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Living Labs: Knowledge Infrastructures to Forge a New Social Contract of Science?
Living Labs (LLs) are heralded as new and inclusive platforms for collective and transformative knowledge production and innovation management with actors from science, practice and society. This begs the question what kinds of social relations emerge between these actors especially as the leading institutions vary, in other words, whether LLs give rise to distinct knowledge infrastructures and new forms of social contracting (of science). A comparative analysis focusing on structural and power-related aspects of four LL case studies with different leading institutions (university, industry, city and civil society) show specific features of social ordering while performing social contracts with regard to the leading institution. The cases result, on the one hand, in rather closed off spaces in which science and innovation for and in society is enacted by technology-oriented industry and university LLs. These are embedded in and solve set problems for society. On the other hand, in less confined spaces science and innovation with and by society is conducted in city and civil society run LLs. Here, a more communal contracting towards defining and solving societal problems is established. A reflexive approach to structuring and governing LLs in practice and a more robust theoretical foundation would therefore be beneficial.
Journal Article
Extracorporeal Life Support in Infarct-Related Cardiogenic Shock
Extracorporeal life support (ECLS) is increasingly used in the treatment of infarct-related cardiogenic shock despite a lack of evidence regarding its effect on mortality.
In this multicenter trial, patients with acute myocardial infarction complicated by cardiogenic shock for whom early revascularization was planned were randomly assigned to receive early ECLS plus usual medical treatment (ECLS group) or usual medical treatment alone (control group). The primary outcome was death from any cause at 30 days. Safety outcomes included bleeding, stroke, and peripheral vascular complications warranting interventional or surgical therapy.
A total of 420 patients underwent randomization, and 417 patients were included in final analyses. At 30 days, death from any cause had occurred in 100 of 209 patients (47.8%) in the ECLS group and in 102 of 208 patients (49.0%) in the control group (relative risk, 0.98; 95% confidence interval [CI], 0.80 to 1.19; P = 0.81). The median duration of mechanical ventilation was 7 days (interquartile range, 4 to 12) in the ECLS group and 5 days (interquartile range, 3 to 9) in the control group (median difference, 1 day; 95% CI, 0 to 2). The safety outcome consisting of moderate or severe bleeding occurred in 23.4% of the patients in the ECLS group and in 9.6% of those in the control group (relative risk, 2.44; 95% CI, 1.50 to 3.95); peripheral vascular complications warranting intervention occurred in 11.0% and 3.8%, respectively (relative risk, 2.86; 95% CI, 1.31 to 6.25).
In patients with acute myocardial infarction complicated by cardiogenic shock with planned early revascularization, the risk of death from any cause at the 30-day follow-up was not lower among the patients who received ECLS therapy than among those who received medical therapy alone. (Funded by the Else Kröner Fresenius Foundation and others; ECLS-SHOCK ClinicalTrials.gov number, NCT03637205.).
Journal Article
Interleukin-6 signalling in health and disease version 1; peer review: awaiting peer review
Biochemically, interleukin-6 belongs to the class of four-helical cytokines. The cytokine can be synthesised and secreted by many cells. It acts via a cell surface-expressed interleukin-6 receptor, which is not signalling competent. This receptor, when complexed with interleukin-6, associates with the signalling receptor glycoprotein 130 kDa (gp130), which becomes dimerised and initiates intracellular signalling via the Janus kinase/signal transducer and activator of transcription and rat sarcoma proto oncogene/mitogen-activated protein kinase/phosphoinositide-3 kinase pathways. Physiologically, interleukin-6 is involved in the regulation of haematopoiesis and the coordination of the innate and acquired immune systems. Additionally, interleukin-6 plays an important role in the regulation of metabolism, in neural development and survival, and in the development and maintenance of various cancers. Although interleukin-6 is mostly regarded as a pro-inflammatory cytokine, there are numerous examples of protective and regenerative functions of this cytokine. This review will explain the molecular mechanisms of the, in part opposing, activities of the cytokine interleukin-6.
Journal Article
Generalization as local and translocal embedding: interrogating governance and deconstructing democratization in living labs
As societies scramble for ways to surmount current sustainability challenges, living labs have emerged as hopeful hybrid institutions to facilitate collaboration. In addition to embedding innovations locally, living labs are also expected to generate transferable or scalable solutions and thus achieve “translocal embedding.” This raises questions about how far existing living lab initiatives attend to and address the dual challenge of local and translocal embedding and in what ways relevant stakeholder groups are included or excluded from scientific research and technological development toward transformative change. Based on a literature review and case-study analysis, this article distinguishes three types of living labs: “solution optimizers,” concerned with the application of technological innovations and their optimization in terms of efficiency, safety, security, and usability; “solution tailors” addressing technology implementation and regulatory framework conditions; and “solution co-creators” fostering participatory approaches toward socio-technical innovation. The findings show that across these three types of living labs, the number of contextual factors and the associated degree of complex interactions between experimental design and experimental outcomes increase alongside the number of actively involved stakeholder groups. Tracing processes of local and translocal embedding in the three types of living labs, this contribution reveals dynamics of stakeholder inclusion and exclusion. Notably, civic actors are often excluded from decision-making processes related to technology appraisal and commitment at the translocal scale. Instead, they can provide feedback as end-users or engage in participatory processes to pave the way for the local embedding of sustainable practices and technologies in and through living labs.
Journal Article
IL-6 biology: implications for clinical targeting in rheumatic disease
Key Points
IL-6 can signal via the membrane-bound and the soluble IL-6 receptor (IL-6R); classic signalling via the membrane-bound receptor is regenerative and protects from bacterial infections, whereas trans-signalling via the soluble receptor is proinflammatory
The soluble gp130Fc fusion protein specifically blocks IL-6 trans-signalling without affecting classic signalling
Preclinical models strongly suggest the efficacy of IL-6-directed therapies for a variety of immunological conditions
The approval and use of tocilizumab, a first-in-class human monoclonal antibody directed at IL-6R, has demonstrated that this strategy is both highly effective and safe
New agents with unique bioengineering features targeting either IL-6 or the soluble IL-6R, with varying selectivity for classic signalling and trans-signalling pathways, are entering clinical trials and offer alternative strategies for IL-6-based therapies
Selective IL-6-based therapeutic targeting has several unique toxicity signatures, including paradoxical effects on surrogate markers of cardiovascular risk, and awaits clinical studies to determine net effects on morbidity and mortality
IL-6 has been linked to numerous inflammatory conditions (such as rheumatoid arthritis), and many IL-6-directed therapies are currently in development. The authors outline the basic biology of IL-6 and IL-6 signalling pathways before discussing the clinical implications of targeting IL-6 in the context of rheumatic diseases. Current and future indications for the use of IL-6-targeted therapies and safety of these agents are discussed.
IL-6 has been linked to numerous diseases associated with inflammation, including rheumatoid arthritis, inflammatory bowel disease, vasculitis and several types of cancer. Moreover, IL-6 is important in the induction of hepatic acute-phase proteins for the trafficking of acute and chronic inflammatory cells, the differentiation of adaptive T-cell responses, and tissue regeneration and homeostatic regulation. Studies have investigated IL-6 biology using cell-bound IL-6 receptors expressed predominantly on hepatocytes and certain haematopoietic cells versus activation mediated by IL-6 and soluble IL-6 receptors via a second protein, gp130, which is expressed throughout the body. Advances in this research elucidating the differential effects of IL-6 activation provide important insights into the role of IL-6 in health and disease, as well as its potential as a therapeutic target. Knowledge of the basic biology of IL-6 and its signalling pathways can better inform both the research agenda for IL-6-based targeted therapies as well as the clinical use of strategies affecting IL-6-mediated inflammation. This Review covers novel, emerging aspects of the biology of IL-6, which might lead to more specific blockade of IL-6 signalling without compromising the protective function of this cytokine in the body's defence against infections.
Journal Article
Epidemiology of sepsis in Germany: results from a national prospective multicenter study
To determine the prevalence and mortality of ICU patients with severe sepsis in Germany, with consideration of hospital size.
Prospective, observational, cross-sectional 1-day point-prevalence study.
454 ICUs from a representative nationwide sample of 310 hospitals stratified by size. Data were collected via 1-day on-site audits by trained external study physicians. Visits were randomly distributed over 1 year (2003).
Inflammatory response of all ICU patients was assessed using the ACCP/SCCM consensus conference criteria. Patients with severe sepsis were followed up after 3 months for hospital mortality and length of ICU stay.
Main outcome measures were prevalence and mortality. A total of 3,877 patients were screened. Prevalence was 12.4% (95% CI, 10.9-13.8%) for sepsis and 11.0% (95% CI, 9.7-12.2%) for severe sepsis including septic shock. The ICU and hospital mortality of patients with severe sepsis was 48.4 and 55.2%, respectively, without significant differences between hospital size. Prevalence and mean length of ICU stay of patients with severe sepsis were significantly higher in larger hospitals and universities (
Journal Article
Intensive Insulin Therapy and Pentastarch Resuscitation in Severe Sepsis
Optimal glucose control and fluid resuscitation in patients with septic shock remain a challenge. In this study involving more than 500 patients, the potential benefit of maintaining euglycemia through intensive insulin therapy and optimal fluid resuscitation with either pentastarch or Ringer's lactate was assessed. There was no benefit in the intensive-therapy group with respect to either 28-day survival or organ function; there was more severe hypoglycemia in the intensive-therapy group and more acute renal failure in the pentastarch group.
The potential benefit of maintaining euglycemia through intensive insulin therapy and optimal fluid resuscitation was assessed. There was no benefit in the intensive-therapy group with respect to either 28-day survival or organ function.
In a study by Van den Berghe et al. involving critically ill surgical patients, intensive insulin therapy to maintain euglycemia (glucose level, 80 to 110 mg per deciliter [4.4 to 6.1 mmol per liter]) lowered in-hospital mortality from 10.9% to 7.2%, mostly by reducing deaths from multiple organ failure with a proven septic focus.
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This beneficial effect occurred predominantly in cardiac surgical patients who received high glucose challenges immediately after surgery (8 to 12 g of glucose intravenously per hour) and was associated with an unusually high rate of death (5.1%) among controls.
Furthermore, in a follow-up study by Van . . .
Journal Article
Low-flow CO2 removal in combination with renal replacement therapy effectively reduces ventilation requirements in hypercapnic patients: a pilot study
BackgroundLung-protective strategies are the cornerstone of mechanical ventilation in critically ill patients with both ARDS and other disorders. Extracorporeal CO2 removal (ECCO2R) may enhance lung protection by allowing even further reductions in tidal volumes and is effective in low-flow settings commonly used for renal replacement therapy. In this study, we describe for the first time the effects of a labeled and certified system combining ECCO2R and renal replacement therapy on pulmonary stress and strain in hypercapnic patients with renal failure.MethodsTwenty patients were treated with the combined system which incorporates a membrane lung (0.32 m2) in a conventional renal replacement circuit. After changes in blood gases under ECCO2R were recorded, baseline hypercapnia was reestablished and the impact on ventilation parameters such as tidal volume and driving pressure was recorded.ResultsThe system delivered ECCO2R at rate of 43.4 ± 14.1 ml/min, PaCO2 decreased from 68.3 ± 11.8 to 61.8 ± 11.5 mmHg (p < 0.05) and pH increased from 7.18 ± 0.09 to 7.22 ± 0.08 (p < 0.05). There was a significant reduction in ventilation requirements with a decrease in tidal volume from 6.2 ± 0.9 to 5.4 ± 1.1 ml/kg PBW (p < 0.05) corresponding to a decrease in plateau pressure from 30.6 ± 4.6 to 27.7 ± 4.1 cmH2O (p < 0.05) and a decrease in driving pressure from 18.3 ± 4.3 to 15.6 ± 3.9 cmH2O (p < 0.05), indicating reduced pulmonary stress and strain. No complications related to the procedure were observed.ConclusionsThe investigated low-flow ECCO2R and renal replacement system can ameliorate respiratory acidosis and decrease ventilation requirements in hypercapnic patients with concomitant renal failure.Trial registration NCT02590575, registered 10/23/2015.
Journal Article