Genomic responses in mouse models poorly mimic human inflammatory diseases.

A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R(2) between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases.

Analysis of factorial time-course microarrays with application to a clinical study of burn injury.

Time-course microarray experiments are capable of capturing dynamic gene expression profiles. It is important to study how these dynamic profiles depend on the multiple factors that characterize the experimental condition under which the time course is observed. Analytic methods are needed to simultaneously handle the time course and factorial structure in the data. We developed a method to evaluate factor effects by pooling information across the time course while accounting for multiple testing and nonnormality of the microarray data. The method effectively extracts gene-specific response features and models their dependency on the experimental factors. Both longitudinal and cross-sectional time-course data can be handled by our approach. The method was used to analyze the impact of age on the temporal gene response to burn injury in a large-scale clinical study. Our analysis reveals that 21% of the genes responsive to burn are age-specific, among which expressions of mitochondria and immunoglobulin genes are differentially perturbed in pediatric and adult patients by burn injury. These new findings in the body's response to burn injury between children and adults support further investigations of therapeutic options targeting specific age groups. The methodology proposed here has been implemented in R package "TANOVA" and submitted to the Comprehensive R Archive Network at http://www.r-project.org/. It is also available for download at http://gluegrant1.stanford.edu/TANOVA/.

Illusions of team working in health care.

PURPOSE: The ubiquity and value of teams in healthcare are well acknowledged. However, in practice, healthcare teams vary dramatically in their structures and effectiveness in ways that can damage team processes and patient outcomes. The aim of this paper is to highlight these characteristics and to extrapolate several important aspects of teamwork that have a powerful impact on team effectiveness across healthcare contexts. DESIGN/METHODOLOGY/APPROACH: The paper draws upon the literature from health services management and organisational behaviour to provide an overview of the current science of healthcare teams. FINDINGS: Underpinned by the input-process-output framework of team effectiveness, team composition, team task, and organisational support are viewed as critical inputs that influence key team processes including team objectives, leadership and reflexivity, which in turn impact staff and patient outcomes. Team training interventions and care pathways can facilitate more effective interdisciplinary teamwork. ORIGINALITY/VALUE: The paper argues that the prevalence of the term "team" in healthcare makes the synthesis and advancement of the scientific understanding of healthcare teams a challenge. Future research therefore needs to better define the fundamental characteristics of teams in studies in order to ensure that findings based on real teams, rather than pseudo-like groups, are accumulated.

Senior management leadership, social support, job design and stressor-to-strain relationships in hospital practice.

PURPOSE: The purpose of this paper is to examine the effect of the quality of senior management leadership on social support and job design, whose main effects on strains, and moderating effects on work stressors-to-strains relationships were assessed. DESIGN/METHODOLOGY/APPROACH: A survey involving distribution of questionnaires was carried out on a random sample of health care employees in acute hospital practice in the UK. The sample comprised 65,142 respondents. The work stressors tested were quantitative overload and hostile environment, whereas strains were measured through job satisfaction and turnover intentions. Structural equation modelling and moderated regression analyses were used in the analysis. FINDINGS: Quality of senior management leadership explained 75 per cent and 94 per cent of the variance of social support and job design respectively, whereas work stressors explained 51 per cent of the variance of strains. Social support and job design predicted job satisfaction and turnover intentions, as well as moderated significantly the relationships between quantitative workload/hostility and job satisfaction/turnover intentions. RESEARCH LIMITATIONS/IMPLICATIONS: The findings are useful to management and to health employees working in acute/specialist hospitals. Further research could be done in other counties to take into account cultural differences and variations in health systems. The limitations included self-reported data and percept-percept bias due to same source data collection. PRACTICAL IMPLICATIONS: The quality of senior management leaders in hospitals has an impact on the social environment, the support given to health employees, their job design, as well as work stressors and strains perceived. ORIGINALITY/VALUE: The study argues in favour of effective senior management leadership of hospitals, as well as ensuring adequate support structures and job design. The findings may be useful to health policy makers and human resources managers.

Benchmarking outcomes in the critically injured trauma patient and the effect of implementing standard operating procedures.

OBJECTIVE: To determine and compare outcomes with accepted benchmarks in trauma care at 7 academic level I trauma centers in which patients were treated on the basis of a series of standard operating procedures (SOPs). BACKGROUND: Injury remains the leading cause of death for those younger than 45 years. This study describes the baseline patient characteristics and well-defined outcomes of persons hospitalized in the United States for severe blunt trauma. METHODS: We followed 1637 trauma patients from 2003 to 2009 up to 28 hospital days using SOPs developed at the onset of the study. An extensive database on patient and injury characteristics, clinical treatment, and outcomes was created. These data were compared with existing trauma benchmarks. RESULTS: The study patients were critically injured and were in shock. SOP compliance improved 10% to 40% during the study period. Multiple organ failure and mortality rates were 34.8% and 16.7%, respectively. Time to recovery, defined as the time until the patient was free of organ failure for at least 2 consecutive days, was developed as a new outcome measure. There was a reduction in mortality rate in the cohort during the study that cannot be explained by changes in the patient population. CONCLUSIONS: This study provides the current benchmark and the overall positive effect of implementing SOPs for severely injured patients. Over the course of the study, there were improvements in morbidity and mortality rates and increasing compliance with SOPs. Mortality was surprisingly low, given the degree of injury, and improved over the duration of the study, which correlated with improved SOP compliance.

The changing pattern and implications of multiple organ failure after blunt injury with hemorrhagic shock.

OBJECTIVES: To describe the incidence of postinjury multiple organ failure and its relationship to nosocomial infection and mortality in trauma centers using evidence-based standard operating procedures. DESIGN: Prospective cohort study wherein standard operating procedures were developed and implemented to optimize postinjury care. SETTING: Seven U.S. level I trauma centers. PATIENTS: Severely injured patients (older than age 16 yrs) with a blunt mechanism, systolic hypotension (<90 mm Hg), and/or base deficit (≥6 mEq/L), need for blood transfusion within the first 12 hrs, and an abbreviated injury score ≥2 excluding brain injury were eligible for inclusion. MEASUREMENTS AND MAIN RESULTS: One thousand two patients were enrolled and 916 met inclusion criteria. Daily markers of organ dysfunction were prospectively recorded for all patients while receiving intensive care. Overall, 29% of patients had multiple organ failure develop. Development of multiple organ failure was early (median time, 2 days), short-lived, and predicted an increased incidence of nosocomial infection, whereas persistence of multiple organ failure predicted mortality. However, surprisingly, nosocomial infection did not increase subsequent multiple organ failure and there was no evidence of a "second-hit"-induced late-onset multiple organ failure. CONCLUSIONS: Multiple organ failure remains common after severe injury. Contrary to current paradigms, the onset is only early, and not bimodal, nor is it associated with a "second-hit"-induced late onset. Multiple organ failure is associated with subsequent nosocomial infection and increased mortality. Standard operating procedure-driven interventions may be associated with a decrease in late multiple organ failure and morbidity.

The relationship between leader support, staff influence over decision making, work pressure and patient satisfaction: a cross-sectional analysis of NHS datasets in England.

OBJECTIVE: To explore the relationships between leader support, staff influence over decisions, work pressure and patient satisfaction. DESIGN: A cross-sectional study of large National Health Service (NHS) datasets in England in 2010. SETTING AND PARTICIPANTS: 158 NHS acute hospital trusts in England (n=63 156) from all staff groups. PRIMARY AND SECONDARY OUTCOME MEASURES: Survey data measuring leader support, staff influence over decision making, staff work pressure and objective outcome data measuring patient satisfaction. RESULTS: Multilevel serial mediation analysis showed a significantly positive association between leader support and staff influence over decisions (B=0.74, SE=0.07, p<0.01). Furthermore, staff influence over decisions showed a negative association with staff work pressure (B=-0.84, SE=0.41, p<0.05) which in turn was negatively linked to patient satisfaction (B=-17.50, SE=4.34, p<0.01). Serial mediation showed a positive indirect effect of leader support on patient satisfaction via staff influence over decisions and work pressure (B=10.96, SE=5.55, p<0.05). CONCLUSIONS AND IMPLICATIONS: Our results provide evidence that leader support influences patient satisfaction through shaping staff experience, particularly staff influence over decisions and work pressure. Patients' care is dependent on the health, well-being, and effectiveness of the NHS workforce. That, in turn, is determined by the extent to which leaders are supportive in ensuring that work environments are managed in a way which protects the well-being of staff.

Team working in intensive care: current evidence and future endeavors.

PURPOSE OF REVIEW: It has recently been argued that the future of intensive care medicine will rely on high quality management and teamwork. Therefore, this review takes an organizational psychology perspective to examine the most recent research on the relationship between teamwork, care processes, and patient outcomes in intensive care. RECENT FINDINGS: Interdisciplinary communication within a team is crucial for the development of negotiated shared treatment goals and short-team patient outcomes. Interventions for maximizing team communication have received substantial interest in recent literature. Intensive care coordination is not a linear process, and intensive care teams often fail to discuss how to implement goals, trigger and align activities, or reflect on their performance. Despite a move toward interdisciplinary team working, clinical decision-making is still problematic and continues to be perceived as a top-down and authoritative process. The topic of team leadership in intensive care is underexplored and requires further research. SUMMARY: Based on findings from the most recent research evidence in medicine and management, four principles are identified for improving the effectiveness of team working in intensive care: engender professional efficacy, create stable teams and leaders, develop trust and participative safety, and enable frequent team reflexivity.

Early release of soluble receptor for advanced glycation endproducts after severe trauma in humans.

BACKGROUND: The receptor for advanced glycation endproducts (RAGE) recognizes a variety of ligands that play an important role in the posttraumatic inflammatory response. However, whether soluble RAGE (sRAGE) is released early after trauma hemorrhage in humans and whether such a release is associated with the development of an inflammatory response and coagulopathy is not known and therefore constitutes the aim of this study. METHODS: One hundred sixty-eight patients were studied as part of a prospective cohort study of severe trauma patients admitted to a single Level I Trauma center. Blood was drawn within 10 minutes of arrival to the emergency department before the administration of any fluid resuscitation. sRAGE, tumor necrosis factor-alpha, interleukin-6, von Willebrand factor, angiopoietin-2, prothrombin time, prothrombin fragments 1 + 2, soluble thrombomodulin, protein C, plasminogen activator inhibitor-1, and d-dimers (fibrin degradation products) were measured using standard techniques. Base deficit was used as a measure of tissue hypoperfusion. Measurements were compared with outcome measures obtained from the electronic medical record and trauma registry. RESULTS: Plasma levels of sRAGE were increased within 30 minutes after severe trauma in humans and correlated with the severity of injury, early posttraumatic coagulopathy and hyperfibrinolysis, and endothelial cell activation (angiopoietin-1 and complement). Furthermore, we found that there was a significant relationship between plasma levels of sRAGE and the development of acute renal failure. This relationship was not quite significant for patients who developed acute lung injury (p = 0.11), although patients with <26 ventilator-free days had significantly higher plasma levels of sRAGE than those with >26 ventilator-free days. Finally, there was no relationship between plasma levels of sRAGE and mortality rate in trauma patients. CONCLUSION: The results of this study demonstrate that the release of sRAGE in the bloodstream of trauma patients requires severe injury and is associated with coagulation abnormalities and endothelial cell and complement activation.

Does splenectomy protect against immune-mediated complications in blunt trauma patients?

Activation of the innate immune system results from severe trauma and the resultant systemic inflammatory response is thought to mediate remote organ injury. In animal models, vagal-mediated innate immune responses have been shown to modulate proinflammatory cytokine release in response to trauma or sepsis. In those models, vagal nerve transaction and splenectomy decreased cytokine release and protected against lung injury and mortality. We hypothesized that, if similar mechanisms are active in humans, patients who require splenectomy for trauma would have better outcomes than injured patients without splenectomy. We performed a retrospective cohort study on 46,858 patients who sustained blunt liver or spleen injury utilizing the 2002 National Trauma Data Bank (NTDB). Blunt trauma patients who underwent splenectomy were compared with all patients with splenic injuries. Demographic parameters and the following outcome variables were compared: mortality, hospital length of stay (LOS), ICU length of stay (ILOS), mean ventilator days (VENT), and incidence of acute respiratory distress syndrome (ARDS). Groups were compared controlling for age, gender, injury severity score (ISS), emergency department (ED) blood pressure, and ED base deficit (BD) using multiple regression analyses. Patients that underwent splenectomy had significantly shorter LOS than patients who were managed nonoperatively or with splenorrhaphy: LOS,15.1 versus 19.3 d, P = 0.002; ILOS, 7.8 versus 10.6 d, P < 0.001; and VENT, 7.1 versus 11.4 d, P < 0.001. Adjusted mortality rates (OR 1.02; 95% CI 0.98-1.05; P = 0.29) and the reported incidence of ARDS were not significantly different between the two groups (2.4% versus 3.6%; P = 0.213). Patients who underwent splenectomy demonstrated better secondary outcomes than patients who were managed nonoperatively or with splenorrhaphy, even when controlling for injury severity and physiologic derangements. It is possible that the improved outcomes seen in the group undergoing splenectomy were due to favorable modulation of the human innate immune inflammatory response after trauma.

Acute uncomplicated appendicitis: case time of day influences hospital length of stay.

BACKGROUND: Acute appendicitis is the most common surgical infection requiring operative intervention, and length of stay (LOS) typically is short. The timing of emergency appendectomies for acute appendicitis depends on many factors, including anesthesia and operating room availability, staffing, convenience, acuity of illness, and surgeon preference. Efforts to decrease LOS in surgery patients have focused largely on elective operations. We hypothesized that operative time of day would determine when patients were discharged after appendectomy. METHODS: Records of patients undergoing appendectomy between July, 2004 and June, 2005 were reviewed retrospectively. Operative date and time, hospital discharge date and time, operative findings, and postoperative complications were reviewed. Hospital LOS was calculated, and the Student t-test used to calculate significance. RESULTS: A total of 199 patients underwent appendectomy during the study period. Twenty-three "outliers," with complicated appendicitis or significant co-morbidities (LOS 4-21 days, 76% perforated), were excluded. Length of stay in uncomplicated appendicitis was influenced significantly by the time of day the operation was performed. Length of stay was shortest if surgery was performed between 0001 and 0400 h (mean LOS 20 h 40 min). In contrast, LOS was 50% greater if the operation was performed during the day (mean LOS 32 h 24 min for cases performed between 0700 and 1500 h). No patients were discharged between 2100 and 0700 h. Surgical site infections occurred in fewer than 5% of patients, and white blood cell count did not predict LOS. CONCLUSIONS: Operative time of day was a surprisingly important determinant of hospital LOS. Efforts to minimize LOS and optimize resource utilization should balance operating room availability, surgeon preferences, shift-dependent costs, nursing policies, and hospital systems.

Abdominal compartment syndrome: a concise clinical review.

OBJECTIVE: There has been an increased awareness of the presence and clinical importance of abdominal compartment syndrome. It is now appreciated that elevations of abdominal pressure occur in a wide variety of critically ill patients. Full-blown abdominal compartment syndrome is a clinical syndrome characterized by progressive intra-abdominal organ dysfunction resulting from elevated intra-abdominal pressure. This review provides a current, clinically focused approach to the diagnosis and management of abdominal compartment syndrome, with a particular emphasis on intensive care. METHODS: Source data were obtained from a PubMed search of the medical literature, with an emphasis on the time period after 2000. PubMed "related articles" search strategies were likewise employed frequently. Additional information was derived from the Web site of the World Society of the Abdominal Compartment Syndrome (http://www.wsacs.org). SUMMARY AND CONCLUSIONS: The detrimental impact of elevated intra-abdominal pressure, progressing to abdominal compartment syndrome, is recognized in both surgical and medical intensive care units. The recent international abdominal compartment syndrome consensus conference has helped to define, characterize, and raise awareness of abdominal compartment syndrome. Because of the frequency of this condition, routine measurement of intra-abdominal pressure should be performed in high-risk patients in the intensive care unit. Evidence-based interventions can be used to minimize the risk of developing elevated intra-abdominal pressure and to aggressively treat intra-abdominal hypertension when identified. Surgical decompression remains the gold standard for rapid, definitive treatment of fully developed abdominal compartment syndrome, but nonsurgical measures can often effectively affect lesser degrees of intra-abdominal hypertension and abdominal compartment syndrome.

Endotoxin tolerance in sepsis: concentration-dependent augmentation or inhibition of LPS-stimulated macrophage TNF secretion by LPS pretreatment.

BACKGROUND: We previously showed that macrophages (MPhi) pretreated with bacterial endotoxin (lipopolysaccharide [LPS]) develop an altered state of LPS-responsiveness--"LPS tolerance": LPS tolerance was associated with inhibition of tumor necrosis factor (TNF) release and decreased extracellular signal-regulated kinase and p38 kinase activation when MPhi were restimulated with LPS. However, the concentration of LPS used for pretreatment (most frequently 10 ng/mL) may be much higher than LPS concentrations observed in patients. Therefore, in the current study we examined the effect of lower and higher pretreatment LPS concentrations on subsequent LPS-stimulated MPhi responses. METHODS: RAW 264.7 MPhi-like cells were pretreated in vitro (PreRx) for 24 hours in medium or a range of LPS concentrations (0 ng/mL, 1 ng/mL, 10 ng/mL, or 100 ng/mL of E. coli 0111B4 LPS). Culture medium was discarded after 24 hours and MPhi were restimulated with LPS (0 ng/mL, 1 ng/mL, 10 ng/mL or 100 ng/mL). Three different lots of LPS (Sigma) were used. Supernatant TNF secretion at 3 hour was measured using enzyme-linked immunosorbent assay (pg/mL +/- SEM). Statistics by Chi-square and student's t test. RESULTS: Pretreatment with 100 ng/mL of LPS profoundly inhibited TNF release at all LPS restimulation concentrations (p < 0.05 vs. Medium PreRx). In contrast, very low dose LPS pretreatment (1 ng/mL) significantly augmented TNF release versus medium (p < 0.05). There was no further augmentation observed when even lower doses of LPS (0.1 ng/mL) were used for pretreatment. Similar results were obtained with three different lots E. coli 0111B4 LPS or using LPS from E. coli 0127B8. CONCLUSION: Prior exposure of MPhi to bacterial ligands alters MPhi cytokine production in response to subsequent LPS-stimulated activation. This modulated MPhi response is critically dependent on the concentration of LPS pretreatment.

Even ephemeral endotoxin exposure establishes endotoxin tolerance.

BACKGROUND: Macrophages previously exposed to bacterial lipopolysaccharide (LPS) develop a "tolerant" response with decreased extracellular signal-regulated kinase (ERK) activation in response to LPS rechallenge. Prior work using 21-hour LPS pretreatment showed that 100 ng/mL of LPS-inhibited tumor necrosis factor (TNF) release, whereas very low dose LPS (1 ng/mL) augmented TNF release. Endotoxin tolerance was also associated with alterations in activation of ERK and p38 kinase when cells were restimulated with LPS. We hypothesized that the interval after pretreatment, before LPS rechallenge, modulates macrophage response to LPS. METHODS: RAW 264.7 macrophage-like cells were pretreated for 4 hours in 0 ng/mL (none), 1 ng/mL, 10 ng/mL, or 100 ng/mL of Escherichia coli 0111:B4 LPS. After 4 hour pretreatment, medium was discarded. Cells were rechallenged immediately or 21 hours later with 0 ng/mL, 1 ng/mL, 10 ng/mL, or 100 ng/mL LPS. Supernatant TNF secretion at 3 hour was measured using enzyme-linked immunosorbent assay. Active phospho-ERK was examined by Western blot using specific monoclonal antibodies 30 minutes after LPS rechallenge. Statistical analysis by chi and student's t test. RESULTS: When macrophages were pretreated for 4 hour and incubated overnight (21-hour interval) 1 ng/mL of LPS augmented and 100 ng/mL inhibited TNF release with LPS rechallenge. In contrast, with immediate rechallenge, we saw additive effects with 100 ng/mL LPS and no difference with 1 ng/mL LPS versus no pretreatment. Western blot revealed that even with immediate rechallenge "tolerant" macrophages were unable to activate ERK. CONCLUSIONS: A short LPS exposure is sufficient to induce alterations in ERK activation in macrophages, but longer intervals are required to express altered cytokine release. In conjunction with other recent findings, these results suggest that both pretreatment dose and interval modulate macrophage responsiveness to LPS rechallenge.

Inflammation and the host response to injury, a large-scale collaborative project: patient-oriented research core--standard operating procedures for clinical care VII--Guidelines for antibiotic administration in severely injured patients.

When the clinical decision to treat a critically ill patient with antibiotics has been made, one must attempt to identify the site of infection based on clinical signs and symptoms, laboratory or diagnostic radiology studies. Identification of site requires, examination of patient, inspection of all wounds, chest radiograph, and calculation of clinical pulmonary infection score if ventilated, obtaining blood cultures, urinalysis, and line change if clinical suspicion of central venous catheter (CVC) source. If it is impossible to identify site, obtain cultures from all accessible suspected sites and initiate empiric, broad spectrum antibiotics. If likely site can be identified answer these questions: Is intra-abdominal site suspected? Is pulmonary source of infection suspected? Is skin, skin structure or soft tissue site suspected? If yes, does the patient have clinical signs suspicion for necrotizing soft tissue infection (NSTI)? Is a CVC infection suspected? Risk factors for more complicated infections are discussed and specific antibiotic recommendations are provided for each type and severity of clinical infection. Decision to continue, discontinue and/or alter antibiotic/antimicrobial treatment should be based on the clinical response to treatment, diagnostic or interventional findings, and culture and sensitivity data, bearing in mind that not all patients with infections will have positive cultures because of limitations of specimen handling, microbiology laboratory variations, time between specimen acquisition and culture, or presence of effective antibiotics at the time that specimens were obtained. It should also be noted that not all patients with increased temperature/WBC have an infection. Discontinuation of antibiotics is appropriate if cultures and other diagnostic studies are negative.

Organizational climate and culture: Reflections on the history of the constructs in the Journal of Applied Psychology.

We review the literature on organizational climate and culture paying specific attention to articles published in the Journal of Applied Psychology (JAP) since its first volume in 1917. The article traces the history of the 2 constructs though JAP has been far more important for climate than culture research. We distinguish 4 main periods: the pre-1971 era, with pioneering work on exploring conceptualization and operationalizations of the climate construct; the 1971-1985 era, with foundational work on aggregation issues, outcome-focused climates (on safety and service) and early writings on culture; the 1986-1999 era, characterized by solidification of a focused climate approach to understanding organizational processes (justice, discrimination) and outcomes (safety, service) and the beginnings of survey approaches to culture; and the 2000-2014 era, characterized by multilevel work on climate, climate strength, demonstrated validity for a climate approach to outcomes and processes, and the relationship between leadership and climate and culture. We summarize and comment on the major theory and research achievements in each period, showing trends observed in the literature and how JAP has contributed greatly to moving research on these constructs, especially climate, forward. We also recommend directions for future research given the current state of knowledge. (PsycINFO Database Record

Harnessing demographic differences in organizations: What moderates the effects of workplace diversity?

To account for the double-edged nature of demographic workplace diversity (i.e,. relational demography, work group diversity, and organizational diversity) effects on social integration, performance, and well-being-related variables, research has moved away from simple main effect approaches and started examining variables that moderate these effects. While there is no shortage of primary studies of the conditions under which diversity leads to positive or negative outcomes, it remains unclear which contingency factors make it work. Using the Categorization-Elaboration Model as our theoretical lens, we review variables moderating the effects of workplace diversity on social integration, performance, and well-being outcomes, focusing on factors that organizations and managers have control over (i.e., strategy, unit design, human resource, leadership, climate/culture, and individual differences). We point out avenues for future research and conclude with practical implications. © 2015 The Authors. Journal of Organizational Behavior published by John Wiley & Sons, Ltd.