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Governance is at the heart of how well governments meet public needs and manage a wide array of common problems. Why do some countries perform poorly in delivering healthcare, reducing inequality, providing a clean environment or delivering some other public good to their populations even while they have the resources to do so? Does the capacity of states to provide the basics for societies to thrive depend on forms of democratic accountability that represents different interests, or are systems under technocratic control that impose solutions and disregard, even suppress, many voices better at meeting public needs? Existing indices do not systematically examine the relationship between the components that contribute to governance performance. In our understanding of governance, depicted as the Governance Triangle, public goods provision is a function of state capacity and accountability. Rather than focusing on a single composite performance measure, the Berggruen Governance Index examines the interactions among these dimensions. We find that the key to good governance is achieving a balance among the three dimensions on an upward and sustainable trajectory. This article introduces the Index and the conceptual and methodological framework that underpins it and then outlines the content of this special issue. [ABSTRACT FROM AUTHOR]

This article presents an overview of some of the main findings from our analysis of the Berggruen Governance Index for the 2000–2019 period. It first examines overall governance performance across world regions, singles out general trends and identifies top and bottom performers. It then briefly reviews the comparative governance performance of world powers like the United States, Brazil, China, major European countries, India and Russia as well as other selected countries in the post‐Soviet space. Finally, we address more analytic questions to show the versatility of the index for hypothesis testing and theoretical purposes. [ABSTRACT FROM AUTHOR]

Background: Pulmonary eosinophils comprise at least two distinct populations of resident eosinophils (rEOS) and inflammatory eosinophils (iEOS), the latter recruited in response to pulmonary inflammation. Here, we determined the impact of complement activation on rEOS and iEOS trafficking and function in two models of pulmonary inflammation. Methods: BALB/c wild‐type and C5ar1−/− mice were exposed to different allergens or IL‐33. Eosinophil populations in the airways, lung, or mediastinal lymph nodes (mLN) were characterized by FACS or immunohistochemistry. rEOS and iEOS functions were determined in vivo and in vitro. Results: HDM and IL‐33 exposure induced a strong accumulation of iEOS but not rEOS in the airways, lungs, and mLNs. rEOS and iEOS expressed C3/C5 and C5aR1, which were significantly higher in iEOS. Initial pulmonary trafficking of iEOS was markedly reduced in C5ar1−/− mice and associated with less IL‐5 production from ILC2 cells. Functionally, adoptively transferred pulmonary iEOS from WT but not from C5ar1−/− mice‐induced airway hyperresponsiveness (AHR), which was associated with significantly reduced C5ar1−/− iEOS degranulation. Pulmonary iEOS but not rEOS were frequently associated with T cells in lung tissue. After HDM or IL‐33 exposure, iEOS but not rEOS were found in mLNs, which were significantly reduced in C5ar1−/− mice. C5ar1−/− iEOS expressed less costimulatory molecules, associated with a decreased potency to drive antigen‐specific T cell proliferation and differentiation into memory T cells. Conclusions: We uncovered novel roles for C5aR1 in iEOS trafficking and activation, which affects key aspects of allergic inflammation such as AHR, ILC2, and T cell activation. [ABSTRACT FROM AUTHOR]

The COVID‐19 pandemic required adjustments and limitations in university teaching, thereby challenging teaching concepts in anatomy requiring in‐person contact, including the gross anatomy course. Therefore, the present study investigates the impact of COVID‐19‐associated adjustments on students' perception of the gross anatomy course's importance and quality, students' preferred learning setting and outcome, and their motivation to involve themselves in academic activities, including becoming a future peer‐teacher of the course. Using paper‐based questionnaires in Ulm, Germany, 397 (response rate: 82.3%) students of the winter term of 2020/2021 were surveyed using quantitative and qualitative items, which were compared with cohorts prior to the pandemic. Students reported a higher global rating on course quality during COVID‐19 (pre‐COVID‐19: 5.3 ± 0.9, during‐COVID‐19: 5.6 ± 0.7, p < 0.001; 1 = very bad, 6 = very good). Students' perceived importance of the gross anatomy course showed a small but significant increase (pre‐COVID‐19: 4.2 ± 0.6, during‐COVID‐19: 4.3 ± 0.6, p < 0.001; 1 = strongly disagree, 6 = strongly agree). Students' motivation to apply as a peer‐teacher remained stable, nevertheless, they reported less interest in transferring their knowledge to junior students. Finally, students reported that they spent significantly more learning time alone and their examination grades remained unchanged during the pandemic. Astonishingly, despite radical changes of the teaching environment due to COVID‐19, students appreciate the offered teaching and highly valued the gross anatomy course. [ABSTRACT FROM AUTHOR]

Objective: To examine concentrations of circulating antibodies targeting C3a and C5a complement receptors in antineutrophil cytoplasmic autoantibody (ANCA)–associated vasculitis (AAV) and analyze their association with disease activity. Methods: Concentrations of antibodies against C3a and C5a complement receptors (anti‐C3aR and anti‐C5aR) and plasma complement fragments C3a and C5a were determined in patients with AAV (n = 110; granulomatosis with polyangiitis [GPA; n = 82] or microscopic polyangiitis [MPA; n = 28]), systemic lupus erythematosus (SLE) patients as disease controls (n = 36), and healthy donors (n = 220). C3aR and C5aR expression by circulating neutrophils, monocytes, and T cells was analyzed using flow cytometry. Clinical data were assessed at time of serum sampling and during follow‐up for 60 months. Results: In AAV, anti‐C3aR and anti‐C5aR antibodies were decreased (P = 0.0026 and P ≤ 0.0001, respectively). In remission, anti‐C3aR antibody concentrations rose to values comparable to healthy donors, whereas anti‐C5aR antibody concentrations did not. In GPA, anti‐C5a and anti‐C5aR antibody concentrations inversely correlated with each other (r = −0.6831, P = 0.0127). In newly diagnosed GPA, decreased concentrations of anti‐C5aR antibodies but not anti‐C3aR antibodies were associated with disease activity (P = 0.0009). Moreover, low anti‐C5aR antibodies were associated with relapse in GPA (hazard ratio 3.54, P = 0.0009) and MPA (hazard ratio 4.41, P = 0.0041). The frequency of C5aR‐expressing cells within T cell populations was increased in GPA (P = 0.0021 for CD4+ T cells; P = 0.0118 for CD8+ T cells), but not in MPA. Conclusion: Low concentrations of anti‐C5aR antibodies reflect disease activity and are associated with an increased risk for relapse in AAV. [ABSTRACT FROM AUTHOR]

Summary: A number of clinical treatment modalities involve contact between blood and biomaterials: these include extracorporeal circuits such as hemodialysis, cardiopulmonary bypass, plasmapheresis, and intravascular treatments. Common side effects arising from these treatments are caused by activation of the cascade systems of the blood. Many of these side effects are mediated via the complement system, including thromboinflammatory reactions and rejection of implants. Depending on the composition of the materials, complement activation is triggered via all the activation pathways but is by far mostly driven by the alternative pathway amplification loop. On biomaterial surfaces the alternative pathway amplification is totally unregulated and leads under optimal conditions to deposition of complement fragments, mostly C3b, on the surface leading to a total masking of the underlying surface. In this review, we discuss the mechanism of the complement activation, clinical consequences of the activation, and potential strategies for therapeutic regulation of the activation, using hemodialysis as demonstrator. [ABSTRACT FROM AUTHOR]

Physical trauma represents a major global burden. The trauma-induced response, including activation of the innate immune system, strives for regeneration but can also lead to post-traumatic complications. The complement cascade is rapidly activated by damaged tissue, hypoxia, exogenous proteases and others. Activated complement can sense, mark and clear both damaged tissue and pathogens. However, excessive and insufficient activation of complement can result in a dysfunctional immune and organ response. Similar to acute coagulopathy, complementopathy can develop with enhanced anaphylatoxin generation and an impairment of complement effector functions. Various remote organ effects are induced or modulated by complement activation. Frequently, established trauma treatments are double-edged. On one hand, they help stabilising haemodynamics and oxygen supply as well as injured organs and on the other hand, they also drive complement activation. Immunomodulatory approaches aim to reset trauma-induced disbalance of complement activation and thus may change surgical trauma management procedures to improve outcome. LINKED ARTICLES: This article is part of a themed issue on Canonical and non-canonical functions of the complement system in health and disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.14/issuetoc. [ABSTRACT FROM AUTHOR]

The glutamate and γ‐aminobutyric acid neuroreceptor subtypes mGluR5 and GABAA are hypothesized to be involved in the development of a variety of psychiatric diseases. However, detailed information relating to their in vivo distribution is generally unavailable. Maps of such distributions could potentially aid clinical studies by providing a reference for the normal distribution of neuroreceptors and may also be useful as covariates in advanced functional magnetic resonance imaging (MR) studies. In this study, we propose a comprehensive processing pipeline for the construction of standard space, in vivo distributions of non‐displaceable binding potential (BPND), and total distribution volume (VT) based on simultaneously acquired bolus‐infusion positron emission tomography (PET) and MR data. The pipeline was applied to [11C]ABP688‐PET/MR (13 healthy male non‐smokers, 26.6 ± 7.0 years) and [11C]Flumazenil‐PET/MR (10 healthy males, 25.8 ± 3.0 years) data. Activity concentration templates, as well as VT and BPND atlases of mGluR5 and GABAA, were generated from these data. The maps were validated by assessing the percent error δ from warped space to native space in a selection of brain regions. We verified that the average δABP = 3.0 ± 1.0% and δFMZ = 3.8 ± 1.4% were lower than the expected variabilities σ of the tracers (σABP = 4.0%–16.0%, σFMZ = 3.9%–9.5%). An evaluation of PET‐to‐PET registrations based on the new maps showed higher registration accuracy compared to registrations based on the commonly used [15O]H2O‐template distributed with SPM12. Thus, we conclude that the resulting maps can be used for further research and the proposed pipeline is a viable tool for the construction of standardized PET data distributions. [ABSTRACT FROM AUTHOR]

Trauma is the leading cause of death in individuals under 44 years of age. Thorax trauma (TxT) is strongly associated with trauma‐related death, an unbalanced innate immune response, sepsis, acute respiratory distress syndrome, and multiple organ dysfunction. It is shown that different in vivo traumata, such as TxT or an in vitro polytrauma cytokine cocktail trigger secretion of small extracellular nanovesicles (sEVs) from endothelial cells with pro‐inflammatory cargo. These sEVs transfer transcripts for ICAM‐1, VCAM‐1, E‐selectin, and cytokines to systemically activate the endothelium, facilitate neutrophil‐endothelium interactions, and destabilize barrier integrity. Inhibition of sEV‐release after TxT in mice ameliorates local as well as systemic inflammation, neutrophil infiltration, and distant organ damage in kidneys (acute kidney injury, AKI). Vice versa, injection of TxT‐plasma‐sEVs into healthy animals is sufficient to trigger pulmonary and systemic inflammation as well as AKI. Accordingly, increased sEV concentrations and transfer of similar cargos are observed in polytrauma patients, suggesting a fundamental pathophysiological mechanism. [ABSTRACT FROM AUTHOR]

Sepsis as life‐threatening organ dysfunction caused by microorganisms represents a dreadful challenge for the immune system. The role of the complement system as major column of innate immunity has been extensively studied in various sepsis models, but its translational value remains in the dark. Complement activation products, such as C3a and C5a, and their corresponding receptors provide useful diagnostic tools and promising targets to improve organ function and outcome. However, a monotherapeutic complement intervention irrespective of the current immune function seems insufficient to reverse the complex sepsis mechanisms. Indeed, sepsis‐induced disturbances of cross talking complement, coagulation, and fibrinolytic cascades lead to systemic 'thromboinflammation', ultimately followed by multiple‐organ failure. We propose to reliably monitor the complement function in the patient and to re‐establish the immune balance by patient‐tailored combined therapies, such as complement and Toll‐like receptor inhibition. Our working hypothesis aims at blocking the 'explosive' innate immune recognition systems early on before downstream mediators are released and the inflammatory response becomes irreversible, a strategy that we name 'upstream approach'. [ABSTRACT FROM AUTHOR]

Background: Food‐induced anaphylaxis is a serious allergic reaction caused by Fcε‐receptor activation on mast cells (MCs). The exact mechanisms breaking oral tolerance and the effector pathways driving food allergy remain elusive. As complement is activated in food‐induced anaphylaxis, we aimed to assess the role of C5a in disease pathogenesis. Methods: Oral antigen‐induced food‐induced anaphylaxis was induced in BALB/c wild‐type (wt) and C5ar1−/− mice. Readouts included diarrhea development, changes in rectal temperature, hematocrit, antigen‐specific serum IgE, MCPT‐1, and intestinal MC numbers, as well as FcεR1‐mediated MC functions including C5a receptor 1 (C5aR1) regulation. Further, histamine‐mediated hypothermia and regulation of endothelial tight junctions were determined. Results: Repeated oral OVA challenge resulted in diarrhea, hypothermia, increased hematocrit, high OVA‐specific serum IgE, and MCPT‐1 levels in wt mice. Male C5ar1−/− mice were completely whereas female C5ar1−/− mice were partially protected from anaphylaxis development. Serum MCPT‐1 levels were reduced gender‐independent, whereas IgE levels were reduced in male but not in female C5ar1−/− mice. Mechanistically, IgE‐mediated degranulation and IL‐6 production from C5ar1−/−BMMCs of both sexes were significantly reduced. Importantly, FcεR1 cross‐linking strongly upregulated C5aR1 MC expression in vitro and in vivo. Finally, C5ar1−/− male mice were largely protected from histamine‐induced hypovolemic shock, which was associated with protection from histamine‐induced barrier dysfunction in vitro following C5aR targeting. Conclusions: Our findings identify C5aR1 activation as an important driver of IgE‐mediated food allergy through regulation of allergen‐specific IgE production, FcεR1‐mediated MC degranulation, and histamine‐driven effector functions preferentially in male mice. The C5a/C5aR1 axis controls the production of allergen‐specific IgE in male mice. FcεR1 aggregation upregulates C5aR1 expression in mast cells which amplifies IgE‐driven mediator release. C5aR1 signaling controls histamine‐mediated effector functions in vivo and in vitro. [ABSTRACT FROM AUTHOR]

The anaphylatoxin C5a is generated upon activation of the complement system, a crucial arm of innate immunity. C5a mediates proinflammatory actions via the C5a receptor C5aR1 and thereby promotes host defence, but also modulates tissue homeostasis. There is evidence that the C5a/C5aR1 axis is critically involved both in physiological bone turnover and in inflammatory conditions affecting bone, including osteoarthritis, periodontitis, and bone fractures. C5a induces the migration and secretion of proinflammatory cytokines of osteoblasts. However, the underlying mechanisms remain elusive. Therefore, in this study we aimed to determine C5a‐mediated downstream signalling in osteoblasts. Using a whole‐genome microarray approach, we demonstrate that C5a activates mitogen‐activated protein kinases (MAPKs) and regulates the expression of genes involved in pathways related to insulin, transforming growth factor‐β and the activator protein‐1 transcription factor. Interestingly, using coimmunoprecipitation, we found an interaction between C5aR1 and Toll‐like receptor 2 (TLR2) in osteoblasts. The C5aR1‐ and TLR2‐signalling pathways converge on the activation of p38 MAPK and the generation of C‐X‐C motif chemokine 10, which functions, among others, as an osteoclastogenic factor. In conclusion, C5a‐stimulated osteoblasts might modulate osteoclast activity and contribute to immunomodulation in inflammatory bone disorders. [ABSTRACT FROM AUTHOR]

ABSTRACT: Background: The world's leading cause of preventable deaths, diseases and disabilities is smoking. Hospitalization can provide an opportunity for smokers to quit. Previous research found that smokers make up a high percentage of patients admitted to intensive care. Health care professionals working in critical care environments can make a valuable contribution to this public health issue by providing smoking cessation advice. Aim: To identify factors that inhibit and facilitate the delivery of smoking cessation advice by nurses and doctors in critical care settings. Design: Quantitative design using an online survey. Methods: This research was a single centre study carried out in a large tertiary hospital. Study sites were two adult critical care departments including a 14‐bed general intensive care and a 16‐bed cardiovascular intensive care unit. The target population for this research was the nursing and medical staff working in adult critical care environments. Results: The data suggests that doctors and nurses have a good understanding of the complications related to tobacco use and also have education on smoking cessation. Additionally the data suggest that doctors and nurses at the study sites generally have positive attitudes towards smoking cessation. Patient acuity and competence were concerns raised in relation to the delivery and effectiveness of smoking cessation advice in critical care environments. Conclusions: The recovery phase following critical illness might be an opportunity to provide cessation advice. This could include focusing cessation advice efforts on awake, orientated and extubated patients. Further research might be required to confirm this. Relevance to clinical practice: The provision of smoking cessation advice is an on‐going World Health Organization and New Zealand Government priority and all parts of the health sector need to provide responses. However, responses need to be adapted to the specific context such as the unique challenges of critical care. [ABSTRACT FROM AUTHOR]

In this article, we examine how non-membership organizations that claim stewardship over a transnational public or common good, such as the environmental or digital commons, develop combinations of formal and informal recursivity to develop and maintain regulatory conversations with their dispersed user communities. Based on a case study of Creative Commons, an organization that developed what have become the most widely used open licenses for digital content, we show how rhetorical openness to informal feedback from legitimacy communities in different sectors and countries can improve the feasibility and diffusion of standards. However, as long as the standard-setter's methods of making decisions on the basis of such feedback remains opaque, its communities are likely to raise accountability demands for more extensive ex post justifications. [ABSTRACT FROM AUTHOR]

Background: The incidence of cardiac injury in immediate fatalities after blunt trauma remains underestimated, and reliable diagnostic strategies are still missing. Furthermore, clinical data concerning heart-specific troponin serum levels, injury severity score (ISS), catecholamine treatment and survival of patients on admission to the hospital have rarely been interrelated so far. Therefore, the object of the present study was to identify predictive parameters for mortality in the context of blunt cardiac injury. Methods: This retrospective observational study included 173 severely injured patients with an ISS ≥25 admitted to the University Hospital of Ulm, a level 1 trauma center, during 2009-2013 . Furthermore, 83 blunt trauma victims who died before hospital admission were subjected to postmortem examination at the Institute of Legal Medicine, University of Ulm, during 2009-2014. ISS, cardiac injury and associated thoracic injuries were determined in both groups. Furthermore, in the hospitalized patients, serum troponin and IL-6 levels were measured. Results: Macroscopic heart injury was observed in 18 % of the patients who died at the scene and only in 1 % of the patients admitted to the hospital, indicating that macroscopic heart injury is associated with an immediate life-threatening condition. Troponin levels were elevated in 43 % of the patients after admission to the hospital. Moreover, troponin serum concentrations were significantly higher in patients treated with norepinephrine (26.4 ± 4 ng/l) and in non-survivors (84.9 ± 22.8 ng/l) compared to patients without catecholamines and survivors, respectively. Conclusions: Macroscopic heart injury was 20 times more frequent in non-survivors than in survivors. Serum troponin levels correlated with mortality after multiple injury and therefore may represent a valuable prognostic marker in trauma patients. [ABSTRACT FROM AUTHOR]

Innate immunity is fundamental to our defense against microorganisms. Physiologically, the intravascular innate immune system acts as a purging system that identifies and removes foreign substances leading to thromboinflammatory responses, tissue remodeling, and repair. It is also a key contributor to the adverse effects observed in many diseases and therapies involving biomaterials and therapeutic cells/organs. The intravascular innate immune system consists of the cascade systems of the blood (the complement, contact, coagulation, and fibrinolytic systems), the blood cells (polymorphonuclear cells, monocytes, platelets), and the endothelial cell lining of the vessels. Activation of the intravascular innate immune system in vivo leads to thromboinflammation that can be activated by several of the system's pathways and that initiates repair after tissue damage and leads to adverse reactions in several disorders and treatment modalities. In this review, we summarize the current knowledge in the field and discuss the obstacles that exist in order to study the cross-talk between the components of the intravascular innate immune system. These include the use of purified in vitro systems, animal models and various types of anticoagulants. In order to avoid some of these obstacles we have developed specialized human whole blood models that allow investigation of the cross-talk between the various cascade systems and the blood cells. We in particular stress that platelets are involved in these interactions and that the lectin pathway of the complement system is an emerging part of innate immunity that interacts with the contact/coagulation system. Understanding the resulting thromboinflammation will allow development of new therapeutic modalities. [ABSTRACT FROM AUTHOR]

The purpose of this study was to define the relationship in polymicrobial sepsis (in adult maleC57BL/ 6 mice) between heart dysfunction and the appearance in plasma of extracellular histones. Procedures included induction of sepsis by cecal ligation and puncture and measurement of heart function using echocardiogram/ Doppler parameters.We assessed the ability of histones to cause disequilibrium in the redox status and intracellular [Ca2+]I levels in cardiomyocytes (CMs) (from mice and rats). We also studied the ability of histones to disturb both functional and electrical responses of hearts perfused with histones. Main findings revealed that extracellular histones appearing in septic plasma required C5a receptors, polymorphonuclear leukocytes (PMNs), and the Nacht-, LRR-, and PYD-domains--containing protein 3 (NLRP3) inflammasome. In vitro exposure of CMs to histones caused loss of homeostasis of the redox systemand in [Ca2+]i, aswell as defects inmitochondrial function. Perfusion of hearts with histones caused electrical and functional dysfunction. Finally, in vivo neutralization of histones in septic mice markedly reduced the parameters of heart dysfunction. Histones caused dysfunction in hearts during polymicrobial sepsis. These events could be attenuated by histone neutralization, suggesting that histones may be targets in the setting of sepsis to reduce cardiac dysfunction. [ABSTRACT FROM AUTHOR]

There is a growing awareness that complement plays an integral role in human physiology and disease, transcending its traditional perception as an accessory system for pathogen clearance and opsonic cell killing. As the list of pathologies linked to dysregulated complement activation grows longer, it has become clear that targeted modulation of this innate immune system opens new windows of therapeutic opportunity for anti-inflammatory drug design. Indeed, the introduction of the first complement-targeting drugs has reignited a vibrant interest in the clinical translation of complement-based inhibitors. Compstatin was discovered as a cyclic peptide that inhibits complement activation by binding C3 and interfering with convertase formation and C3 cleavage. As the convergence point of all activation pathways and a molecular hub for crosstalk with multiple pathogenic pathways, C3 represents an attractive target for therapeutic modulation of the complement cascade. A multidisciplinary drug optimization effort encompassing rational 'wet' and in silico synthetic approaches and an array of biophysical, structural and analytical tools has culminated in an impressive structure-function refinement of compstatin, yielding a series of analogues that show promise for a wide spectrum of clinical applications. These new derivatives have improved inhibitory potency and pharmacokinetic profiles and show efficacy in clinically relevant primate models of disease. This review provides an up-to-date survey of the drug design effort placed on the compstatin family of C3 inhibitors, highlighting the most promising drug candidates. It also discusses translational challenges in complement drug discovery and peptide drug development and reviews concerns related to systemic C3 interception. [ABSTRACT FROM AUTHOR]

This paper analyzes spillover effects in sports leagues that are embedded in a system of promotion and relegation. Based on a contest model of a professional sports league with a top division and a second division, we show that league prizes and club efficiencies have opposing effects; while a stronger second division that offers a higher league prize leads to a more balanced top division, the opposite is true for a stronger second division whose clubs become more cost efficient. Moreover, we demonstrate that a higher second-division prize induces a lower investment level, but higher profits in the top division, while higher club efficiency in the second division leads to both a lower investment level and lower profits in the top division. These results have important policy implications for the organization of sports leagues. [ABSTRACT FROM AUTHOR]

This paper analyzes the adverse incentive effects produced by money injections of benefactors [sugar daddies (SD)]. We show that the existence of a SD induces the club to choose a riskier investment strategy and the more the SD commits to bailout the club, the more the clubs' optimal level of riskiness increases. Moreover, a private SD bails out the club less often than a public SD. Our model further shows that a 'too-big-to-fail' phenomenon exists because it is optimal to always bailout a club if its market size is sufficiently large. [ABSTRACT FROM AUTHOR]

This paper develops a model of a cooperative enterprise and compares it to a vertically separated market. In our model of a multi-stage production process, agents can acquire costly knowledge to decrease production costs. Our model shows that the cooperative acquires less non-generalizable knowledge than the market, but more generalizable knowledge if the large member in the cooperative receives a sufficiently large share of the cooperative's profits. Additionally, we derive that the cooperative generates larger aggregate surplus than the market if the influence of generalizable knowledge on production costs is large. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

In poly-traumatic patients, second hits are known to potentiate the posttraumatic systemic inflammatory response, thus increasing the risk of multi-organ dysfunction. In accordance with 'damage control orthopaedic surgery' principles, fractures are initially treated with external fixators, which are replaced by internal osteosynthesis once the immunological status of the patient is considered stable. Recently, we demonstrated that a severe trauma impaired the healing of fractures stabilized by external fixation during the entire healing period. The question arose, whether switching to intramedullary nailing increases the inflammatory response in terms of a second hit, leading to a further impairment of bone healing. Wistar rats received a femoral osteotomy stabilized by an external fixator. Simultaneously half of the rats underwent an additional thoracic trauma. After 4 days, the external fixator was replaced by an intramedullary nail in half of the rats of the two groups. The inflammatory response was evaluated by measuring serum C5a levels. Fracture healing was determined by three-point-bending, µCT, and histomorphometry. The thoracic trauma significantly increased C5a concentrations 6, 24, and 72 h after the second surgical intervention. After 40 days, conversion to intramedullary nailing considerably decreased the flexural rigidity of the callus, with no significant differences between rats with or without thoracic trauma. After 47 days, flexural rigidity in rats subjected to conversion remained decreased compared to animals solely treated by external fixation, particularly in combination with blunt chest trauma. The results indicate that accumulation of second hits after multiple injuries could lead to aggravation of the fracture healing outcome. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 465-471, 2013 [ABSTRACT FROM AUTHOR]

This paper analyzes the effects of a percentage-of-revenue salary cap in a team sports league with win-maximizing clubs and flexible talent supply. It shows that a percentage-of-revenue cap produces a more balanced league and decreases aggregate salary payments. Taking into account the idiosyncrasies of European football, our paper further highlights the potential conflicts between the league and society. From the perspective of a league governing body, a percentage-of-revenue cap always enhances financial stability of win-maximizing clubs. A social planner, however, will not permit the introduction of such a cap if fans and players unduly suffer. This paper shows under which conditions the social planner accepts (rejects) a salary cap proposed by the league regulator. ( JEL D02, D60, L83) [ABSTRACT FROM AUTHOR]

Confirming clinical evidence, we recently demonstrated that a blunt chest trauma considerably impaired fracture healing in rats, possibly via the interaction of posttraumatic systemic inflammation with local healing processes, the underlying mechanisms being unknown. An important trigger of systemic inflammation is the complement system, with the potent anaphylatoxin C5a. Therefore, we investigated whether the impairment of fracture healing by a severe trauma resulted from systemically activated complement. Rats received a blunt chest trauma and a femur osteotomy stabilized with an external fixator. To inhibit the C5a-dependent posttraumatic systemic inflammation, half of the rats received a C5aR-antagonist intravenously immediately and 12 h after the thoracic trauma. Compared to the controls (control peptide), the treatment with the C5aR-antagonist led to a significantly increased flexural rigidity (three-point-bending test), an improved bony bridging of the fracture gap, and a slightly larger and qualitatively improved callus (µCT, histomorphometry) after 35 days. In conclusion, immunomodulation by a C5aR-antagonist could abolish the deleterious effects of a thoracic trauma on fracture healing, possibly by influencing the function of inflammatory and bone cells locally at the fracture site. C5a could possibly represent a target to prevent delayed bone healing in patients with severe trauma. © 2011 Orthopaedic Research Society. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 30:581-586, 2012 [ABSTRACT FROM AUTHOR]

In poly-traumatic patients a blunt chest trauma is an important trigger of the posttraumatic systemic inflammatory response. There is clinical evidence that fracture healing is delayed in such patients, however, experimental data are lacking. Therefore, we investigated the influence of a thoracic trauma on fracture healing in a rat model. Male Wistar rats received either a blunt chest trauma combined with a femur osteotomy or an isolated osteotomy. A more rigid or a more flexible external fixator was used for fracture stabilization to analyze whether the thoracic trauma influences regular healing and mechanically induced delayed bone healing differently. The blunt chest trauma induced a significant increase of IL-6 serum levels after 6 and 24 h, suggesting the induction of a systemic inflammation, whereas the isolated fracture had no effect. Under a more rigid fixation the thoracic trauma considerably impaired fracture healing after 35 days, reflected by a significantly reduced flexural rigidity (three-point-bending test), as well as a significantly diminished callus volume, moment of inertia, and relative bone surface (µCT analysis). In confirming the clinical evidence, this study reports for the first time that a blunt chest trauma considerably impaired bone healing, possibly via the interaction of the induced systemic inflammation with local inflammatory processes. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29:734-739, 2011 [ABSTRACT FROM AUTHOR]

Many major sports leagues are characterized by a combination of cross-subsidization mechanisms like revenue-sharing arrangements and payroll restrictions. Up to now, the effects of these policy tools have only been analyzed separately. This article provides a theoretical model of a team sports league and analyzes the combined effect of salary restrictions (caps and floors) and revenue sharing. It shows that the effect on club profits, player salaries, and competitive balance crucially depends on the mix of these policy tools. Moreover, the invariance proposition does not hold even under Walrasian-conjectures if revenue sharing is combined with a salary cap or floor. ( JEL L83, C72, L11) [ABSTRACT FROM AUTHOR]

Background: Complement activation contributes to the regulation of liver regeneration after liver resection (LR) in mice. Methods: We hypothesized that complement activation and changes in C5a-receptors (C5aR, C5L2) on polymorphonuclear cells (PMN) and monocytes are important in clinical LR. Anaphylatoxin and C5b9 plasma levels were measured (bead-array, ELISA) (25 patients) and receptor expression was assessed after LR (19 patients) (FACS). In vitro PMN C5a-dependent chemotactic response (7 patients) as well as l-selectin shedding and Mac-1 expression (3 patients) was determined. Results: C3a increased after LR (31.1 ± 4 before LR vs. 41.6 ± 5 ng/ml, 30 min after LR, P < 0.01), as did C5b9 (12.7 ± 1 before LR vs. 26.9 ± 3 ng/ml, 60 min after LR, P < 0.001). C4a and C5a decreased after LR, by 25% 24 h after LR and 30% 2 h after LR, respectively ( P < 0.01). C5L2 expression decreased at 4 h, rising at 24 h after LR (PMN: 6.3 ± 1 before LR, 3.1 ± 1, 4 h, 8.3 ± 2, 24 h; P < 0.01). The receptor-related changes accompanied a diminished C5a-dependent chemotactic response by PMN (42.1 ± 17 before LR vs. 2.1 ± 3 4 h after LR; P < 0.01) and a reduction of activation upon C5a-R stimulation as measured by l-selectin shedding and Mac-1 expression on PMN. Changes in C5L2 expression on monocytes paralleled postoperative impairment of liver function. Conclusions: These results indicate that complement components are released after clinical LR and subsequently PMN display altered C5a-dependent functional responses. [ABSTRACT FROM AUTHOR]

This article develops a contest model to compare social welfare in homogeneous leagues in which all clubs maximize identical objective functions with mixed leagues in which clubs maximize different objective functions. We show that homogeneous leagues in which all clubs are profit maximizers dominate all other leagues. Mixed leagues in which small-market clubs are profit maximizers and large-market clubs are win maximizers (type-I mixed leagues) are dominated by all other leagues. From a welfare perspective, large-market clubs win too often in (purely) win-maximizing and type-I mixed leagues; whereas, small-market clubs win too many games in (purely) profit-maximizing leagues and in mixed leagues in which large-market clubs are profit maximizers and small-market clubs are win maximizers (type-Il mixed leagues). These results have important policy implications: Social welfare will increase if clubs are reorganized from non-profit member associations to profit-maximizing corporations. Moreover, we show that revenue sharing decreases (increases) social welfare in mixed (homogeneous) leagues. [ABSTRACT FROM AUTHOR]

Published lethality rates of esophageal perforation (EP) vary depending on patient- and disease-related factors. This study was designed to evaluate how these factors impact death. Furthermore, we calculated the predictive accuracy of the Mortality Prediction Model (MPM II) and the Simplified Acute Physiology Score (SAPS II) for in-hospital death. Conclusions about treatment decisions were drawn based on our data and analysis of recent literature. Every patient who was treated for EP at our department from December 2001 to July 2008 is included in this study. Logistic regression analyses of various risk factors, such as etiology, time interval, size, comorbidities, localization, type of treatment, and preexisting pathologies of the esophagus on death, were performed. Of the 41 patients diagnosed with EP, nine died (21%). The most important risk factor concerning death was cirrhosis of the liver (0 vs. 89% mortality; odds ratio, 208; P < 0.001). Accuracy for lethality risk prediction was calculated with MPM II and SAPS II on admission, and afterward the characteristic increase that occurred was evaluated by using receiver operator characteristic curves. Optimal results were achieved by using a characteristic SAPS II increase (AUC 0.86; P: 0.009) after the patient was admitted to the intensive care unit. Our study was the first to demonstrate that a rapid or continuous increase more than 40 of the daily SAPS II clearly indicates that a high risk of death is imminent. This should be used as a reevaluation factor when choosing a treatment strategy. [ABSTRACT FROM AUTHOR]

Activation of the complement system is a key event in the pathogenesis of sepsis. Nevertheless, the exact mechanisms remain inadequately understood. In the current study, we examined the role of complement C3 and C5 in sepsis in wild-type and C3- or C5-deficient mice induced by cecal ligation and puncture. When compared to wild-type mice, C5-/- showed identical survival, and C3-/- presented significantly reduced survival. Interestingly, this was associated with significant decreases in plasma levels of proinflammatory mediators. Moreover, although septic C3-/- animals displayed a 10-fold increase of blood-borne bacteria, C5-/- animals exhibited a 400-fold increase in bacteremia when compared to wild-type mice. These effects were linked to the inability of C5-/- mice to assemble the terminal membrane attack complex (MAC), as determined by complement hemolytic activity (CH-50). Surprisingly, although negative control C3-/- mice failed to generate the MAC, significant increases of MAC formation was found in septic C3-/- mice. In conclusion, our data corroborate that hemolytic complement activity is essential for control of bacteremia in septic mice. Thus, during sepsis, blockade of C5a or its receptors (rather than C5) seems a more promising strategy, because C5a-blockade still allows for MAC formation while the adverse effects of C5a are prevented. [ABSTRACT FROM AUTHOR]

IL-17A is a proinflammatory cytokine produced by a variety of cells. In the current study, we examined the role of IL-17A in sepsis induced in mice by cecal ligation and puncture (CLP). IL-17A levels, which rose time-dependently in plasma after CLP, were not affected in the absence of αβ T cells or neutrophils. In sharp contrast, γδ T cell-knockout or γδ T cell-depleted mice displayed baseline IL-17A plasma levels after CLP. Neutralization of IL-17A by two different antibodies improved sepsis (survival from ∼10% to nearly 60%). Unexpectedly, antibody treatment was protective, even when administration of anti-IL-17A was delayed for up to 12 h after CLP. These protective effects of IL-17A blockade were associated with substantially reduced levels of bacteremia together with significant reductions of systemic proinflammatory cytokines and chemokines in plasma. In vitro incubation of mouse peritoneal macrophages with lipopolysaccharide (LPS) in the copresence of IL-17A substantially increased the production of TNF-α, IL-1β, and IL-6 by these cells. These data suggest that, during experimental sepsis, γδ T cell-derived IL-17A promotes high levels of proinflammatory mediators and bacteremia, resulting in enhanced lethality. IL-17A may be a potential therapeutic target in sepsis.--Flierl, M. A., Rittirsch, D., Gao, H., Hoesel, L. M., Nadeau, B. A., Day, D. E., Zetoune, F. S., Sarma, J. V., Huber-Lang, M. S., Ferrara, J. L. M., Ward, P. A. Adverse functions of IL-17A in experimental sepsis. [ABSTRACT FROM AUTHOR]

This paper applies contest theory to provide an integrated framework of a team sports league and analyzes the competitive interaction between clubs. We show that dissipation of the league revenue arises from ‘overinvestment’ in playing talent as a direct consequence of the ruinous competitive interaction between clubs. This overinvestment problem increases if the discriminatory power of the contest function increases, revenue-sharing decreases, and the size of an additional exogenous prize increases. We further show that clubs invest more when they play in an open league compared with a closed league. Moreover, the overinvestment problem within open leagues increases with the revenue differential between leagues. [ABSTRACT FROM AUTHOR]

This paper provides a theoretical model of a team sports league based on contest theory and studies the welfare effect of gate revenue sharing. It derives two counter-intuitive results. First, it challenges the "invariance proposition" by showing that revenue sharing reduces competitive balance and thus produces a more unbalanced league. Second. the paper concludes that a lower degree of competitive balance compared with the noncooperative league equilibrium yields a higher level of social welfare and club profits. Combining both results, it concludes that gate revenue sharing increases social welfare and club profits in our model. [ABSTRACT FROM AUTHOR]

Skin is the first barrier preventing microorganism invasion in host. Wounds destroy this defense barrier and, without an appropriate care, may lead to sepsis. Neutrophil activation and immigration plays an important role at the inflammatory stage of wound healing. Neutrophils are known to express proteinase-activated receptors (PARs), which can be activated by serine proteases, also by enzymes involved in wound healing. We previously reported that PAR2 agonists up-regulate cell adhesion molecule expression and cytokine production by human neutrophils. Here, we demonstrate that PAR2 agonists (serine proteases as well as synthetic peptides) reduce transendothelial migration of neutrophils and prolong their life in vitro. Synthetic PAR2 agonist also enhanced protective interferon (IFN)γ-induced FcγRI expression at neutrophil cell surface. Of note, IFNγ is a cytokine, which was used in clinical trials to reactivate human neutrophil functions during sepsis. Moreover, we observed a significant increase of PAR2 expression on cell surface of neutrophils from septic patients as compared with healthy volunteers. Together, our results indicate that PAR2 may be involved in the pathophysiology of neutrophil-endothelial interactions during wound healing or later during sepsis in humans, potentially by affecting neutrophil apoptosis, transendothelial migration and Fcγ receptor-mediated phagocytosis. [ABSTRACT FROM AUTHOR]

After severe trauma, the resulting excessive inflammatory response is countered by compensatory anti‐inflammatory mechanisms. The systemic inflammatory response to trauma enhanced by inappropriately timed surgical second hits may be detrimental for the patient. On the other hand, overwhelming anti‐inflammatory mechanisms may put patients at increased risk from secondary local and systemic infections. The ensuing sepsis and organ dysfunction due to immune dysregulation remain the leading causes of death after injury. To date, there are no clinically applicable techniques to monitor the pro‐/anti‐inflammatory immune status of the patients and the remaining ability to react to microbial stimuli. Therefore, in the present study, we used a highly standardized and easy‐to‐use system to draw peripheral whole blood from polytraumatized patients (ISS ≥ 32, n = 7) and to challenge it with bacterial lipopolysaccharide. Secreted cytokines were compared with those in samples from healthy volunteers. We observed a significant decrease in the release of monocyte‐derived mediators. Surprisingly, we detected stable or even increased concentrations of cytokines related to T cell maturation and function. For clinical practicability, we reduced the incubation time before supernatants were collected. Even after an abbreviated stimulation period, a stable release of almost all analysed parameters in patient blood could be detected. In conclusion, the data are indicative of a clinically well‐applicable approach to monitor the immune status in severely injured patients in a short time. This may be used to optimize the timing of necessary surgical interventions to avoid a boost of proinflammation and reduce risk of secondary infections. [ABSTRACT FROM AUTHOR]

Background: Food-induced anaphylaxis is a serious allergic reaction caused by Fcε-receptor activation on mast cells (MCs). The exact mechanisms breaking oral tolerance and the effector pathways driving food allergy remain elusive. As complement is activated in food-induced anaphylaxis, we aimed to assess the role of C5a in disease pathogenesis., Methods: Oral antigen-induced food-induced anaphylaxis was induced in BALB/c wild-type (wt) and C5ar1 -/- mice. Readouts included diarrhea development, changes in rectal temperature, hematocrit, antigen-specific serum IgE, MCPT-1, and intestinal MC numbers, as well as FcεR1-mediated MC functions including C5a receptor 1 (C5aR1) regulation. Further, histamine-mediated hypothermia and regulation of endothelial tight junctions were determined., Results: Repeated oral OVA challenge resulted in diarrhea, hypothermia, increased hematocrit, high OVA-specific serum IgE, and MCPT-1 levels in wt mice. Male C5ar1 -/- mice were completely whereas female C5ar1 -/- mice were partially protected from anaphylaxis development. Serum MCPT-1 levels were reduced gender-independent, whereas IgE levels were reduced in male but not in female C5ar1 -/- mice. Mechanistically, IgE-mediated degranulation and IL-6 production from C5ar1 -/- BMMCs of both sexes were significantly reduced. Importantly, FcεR1 cross-linking strongly upregulated C5aR1 MC expression in vitro and in vivo. Finally, C5ar1 -/- male mice were largely protected from histamine-induced hypovolemic shock, which was associated with protection from histamine-induced barrier dysfunction in vitro following C5aR targeting., Conclusions: Our findings identify C5aR1 activation as an important driver of IgE-mediated food allergy through regulation of allergen-specific IgE production, FcεR1-mediated MC degranulation, and histamine-driven effector functions preferentially in male mice., (© 2018 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)