research and family due to fewer clinical duties. Conclusions Productivity strategies developed during the pandemic, including writing, remote work and meetings, and structured scheduling, are lessons that will allow the surgical research community to be resilient in the face of future disruptions., Highlights TOC Statement- 20201159 In this study, surgeon-scientists were surveyed to assess the impact of the COVID-19 pandemic on research activities and the resulting challenges, as well as potential solutions implemented to maintain research productivity. The importance of this study is to identify opportunities in optimizing research during this pandemic and extrapolate lessons for futures disasters.

IMPORTANCE: In-hospital administration of tranexamic acid after injury improves outcomes in patients at risk for hemorrhage. Data demonstrating the benefit and safety of the pragmatic use of tranexamic acid in the prehospital phase of care are lacking for these patients. OBJECTIVE: To assess the effectiveness and safety of tranexamic acid administered before hospitalization compared with placebo in injured patients at risk for hemorrhage. DESIGN, SETTING, AND PARTICIPANTS: This pragmatic, phase 3, multicenter, double-blind, placebo-controlled, superiority randomized clinical trial included injured patients with prehospital hypotension (systolic blood pressure ≤90 mm Hg) or tachycardia (heart rate ≥110/min) before arrival at 1 of 4 US level 1 trauma centers, within an estimated 2 hours of injury, from May 1, 2015, through October 31, 2019. INTERVENTIONS: Patients received 1 g of tranexamic acid before hospitalization (447 patients) or placebo (456 patients) infused for 10 minutes in 100 mL of saline. The randomization scheme used prehospital and in-hospital phase assignments, and patients administered tranexamic acid were allocated to abbreviated, standard, and repeat bolus dosing regimens on trauma center arrival. MAIN OUTCOMES AND MEASURES: The primary outcome was 30-day all-cause mortality. RESULTS: In all, 927 patients (mean [SD] age, 42 [18] years; 686 [74.0%] male) were eligible for prehospital enrollment (460 randomized to tranexamic acid intervention; 467 to placebo intervention). After exclusions, the intention-to-treat study cohort comprised 903 patients: 447 in the tranexamic acid arm and 456 in the placebo arm. Mortality at 30 days was 8.1% in patients receiving tranexamic acid compared with 9.9% in patients receiving placebo (difference, –1.8%; 95% CI, –5.6% to 1.9%; P = .17). Results of Cox proportional hazards regression analysis, accounting for site, verified that randomization to tranexamic acid was not associated with a significant reduction in 30-day mortality (hazard ratio, 0.81; 95% CI, 0.59-1.11, P = .18). Prespecified dosing regimens and post-hoc subgroup analyses found that prehospital tranexamic acid were associated with significantly lower 30-day mortality. When comparing tranexamic acid effect stratified by time to treatment and qualifying shock severity in a post hoc comparison, 30-day mortality was lower when tranexamic acid was administered within 1 hour of injury (4.6% vs 7.6%; difference, −3.0%; 95% CI, −5.7% to −0.3%; P

Trauma is the leading cause of death and disability for individuals under age 55. Many severely injured trauma patients experience complicated clinical courses despite appropriate initial therapy. We sought to identify novel circulating metabolomic signatures associated with clinical outcomes following trauma.Untargeted metabolomics and circulating plasma immune mediator analysis was performed on plasma collected during 3 post-injury time periods (6 hours [h], 6 h-24h, day 2-day 5) in critically ill trauma patients enrolled between April 2004 and May 2013 at UPMC Presbyterian Hospital in Pittsburgh, PA. Inclusion criteria were age ≥ 18 years, blunt mechanism, ICU admission, and expected survival ≥ 24 h. Exclusion criteria were isolated head injury, spinal cord injury, and pregnancy. Exploratory endpoints included length of stay (overall and ICU), ventilator requirements, nosocomial infection, and Marshall organ dysfunction (MOD) score. The top 50 metabolites were isolated using repeated measures ANOVA and multivariate empirical Bayesian analysis for further study.Eighty-six patients were included for analysis. Sphingolipids were enriched significantly (chi-square, p10Metabolomic analysis identified broad alterations in circulating plasma sphingolipids after blunt trauma. Circulating sphingolipid signatures and their association with both clinical outcomes and circulating inflammatory mediators suggest a possible link between sphingolipid metabolism and the immune response to trauma.

BACKGROUND Since 2005, the American College of Surgeons has administered the Jacobson Promising Investigator Award (JPIA), which recognizes surgeon-scientists at the "tipping point" of their research careers. OBJECTIVE We retrospectively reviewed JPIA applicants to identify factors associated with selection for the award and future research success. METHODS Profiles were reviewed for all applicants between 2008 and 2018, at the time of application and as of 2019. Web of Science and NIH Reporter metrics were also reviewed for each applicant. RESULTS Eleven of 97 applicants were selected for the JPIA. At the time of application, awardees were more likely to have extramural (NIH K-award) versus intramural (KL2) or other career development award funding (55% vs 33%, P = 0.03) and more publications [median 70 (interquartile range, IQR 55-100) vs 40 (IQR 22-67), P = 0.03]. Post-application, JPIA awardees were more likely to achieve a higher h-Index and m-quotient compared to nonawardees (P < 0.001 for both). All JPIA recipients received new NIH funding post-award, including 82% with R01 funding, compared to 23% of nonselected applicants (P < 0.0001). Over $48 million from NIH was awarded to JPIA recipients since 2008, representing a 147-fold return on investment. CONCLUSIONS Selection for the JPIA is associated with previous extramural NIH K award and, on average, 70 peer-reviewed publications at the time of application. Receipt of the JPIA is associated with a high rate of subsequent NIH R01 funding and publication metrics. The JPIA is an excellent indicator of "tipping point" success in academic surgery and demonstrates the huge potential impact of philanthropic support on early career surgeon-investigators.

The most vital part of a grant is the specific-aims section. As the leading section of the proposal, the specific-aims section serves as a 1-page synopsis that needs to gain the attention and interest of the reviewers. It must present a compelling case for the importance of the proposed work and provide a convincing rationale and evidence that you and your team are the best people to carry out the project. Developing the specific-aims page is usually the first stage of the grant writing process, as it provides an overview of the proposal and research directions. Furthermore, it can be instrumental in getting external feedback from program officers, collaborators, and others as the grant develops. The process of writing the Specific Aims page requires that one touch on each of the elements that comprise the scoring criteria of the proposal (eg, significance, innovation, investigator(s), approach, and environment) and succinctly introduce all the main topics that will be addressed in the application, but focus especially on the knowledge gap and the importance of filling it, the central hypothesis and the aims that will address it, and the overall impact of the work. This page sets a clear framework for writing the rest of the grant. In this article, we present a set of recommendations and guidelines on how to utilize an algorithmic approach to develop the specific-aims page, what elements to include, and how to maximize its value to create a competitive grant.

Background Randomized clinical trials (RCTs) support the use of prehospital plasma in traumatic hemorrhagic shock, especially in long transports. The citrate added to plasma binds with calcium, yet most prehospital trauma protocols have no guidelines for calcium replacement. We reviewed the experience of two recent prehospital plasma RCTs regarding admission ionized-calcium (i-Ca) blood levels and its impact on survival. We hypothesized that prehospital plasma is associated with hypocalcemia, which in turn is associated with lower survival. Methods We studied patients enrolled in two institutions participating in prehospital plasma RCTs (control, standard of care; experimental, plasma), with i-Ca collected before calcium supplementation. Adults with traumatic hemorrhagic shock (systolic blood pressure ≤70 mm Hg or 71-90 mm Hg + heart rate ≥108 bpm) were eligible. We use generalized linear mixed models with random intercepts and Cox proportional hazards models with robust standard errors to account for clustered data by institution. Hypocalcemia was defined as i-Ca of 1.0 mmol/L or less. Results Of 160 subjects (76% men), 48% received prehospital plasma (median age, 40 years [interquartile range, 28-53 years]) and 71% suffered blunt trauma (median Injury Severity Score [ISS], 22 [interquartile range, 17-34]). Prehospital plasma and control patients were similar regarding age, sex, ISS, blunt mechanism, and brain injury. Prehospital plasma recipients had significantly higher rates of hypocalcemia compared with controls (53% vs. 36%; adjusted relative risk, 1.48; 95% confidence interval [CI], 1.03-2.12; p = 0.03). Severe hypocalcemia was significantly associated with decreased survival (adjusted hazard ratio, 1.07; 95% CI, 1.02-1.13; p = 0.01) and massive transfusion (adjusted relative risk, 2.70; 95% CI, 1.13-6.46; p = 0.03), after adjustment for confounders (randomization group, age, ISS, and shock index). Conclusion Prehospital plasma in civilian trauma is associated with hypocalcemia, which in turn predicts lower survival and massive transfusion. These data underscore the need for explicit calcium supplementation guidelines in prehospital hemotherapy. Level of evidence Therapeutic, level II.

BACKGROUND: Prehospital plasma improves survival in severely injured patients transported by air ambulance. We hypothesized that prehospital plasma would be associated with a reduction in immune imbalance and endothelial damage. METHODS: We sampled blood from 405 trauma patients enrolled in the Prehospital Air Medical Plasma (PAMPer) trial upon hospital admission (0 hours) and 24 hours post admission across 6 U.S. sites. We assayed samples for 21 inflammatory mediators and 7 markers associated with endothelial function and damage. We performed hierarchical clustering analysis (HCA) of these biomarkers of the immune response and endothelial injury. Regression analysis was used to control for differences across study and to assess any association with prehospital plasma resuscitation. RESULTS: HCA distinguished two patient clusters with different injury patterns and outcomes. Patients in cluster A had greater injury severity and incidence of blunt trauma, traumatic brain injury, and mortality. Cluster A patients that received prehospital plasma showed improved 30-day survival. Prehospital plasma did not improve survival in cluster B patients. In an adjusted analysis of the most seriously injured patients, prehospital plasma was associated with an increase in adiponectin, IL-1β, IL-17A, IL-23, and IL-17E upon admission, and a reduction in syndecan-1, TM, VEGF, IL-6, IP-10, MCP-1, and TNF-α, and an increase in IL-33, IL-21, IL-23, and IL-17E 24 hours later. CONCLUSION: Prehospital plasma may ameliorate immune dysfunction and the endotheliopathy of trauma. These effects of plasma may contribute to improved survival in injured patients. TRIAL REGISTRATION: NCT01818427. FUNDING: Department of Defense; National Institutes of Health, U.S. Army.

Background Perioperative stroke-related mortality in the non-cardiovascular, non-neurological surgery population is an uncommon, yet devastating outcome. A combination of emboli and hypoperfusion may cause large vessel occlusions leading to perioperative strokes and mortality. Identifying independent risk factors for perioperative stroke-related mortality may enhance risk-stratification algorithms and preventative therapies. Objectives This study utilised cause-of-death data to determine independent risk scores for common surgical comorbidities that may lead to perioperative stroke-related mortality, including atrial fibrillation and asymptomatic carotid stenosis. Methods This retrospective, IRB-exempt, case–control study evaluated non-cardiovascular, non-neurological surgical patients in a claims-based database. ICD-10-CM and ICD-9-CM codes identified cause of death and comorbidity incidences, respectively. A multivariate regression analysis then established adjusted independent risk scores of each comorbidity in relation to perioperative stroke-related mortality. Results Patients with atrial fibrillation were more likely (1.7 aOR, 95% CI (1.1, 2.8) p = 0.02) to die from perioperative stroke-related mortality than from other causes. No association was found with asymptomatic carotid stenosis. Further, in-hospital strokes (25.9 aOR, 95% CI (16.0, 41.8) p Conclusions Atrial fibrillation, diabetes and in-hospital strokes may be independent risk factors for perioperative stroke-related mortality in the non-cardiovascular, non-neurological surgery population.

ADAMTS13 is an enzyme that acts by cleaving prothrombotic von Willebrand factor (VWF) multimers from the vasculature in a highly regulated manner. In pathologic states such as thrombotic thrombocytopenic purpura (TTP) and other thrombotic microangiopathies (TMAs), VWF can bind to the endothelium and form large multimers. As the anchored VWF chains grow, they provide a greater surface area to bind circulating platelets (PLTs), generating unique thrombi that characterize TTP. This results in microvasculature thrombosis, obstruction of blood flow, and ultimately end-organ damage. Initial presentations of TTP usually occur in an acute manner, typically developing due to an autoimmune response toward, or less commonly a congenital deficiency of, ADAMTS13. Triggers for TMAs that can be associated with ADAMTS13 deficiency, including TTP, have been linked to events that place a burden on hemostatic regulation, such as major trauma and pregnancy. The treatment plan for cases of suspected TTP consists of emergent therapeutic plasma exchange that is continued on a daily basis until normalization of PLT counts. However, a subset of these patients does not respond favorably to standard therapies. These patients necessitate a better understanding of their diseases for the advancement of future therapeutic options. Given ADAMTS13's key role in the cleavage of VWF and the prevention of PLT-rich thrombi within the microvasculature, future treatments may include anti-VWF therapeutics, recombinant ADAMTS13 infusions, and ADAMTS13 expression via gene therapy.

Summary Polymorphonuclear (PMN) leucocytes participate in acute inflammatory pathologies such as acute respiratory distress syndrome (ARDS) following traumatic injury and shock, which also activates the coagulation system systemically. Trauma can prime the PMN nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex for an enhanced respiratory burst, but the relative role of various priming agents in this process remains incompletely understood. We therefore set out to identify mediators of PMN priming during coagulation and trauma-shock and determine whether PMN reactive oxygen species (ROS) generated in this manner could influence organ injury and coagulation. Initial experiments demonstrated that PMN are primed for predominantly extracellular ROS production by products of coagulation, which was abrogated by CD88/C5a receptor(C5aR) inhibition. The importance of this was highlighted further by demonstrating that known PMN priming agents result in fractionally different amounts of extracellular versus intracellular ROS release depending on the agent used. Plasma from trauma patients in haemodynamic shock (n = 10) also primed PMN for extracellular ROS in a C5a-dependent manner, which correlated with both complement alternative pathway activation and thrombin generation. Furthermore, PMN primed by preincubation with products of blood coagulation directly caused loss of endothelial barrier function in vitro that was abrogated by C5aR blockade or NADPH oxidase inhibition. Finally, we show in a murine model of trauma-shock that p47phox knock-out (KO) mice with PMN incapable of generating ROS were protected from inflammatory end-organ injury and activated protein C-mediated coagulopathy. In summary, we demonstrate that trauma-shock and coagulation primes PMN for predominantly extracellular ROS production in a C5a-dependent manner that contributes to endothelial barrier loss and organ injury, and potentially enhances traumatic coagulopathy.

OBJECTIVES The physiology of nearly all mammalian organisms are entrained by light and exhibit circadian rhythm. The data derived from animal studies show that light influences immunity, and these neurophysiologic pathways are maximally entrained by the blue spectrum. Here, we hypothesize that bright blue light reduces acute kidney injury by comparison with either bright red or standard, white fluorescent light in mice subjected to sepsis. To further translational relevance, we performed a pilot clinical trial of blue light therapy in human subjects with appendicitis. DESIGN Laboratory animal research, pilot human feasibility trial. SETTING University basic science laboratory and tertiary care hospital. SUBJECTS Male C57BL/6J mice, adult (> 17 yr) patients with acute appendicitis. INTERVENTIONS Mice underwent cecal ligation and puncture and were randomly assigned to a 24-hour photoperiod of bright blue, bright red, or ambient white fluorescent light. Subjects with appendicitis were randomized to receive postoperatively standard care or standard care plus high-illuminance blue light. MEASUREMENTS AND MAIN RESULTS Exposure to bright blue light enhanced bacterial clearance from the peritoneum, reduced bacteremia and systemic inflammation, and attenuated the degree of acute kidney injury. The mechanism involved an elevation in cholinergic tone that augmented tissue expression of the nuclear orphan receptor REV-ERBα and occurred independent of alterations in melatonin or corticosterone concentrations. Clinically, exposure to blue light after appendectomy was feasible and reduced serum interleukin-6 and interleukin-10 concentrations. CONCLUSIONS Modifying the spectrum of light may offer therapeutic utility in sepsis.

Background After a person has been injured, prehospital administration of plasma in addition to the initiation of standard resuscitation procedures in the prehospital environment may reduc...

Clostridium difficile infection (CDI) is a common nosocomial infection that all medical practitioners must be familiar with, as all patients are at risk of developing this infectious disease. Although it has long been appreciated that this infectious disease arises secondary to the development of a colonic dysbiosis, as our understanding of the microbiome has grown substantially broader, the utilization of fecal microbiota therapy for this disease has also become a widespread reality. In addition to understanding the role of the microbiome in CDI, the poor prognosis of patients with severe, complicated CDI must also be recognized by critical care providers and abdominal surgeons. Strategies to lower the threshold for surgical consultation, and guidelines to help decide when surgery is indicated, can decrease mortality for patients. This chapter reviews these issues, as well as other aspects relevant to the treatment and care of patients with CDI.

Summary Trauma is a leading cause of death and morbidity worldwide. Here, we present the analysis of a longitudinal multi-omic dataset comprising clinical, cytokine, endotheliopathy biomarker, lipidome, metabolome, and proteome data from severely injured humans. A “systemic storm” pattern with release of 1,061 markers, together with a pattern suggestive of the “massive consumption” of 892 constitutive circulating markers, is identified in the acute phase post-trauma. Data integration reveals two human injury response endotypes, which align with clinical trajectory. Prehospital thawed plasma rescues only endotype 2 patients with traumatic brain injury (30-day mortality: 30.3 versus 75.0%; p = 0.0015). Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) was identified as the most predictive circulating biomarker to identify endotype 2-traumatic brain injury (TBI) patients. These response patterns refine the paradigm for human injury, while the datasets provide a resource for the study of critical illness, trauma, and human stress responses., Graphical abstract, Highlights An integrated longitudinal multi-omic analysis of the human response to trauma Systemic storm and massive consumption patterns are related to early mortality Unique resolution and non-resolution signatures across multiple “omics” platforms Only endotype 2-TBI patients with high UCHL1 levels benefit from early plasma, Wu et al. report a longitudinal multi-omic analysis of the circulation in trauma patients. Cross-platform data integration reveals a massive systemic release of cellular contents (“systemic storm”) and simultaneous consumption of blood constituents. Also defined are patient endotypes that differ in outcomes and responses to early plasma administration.

This cross-sectional study compares adverse outcomes and health care use associated with primary anastomosis with proximal diversion vs Hartmann procedure for patients with acute diverticulitis., Key Points Question Among patients with acute diverticulitis treated with an urgent surgical procedure (ie, Hartmann procedure [HP] or primary anastomosis with proximal diversion [PAPD]), is the procedure used associated with index readmission outcomes and resource use? Findings In this cross-sectional study of an estimated 1 072 395 hospitalized patients with acute diverticulitis, 34 126 patients required diversion within 48 hours of admission, and PAPD was associated with comparable index outcomes vs HP but an increased rate of readmission and risk of ostomy reversal. Total index and readmission hospitalization costs were similar between procedures. Meaning These findings suggest that PAPD is associated with increased risk of ostomy reversal compared with HP and that patient characteristics that bias operative strategy selection are the primary factors associated with index patient outcomes., Importance Diverticulitis of the colon is an increasingly prevalent disease with significant implications for patient quality of life and health system resource expenditure. Although several randomized clinical trials and meta-analyses of Hartman procedure (HP) and primary anastomosis and proximal diversion (PAPD) have found surgical equipoise, questions regarding the relative performance of these treatments when applied broadly remain. Objective To examine use of and outcomes after urgent sigmoid colectomy with end colostomy (ie, HP) vs PAPD in management of complicated diverticulitis. Design, Setting, and Participants This retrospective cross-sectional study was a multicenter, population-based examination of inpatient hospitalizations, not including long-term rehabilitation facilities, using data from the 2014 to 2017 Nationwide Readmissions Database. It was performed from November 2020 to January 2021. Included patients were adults admitted with acute diverticulitis requiring HP or PAPD within 48 hours of admission. Exposures Undergoing HP vs PAPD. Main Outcomes and Measures Inverse probability treatment analysis was used to compare outcomes, including index mortality, composite complications (ie, neurologic, infectious, and cardiovascular complications), length of stay, and readmissions within 90 days. Results During the study period, an estimated 1 072 395 adults (615 954 [57.4%] women; median [IQR] age, 64 [52-76] years) required nonelective hospitalization for acute colonic diverticulutus. A total of 34 126 patients required diversion, with 32 326 patients (94.7%) undergoing HP and 1800 patients (5.3%) undergoing PAPD within 48 hours of admission. Patients undergoing PAPD had a decreased median (IQR) age (60 [51-70] years vs 65 [54-74] years; P

Animal models of sepsis exhibit considerable variability in the temporal development of the physiologic response, which reduces the power of studies, particularly if interventions are tested at arbitrary time points. We developed a biotelemetry-based model of cecal ligation and puncture (CLP) that standardizes the testing of time-sensitive therapies to specific criteria of physiologic deterioration. In this study we seek to further define the variability in physiologic response to CLP sepsis and conduct a cost analysis detailing the potential for reducing animal usage. We have further characterized the variability in physiologic response after CLP in mice and determined peaks in the temporal distribution of points of physiologic decline. Testing therapies at physiologic thresholds reduces the variability found in historical fixed time-based models. Though initial cost is higher with biotelemetry, this is eventually offset by the significantly reduced number of mice needed to conduct physiologically relevant sepsis experiments.

Surgical site infection (SSI) contributes significantly to surgical morbidity. Patient factors and operative factors contribute to the risk of development of SSI. This review focuses on understanding operative characteristics that are associated with an increased risk of SSI. Much attention has been given to protocol care to reduce SSI, such as hair removal, skin preparation, and pre-operative antibiotic agents. Even with this, the appropriate antibiotic and re-dosing regimens often remain a challenge. Other operative factors such as blood loss/transfusion, emergency/urgent cases, duration of the operation, type of anesthesia, and resident involvement are also potentially modifiable to reduce the risk of SSI. Data are reviewed to highlight the increased risk associated with such factors. Strategies to reduce risk, such as operative care bundles, have significant promise to reduce the incidence of SSI for any given procedure.

Importance Groin pain in active individuals and athletes without clinical evidence of hernia or hip pathologic findings is challenging for health care clinicians and aggravating for those experiencing pain. Frequently calledsports herniaorathletic pubalgia, many surgeons continue to refute the diagnosis because there is a lack of consensus and clear comprehension of the basic pathophysiologic features of this groin pain syndrome. Observations Understanding the anatomic and pathophysiologic findings of groin pain syndrome is necessary to appropriately treat this problem. In general, the level of evidence of the literature is of relatively low quality. Exercise-based therapy can be an effective first-line therapy in individuals who develop groin pain syndrome. Surgical therapies are typically reserved for those who experience nonoperative management failure. The common features of the varied surgical procedures include the resultant changes in the vectors of pull on the pubic bone or joint, the defects in the inguinal canal, and the inguinal sensory nerve compression or bowstringing. Conclusions and Relevance The diagnosis of nonhip, nonhernia, chronic groin pain is common. Understanding the diagnosis and treatment options may facilitate recovery and allow return to an active lifestyle and sport.

INTRODUCTION Recent evidence demonstrated that prehospital plasma in patients at risk of hemorrhagic shock was safe for ground transport and resulted in a 28-day survival benefit for air medical transport patients. Whether any beneficial effect of prehospital plasma varies across injury mechanism remains unknown. METHODS We performed a secondary analysis using a harmonized data set derived from two recent prehospital plasma randomized trials. Identical inclusion/exclusion criteria and primary/secondary outcomes were used for the trials. Prehospital time, arrival shock parameters, and 24-hour transfusion requirements were compared across plasma and control groups stratified by mechanism of injury. Stratified survival analysis and Cox hazard regression were performed to determine the independent survival benefits of plasma across blunt and penetrating injury. RESULTS Blunt patients had higher injury severity, were older, and had a lower Glasgow Coma Scale. Arrival indices of shock and coagulation parameters were similar across blunt and penetrating injury. The percentage of patients with a prehospital time less than 20 minutes was significantly higher for penetrating patients relative to blunt injured patients (28.0% vs. 11.6%, p < 0.01). Stratified Kaplan-Meier curves demonstrated a significant separation for blunt injured patients (n = 465, p = 0.01) with no separation demonstrated for penetrating injured patients (n = 161, p = 0.60) Stratified Cox hazard regression verified, after controlling for all important confounders, that prehospital plasma was associated with a 32% lower independent hazard for 28-day mortality in blunt injured patients (hazard ratio, 0.68; 95% confidence interval, 0.47-0.96; p = 0.03) with no independent survival benefit found in penetrating patients (hazard ratio, 1.16; 95% confidence interval, 0.4-3.1; p = 0.78). CONCLUSION A survival benefit associated with prehospital plasma at 24 hours and 28 days exists primarily in blunt injured patients with no benefit shown in penetrating trauma patients. No detrimental effects attributable to plasma are demonstrated in penetrating injury. These results have important relevance to military and civilian trauma systems. LEVEL OF EVIDENCE Therapeutic, I.