The Risk of Incarceration During Nonoperative Management of Incisional Hernias: A Population-based Analysis of 30,998 Patients.

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 ±â€Š15.9 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.

Consensus Current Procedural Terminology Code Definition of Source Control for Sepsis.

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.

Rationale and design of the Kidney Precision Medicine Project.

Chronic kidney disease (CKD) and acute kidney injury (AKI) are common, heterogeneous, and morbid diseases. Mechanistic characterization of CKD and AKI in patients may facilitate a precision-medicine approach to prevention, diagnosis, and treatment. The Kidney Precision Medicine Project aims to ethically and safely obtain kidney biopsies from participants with CKD or AKI, create a reference kidney atlas, and characterize disease subgroups to stratify patients based on molecular features of disease, clinical characteristics, and associated outcomes. An additional aim is to identify critical cells, pathways, and targets for novel therapies and preventive strategies. This project is a multicenter prospective cohort study of adults with CKD or AKI who undergo a protocol kidney biopsy for research purposes. This investigation focuses on kidney diseases that are most prevalent and therefore substantially burden the public health, including CKD attributed to diabetes or hypertension and AKI attributed to ischemic and toxic injuries. Reference kidney tissues (for example, living-donor kidney biopsies) will also be evaluated. Traditional and digital pathology will be combined with transcriptomic, proteomic, and metabolomic analysis of the kidney tissue as well as deep clinical phenotyping for supervised and unsupervised subgroup analysis and systems biology analysis. Participants will be followed prospectively for 10 years to ascertain clinical outcomes. Cell types, locations, and functions will be characterized in health and disease in an open, searchable, online kidney tissue atlas. All data from the Kidney Precision Medicine Project will be made readily available for broad use by scientists, clinicians, and patients.

Inner Deliberations of Surgeons Treating Critically-ill Emergency General Surgery Patients: A Qualitative Analysis.

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.

Prehospital Plasma during Air Medical Transport in Trauma Patients at Risk for Hemorrhagic Shock.

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 reduce the risk of downstream complications from hemorrhage and shock. Data from large clinical trials are lacking to show either the efficacy or the risks associated with plasma transfusion in the prehospital setting. METHODS: To determine the efficacy and safety of prehospital administration of thawed plasma in injured patients who are at risk for hemorrhagic shock, we conducted a pragmatic, multicenter, cluster-randomized, phase 3 superiority trial that compared the administration of thawed plasma with standard-care resuscitation during air medical transport. The primary outcome was mortality at 30 days. RESULTS: A total of 501 patients were evaluated: 230 patients received plasma (plasma group) and 271 received standard-care resuscitation (standard-care group). Mortality at 30 days was significantly lower in the plasma group than in the standard-care group (23.2% vs. 33.0%; difference, -9.8 percentage points; 95% confidence interval, -18.6 to -1.0%; P=0.03). A similar treatment effect was observed across nine prespecified subgroups (heterogeneity chi-square test, 12.21; P=0.79). Kaplan-Meier curves showed an early separation of the two treatment groups that began 3 hours after randomization and persisted until 30 days after randomization (log-rank chi-square test, 5.70; P=0.02). The median prothrombin-time ratio was lower in the plasma group than in the standard-care group (1.2 [interquartile range, 1.1 to 1.4] vs. 1.3 [interquartile range, 1.1 to 1.6], P<0.001) after the patients' arrival at the trauma center. No significant differences between the two groups were noted with respect to multiorgan failure, acute lung injury-acute respiratory distress syndrome, nosocomial infections, or allergic or transfusion-related reactions. CONCLUSIONS: In injured patients at risk for hemorrhagic shock, the prehospital administration of thawed plasma was safe and resulted in lower 30-day mortality and a lower median prothrombin-time ratio than standard-care resuscitation. (Funded by the U.S. Army Medical Research and Materiel Command; PAMPer ClinicalTrials.gov number, NCT01818427 .).

Outcomes after a Digital Behavior Change Intervention to Improve Trauma Triage: An Analysis of Medicare Claims.

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.

Serious games may improve physician heuristics in trauma triage.

Trauma triage depends on fallible human judgment. We created two "serious" video game training interventions to improve that judgment. The interventions' central theoretical construct was the representativeness heuristic, which, in trauma triage, would mean judging the severity of an injury by how well it captures (or "represents") the key features of archetypes of cases requiring transfer to a trauma center. Drawing on clinical experience, medical records, and an expert panel, we identified features characteristic of representative and nonrepresentative cases. The two interventions instantiated both kinds of cases. One was an adventure game, seeking narrative engagement; the second was a puzzle-based game, emphasizing analogical reasoning. Both incorporated feedback on diagnostic errors, explaining their sources and consequences. In a four-arm study, they were compared with an intervention using traditional text-based continuing medical education materials (active control) and a no-intervention (passive control) condition. A sample of 320 physicians working at nontrauma centers in the United States was recruited and randomized to a study arm. The primary outcome was performance on a validated virtual simulation, measured as the proportion of undertriaged patients, defined as ones who had severe injuries (according to American College of Surgeons guidelines) but were not transferred. Compared with the control group, physicians exposed to either game undertriaged fewer such patients [difference = -18%, 95% CI: -30 to -6%, P = 0.002 (adventure game); -17%, 95% CI: -28 to -6%, P = 0.003 (puzzle game)]; those exposed to the text-based education undertriaged similar proportions (difference = +8%, 95% CI: -3 to +19%, P = 0.15).

Calcium/calmodulin-dependent protein kinase IV (CaMKIV) activation contributes to the pathogenesis of experimental colitis via inhibition of intestinal epithelial cell proliferation.

The incidence and prevalence of inflammatory bowel disease (IBD) are increasing worldwide. IBD is known to be multifactorial, but inflammatory signaling within the intestinal epithelium and a subsequent failure of the intestinal epithelial barrier have been shown to play essential roles in disease pathogenesis. CaMKIV is a multifunctional protein kinase associated with inflammation and cell cycle regulation. CaMKIV has been extensively studied in autoimmune diseases, but a role in idiopathic intestinal inflammation has not been described. In this study, active CaMKIV was highly expressed within the intestinal epithelium of humans with ulcerative colitis and wild-type (WT) mice with experimental induced colitis. Clinical disease severity directly correlates with CaMKIV activation, as does expression of proinflammatory cytokines and histologic features of colitis. In WT mice, CaMKIV activation is associated with increases in expression of 2 cell cycle proarrest signals: p53 and p21. Cell cycle arrest inhibits proliferation of the intestinal epithelium and ultimately results in compromised intestinal epithelial barrier integrity, further perpetuating intestinal inflammation during experimental colitis. Using a CaMKIV null mutant mouse, we demonstrate that a loss of CaMKIV protects against murine DSS colitis. Small molecules targeting CaMKIV activation may provide therapeutic benefit for patients with IBD.-Cunningham, K. E., Novak, E. A., Vincent, G., Siow, V. S., Griffith, B. D., Ranganathan, S., Rosengart, M. R., Piganelli, J. D., Mollen, K. P. Calcium/calmodulin-dependent protein kinase IV (CaMKIV) activation contributes to the pathogenesis of experimental colitis via inhibition of intestinal epithelial cell proliferation.

Correlation of Thromboelastography with Apparent Rivaroxaban Concentration: Has Point-of-Care Testing Improved?

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.

Does Preexisting Practice Modify How Video Games Recalibrate Physician Heuristics in Trauma Triage?

BACKGROUND: A majority of severely injured patients fail to receive care at trauma centers (undertriage), in part, because of physician judgment. We previously developed two educational video games that reduced physicians' undertriage compared with control in two clinical trials. In this secondary analysis, we investigated heterogeneity of treatment effect of the interventions by assessing physicians' preexisting practice patterns in claims data. We hypothesized that physicians with high preexisting undertriage would benefit most from game-based training. METHODS: Using Medicare claims records from 2010 to 2015, we measured physicians' preexisting triage practices before their participation in one of two trials conducted in 2016 and 2017. We categorized physicians as having received game-based training versus control and noted their postintervention simulation triage performance in the trials. We used multivariable linear regression models to assess the heterogeneity of game-based training effect among physicians with high and low preexisting undertriage. RESULTS: Of the 394 eligible physicians from our trials, we identified 275 (70%) with claims for Medicare fee-for-service beneficiaries suffering severe injury between 2010 and 2015. On average, the physicians were 44 y old (SD 8.4) with 12 y (SD 8.2) of experience. We found significant interaction between preexisting practice and intervention efficacy (P = 0.04). Physicians with high undertriage before enrollment improved significantly with game-based training compared with the control (46% versus 63%, P < 0.001). Those with low preexisting undertriage did not (58% versus 56%, P = 0.76). CONCLUSIONS: Using claims-based data, we found heterogeneity of treatment effect of interventions designed to recalibrate physician heuristics. Physicians with high preexisting undertriage benefited most from game-based training.

A Systematic Review of Gender-Based Differences in Hirsch Index Among Academic Surgeons.

BACKGROUND: The h-index is a commonly used bibliometric in academic medicine which enumerates the number of publications (h) that have been cited h times. Recent investigations have suggested that gender-based differences in h-index may exist among academic physicians. We systematically reviewed studies of academic surgeons' h-index, hypothesizing that a significant difference would exist between the h-index of men and women at all academic ranks. METHODS: Peer-reviewed journal articles authored by academic surgeons of any subspecialization in the United States between January 1, 2006, and November 20, 2017, were reviewed. We excluded studies of trainees or gender-based differences in funding without mention of h-index. Two reviewers assessed article quality using the Newcastle-Ottawa criteria. Pooled estimates of standard mean differences (SMD) in h-index between genders were calculated using random-effects meta-analyses. A subgroup analysis based on the academic rank was performed. Heterogeneity was assessed using the I2 statistic. Sensitivity analyses determined the effect of study on h-index. Meta-regression identified whether surgical specialty contributed to heterogeneity. RESULTS: Twelve articles comparing h-index between genders were selected from 7950. Men possessed higher h-indices than women (SMD, 0.547; P < 0.001; I2 = 89.5%). Men exhibited higher h-indices at the assistant rank (SMD, 0.12; 95% confidence interval [CI], 0.01-0.24; P = 0.039) but not at the associate (SMD, 0.14; 95% CI, -0.06 to 0.33; P = 0.165) or full professor (SMD, 0.12; 95% CI, -0.08 to -0.31; P = 0.25) ranks. CONCLUSIONS: The h-index is higher for men than that for women in academic surgery overall but not at individual ranks. Further investigations are necessary to address limitations in h-index and to further characterize the relationship between h-index, gender, and promotion.

Murine sepsis phenotypes and differential treatment effects in a randomized trial of prompt antibiotics and fluids.

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.

Blue light reduces organ injury from ischemia and reperfusion.

Evidence suggests that light and circadian rhythms profoundly influence the physiologic capacity with which an organism responds to stress. However, the ramifications of light spectrum on the course of critical illness remain to be determined. Here, we show that acute exposure to bright blue spectrum light reduces organ injury by comparison with bright red spectrum or ambient white fluorescent light in two murine models of sterile insult: warm liver ischemia/reperfusion (I/R) and unilateral renal I/R. Exposure to bright blue light before I/R reduced hepatocellular injury and necrosis and reduced acute kidney injury and necrosis. In both models, blue light reduced neutrophil influx, as evidenced by reduced myeloperoxidase (MPO) within each organ, and reduced the release of high-mobility group box 1 (HMGB1), a neutrophil chemotactant and key mediator in the pathogenesis of I/R injury. The protective mechanism appeared to involve an optic pathway and was mediated, in part, by a sympathetic (ß3 adrenergic) pathway that functioned independent of significant alterations in melatonin or corticosterone concentrations to regulate neutrophil recruitment. These data suggest that modifying the spectrum of light may offer therapeutic utility in sterile forms of cellular injury.

Translational Sepsis Research: Spanning the Divide.

OBJECTIVE: Our knowledge of the molecular mechanisms of sepsis has attained exponential growth. Yet, the pillars of its care remain antibiotics, fluid resuscitation, and physiologic support of failing organ systems. The inability to bring biologic breakthroughs to the bedside is not for lack of effort. Over 60 clinical trials of novel therapies, each heavily supported by the momentum of biologic data suggesting clinical utility, have been conducted and have failed to identify benefit. This mass of "negative" clinical data abut an equally towering mound of knowledge of sepsis biology, which collectively have led investigators to ask, "what happened?" DATA SOURCES: Review of published scientific literature via MEDLINE searches using key terms related to the article topics. STUDY SELECTION: Original articles, review articles, and systematic reviews were considered. DATA EXTRACTION: Articles were selected for inclusion based upon author consensus. DATA SYNTHESIS: Here, we present a synthetic review of some of the challenges in translating experimental animal models of sepsis to the bedside. We commence with the concept that the heterogeneity in the kinetics of the sepsis response serves as an important, often underappreciated but surmountable, source of translational impedance. Upon this groundwork, we discuss distinctions between animal experimentation and clinical trial design in the elements for hypothesis testing: cohort selection, power and sample size, randomization and blinding, and timing of intervention. From this concept, we develop a contextual framework for advancing the paradigm of animal-based investigations to facilitate science that transitions from molecule to medicine. CONCLUSIONS: A persistent divide exists between the laboratory and clinical research arenas, which may be addressable via systematic targeting of identified translational gaps.

Prompt Administration of Antibiotics and Fluids in the Treatment of Sepsis: A Murine Trial.

OBJECTIVES: Sepsis, the acute organ dysfunction caused by a dysregulated host response to infection, poses a serious public health burden. Current management includes early detection, initiation of antibiotics and fluids, and source control as necessary. Although observational data suggest that delays of even a few hours in the initiation of antibiotics or IV fluids is associated with survival, these findings are controversial. There are no randomized data in humans, and prior animal studies studied time from experimental manipulation, not from the onset of clinical features of sepsis. Using a recently developed murine cecal ligation and puncture model that precisely monitors physiologic deterioration, we hypothesize that incremental hourly delays in the first dose of antibiotics, in the first bolus of fluid resuscitation, or a combination of the two at a clinically relevant point of physiologic deterioration during polymicrobial sepsis will shorten survival. DESIGN: Randomized laboratory animal experimental trial. SETTING: University basic science laboratory. SUBJECTS: Male C57BL/6J, female C57BL/6J, aged (40-50 wk old) male C57BL/6J, and BALB/C mice. INTERVENTIONS: Mice (n = 200) underwent biotelemetry-enhanced cecal ligation and puncture and were randomized after meeting validated criteria for acute physiologic deterioration. Treatment groups consisted of a single dose of imipenem/cilastatin, a single bolus of 30 mL/kg fluid resuscitation, or a combination of the two. Mice were allocated to receive treatment at the time of meeting deterioration criteria, after a 2-hour delay or after a 4-hour delay. MEASUREMENTS AND MAIN RESULTS: Hourly delays in the initiation of antibiotic therapy led to progressively shortened survival in our model (p < 0.001). The addition of fluid resuscitation was unable to rescue animals, which received treatment 4 hours after meeting enrollment criteria. Systemic inflammation was increased, and host physiology was increasingly deranged with hourly delays to antibiotics. CONCLUSIONS: We conclude that antibiotic therapy is highly time sensitive, and efforts should be made to deliver this critical therapy as early as possible in sepsis, perhaps extending into the first point of medical contact outside the hospital.

Blue Light Enhances Bacterial Clearance and Reduces Organ Injury During Sepsis.

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.

Calcium/calmodulin-dependent protein kinase regulates the PINK1/Parkin and DJ-1 pathways of mitophagy during sepsis.

During sepsis and shock states, mitochondrial dysfunction occurs. Consequently, adaptive mechanisms, such as fission, fusion, and mitophagy, are induced to eliminate damaged portions or entire dysfunctional mitochondria. The regulatory PINK1/Parkin and DJ-1 pathways are strongly induced by mitochondrial depolarization, although a direct link between loss of mitochondrial membrane potential (ΔΨ) and mitophagy has not been identified. Mitochondria also buffer Ca2+, and their buffering capacity is dependent on ΔΨ Here, we characterize a role for calcium/calmodulin-dependent protein kinase (CaMK) I in the regulation of these mechanisms. Loss of ΔΨ with either pharmacologic depolarization or LPS leads to Ca2+-dependent mitochondrial recruitment and activation of CaMKI that precedes the colocalization of PINK1/Parkin and DJ-1. CaMKI is required and serves as both a PINK1 and Parkin kinase. The mechanisms operate in both immune and nonimmune cells and are induced in in vivo models of endotoxemia, sepsis, and hemorrhagic shock. These data support the idea that CaMKI links mitochondrial stress with the PINK1/Parkin and DJ-1 mechanisms of mitophagy.-Zhang, X., Yuan, D., Sun, Q., Xu, L., Lee, E., Lewis, A. J., Zuckerbraun, B. S., Rosengart, M. R. Calcium/calmodulin-dependent protein kinase regulates the PINK1/Parkin and DJ-1 pathways of mitophagy during sepsis.

A qualitative study of gender differences in the experiences of general surgery trainees.

BACKGROUND: Women surgeons continue to face unique challenges to professional advancement. Higher attrition rates and lower confidence among female surgical residents suggest that experiences during residency differ by gender. Few studies have investigated gender-specific experiences during training. This study identifies gender-based differences in the experiences of general surgery residents that could affect professional development. MATERIALS AND METHODS: Male and female general surgery residents at the University of Pittsburgh Medical Center participated in a semi-structured interview study exploring the significance of gender in training. Recurring themes were identified from transcribed interviews using inductive methods. Two individuals independently coded interviews. Themes were compared for male and female residents. Certain themes arose with greater frequency in reference to one gender over the other. RESULTS: Twenty-four male and eighteen female residents participated (87.5%) in the study. Fewer female residents self-identified as a "surgeon" (11.1% versus 37.5%, P < 0.001). Residents felt that patients and physicians more frequently disregarded female residents' professional role (P < 0.001). Female residents also more often mentioned perceiving aggressive behaviors from attendings and support staff (9% versus 1% and 10% versus 3%, respectively). Relative to men, women more often mentioned lack of mentorship (0% versus 8%), discomfort (4% versus 8%), feeling pressured to participate in unprofessional behaviors (2% versus 5%), and having difficulty completing tasks (5% versus 10%, P < 0.001). CONCLUSIONS: Women experience gender-based challenges during surgical training. Further investigation is needed to determine how these experiences affect professional development.

Bright environmental light improves the sleepiness of nightshift ICU nurses.

BACKGROUND: Shift work can disturb circadian homeostasis and result in fatigue, excessive sleepiness, and reduced quality of life. Light therapy has been shown to impart positive effects in night shift workers. We sought to determine whether or not prolonged exposure to bright light during a night shift reduces sleepiness and enhances psychomotor performance among ICU nurses. METHODS: This is a single-center randomized, crossover clinical trial at a surgical trauma ICU. ICU nurses working a night shift were exposed to a 10-h period of high illuminance (1500-2000 lx) white light compared to standard ambient fluorescent lighting of the hospital. They then completed the Stanford Sleepiness Scale and the Psychomotor Vigilance Test. The primary and secondary endpoints were analyzed using the paired t test. A p value <0.05 was considered significant. RESULTS: A total of 43 matched pairs completed both lighting exposures and were analyzed. When exposed to high illuminance lighting subjects experienced reduced sleepiness scores on the Stanford Sleepiness Scale than when exposed to standard hospital lighting: mean (sem) 2.6 (0.2) vs. 3.0 (0.2), p = 0.03. However, they committed more psychomotor errors: 2.3 (0.2) vs. 1.7 (0.2), p = 0.03. CONCLUSIONS: A bright lighting environment for ICU nurses working the night shift reduces sleepiness but increases the number of psychomotor errors. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03331822 . Retrospectively registered on 6 November 2017.

Impact of Volume Change Over Time on Trauma Mortality in the United States.

OBJECTIVE: To evaluate the association of trauma center volume change over time with mortality. BACKGROUND: Regionalization of trauma systems assumes a volume-outcome relationship for severe injury. Whereas this has been shown for cross-sectional volume, it is unclear whether volume changes over time translate into predictable outcome changes. METHODS: Retrospective cohort study of severely injured (injury severity score >15) patients from the National Trauma Databank 2000 to 2012. A center-level standardized mortality ratio (SMR) was constructed (ratio of observed to expected deaths). Expected mortality was obtained from multilevel logistic regression model, adjusting for demographics, mechanism, vital signs, and injury severity. Center-level percent volume change was assessed across early (2000-2006) and late (2007-2012) periods. Longitudinal panel modeling evaluated association between annual SMR change and volume change over preceding years. RESULTS: There were 839,809 patients included from 287 centers. Each 1% increase in volume was associated with 73% increased odds of improving SMR over time [odds ratio (OR) 1.73; 95% confidence interval (CI) 1.03-2.91; P = 0.03]. Each 1% decrease in volume was associated with 2-fold increase in odds of worsening SMR over time (OR 2.14; 95% CI 1.07-4.26, P = 0.03). Significant improvement in the SMR emerged after 3 or more preceding years of increasing volume (SMR change -0.008; 95% CI -0.015, -0.002; P = 0.01). This benefit occurred only in centers that were level I or II verified. CONCLUSIONS: Increasing volume was associated with improving outcomes, whereas decreasing volume was associated with worsening outcomes. High-level trauma center infrastructure seems to facilitate the volume-outcome relationship. The trauma center designation process should consider volume changes in the overall system.