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Background: Serial neurological examinations (NEs) are routinely recommended in the intensive care unit (ICU) within the first 24 hours following a traumatic brain injury (TBI). There are currently no widely accepted guidelines for the frequency of NEs. Disruptions to the sleep-wake cycles increase the delirium rate. We aimed to evaluate whether there is a correlation between prolonged hourly (Q1)-NE and development of delirium and to determine if this practice reduces the likelihood of missing the detection of a process requiring emergent intervention., Methods: A retrospective analysis of patients with mild/moderate TBI, admitted to the ICU with serial NEs, was performed. Cohorts were stratified by the duration of exposure to Q1-NE, into prolonged (≥24 hours) and nonprolonged (<24 hours). Our primary outcomes of interest were delirium, evaluated using the Confusion Assessment Method; radiological progression from baseline images; neurological deterioration (focal neurological deficit, abnormal pupillary examination, or Glasgow Coma Scale score decrease >2); and neurosurgical procedures., Results: A total of 522 patients were included. No significant differences were found in demographics. Patients in the prolonged Q1-NE group (26.1%) had higher Injury Severity Score with similar head Abbreviated Injury Score, significantly higher delirium rate (59% vs. 35%, p < 0.001), and a longer hospital/ICU length of stay when compared with the nonprolonged Q1-NE group. No neurosurgical interventions were found to be performed emergently as a result of findings on NEs. Multivariate analysis demonstrated that prolonged Q1-NE was the only independent risk factor associated with a 2.5-fold increase in delirium rate. The number needed to harm for prolonged Q1-NE was 4., Conclusion: Geriatric patients with mild/moderate TBI exposed to Q1-NE for periods longer than 24 hours had nearly a threefold increase in ICU delirium rate. One of five patients exposed to prolonged Q1-NE is harmed by the development of delirium. No patients were found to directly benefit as a result of more frequent NEs., Level of Evidence: Prognostic and Epidemiological; Level IV., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Evidence suggests that variation in light exposure strongly influences the dynamic of inflammation, coagulation, and the immune system. Multiple injuries induce systemic inflammation that can lead to end-organ injury. Here, we hypothesize that alterations in light exposure influence posttrauma inflammation, coagulopathy, and end-organ injury., Methods: C57BL/6 mice underwent a validated multiple-injury and hemorrhage model performed following 72 hours of exposure to red (617 nm, 1,700 lux), blue (321 nm, 1,700 lux), and fluorescent white light (300 lux) (n = 6-8/group). The animals were sacrificed at 6 hours posttrauma. Plasma samples were evaluated and compared for proinflammatory cytokine expression levels, coagulation parameters, markers of liver and renal injury, and histological changes (Carstairs staining). One-way analysis of variance statistical tests were applied to compare study groups., Results: Preexposure to long-wavelength red light significantly reduced the inflammatory response at 6 hours after multiple injuries compared with blue and ambient light, as evidenced by decreased levels of interleukin 6, monocyte chemoattractant protein-1 (both p < 0.001), liver injury markers (alanine transaminase, p < 0.05), and kidney injury markers (cystatin C, p < 0.01). In addition, Carstairs staining of organ tissues revealed milder histological changes in the red light-exposed group, indicating reduced end-organ damage. Furthermore, prothrombin time was significantly lower ( p < 0.001), and fibrinogen levels were better maintained ( p < 0.01) in the red light-exposed mice compared with those exposed to blue and ambient light., Conclusion: Prophylactic light exposure can be optimized to reduce systemic inflammation and coagulopathy and minimize acute organ injury following multiple injuries. Understanding the mechanisms by which light exposure attenuates inflammation may provide a novel strategy to reducing trauma-related morbidity., (Copyright © 2023 American Association for the Surgery of Trauma.)

Background: We sought to explore the impact of sex, race, and insurance status on operative management of incisional hernias., Methods: A retrospective cohort study was conducted to explore adult patients diagnosed with an incisional hernia. Adjusted odds for non-operative versus operative management and time to repair were queried., Results: Of the 29,475 patients with an incisional hernia, 20,767 (70.5%) underwent non-operative management. In relation to private insurance, Medicaid (aOR 1.40, 95% CI 1.27-1.54), Medicare (aOR 1.53, 95% CI 1.42-1.65), and uninsured status (aOR 1.99, 95% CI 1.71-2.36) were independently associated with non-operative management. African American race (aOR 1.30, 95% CI 1.17-1.47) was associated with non-operative management while female sex (aOR 0.81, 95% CI 0.77-0.86) was predictive of elective repair. For patients who underwent elective repair, both Medicare (aOR 1.40, 95% CI 1.18-1.66) and Medicaid (aOR 1.49, 95% CI 1.29-1.71) insurance, but not race, were predictive of delayed repair (>90 days after diagnosis)., Conclusions: Sex, race, and insurance status influence incisional hernia management. Development of evidence-based management guidelines may help to ensure equitable care., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: Diversity in the physician workforce improves patient-centred outcomes. Patients are more likely to trust in and comply with care when seeing gender/racially concordant providers. A current emphasis on standardised metrics in academic achievement often serves as a barrier to the recruitment and retention of gender and racial minorities in medicine. Holistic review of residency applicants has been supported as a means of encouraging diversification but is not yet standardised. The current body of evidence examining the effects of holistic review on the recruitment of racial and gender minorities in surgical residencies is small. We therefore propose a systematic review to summarise the state of holistic review in graduate medical education in the USA and its impact on diversification., Methods and Analysis: Our systematic review protocol has been designed with plans to report our review findings in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols guidelines. PubMed and Embase will be searched with the assistance of a health sciences librarian with expertise in systematic review. We will include studies of graduate medical education programmes that describe the implementation of holistic review, outline the components of their holistic review process and compare proportions of under-represented minorities (URM) and women interviewed and matriculating before and after holistic review implementation. We will first report a summary of the findings regarding the operationalisation of holistic review as described by studies included. We will then pool the percentages of URM and women for interviewee and matriculant populations from each study and report the collective odds ratios of each for holistic review compared with traditional review as our primary outcome., Ethics and Dissemination: This study is a protocol for systematic review, and therefore does not involve any human subjects. Findings will be published in the form of a manuscript submitted to a peer-reviewed journal., Prospero Registration Number: CRD42023401389., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Necrotizing soft tissue infections (NSTIs) are life-threatening infections. The aim of this study is to evaluate the safety of clindamycin plus vancomycin versus linezolid as empiric treatment of NSTIs., Methods: This was a retrospective, single-center, quasi-experimental study of patients admitted from 1 June 2018 to 30 June 2019 (preintervention) and 1 May 2020 to 15 October 2021 (postintervention). Patients who received surgical management within 24 hours of NSTI diagnosis and at least 1 dose of linezolid or clindamycin were included. The primary endpoint was death at 30 days. The secondary outcomes included rates of acute kidney injury (AKI) and Clostridioides difficile infection (CDI)., Results: A total of 274 patients were identified by admission diagnosis code for NSTI or Fournier gangrene; 164 patients met the inclusion criteria. Sixty-two matched pairs were evaluated. There was no difference in rates of 30-day mortality (8.06% vs 6.45%; hazard ratio [HR], 1.67 [95% confidence interval {CI}, .32-10.73]; P = .65). There was no difference in CDI (6.45% vs 1.61%; HR, Infinite [Inf], [95% CI, .66-Inf]; P = .07) but more AKI in the preintervention group (9.68% vs 1.61%; HR, 6 [95% CI, .73-276]; P = .05)., Conclusions: In this small, retrospective, single-center, quasi-experimental study, there was no difference in 30-day mortality in patients receiving treatment with clindamycin plus vancomycin versus linezolid in combination with standard gram-negative and anaerobic therapy and surgical debridement for the treatment of NSTIs. A composite outcome of death, AKI, or CDI within 30 days was more common in the clindamycin plus vancomycin group., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Study of telemedicine and telerounding in surgical specialties is limited. The push for telemedicine during the COVID-19 pandemic has challenged the face-to-face rounding paradigm and creates an opportunity for reflection on the benefits of telemedicine, especially for balancing competing corporate and clinical demands., Methods: The 117-month video-based inpatient telerounding experience of a colorectal surgeon in an academic medical system was recorded, including patient characteristics, diagnoses, technology, content of telerounding encounters, and logistical considerations. Data were analyzed using descriptive statistics., Results: 163 patients were seen in 201 telerounding encounters, primarily for routine postoperative care (90.5%). Most were admitted for inflammatory bowel disease (63.2%). Changes were made to plans of care during 28.9% of encounters, and discharge planning was part of 26.4%. Encounters were conducted primarily from the surgeon's administrative office (68.7%) or other work-related locations (10.9%), while 6.5% originated from the surgeon's home. Technologic issues occurred in 5.5% of encounters. 89.1% of patient feedback was positive and none was negative., Conclusion: Telerounding is technologically feasible and has clinical value, including for patients with complex surgical problems. Technologic problems are rare and patient satisfaction is high. Surgeons should consider telerounding as a means to balance competing demands.

Objective: Holistic review, which emphasizes qualitative attributes over objective measures, has been proposed as a method for selecting candidates for surgical residency in order to improve diversity in graduate medical education, and, ultimately, the field of surgery. This study seeks to articulate desirable traits of applicants as a first-step in standardizing the holistic review process., Design: Using Group Concept Mapping, a web-based mixed-methods participatory research methodology, residency selection committee members were asked to 1) list desirable characteristics of applicants, 2) group these into categories, 3) rate their importance to academic/clinical success on a 5-point Likert scale (1 = not at all important, 5 = extremely important), and 4) rate the degree to which each characteristic is feasible to assess on a 3-point Likert scale (1 = not at all feasible, 3 = very feasible). Grouped characteristics submitted to hierarchical cluster analysis depicted committee's consensus about desirable qualities/criteria for applicants. Bivariate scatter-plots and pattern-matching graphics demonstrated which of these criteria were most important and reliably assessed., Setting: A single academic general surgery residency training program in Western Pennsylvania., Participants: Members of the selection committee for the UPMC General Surgery Residency program who had participated in at least 1 prior cycle of applicant selection., Results: Desirable characteristics of highly qualified applicants into an academic general surgery residency were clustered into domains of 1) scholarly work and research, 2) grades/formal assessments, 3) program fit, 4) behavioral assets, and 5) aspiration. Behavioral assets, which was felt to be the most important to clinical and academic success were considered to be the least feasible to reliably assess. Within this domain, initiative, being self-motivated, intellectual curiosity, work ethic, communication skills, maturity and self-awareness, and thoughtfulness were viewed as most frequently reliably assessed from the application and interview process., Conclusions: High quality applicants possess several behavioral assets that faculty deem are important to academic and clinical success. Adapting validated metrics for assessing these assets, may provide a solution for addressing subjectivity and other challenges scrutinized by critics of holistic review., Competing Interests: Conflict of Interest Disclosures No authors report disclosures, conflict of interest or relevant financial interests related to the content of the manuscript., (Copyright © 2022. Published by Elsevier Inc.)

Introduction: Unlike antibiotic and perfusion support, guidelines for sepsis source control lack high-quality evidence and are ungraded. Internally valid administrative data methods are needed to identify cases representing source control procedures to evaluate outcomes., Methods: Over five modified Delphi rounds, two independent reviewers identified Current Procedural Terminology (CPT) codes pertinent to source control. In each round, codes with perfect agreement were retained or excluded, whereas disagreements were reviewed by the panelists. Manual review of 400 patient records meeting Sepsis-3 criteria (2010-2017) clinically adjudicated which encounters included source control procedures (gold standard). The performance of consensus codes was compared with the gold standard to assess sensitivity, specificity, predictive values, and likelihood ratios., Results: Of 5752 CPT codes, 609 consensus codes represented source control procedures. Of 400 hospitalizations for sepsis, 39 (9.8%; 95% confidence interval [CI] 7.0%-13.1%) underwent gold standard source control procedures and 29 (7.3%; 95% CI 4.9-10.3%) consensus code-defined source control procedures. Thirty consensus codes were identified (20.0% gastrointestinal/intraabdominal, 10.0% genitourinary, 13.3% hepatopancreatobiliary, 23.3% orthopedic/cranial, 23.3% soft tissue, and 10.0% intrathoracic), which had 61.5% (95% CI 44.6%-76.6%) sensitivity, 98.6% (95% CI 96.8%-99.6%) specificity, 83.2% (95% CI 66.6%-92.4%) positive, and 95.9% (95% CI 93.9%-97.2%) negative predictive values. With pretest probability at sample prevalence, an identified consensus code had a posttest probability of 83.0% (95% CI 66.0%-92.0%), whereas consensus code absence had a probability of 4.0% (95% CI 3.0-6.0) for undergoing a source control procedure., Conclusions: Using modified Delphi methodology, we created and validated CPT codes identifying source control procedures, providing a framework for evaluation of the surgical care of patients with sepsis., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Rationale: Extremity threat and amputation after sepsis is a well-publicized and devastating event. However, there is a paucity of data about the epidemiology of extremity threat after sepsis onset. Objectives: To estimate the incidence of extremity threat with or without surgical amputation in community sepsis. Methods: Retrospective cohort study of adults with Sepsis-3 hospitalized at 14 academic and community sites from 2013 to 2017. Vasopressor-dependent sepsis was identified by administration of epinephrine, norepinephrine, phenylephrine, vasopressin, or dopamine for more than 1 hour during the 48 hours before to 24 hours after sepsis onset. Outcomes included the incidence of extremity threat, defined as acute onset ischemia, with or without amputation, in the 90 days after sepsis onset. The association between extremity threat, demographics, comorbid conditions, and time-varying sepsis treatments was evaluated using a Cox proportional hazards model. Results: Among 24,365 adults with sepsis, 12,060 (54%) were vasopressor dependent (mean ± standard deviation age, 64 ± 16 years; male, 6,548 [54%]; sequential organ failure assessment [SOFA], 10 ± 4). Of these, 231 (2%) patients had a threatened extremity with 26 undergoing 37 amputations, a risk of 2.2 (95% confidence interval [CI], 1.4-3.2) per 1,000, and 205 not undergoing amputation, a risk of 17.0 (95% CI, 14.8-19.5) per 1,000. Most amputations occurred in lower extremities (95%), a median (interquartile range) of 16 (6-40) days after sepsis onset. Compared with patients with no extremity threat, patients with threat had a higher SOFA score (11 ± 4 vs. 10 ± 4; P  < 0.001), serum lactate (4.6 mmol/L [2.4-8.7] vs. 3.1 [1.7-6.0]; P  < 0.001), and more bacteremia ( n  = 37 [37%] vs. n  = 2,087 [26%]; P  < 0.001) at sepsis onset. Peripheral vascular disease, congestive heart failure, SOFA score, and norepinephrine equivalents were significantly associated with extremity threat. Conclusions: The evaluation of a threatened extremity resulting in surgical amputation occurred in 2 per 1,000 patients with vasopressor-dependent sepsis.

Objective: The aim of the study was to quantify the risk of incarceration of incisional hernias., Background: Operative repair is the definitive treatment for incisional ventral hernias but is often deferred if the perceived risk of elective operation is elevated secondary to comorbid conditions. The risk of incarceration during nonoperative management (NOM) factors into shared decision making by patient and surgeon; however, the incidence of acute incarceration remains largely unknown., Methods: A retrospective analysis of adult patients with an International Classification of Diseases, Ninth Revision or Tenth Revision diagnosis of incisional hernia was conducted from 2010 to 2017 in 15 hospitals of a single healthcare system. The primary outcome was incarceration necessitating emergent operation. The secondary outcome was 30-, 90-, and 365-day mortality. Univariate and multivariate analyses were used to determine independent predictors of incarceration., Results: Among 30,998 patients with an incisional hernia (mean age 58.1 ± 15.9 years; 52.7% female), 23,022 (78.1%) underwent NOM of whom 540 (2.3%) experienced incarceration, yielding a 1- and 5-year cumulative incidence of 1.24% and 2.59%, respectively. Independent variables associated with incarceration included: age older than 40 years, female sex, current smoker, body mass index 30 or greater, and a hernia-related inpatient admission. All-cause mortality rates at 30, 90, and 365 days were significantly higher in the incarceration group at 7.2%, 10%, and 14% versus 1.1%, 2.3%, and 5.3% in patients undergoing successful NOM, respectively., Conclusions: Incarceration is an uncommon complication of NOM but is associated with a significant risk of death. Tailored decision making for elective repair and considering the aforementioned risk factors for incarceration provides an initial step toward mitigating the excess morbidity and mortality of an incarceration event., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Severely injured patients are at particularly high risk for venous thromboembolism (VTE). Although thromboprophylaxis (PPX) is employed during the inpatient period, patients may continue to be at high risk after discharge. Comparative evidence from surgical subspecialities (eg oncology) reveals benefits of postdischarge (ie extended) PPX. We hypothesized that an extended, postinjury oral thromboprophylaxis regimen would be cost-effective., Study Design: A cost-utility model compared no PPX with a 30-day course of apixaban, dabigatran, enoxaparin, fondaparinux, or rivaroxaban in trauma patients. Immediate events including deep venous thrombosis, pulmonary embolus, or bleeding within 30 days of injury were modeled in a decision tree with patients entering a Markov process to account for sequelae of VTE, including postthrombotic syndrome and chronic thromboembolic pulmonary hypertension. Effectiveness was measured in quality-adjusted life years. One-way and probabilistic sensitivity analyses were performed to identify conditions under which the preferred PPX strategy changed., Results: Rivaroxaban was the dominant strategy (ie less costly and more effective) compared with no PPX or alternative regimens, delivering 30.21 quality-adjusted life years for $404,546.38. One-way sensitivity analyses demonstrated robust preference for rivaroxaban. When examining only patients with moderate-high or high VTE Risk Assessment Profile scores, rivaroxaban remained the preferred strategy. Probabilistic sensitivity analysis demonstrated a preference for rivaroxaban in 100% of cases at a standard willingness-to-pay threshold of $100,000/quality-adjusted life year., Conclusions: A 30-day course of rivaroxaban is a cost-effective extended thromboprophylaxis strategy in trauma patients in this theoretical study. Prospective studies of postdischarge thromboprophylaxis to prevent postinjury VTE are warranted., (Copyright © 2022 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background: Under-triage in trauma remains prevalent, in part because of decisions made by physicians at non-trauma centers. We developed two digital behavior change interventions to recalibrate physician heuristics (pattern recognition), and randomized 688 emergency medicine physicians to use the interventions or to a control. In this observational follow-up, we evaluated whether exposure to the interventions changed physician performance in practice., Methods: We obtained 2016 - 2018 Medicare claims for severely injured patients, linked the names of trial participants to National Provider Identifiers (NPIs), and identified claims filed by trial participants for injured patients presenting to non-trauma centers in the year before and after their trial. The primary outcome measure was the triage status of severely injured patients., Results: We linked 670 (97%) participants to NPIs, identified claims filed for severely injured patients by 520 (76%) participants, and claims filed at non-trauma centers by 228 (33%). Most participants were white (64%), male (67%), and had more than three years of experience (91%). Patients had a median Injury Severity Score of 16 (IQR 16 - 17), and primarily sustained neuro-trauma. After adjustment, patients treated by physicians randomized to the interventions experienced less under-triage in the year after the trial than before (41% versus 58% [-17%], P = 0.015); patients treated by physicians randomized to the control experienced no difference in under-triage (49% versus 56% [-7%], P = 0.35). The difference-in-the-difference was non-significant (10%, P = 0.18)., Conclusions: It was feasible to track trial participants' performance in national claims. Sample size limitations constrained causal inference about the effect of the interventions., Competing Interests: Conflict of Interest DM, CCC, BF, MRR, DCA, DMY, AEB report no conflict of interest., (Copyright © 2021. Published by Elsevier Inc.)

Background: 30% of elderly patients who require emergency general surgery (EGS) die in the year after the operation. Preoperative discussions can determine whether patients receive preference-sensitive care. Theoretically, surgeons frame their conversations after systematically assessing the risks and benefits of management options based on the clinical characteristics of each case. However, little is known about how surgeons actually deliberate about those options., Objective: To identify variables that influence surgeons' assessment of management options for critically-ill EGS patients., Methods: We conducted semi-structured interviews with 40 general surgeons in western Pennsylvania who worked in a variety of hospital settings. Interviews explored perioperative decision-making by asking surgeons to think aloud about selected memorable cases and a standardized case vignette of a frail patient with acute mesenteric ischemia. We used constant comparative methods to analyze interview transcripts and inductively developed a framework for the decision-making process., Results: Surgeons averaged 13 years (standard deviation (SD) 10.4) of experience; 40% specialized in trauma/acute care surgery. Important themes regarding the main topic of "perioperative decision-making" included many considerations beyond the clinical characteristics of cases. Surgeons described the importance of variables ranging from the availability of institutional resources to professional norms. Surgeons often remarked on their desire to achieve individual flow, team efficiency, and concordant expectations of treatment and prognosis with patients., Conclusions: This is the first study to explore how surgeons decide among management options for critically-ill EGS patients. Surgeons' decision-making reflected a broad array of clinical, personal, and institutional variables. Effective interventions to ensure preference-sensitive care for EGS patients must address all of these variables., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Professional burnout represents a significant threat to the American healthcare system. Organizational and individual factors may increase healthcare providers' susceptibility or resistance to burnout. We hypothesized that during the COVID-19 pandemic, 1) higher levels of perceived organizational support (POS) are associated with lower risk for burnout and anxiety, and 2) anxiety mediates the association between POS and burnout., Methods: In this longitudinal prospective study, we surveyed healthcare providers employed full-time at a large, multihospital healthcare system monthly over 6 months (April to November 2020). Participants were randomized using a 1:1 allocation stratified by provider type, gender, and academic hospital status to receive one of two versions of the survey instrument formulated with different ordering of the measures to minimize response bias due to context effects. The exposure of interest was POS measured using the validated 8-item Survey of POS (SPOS) scale. Primary outcomes of interest were anxiety and risk for burnout as measured by the validated 10-item Burnout scale from the Professional Quality (Pro-QOL) instrument and 4-item Emotional Distress-Anxiety short form of the Patient Reported Outcome Measurement Information System (PROMIS) scale, respectively. Linear mixed models evaluated the associations between POS and both burnout and anxiety. A mediation analysis evaluated whether anxiety mediated the POS-burnout association., Results: Of the 538 participants recruited, 402 (75%) were included in the primary analysis. 55% of participants were physicians, 73% 25-44 years of age, 73% female, 83% White, and 44% had ≥1 dependent. Higher POS was significantly associated with a lower risk for burnout (-0.23; 95% CI -0.26, -0.21; p<0.001) and lower degree of anxiety (-0.07; 95% CI -0.09, -0.06; p = 0.010). Anxiety mediated the associated between POS and burnout (direct effect -0.17; 95% CI -0.21, -0.13; p<0.001; total effect -0.23; 95% CI -0.28, -0.19; p<0.001)., Conclusion: During a health crisis, increasing the organizational support perceived by healthcare employees may reduce the risk for burnout through a reduction in anxiety. Improving the relationship between healthcare organizations and the individuals they employ may reduce detrimental effects of psychological distress among healthcare providers and ultimately improve patient care., Competing Interests: No author have competing interests.

Background: Emergency general surgery conditions are common, require urgent surgical evaluation, and are associated with high mortality and costs. Although appropriate interhospital transfers are critical to successful emergency general surgery care, the performance of emergency general surgery transfer systems remains unclear. We aimed to describe emergency general surgery transfer patterns and identify factors associated with potentially avoidable transfers., Methods: We performed a retrospective cohort study of emergency general surgery episodes in 8 US states using the 2016 Healthcare Cost and Utilization Project State Inpatient and Emergency Department Databases and the American Hospital Association Annual Surveys. We identified Emergency Department-to-Inpatient and Inpatient-to-Inpatient interhospital emergency general surgery transfers. Potentially avoidable transfers were defined as discharge within 72 hours after transfer without undergoing any procedure or operation at the destination hospital. We examined transfer incidence and characteristics. We performed multilevel regression examining patient-level and hospital-level factors associated with potentially avoidable transfers., Results: Of 514,410 adult emergency general surgery episodes, 26,281 (5.1%) involved interhospital transfers (Emergency Department-to-Inpatient: 65.0%, Inpatient-to-Inpatient: 35.1%). Over 1 in 4 transfers were potentially avoidable (7,188, 27.4%), with the majority occurring from the emergency department. Factors associated with increased odds of potentially avoidable transfers included self-pay (versus government insurance, odds ratio: 1.26, 95% confidence interval: 1.09-1.45, P = .002), level 1 trauma centers (versus non-trauma centers, odds ratio: 1.24, 95% confidence interval: 1.05-1.47, P = .01), and critical access hospitals (versus non-critical access, odds ratio: 1.30, 95% confidence interval: 1.15-1.47, P < .001). Hospital-level factors (size, trauma center, ownership, critical access, location) accounted for 36.1% of potentially avoidable transfers variability., Conclusion: Over 1 in 4 emergency general surgery transfers are potentially avoidable. Understanding factors associated with potentially avoidable transfers can guide research, quality improvement, and infrastructure development to optimize emergency general surgery care., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Importance: Although patients with emergency general surgery (EGS) conditions frequently undergo interhospital transfers, the transfer patterns and associated factors are not well understood., Objective: To examine whether patients with EGS conditions are consistently directed to hospitals with more resources and better outcomes., Design, Setting, and Participants: This cohort study performed a network analysis of interhospital transfers among adults with EGS conditions from January 1 to December 31, 2016. The analysis used all-payer claims data from the 2016 Healthcare Cost and Utilization Project state inpatient and emergency department databases in 8 states. A total of 728 hospitals involving 85 415 transfers of 80 307 patients were included. Patients were eligible for inclusion if they were 18 years or older and had an acute care hospital encounter with a diagnosis of an EGS condition as defined by the American Association for the Surgery of Trauma. Data were analyzed from January 1, 2020, to June 17, 2021., Exposures: Hospital-level measures of size (total bed capacity), resources (intensive care unit [ICU] bed capacity, teaching status, trauma center designation, and presence of trauma and/or surgical critical care fellowships), EGS volume (annual EGS encounters), and EGS outcomes (risk-adjusted failure to rescue and in-hospital mortality)., Main Outcomes and Measures: The main outcome was hospital-level centrality ratio, defined as the normalized number of incoming transfers divided by the number of outgoing transfers. A higher centrality ratio indicated more incoming transfers per outgoing transfer. Multivariable regression analysis was used to test the hypothesis that a higher hospital centrality ratio would be associated with more resources, higher volume, and better outcomes., Results: Among 80 307 total patients, the median age was 63 years (interquartile range [IQR], 50-75 years); 52.1% of patients were male and 78.8% were White. The median number of outgoing and incoming transfers per hospital were 106 (IQR, 61-157) and 36 (IQR, 8-137), respectively. A higher log-transformed centrality ratio was associated with more resources, such as higher ICU capacity (eg, >25 beds vs 0-10 beds: β = 1.67 [95% CI, 1.16-2.17]; P < .001), and higher EGS volume (eg, quartile 4 [highest] vs quartile 1 [lowest]: β = 0.78 [95% CI, 0-1.57]; P = .01). However, a higher log-transformed centrality ratio was not associated with better outcomes, such as lower in-hospital mortality (eg, quartile 4 [highest] vs quartile 1 [lowest]: β = 0.30 [95% CI, -0.09 to 0.68]; P = .83) and lower failure to rescue (eg, quartile 4 [highest] vs quartile 1 [lowest]: β = -0.50 [95% CI, -1.13 to 0.12]; P = .27)., Conclusions and Relevance: In this study, EGS transfers were directed to high-volume hospitals with more resources but were not necessarily directed to hospitals with better clinical outcomes. Optimizing transfer destination in the interhospital transfer network has the potential to improve EGS outcomes.

Background: The significance of pneumatosis intestinalis (PI) remains challenging. While certain clinical scenarios are predictive of transmural ischemia, risk models to assess the presence of pathologic PI are needed. The aim of this study was to determine what patient factors at the time of radiographic diagnosis of PI predict the risk for pathologic PI., Methods: We conducted a retrospective cohort study examining patients with PI from 2010 to 2016 at a multicenter hospital network. Multivariate logistic regression was used to develop a predictive model for pathologic PI in a derivation cohort. Using regression-coefficient-based methods, the final multivariate model was converted into a five-factor-based score. Calibration and discrimination of the score were then assessed in a validation cohort., Results: Of 305 patients analyzed, 102 (33.4%) had pathologic PI. We identified five factors associated with pathologic PI at the time of radiographic diagnosis: small bowel PI, age 70 years or older, heart rate 110 bpm or greater, lactate of 2 mmol/L or greater, and neutrophil-lymphocyte ratio 10 or greater. Using this model, patients in the validation cohort were assigned risk scores ranging from 0 to 11. Low-risk patients were categorized when scores are 0 to 4; intermediate, score of 5 to 6; high, score of 7 to 8; and very high risk, 9+. In the validation cohort, very high-risk patients (n = 17; 18.1%) had predicted rates of pathologic pneumatosis of 88.9% and an observed rate of 82.4%. In contrast, patients labeled as low risk (n = 37; 39.4%) had expected rates of pathologic pneumatosis of 1.3% and an observed rate of 0%. The model showed excellent discrimination (area under the curve, 0.90) and good calibration (Hosmer-Lemeshow goodness-of-fit, p = 0.37)., Conclusion: Our score accurately stratifies patient risk of pathologic pneumatosis. This score has the potential to target high-risk individuals for expedient operation and spare low-risk individuals invasive interventions., Level of Evidence: Prognostic Study, Level III., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Macrophages are main effectors of heme metabolism, increasing transiently in the liver during heightened disposal of damaged or senescent RBCs (sRBCs). Macrophages are also essential in defense against microbial threats, but pathological states of heme excess may be immunosuppressive. Herein, we uncovered a mechanism whereby an acute rise in sRBC disposal by macrophages led to an immunosuppressive phenotype after intrapulmonary Klebsiella pneumoniae infection characterized by increased extrapulmonary bacterial proliferation and reduced survival from sepsis in mice. The impaired immunity to K. pneumoniae during heightened sRBC disposal was independent of iron acquisition by bacterial siderophores, in that K. pneumoniae mutants lacking siderophore function recapitulated the findings observed with the WT strain. Rather, sRBC disposal induced a liver transcriptomic profile notable for suppression of Stat1 and IFN-related responses during K. pneumoniae sepsis. Excess heme handling by macrophages recapitulated STAT1 suppression during infection that required synergistic NRF1 and NRF2 activation but was independent of heme oxygenase-1 induction. Whereas iron was dispensable, the porphyrin moiety of heme was sufficient to mediate suppression of STAT1-dependent responses in human and mouse macrophages and promoted liver dissemination of K. pneumoniae in vivo. Thus, cellular heme metabolism dysfunction negatively regulated the STAT1 pathway, with implications in severe infection.

Circadian rhythms regulate adaptive alterations in mammalian physiology and are maximally entrained by the short wavelength blue spectrum; cataracts block the transmission of light, particularly blue light. Cataract surgery is performed with two types of intraocular lenses (IOL): (1) conventional IOL that transmit the entire visible spectrum and (2) blue-light-filtering (BF) IOL that block the short wavelength blue spectrum. We hypothesized that the transmission properties of IOL are associated with long-term survival. This retrospective cohort study of a 15-hospital healthcare system identified 9,108 participants who underwent bilateral cataract surgery; 3,087 were implanted with conventional IOL and 6,021 received BF-IOL. Multivariable Cox proportional hazards models that included several a priori determined subgroup and sensitivity analyses yielded estimates supporting that conventional IOL compared with BF-IOL may be associated with significantly reduced risk of long-term death. Confirming these differences and identifying any potential causal mechanisms await the conduct of appropriately controlled prospective translational trials., Competing Interests: All authors declare no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work; no other relationships or activities that could appear to have influenced the submitted work., (© 2020 The Authors.)

Sepsis and shock states impose mitochondrial stress, and in response, adaptive mechanisms such as fission, fusion and mitophagy are induced to eliminate damaged portions of or entire dysfunctional mitochondria. The mechanisms underlying these events are being elucidated; yet a direct link between loss of mitochondrial membrane potential ΔΨm and the initiation of fission, fusion and mitophagy remains to be well characterized. The direct association between the magnitude of the ΔΨm and the capacity for mitochondria to buffer Ca 2+ renders Ca 2+ uniquely suited as the signal engaging these mechanisms in circumstances of mitochondrial stress that lower the ΔΨm. Herein, we show that the calcium/calmodulin-dependent protein kinase (CaMK) IV mediates an adaptive slowing in oxidative respiration that minimizes oxidative stress in the kidneys of mice subjected to either cecal ligation and puncture (CLP) sepsis or endotoxemia. CaMKIV shifts the balance towards mitochondrial fission and away from fusion by 1) directly phosphorylating an activating Serine616 on the fission protein DRP1 and 2) reducing the expression of the fusion proteins Mfn1/2 and OPA-1. CaMKIV, through its function as a direct PINK1 kinase and regulator of Parkin expression, also enables mitophagy. These data support that CaMKIV serves as a keystone linking mitochondrial stress with the adaptive mechanisms of mitochondrial fission, fusion and mitophagy that mitigate oxidative stress in the kidneys of mice responding to sepsis., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Incisional hernia develops in up to 20% of patients undergoing abdominal operations. We sought to identify characteristics associated with poor outcomes after acute incisional hernia incarceration., Study Design: We performed a retrospective cohort study of adult patients with incisional hernias undergoing elective repair or with acute incarceration between 2010 and 2017. The primary end point was 30-day mortality. Logistic regression was used to determine adjusted odds associated with 30-day mortality. The American College of Surgeons Surgical Risk Calculator was used to estimate outcomes had these patients undergone elective repair., Results: A total of 483 patients experienced acute incarceration; 30-day mortality was 9.52%. Increasing age (adjusted odds ratio 1.05; 95% CI, 1.02 to 1.08) and bowel resection (adjusted odds ratio 3.18; 95% CI, 1.45 to 6.95) were associated with mortality. Among those with acute incarceration, 231 patients (47.9%) had no documentation of an earlier surgical evaluation and 252 (52.2%) had been evaluated but had not undergone elective repair. Among patients 80 years and older, 30-day mortality after emergent repair was high (22.9%) compared with estimated 30-day mortality for elective repair (0.73%), based on the American College of Surgeons Surgical Risk Calculator. Estimated mortality was comparable with observed elective repair mortality (0.82%) in an age-matched cohort. Similar mortality trends were noted for patients younger than 60 years and aged 60 to 79 years., Conclusions: Comparison of predicted elective repair and observed emergent repair mortality in patients with acute incarceration suggests that acceptable outcomes could have been achieved with elective repair. Almost one-half of acute incarceration patients had no earlier surgical evaluation, therefore, targeted interventions to address surgical referral can potentially result in fewer incarceration-related deaths., (Copyright © 2020. Published by Elsevier Inc.)

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 < .002). Patients with severe shock (systolic blood pressure ≤70 mm Hg) who received tranexamic acid demonstrated lower 30-day mortality compared with placebo (18.5% vs 35.5%; difference, -17%; 95% CI, -25.8% to -8.1%; P < .003)., Conclusions and Relevance: In injured patients at risk for hemorrhage, tranexamic acid administered before hospitalization did not result in significantly lower 30-day mortality. The prehospital administration of tranexamic acid after injury did not result in a higher incidence of thrombotic complications or adverse events. Tranexamic acid given to injured patients at risk for hemorrhage in the prehospital setting is safe and associated with survival benefit in specific subgroups of patients., Trial Registration: ClinicalTrials.gov Identifier: NCT02086500.

Importance: Factors contributing to underrepresentation of women in surgery are incompletely understood. Pro-male bias and stereotype threat appear to contribute to gender imbalance in surgery., Objectives: To evaluate the association between pro-male gender bias and career engagement and the effect of stereotype threat on skill performance among trainees in academic surgery., Design, Setting, and Participants: A 2-phase study with a double-blind, randomized clinical trial component was conducted in 3 academic general surgery training programs. Residents were recruited between August 1 and August 15, 2018, and the study was completed at the end of that academic year. In phase 1, surveys administered 5 to 6 months apart investigated the association of gender bias with career engagement. In phase 2, residents were randomized 1:1 using permuted-block design stratified by site, training level, and gender to receive either a trigger of or protection against stereotype threat. Immediately after the interventions, residents completed the Fundamentals of Laparoscopic Surgery (FLS) assessment followed by a final survey. A total of 131 general surgery residents were recruited; of these 96 individuals with academic career interests met eligibility criteria; 86 residents completed phase 1. Eighty-five residents were randomized in phase 2, and 4 residents in each arm were lost to follow-up., Intervention: Residents read abstracts that either reported that women had worse laparoscopic skill performance than men (trigger of stereotype threat [A]) or had no difference in performance (protection against stereotype threat [B])., Main Outcomes and Measures: Association between perception of pro-male gender bias and career engagement survey scores (phase 1) and stereotype threat intervention and FLS scores (phase 2) were the outcomes. Intention-to-treat analysis was conducted., Results: Seventy-seven residents (38 women [49.4%]) completed both phases of the study. The association between pro-male gender bias and career engagement differed by gender (interaction coefficient, -1.19; 95% CI, -1.90 to -0.49; P = .02); higher perception of bias was associated with higher engagement among men (coefficient, 1.02; 95% CI, 0.19-2.24; P = .04), but no significant association was observed among women (coefficient, -0.25; 95% CI, -1.59 to 1.08; P = .50). There was no evidence of a difference in FLS score between interventions (mean [SD], A: 395 [150] vs B: 367 [157]; P = .51). The response to stereotype threat activation was similar in men and women (interaction coefficient, 15.1; 95% CI, -124.5 to 154.7; P = .39). The association between stereotype threat activation and FLS score differed by gender across levels of susceptibility to stereotype threat (interaction coefficient, -35.3; 95% CI, -47.0 to -23.6; P = .006). Higher susceptibility to stereotype threat was associated with lower FLS scores among women who received a stereotype threat trigger (coefficient, -43.4; 95% CI, -48.0 to -38.9; P = .001)., Conclusions and Relevance: Perception of pro-male bias and gender stereotypes may influence career engagement and skill performance, respectively, among surgical trainees., Trial Registration: ClinicalTrials.gov Identifier: NCT03623009.

Importance: Adults with comorbidity have less physiological reserve and an increased rate of postoperative mortality and readmission after the stress of a major surgical intervention., Objective: To assess postoperative mortality and readmission among individuals with diabetes with or without preoperative prescriptions for metformin., Design, Setting, and Participants: This cohort study obtained data from the electronic health record of a multicenter, single health care system in Pennsylvania. Included were adults with diabetes who underwent a major operation with hospital admission from January 1, 2010, to January 1, 2016, at 15 community and academic hospitals within the system. Individuals without a clinical indication for metformin therapy were excluded. Follow-up continued until December 18, 2018., Exposures: Preoperative metformin exposure was defined as 1 or more prescriptions for metformin in the 180 days before the surgical procedure., Main Outcomes and Measures: All-cause postoperative mortality, hospital readmission within 90 days of discharge, and preoperative inflammation measured by the neutrophil to leukocyte ratio were compared between those with and without preoperative prescriptions for metformin. The corresponding absolute risk reduction (ARR) and adjusted hazard ratio (HR) with 95% CI were calculated in a propensity score-matched cohort., Results: Among the 10 088 individuals with diabetes who underwent a major surgical intervention, 5962 (59%) had preoperative metformin prescriptions. A total of 5460 patients were propensity score-matched, among whom the mean (SD) age was 67.7 (12.2) years, and 2866 (53%) were women. In the propensity score-matched cohort, preoperative metformin prescriptions were associated with a reduced hazard for 90-day mortality (adjusted HR, 0.72 [95% CI, 0.55-0.95]; ARR, 1.28% [95% CI, 0.26-2.31]) and hazard of readmission, with mortality as a competing risk at both 30 days (ARR, 2.09% [95% CI, 0.35-3.82]; sub-HR, 0.84 [95% CI, 0.72-0.98]) and 90 days (ARR, 2.78% [95% CI, 0.62-4.95]; sub-HR, 0.86 [95% CI, 0.77-0.97]). Preoperative inflammation was reduced in those with metformin prescriptions compared with those without (mean neutrophil to leukocyte ratio, 4.5 [95% CI, 4.3-4.6] vs 5.0 [95% CI, 4.8-5.3]; P < .001). E-value analysis suggested robustness to unmeasured confounding., Conclusions and Relevance: This study found an association between metformin prescriptions provided to individuals with type 2 diabetes before a major surgical procedure and reduced risk-adjusted mortality and readmission after the operation. This association warrants further investigation.

Background: Platelet transfusion has been utilized to reverse platelet dysfunction in patients on preinjury antiplatelets who have sustained a traumatic intracranial hemorrhage (tICH); however, there is little evidence to substantiate this practice. The objective of this study was to perform a systematic review on the impact of platelet transfusion on survival, hemorrhage progression and need for neurosurgical intervention in patients with tICH on prehospital antiplatelet medication., Methods: Controlled, observational and randomized, prospective and retrospective studies describing tICH, preinjury antiplatelet use, and platelet transfusion reported in PubMed, Embase, Cochrane Reviews, Cochrane Trials and Cochrane DARE databases between January 1987 and March 2019 were included. Investigations of concomitant anticoagulant use were excluded. Risk of bias was assessed using the Newcastle-Ottawa scale. We calculated pooled estimates of relative effect of platelet transfusion on the risk of death, hemorrhage progression and need for neurosurgical intervention using the methods of Dersimonian-Laird random-effects meta-analysis. Sensitivity analysis established whether study size contributed to heterogeneity. Subgroup analyses determined whether antiplatelet type, additional blood products/reversal agents, or platelet function assays impacted effect size using meta-regression., Results: Twelve of 18,609 screened references were applicable to our questions and were qualitatively and quantitatively analyzed. We found no association between platelet transfusion and the risk of death in patients with tICH taking prehospital antiplatelets (odds ratio [OR], 1.29; 95% confidence interval [CI], 0.76-2.18; p = 0.346; I = 32.5%). There was no significant reduction in hemorrhage progression (OR, 0.88; 95% CI, 0.34-2.28; p = 0.788; I = 78.1%). There was no significant reduction in the need for neurosurgical intervention (OR, 1.00; 95% CI, 0.53-1.90, p = 0.996; I = 59.1%; p = 0.032)., Conclusion: Current evidence does not support the use of platelet transfusion in patients with tICH on prehospital antiplatelets, highlighting the need for a prospective evaluation of this practice., Level of Evidence: Systematic Reviews and Meta-Analyses, Level III.

Background: Concern remains over reliable point-of-care testing to guide reversal of rivaroxaban, a commonly used factor Xa inhibitor, in high-acuity settings. Thromboelastography (TEG), a point-of-care viscoelastic assay, may have the ability to detect the anticoagulant effect of rivaroxaban. The authors ascertained the association of apparent rivaroxaban concentration with thromboelastography reaction time, i.e., time elapsed from blood sample placement in analyzer until beginning of clot formation, as measured using TEG and TEG6S instruments (Haemonetics Corporation, USA), hypothesizing that reaction time would correlate to degree of functional factor Xa impairment., Methods: The authors prospectively performed a diagnostic accuracy study comparing coagulation assays to apparent (i.e., indirectly assessed) rivaroxaban concentration in trauma patients with and without preinjury rivaroxaban presenting to a single center between April 2016 and July 2018. Blood samples at admission and after reversal or 24 h postadmission underwent TEG, TEG6S, thrombin generation assay, anti-factor Xa chromogenic assay, prothrombin time (PT), and ecarin chromogenic assay testing. The authors determined correlation of kaolin TEG, TEG6S, and prothrombin time to apparent rivaroxaban concentration. Receiver operating characteristic curve compared capacity to distinguish therapeutic rivaroxaban concentration (i.e., greater than or equal to 50 ng/ml) from nontherapeutic concentrations., Results: Eighty rivaroxaban patients were compared to 20 controls. Significant strong correlations existed between rivaroxaban concentration and TEG reaction time (ρ = 0.67; P < 0.001), TEG6S reaction time (ρ = 0.68; P < 0.001), and prothrombin time (ρ = 0.73; P < 0.001), however reaction time remained within the defined normal range for the assay. Rivaroxaban concentration demonstrated strong but not significant association with coagulation assays postreversal (n = 9; TEG reaction time ρ = 0.62; P = 0.101; TEG6S reaction time ρ = 0.57; P = 0.112) and small nonsignificant association for controls (TEG reaction time: ρ = -0.04; P = 0.845; TEG6S reaction time: ρ = -0.09; P = 0.667; PT-neoplastine: ρ = 0.19; P = 0.301). Rivaroxaban concentration (area under the curve, 0.91) and TEG6S reaction time (area under the curve, 0.84) best predicted therapeutic rivaroxaban concentration and exhibited similar receiver operating characteristic curves (P = 0.180)., Conclusions: Although TEG6S demonstrates significant strong correlation with rivaroxaban concentration, values within normal range limit clinical utility rendering rivaroxaban concentration the gold standard in measuring anticoagulant effect.

The wavelength of light is a critical determinant of light's capacity to entrain adaptive biological mechanisms, such as enhanced immune surveillance, that precede and prepare us for the active circadian day, a time when the risk of encountering pathogen is highest. Light rich in the shorter wavelength visible blue spectrum maximally entrains these circadian rhythms. We hypothesized that exposure to blue light during sepsis will augment immunity and improve outcome. Using a clinically relevant Klebsiella pneumoniae acute lower respiratory tract infection model, we show that blue spectrum light shifts autonomic tone toward parasympathetic predominance and enhances immune competence, as characterized by accelerated pathogen clearance that is accompanied by reduced alveolar neutrophil influx, inflammation, and improved survival. Blue light functioned through an optic-cholinergic pathway and expansion of splenic Ccr2 + monocytes to increase control of the infection and improve survival. The "keystone" mediating these effects is the circadian clock protein Rev-Erbα, and biochemical activation with Rev-Erbα agonist SR9009 enhanced mononuclear cell phagocytosis in vitro and recapitulated the enhanced pathogen elimination in vivo observed with blue light. These findings underscore the potential therapeutic value of blue light and modulating Rev-Erbα to enhance host immunity against infection., (©2019 Society for Leukocyte Biology.)

Importance: Despite evidence that treatment of severely injured patients at trauma centers is associated with reduced mortality, nearly half of all such patients are treated at nontrauma centers (undertriaged). Little is known about whether interfacility undertriage occurs because of practitioner decision-making or institutional and regional factors., Objectives: To assess the associations between variation in triage practitioners at nontrauma centers and between practitioner-level variation and patient outcomes after injury., Design, Setting, and Participants: This retrospective cohort study used Medicare claims data from severely injured patients presenting to nontrauma centers and the practitioners who evaluated them in the emergency department from January 1, 2010, to October 15, 2015. Data analysis was performed from January 15, 2018, to March 21, 2019., Main Outcomes and Measures: Proportion of variation in undertriage associated with practitioners, practitioner rates of undertriage, practitioner characteristics associated with undertriage, and 30-day case-fatality rate., Results: A total of 124 008 severely injured patients (mean [SD] age, 81 [8.4] years; 67 253 [54.2%] female) and the 25 376 practitioners (5564 [21.9%] female) who evaluated the patients in the emergency department of nontrauma centers were included in the study. Undertriage occurred among 85 403 patients (68.9%), with 40.6% of total variation associated with practitioners, 37.8% with hospitals, and 6.7% with regions. Compared with physicians with National Provider Identification (NPI) enumeration before 2007, those with an NPI enumerated between 2007 and 2010 had an undertriage risk ratio (RR) of 0.98 (95% CI, 0.97-0.99), and those with an NPI enumerated after 2010 had an undertriage RR of 0.96 (95% CI, 0.94-0.99). Hospitals with neurosurgeons had an undertriage RR of 1.51 (95% CI, 1.45-1.57) compared with those that did not; hospitals with spine surgeons had an undertriage RR of 1.10 (95% CI, 1.06-1.13); hospitals with general surgeons had an undertriage RR of 1.13 (95% CI, 1.09-1.17). Compared with practitioners who undertriaged 25% or less of patients, a statistically significant increase was found in the odds of death for patients treated by practitioners with a triage rate of less than 25% to 50% (odds ratio [OR], 1.08; 95% CI, 1.05-1.20) and less than 50% to 75% undertriage (OR, 1.12; 95% CI, 1.09-1.26) but not undertriage at greater than 75% (OR, 1.03, 95% CI, 1.00-1.18). In sensitivity analyses to adjust for unmeasured confounding, the association between triage practices and the case fatality rate became monotonic; compared with patients treated by practitioners with an undertriage rate of 25% or less, the odds of case fatality were 1.13 (95% CI, 1.05-1.21; P = .001) among patients treated by practitioners with undertriage rates less than 25% to 50%, 1.22 (95% CI, 1.13-1.32; P < .001) for patients treated by practitioners with undertriage rates less than 50% to 75%, and 1.20 (95% CI, 1.10-1.30; P < .001) for patients treated by practitioners with undertriage rates greater than 75%., Conclusions and Relevance: The findings suggest that individual practitioner practices are an important source of variation in triage and represent a potential locus of intervention to reduce preventable deaths after injury.

Background: Clinical and biologic phenotypes of sepsis are proposed in human studies, yet it is unknown whether prognostic or drug response phenotypes are present in animal models of sepsis. Using a biotelemetry-enhanced, murine cecal ligation and puncture (CLP) model, we determined phenotypes of polymicrobial sepsis prior to physiologic deterioration, and the association between phenotypes and outcome in a randomized trial of prompt or delayed antibiotics and fluids., Methods: We performed a secondary analysis of male C57BL/6J mice in two observational cohorts and two randomized, laboratory animal experimental trials. In cohort 1, mice (n = 118) underwent biotelemetry-enhanced CLP, and we applied latent class mixed models to determine optimal number of phenotypes using clinical data collected between injury and physiologic deterioration. In cohort 2 (N = 73 mice), inflammatory cytokines measured at 24 h after deterioration were explored by phenotype. In a subset of 46 mice enrolled in two trials from cohort 1, we tested the association of phenotypes with the response to immediate (0 h) vs. delayed (2 to 4 h) antibiotics or fluids initiated after physiologic deterioration., Results: Latent class mixture modeling derived a two-class model in cohort 1. Class 2 (N = 97) demonstrated a shorter time to deterioration (mean SD 7.3 (0.9) vs. 9.7 (3.2) h, p < 0.001) and lower heart rate at 7 h after injury (mean (SD) 564 (55) vs. 626 (35) beats per minute, p < 0.001). Overall mortality was similar between phenotypes (p = 0.75). In cohort 2 used for biomarker measurement, class 2 mice had greater plasma concentrations of IL6 and IL10 at 24 h after CLP (p = 0.05). In pilot randomized trials, the effects of sepsis treatment (immediate vs. delayed antibiotics) differed by phenotype (p = 0.03), with immediate treatment associated with greater survival in class 2 mice only. Similar differential treatment effect by class was observed in the trial of immediate vs. delayed fluids (p = 0.02)., Conclusions: We identified two sepsis phenotypes in a murine cecal ligation and puncture model, one of which is characterized by faster deterioration and more severe inflammation. Response to treatment in a randomized trial of immediate versus delayed antibiotics and fluids differed on the basis of phenotype.

Animal studies suggest that the time of day is a determinant of the immunological response to both injury and infection. We hypothesized that due to this diurnal variation, time of injury could affect the systemic inflammatory response and outcomes post-trauma and tested this hypothesis by examining the dynamics of circulating inflammatory mediators in blunt trauma patients injured during daytime vs. nighttime. From a cohort of 472 blunt trauma survivors, two stringently matched sub-cohorts of moderately/severely injured patients [injury severity score (ISS) >20] were identified. Fifteen propensity-matched, daytime-inured ("mDay") patients (age 43.6 ± 5.2, M/F 11/4, ISS 22.9 ± 0.7) presented during the shortest local annual period (8:00 am-5:00 pm), and 15 propensity-matched "mNight" patients (age 43 ± 4.3, M/F 11/4, ISS 24.5 ± 2.5) presented during the shortest night period (10:00 pm-5:00 am). Serial blood samples were obtained (3 samples within the first 24 h and daily from days 1-7) from all patients. Thirty-two plasma inflammatory mediators were assayed. Two-way Analysis of Variance (ANOVA) was used to compare groups. Dynamic Network Analysis (DyNA) and Dynamic Bayesian Network (DyBN) inference were utilized to infer dynamic interrelationships among inflammatory mediators. Both total hospital and intensive care unit length of stay were significantly prolonged in the mNight group. Circulating IL-17A was elevated significantly in the mNight group from 24 h to 7 days post-injury. Circulating MIP-1α, IL-7, IL-15, GM-CSF, and sST2 were elevated in the mDay group. DyNA demonstrated elevated network complexity in the mNight vs. the mDay group. DyBN suggested that cortisol and sST2 were central nodes upstream of TGF-β1, chemokines, and Th17/protective mediators in both groups, with IL-6 being an additional downstream node in the mNight group only. Our results suggest that time of injury affects clinical outcomes in severely injured patients in a manner associated with an altered systemic inflammation program, possibly implying a role for diurnal or circadian variation in the response to traumatic injury., (Copyright © 2019 Zaaqoq, Namas, Abdul-Malak, Almahmoud, Barclay, Yin, Zamora, Rosengart, Billiar and Vodovotz.)