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While the initial minutes of acute emergencies significantly influence clinical outcomes, prehospital research often receives inadequate attention due to several challenges. Retrospective chart reviews carry the risk of incomplete and inaccurate data. Furthermore, prehospital intervention trials frequently encounter difficulties related to extensive training requirements, even during the planning phase. Consequently, we have implemented prospective research concepts involving additional paramedics and physicians directly at the scene during major emergency calls. Three concepts were used: (I) Paramedic field supervisor units, (II) a paramedic + physician field supervisor unit, (III) a special physician-based research car. This paper provides insights into our historical perspective, the current situation, and the lessons learned while overcoming certain barriers and using existing and novel facilitators. Our objective is to support other research groups with our experiences in their planning of upcoming prehospital trials.

IntroductionExtracorporeal cardiopulmonary resuscitation (ECPR) is an emerging strategy in highly selected patients with refractory cardiac arrest (CA). Animal models can help to identify new therapeutic strategies to improve neurological outcome and cardiac function after global ischemia in CA. Aim of the study was to establish a reproducible ECPR rat model of ventricular fibrillation CA (VFCA) that leads to consistent neuronal damage with acceptable long-term survival rates, which can be used for future research.Materials and methodsMale Sprague Dawley rats were resuscitated with ECPR from 6 min (n = 15) and 8 min (n = 16) VFCA. Animals surviving for 14 days after return of spontaneous resuscitation (ROSC) were compared with sham operated animals (n = 10); neurological outcome was assessed daily until day 14. In the hippocampal cornu ammonis 1 region viable neurons were counted. Microglia and astrocyte reaction was assessed by Iba1 and GFAP immunohistochemistry, and collagen fibers in the myocardium were detected in Azan staining. QuPath was applied for quantification.ResultsOf the 15 rats included in the 6 min CA group, all achieved ROSC (100%) and 10 (67%) survived to 14 days; in the 8 min CA group, 15 (94%) achieved ROSC and 5 (31%) reached the endpoint. All sham animals (n = 10) survived 2 weeks. The quantity of viable neurons was significantly decreased, while the area displaying Iba1 and GFAP positive pixels was significantly increased in the hippocampus across both groups that experienced CA. Interestingly, there was no difference between the two CA groups regarding these changes. The myocardium in the 8 min CA group exhibited significantly more collagen fibers compared to the sham animals, without differences between 6- and 8-min CA groups. However, this significant increase was not observed in the 6 min CA group.ConclusionOur findings indicate a uniform occurrence of neuronal damage in the hippocampus across both CA groups. However, there was a decrease in survival following an 8-min CA. Consequently, a 6-min duration of CA resulted in predictable neurological damage without significant cardiac damage and ensured adequate survival rates up to 14 days. This appears to offer a reliable model for investigating neuroprotective therapies.

Background Management of patients with non–ST‐segment–elevation acute coronary syndrome (NSTE‐ACS) is based on 2020 European Society of Cardiology guidelines, which recommend the preferential use of prasugrel over ticagrelor. Because the selection of the respective P2Y12 inhibitor has to consider label restrictions, we sought to evaluate the proportion of patients qualifying for either ticagrelor or prasugrel and reasons for noneligibility in an unselected cohort of patients with acute coronary syndrome. Methods and Results In this retrospective observational study, patients with ST‐segment–elevation myocardial infarction (STEMI) or NSTE‐ACS presenting consecutively during a 24‐month period were enrolled. The eligibility of patients for a dual antiplatelet therapy option was assessed retrospectively. A total of 1502 patients had confirmed acute coronary syndrome (287 STEMI and 1215 NSTE‐ACS). Eligibility for ticagrelor and full‐dose prasugrel differed significantly for STEMI and NSTE‐ACS (93% versus 51%, P

Background and aimsPreclinical data suggest that activation of the adaptive immune system is critical for myocardial repair processes in acute myocardial infarction. The aim of the present study was to determine the clinical value of baseline effector T cell chemokine IP-10 blood levels in the acute phase of ST-segment elevation myocardial infarction (STEMI) for the prediction of the left ventricular function changes and cardiovascular outcomes after STEMI.MethodsSerum IP-10 levels were retrospectively quantified in two independent cohorts of STEMI patients undergoing primary percutaneous coronary intervention.ResultsWe report a biphasic response of the effector T cell trafficking chemokine IP-10 characterized by an initial increase of its serum levels in the acute phase of STEMI followed by a rapid reduction at 90min post reperfusion. Patients at the highest IP-10 tertile presented also with more CD4 effector memory T cells (CD4 TEM cells), but not other T cell subtypes, in blood. In the Newcastle cohort (n=47), patients in the highest IP-10 tertile or CD4 TEM cells at admission exhibited an improved cardiac systolic function 12 weeks after STEMI compared to patients in the lowest IP-10 tertile. In the Heidelberg cohort (n=331), STEMI patients were followed for a median of 540 days for major adverse cardiovascular events (MACE). Patients presenting with higher serum IP-10 levels at admission had a lower risk for MACE after adjustment for traditional risk factors, CRP and high-sensitivity troponin-T levels (highest vs. rest quarters: HR [95% CI]=0.420 [0.218-0.808]).ConclusionIncreased serum levels of IP-10 in the acute phase of STEMI predict a better recovery in cardiac systolic function and less adverse events in patients after STEMI.

BackgroundFace-to-face medical education was restricted during the COVID-19 pandemic, leading to alternative teaching methods. Moodle® (Modular Object-Oriented Dynamic Learning Environment) – an online course format – has not yet been sufficiently evaluated for its feasibility and effectiveness in teaching cardiopulmonary resuscitation.MethodsMedical students in the eighth semester took part in a Moodle® course teaching basic life support, the ABCDE-approach, airway management, and advanced life support. The content was presented using digital background information and interactive videos. A multiple-choice test was conducted at the beginning and at the end of the course. Subjective ratings were included as well.ResultsOut of 594 students, who were enrolled in the online course, 531 could be included in this study. The median percentage of correctly answered multiple-choice test questions increased after completing the course [78.9%, interquartile range (IQR) 69.3–86.8 vs. 97.4%, IQR 92.1–100, p < 0.001]. There was no gender difference in the median percentage of correctly answered questions before (female: 79.8%, IQR 70.2–86.8, male: 78.1%, IQR 68.4–86.8, p = 0.412) or after (female: 97.4%, IQR 92.1–100, male: 96.5%, IQR 92.6–100, p = 0.233) the course. On a 5-point Likert scale, 78.7% of students self-reported ≥4 when asked for a subjective increase in knowledge. Noteworthy, on a 10-point Likert scale, male students self-reported their higher confidence in performing CPR [female 6 (5–7), male 7 (6–8), p < 0.001].ConclusionThe Moodle® course led to a significant increase in theoretical knowledge. It proved to be a feasible substitute for face-to-face courses – both objectively and subjectively.

We present data collected for the research article “Advances in Spiral fMRI: A High-resolution Study with Single-shot Acquisition” (Kasper et al. 2022). All data was acquired on a 7T ultra-high field MR system (Philips Achieva), equipped with a concurrent magnetic field monitoring setup based on 16 NMR probes. For task-based fMRI, a visual quarterfield stimulation paradigm was employed, alongside physiological monitoring via peripheral recordings.This data collection contains different datasets pertaining to different purposes:(1) Measured magnetic field dynamics (k0, spiral k-space trajectories, 2nd order spherical harmonics, concomitant fields) during ultra-high field fMRI sessions from six subjects, as well as concurrent temperature curves of the gradient coil, to explore MR system and subject-induced variability of field fluctuations and assess the impact of potential correction methods.(2) MR Raw Data, i.e., coil and concurrent encoding magnetic field (trajectory) data, of a single subject, as well as nominal spiral gradient waveforms, precomputed B0 and coil sensitivity maps, to enable testing of alternative image reconstruction approaches for spiral fMRI data.(3) Reconstructed image time series of the same subject alongside behavioral and physiological logfiles, to reproduce the fMRI preprocessing and analysis, as well as figures presented in the research article related to this article, using the published analysis code repository.All data is provided in standardized formats for the respective research area. In particular, ISMRMRD (HDF5) is used to store raw coil data and spiral trajectories, as well as measured field dynamics. Likewise, the NIfTI format is used for all imaging data (anatomical MRI and spiral fMRI, B0 and coil sensitivity maps).

Abstract Whether admission C-reactive protein (aCRP) concentrations are associated with neurological outcome after out-of-hospital cardiac arrest (OHCA) is controversial. Based on established kinetics of CRP, we hypothesized that aCRP may reflect the pre-arrest state of health and investigated associations with neurological outcome. Prospectively collected data from the Vienna Clinical Cardiac Arrest Registry of the Department of Emergency Medicine were analysed. Adults (≥ 18 years) who suffered a non-traumatic OHCA between January 2013 and December 2018, without return of spontaneous circulation or extracorporeal cardiopulmonary resuscitation therapy were eligible. The primary endpoint was a composite of unfavourable neurologic function or death (defined as Cerebral Performance Category 3–5) at 30 days. Associations of CRP levels drawn within 30 min of hospital admission were assessed using binary logistic regression. ACRP concentrations were overall low in our population (n = 832), but higher in the unfavourable outcome group [median: 0.44 (quartiles 0.15–1.44) mg/dL vs. 0.26 (0.11–0.62) mg/dL, p

Objective: Targeted temperature management (TTM) is part of standard post-resuscitation care. TTM may downregulate cytochrome enzyme activity and thus impact drug metabolism. This study compared the pharmacokinetics (PK) of pantoprazole, a probe drug of CYP2C19-dependent metabolism, at different stages of TTM following cardiac arrest. Methods: This prospective controlled study was performed at the Medical University of Vienna and enrolled 16 patients following cardiac arrest. The patients completed up to three study periods (each lasting 24 h) in which plasma concentrations of pantoprazole were quantified: (P1) hypothermia (33 °C) after admission, (P2) normothermia after rewarming (36 °C, intensive care), and (P3) normothermia during recovery (normal ward, control group). PK was analysed using non-compartmental analysis and nonlinear mixed-effects modelling. Results: 16 patients completed periods P1 and P2; ten completed P3. The median half-life of pantoprazole was 2.4 h (quartiles: 1.8–4.8 h) in P1, 2.8 h (2.1–6.8 h, p = 0.046 vs. P1, p = 0.005 vs. P3) in P2 and 1.2 h (0.9 – 2.3 h, p = 0.007 vs. P1) in P3. A two-compartment model described the PK data best. Typical values for clearance were estimated separately for each study period, indicating 40% and 29% reductions during P1 and P2, respectively, compared to P3. The central volume of distribution was estimated separately for P2, indicating a 64% increase compared to P1 and P3. Conclusion: CYP2C19-dependent drug metabolism is downregulated during TTM following cardiac arrest. These results may influence drug choice and dosing of similarly metabolized drugs and may be helpful for designing studies in similar clinical situations.

Spiral fMRI has been put forward as a viable alternative to rectilinear echo-planar imaging, in particular due to its enhanced average k-space speed and thus high acquisition efficiency. This renders spirals attractive for contemporary fMRI applications that require high spatiotemporal resolution, such as laminar or columnar fMRI. However, in practice, spiral fMRI is typically hampered by its reduced robustness and ensuing blurring artifacts, which arise from imperfections in both static and dynamic magnetic fields.Recently, these limitations have been overcome by the concerted application of an expanded signal model that accounts for such field imperfections, and its inversion by iterative image reconstruction. In the challenging ultra-high field environment of 7 Tesla, where field inhomogeneity effects are aggravated, both multi-shot and single-shot 2D spiral imaging at sub-millimeter resolution was demonstrated with high depiction quality and anatomical congruency.In this work, we further these advances towards a time series application of spiral readouts, namely, single-shot spiral BOLD fMRI at 0.8 mm in-plane resolution. We demonstrate that high-resolution spiral fMRI at 7 T is not only feasible, but delivers both excellent image quality, BOLD sensitivity, and spatial specificity of the activation maps, with little artifactual blurring. Furthermore, we show the versatility of the approach with a combined in/out spiral readout at a more typical resolution (1.5 mm), where the high acquisition efficiency allows to acquire two images per shot for improved sensitivity by echo combination.

Summary: Inflammatory responses are crucial for regeneration following peripheral nerve injury (PNI). PNI triggers inflammatory responses at the site of injury. The DNA-sensing receptor cyclic GMP-AMP synthase (cGAS) and its downstream effector stimulator of interferon genes (STING) sense foreign and self-DNA and trigger type I interferon (IFN) immune responses. We demonstrate here that following PNI, the cGAS/STING pathway is upregulated in the sciatic nerve of naive rats and dysregulated in old rats. In a nerve crush mouse model where STING is knocked out, myelin content in sciatic nerve is increased resulting in accelerated functional axon recovery. STING KO mice have lower macrophage number in sciatic nerve and decreased microglia activation in spinal cord 1 week post injury. STING activation regulated processing of colony stimulating factor 1 receptor (CSF1R) and microglia survival in vitro. Taking together, these data highlight a previously unrecognized role of STING in the regulation of nerve regeneration.

Background: In cardiac arrest survivors, metabolic parameters [pH value, lactate concentration, and base deficit (BD)] are routinely added to peri-arrest factors (including age, sex, bystander cardiopulmonary resuscitation, shockable first rhythm, resuscitation duration, adrenaline dose) to enhance early outcome prediction. However, the additional value of this strategy remains unclear.Methods: We used our resuscitation database to screen all patients ≥18 years who had suffered in- or out-of-hospital cardiac arrest (IHCA, OHCA) between January 1st, 2005 and May 1st, 2019. Patients with incomplete data, without return of spontaneous circulation or treatment with sodium bicarbonate were excluded. To analyse the added value of metabolic parameters to prognosticate neurological function, we built three models using logistic regression. These models included: (1) Peri-arrest factors only, (2) peri-arrest factors plus metabolic parameters and (3) metabolic parameters only. Receiver operating characteristics curves regarding 30-day good neurological function (Cerebral Performance Category 1-2) were analysed.Results: A total of 2,317 patients (OHCA: n = 1842) were included. In patients with OHCA, model 1 and 2 had comparable predictive value. Model 3 was inferior compared to model 1. In IHCA patients, model 2 performed best, whereas both metabolic (model 3) and peri-arrest factors (model 1) demonstrated similar power. PH, lactate and BD had interchangeable areas under the curve in both IHCA and OHCA.Conclusion: Although metabolic parameters may play a role in IHCA, no additional value in the prediction of good neurological outcome could be found in patients with OHCA. This highlights the importance of accurate anamnesis especially in patients with OHCA.

Background: The post-cardiac arrest (CA) phase is characterized by high fluid requirements, endothelial activation and increased vascular permeability. Erythrocytes are large cells and may not leave circulation despite massive capillary leak. We hypothesized that dynamic changes in hemoglobin concentrations may reflect the degree of vascular permeability and may be associated with neurologic function after CA.Methods: We included patients ≥18 years, who suffered a non-traumatic CA between 2013 and 2018 from the prospective Vienna Clinical Cardiac Arrest Registry. Patients without return of spontaneous circulation (ROSC), with extracorporeal life support, with any form of bleeding, undergoing surgery, receiving transfusions, without targeted temperature management or with incomplete datasets for multivariable analysis were excluded. The primary outcome was neurologic function at day 30 assessed by the Cerebral Performance Category scale. Differences of hemoglobin concentrations at admission and 12 h after ROSC were calculated and associations with neurologic function were investigated by uni- and multivariable logistic regression.Results: Two hundred and seventy-five patients were eligible for analysis of which 143 (52%) had poor neurologic function. For every g/dl increase in hemoglobin from admission to 12 h the odds of poor neurologic function increased by 26% (crude OR 1.26, 1.07–1.49, p = 0.006). The effect remained unchanged after adjustment for fluid balance and traditional prognostication markers (adjusted OR 1.27, 1.05–1.54, p = 0.014).Conclusion: Increasing hemoglobin levels in spite of a positive fluid balance may serve as a surrogate parameter of vascular permeability and are associated with poor neurologic function in the early post-cardiac arrest period.

BackgroundAn established objective and standardized reporting of clinical severity and disease progression in COVID-19 is still not established. We validated and compared the usefulness of two classification systems reported earlier-a severity grading proposed by Siddiqi and a system from the National Australian COVID-19 guideline. Both had not been validated externally and were now tested for their ability to predict complications.MethodsIn this retrospective, single-centre observational study, patients hospitalized with confirmed COVID-19 across all severity stages were enrolled. The clinical severity was graded at admission and during hospitalization. Multivariate Cox regression was used to identify independent risk factors for mortality, a composite primary (mortality, incident acute respiratory distress syndrome, incident mechanical ventilation), a secondary endpoint (mortality, incident acute myocardial injury, incident venous thrombosis, pulmonary embolism or stroke) and progression of severity grades.ResultsOf 109 patients 17 died, 31 and 48 developed the primary and secondary endpoint, respectively. Worsening of the severity grade by at least one stage occurred in 27 and 28 patients, respectively. Siddiqi and Australian classification were identified as independent predictors for the primary endpoint (adjusted hazard ratio (aHR) 2.30, pConclusionsStandardized and objective severity grading is useful to unequivocally stratify patients presenting with COVID-19 for their individual risk of complications.

Background: The COVID-19 pandemic has resulted in the suspension of the entire teaching program at the Medical University of Vienna till the end of the summer semester. As the department that is responsible for emergency medicine teaching, we adapted the program to continue the courses and maintain the learning progress. Our objective is to evaluate the number of courses conducted and report the methods used.Methods: Teaching was measured as credit hours per week (CHW) in accordance with the university's prospectus. One CHW represents 15 academic hours (45 min) in one semester. Webinars were conducted using the CISCO Webex Events®, Webex Training, and ZOOM®. The Moodle® was utilized for resuscitation courses.Results: Courses and clerkships equivalent to 80.2 out of 101.4 CHW (79.1%) could be held during the ongoing crisis in the summer semester. Courses in the winter semester were all completed. In the human medicine curriculum, 73.7 out of 94.9 CHW (77.7%) could be conducted. In the case of emergency lectures for the dentistry curriculum, all courses were conducted through webinars (6.5 CHW, 100%). After calculating the exact number of students in each class, it has been determined that courses and clerkships equivalent to 78.7% could be conducted.Conclusion: Despite the challenge of preparing for the treatment of numerous patients during the ongoing pandemic, we could shoulder a majority of our teaching responsibilities. Although sufficient skill training could not be imparted under these circumstances, we could provide sufficient theoretical knowledge to allow students to continue studies.

Straightforward and versatile surface modification, functionalization and coating have become a significant topic in material sciences. While physical modification suffers from severe drawbacks, such as insufficient stability, chemical induced grafting processes efficiently modify organic and inorganic materials and surfaces due to covalent linkage. These processes include the “grafting from” method, where polymer chains are directly grown from the surface in terms of a surface-initiated polymerization and the “grafting to” method where a preformed (macro)-molecule is introduced to a preliminary treated surface via a coupling reaction. Both methods require an initiating species that is immobilized at the surface and can be triggered either by heat or light, whereas light induced processes have recently received increasing interest. Therefore, a major challenge is the ongoing search for suitable anchor moieties that provide covalent linkage to the surface and include initiators for surface-initiated polymerization and coupling reactions, respectively. This review containing 205 references provides an overview on photoinitiators which are covalently coupled to different surfaces, and are utilized for subsequent photopolymerizations and photocoupling reactions. An emphasis is placed on the coupling strategies for different surfaces, including oxides, metals, and cellulosic materials, with a focus on surface coupled free radical photoinitiators (type I and type II). Furthermore, the concept of surface initiation mediated by photoiniferters (PIMP) is reviewed. Regarding controlled radical polymerization from surfaces, a large section of the paper reviews surface-tethered co-initiators, ATRP initiators, and RAFT agents. In combination with photoinitiators or photoredox catalysts, these compounds are employed for surface initiated photopolymerizations. Moreover, examples for coupled photoacids and photoacid generators are presented. Another large section of the article reviews photocoupling and photoclick techniques. Here, the focus is set on light sensitive groups, such as organic azides, tetrazoles and diazirines, which have proven useful in biochemistry, composite technology and many other fields.

Background: Mild therapeutic hypothermia (MTH) is a treatment adjunct in ST-segment elevation myocardial infarction (STEMI) that deserves investigation. Copeptin―a surrogate marker for vasopressin―is an early biomarker in STEMI. Data from cardiac arrest patients suggest a reduction of copeptin levels through MTH; however, copeptin levels have not been investigated in MTH during STEMI. Methods: We analyzed patients treated with MTH during STEMI in a sub-study of the STATIM trial (Testori, Heart 2019). Patients were randomized to normothermia or MTH with out-of-hospital initiation. Seven copeptin samples were collected from each patient. Primary endpoint was the difference in copeptin levels between the groups. As secondary endpoints, we defined differences in the kinetics between the sampling timepoints and the correlation between copeptin and the infarct size in relation to left ventricular myocardium. Results: We included 99 patients (MTH n = 47, control n = 52) in our intention to treat analysis. No differences in copeptin values at first medical contact between the MTH and normothermia groups were found. MTH showed no effect on copeptin levels, neither during cooling phase nor through the course. Copeptin peaked at first medical contact and hospital admission in both groups. No differences in kinetics between the timepoints were found. Copeptin showed no correlation with infarct size, neither at first medical contact nor hospital admission. Conclusions: Copeptin levels were not influenced by MTH in STEMI, suggesting the use of this biomarker also during temperature management. Furthermore, copeptin levels were not usable as a surrogate marker for infarct size at any timepoint.

Summary: Age-related loss of skeletal muscle innervation by motor neurons leads to impaired neuromuscular function and is a well-established clinical phenomenon. However, the underlying pathogenesis remains unclear. Studying mice, we find that the number of motor units (MUs) can be maintained by counteracting neurotoxic microglia in the aged spinal cord. We observe that marked innervation changes, detected by motor unit number estimation (MUNE), occur prior to loss of muscle function in aged mice. This coincides with gene expression changes indicative of neuronal remodeling and microglial activation in aged spinal cord. Voluntary exercise prevents loss of MUs and reverses microglia activation. Depleting microglia by CSF1R inhibition also prevents the age-related decline in MUNE and neuromuscular junction disruption, implying a causal link. Our results suggest that age-related changes in spinal cord microglia contribute to neuromuscular decline in aged mice and demonstrate that removal of aged neurotoxic microglia can prevent or reverse MU loss. : Aging is characterized by progressive loss of functional motor units. Giorgetti et al. report that age-related defects at the neuromuscular junction are associated with a switch in microglia to an activated phenotype. Exercise or CSF1R inhibition prevents loss of innervation in aged mice through modulation of microglia. Keywords: aging, motor unit, exercise, microglia, CSF1R inhibition, neuroinflammation, innervation, neuromuscular system, neuromuscular junction, spinal cord

Aberrant activation of the JAK/STAT pathway is thought to be the critical event in the pathogenesis of the chronic myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia and primary myelofibrosis. The most frequent genetic alteration in these pathologies is the activating JAK2V617F mutation, and expression of the mutant gene in mouse models was shown to cause a phenotype resembling the human diseases. Given the body of genetic evidence, it has come as a sobering finding that JAK inhibitor therapy only modestly suppresses the JAK2V617F allele burden, despite showing clear benefits in terms of reducing splenomegaly and constitutional symptoms in patients. To gain a better understanding if JAK2V617F is required for maintenance of myeloproliferative disease once it has evolved, we generated a conditional inducible transgenic JAK2V617F mouse model using the SCL-tTA-2S tet-off system. Our model corroborates that expression of JAK2V617F in hematopoietic stem and progenitor cells recapitulates key hallmarks of human myeloproliferative neoplasms, and exhibits gender differences in disease manifestation. The disease was found to be transplantable, and importantly, reversible when transgenic JAK2V617F expression was switched off. Our results indicate that mutant JAK2V617F-specific inhibitors should result in profound disease modification by disabling the myeloproliferative clone bearing mutant JAK2.

AimsElevated levels of high-sensitivity cardiac troponin T (hsTnT) are associated with adverse outcomes in numerous patient populations. Their value in prediction of stroke risk in patients with atrial fibrillation (AF) is in debate.MethodsThe study population included 2898 consecutive patients presenting with AF to the emergency department of the Department of Cardiology, Heidelberg University Hospital. Associations between hsTnT and stroke risk were assessed using multivariable Cox regression.ResultsElevated hsTnT levels (>14 ng/L) were associated with increased risk of stroke. Even after adjustment for various risk factors, elevated hsTnT remained independently associated with stroke risk in patients with AF, adjusted hazard ratio 2.35 [95% confidence interval (CI): 1.26-4.36] (P = 0.007). These results were consistent across important subgroups (age, renal function, ejection fraction, CHA2DS2-VASc score and main admission diagnosis). For hsTnT, area under the receiver-operating-characteristic curve (AUC) was 0.659 [95% CI: 0.575-0.742], compared to 0.610 [95% CI: 0.526-0.694] for the CHA2DS2-VASc score. Inclusion of hsTnT in the multivariable model for stroke risk prediction consisting of all variables of the CHA2DS2-VASc score was associated with a significant improvement of its discriminatory power.ConclusionElevated hsTnT levels are significantly associated with higher risk of stroke and provide prognostic information independent of CHA2DS2-VASc score variables. Measurement of hsTnT may improve prediction of stroke risk in patients presenting to an emergency department with AF as compared to risk stratification based only on clinical variables.

Innovation policy and business strategy often expect that investing in private and public research and development will immediately produce a flow of products and processes with high commercial and social returns. Policymakers and managers implicitly follow the logic underlying most linear innovation models assuming a well-defined and uni-directional relationship between R&D spending as input and innovation rents as output of the innovation process. Modern innovation economics dismisses the simplified approximation of knowledge by R&D investment and, instead, considers complex knowledge generation and diffusion processes in innovation networks. From this angle, the disappointing performance of traditional approaches is traced back to strong limits of conventional steering, control, and policy instruments. In this paper, we show that the new view of knowledge generation and diffusion in innovation networks allows for an alternative and has led to systemic approaches in innovation analyses. Combined with computational approaches like agent-based modeling, this new view enables today innovative tools in policy consulting. Using the example of regional innovation policy, we introduce a policy laboratory in which innovation processes can be analyzed in depth to see the impact of different innovation policy instruments in-silico. This ex-ante evaluation helps considerably to improve the understanding of innovation processes and with it the performance of innovation policy.

OBJECTIVE: The objective of the current study was to find a metabolic signature associated with the early manifestations of type-2 diabetes mellitus. RESEARCH DESIGN AND METHOD: Modern metabolic profiling technology (MxP™ Broad Profiling) was applied to find early alterations in the plasma metabolome of type-2 diabetic patients. The results were validated in an independent study. Eicosanoid and single inon monitoring analysis (MxP™ Eicosanoid and MxP™ SIM analysis) were performed in subsets of samples. RESULTS: A metabolic signature including significantly increased levels of glyoxylate as a potential novel marker for early detection of type-2 diabetes mellitus was identified in an initial study (Study1). The signature was significantly altered in fasted diabetic and pre-diabetic subjects and in non-fasted subjects up to three years prior to the diagnosis of type-2 diabetes; most alterations were also consistently found in an independent patient group (Study 2). In Study 2 diabetic and most control subjects suffered from heart failure. In Study 1 a subgroup of diabetic subjects, with a history of use of anti-hypertensive medication further showed a more pronounced increase of glyoxylate levels, compared to a non-diabetic control group when tested in a hyperglycemic state. In the context of a prior history of anti-hypertensive medication, alterations in hexosamine and eicosanoid levels were also found. CONCLUSION: A metabolic signature including glyoxylate was associated with type-2 diabetes mellitus, independent of the fasting status and of occurrence of another major disease. The same signature was also found to be associated with pre-diabetic subjects. Glyoxylate levels further showed a specifically strong increase in a subgroup of diabetic subjects. It could represent a new marker for the detection of medical subgroups of diabetic subjects.

BACKGROUND: Sphingosine-1-phosphate (S1P) regulates the egress of T cells from lymphoid organs; levels of S1P in the tissues are controlled by S1P lyase (Sgpl1). Hence, Sgpl1 offers a target to block T cell-dependent inflammatory processes. However, the involvement of Sgpl1 in models of disease has not been fully elucidated yet, since Sgpl1 KO mice have a short life-span. METHODOLOGY: We generated inducible Sgpl1 KO mice featuring partial reduction of Sgpl1 activity and analyzed them with respect to sphingolipid levels, T-cell distribution, and response in models of inflammation. PRINCIPAL FINDINGS: The partially Sgpl1 deficient mice are viable but feature profound reduction of peripheral T cells, similar to the constitutive KO mice. While thymic T cell development in these mice appears normal, mature T cells are retained in thymus and lymph nodes, leading to reduced T cell numbers in spleen and blood, with a skewing towards increased proportions of memory T cells and T regulatory cells. The therapeutic relevance of Sgpl1 is demonstrated by the fact that the inducible KO mice are protected in experimental autoimmune encephalomyelitis (EAE). T cell immigration into the CNS was found to be profoundly reduced. Since S1P levels in the brain of the animals are unchanged, we conclude that protection in EAE is due to the peripheral effect on T cells, leading to reduced CNS immigration, rather than on local effects in the CNS. SIGNIFICANCE: The data suggest Sgpl1 as a novel therapeutic target for the treatment of multiple sclerosis.

Generation of gain-of-function transgenic mice by targeting the Rosa26 locus has been established as an alternative to classical transgenic mice produced by pronuclear microinjection. However, targeting transgenes to the endogenous Rosa26 promoter results in moderate ubiquitous expression and is not suitable for high expression levels. Therefore, we now generated a modified Rosa26 (modRosa26) locus that combines efficient targeted transgenesis using recombinase-mediated cassette exchange (RMCE) by Flipase (Flp-RMCE) or Cre recombinase (Cre-RMCE) with transgene expression from exogenous promoters. We silenced the endogenous Rosa26 promoter and characterized several ubiquitous (pCAG, EF1α and CMV) and tissue-specific (VeCad, αSMA) promoters in the modRosa26 locus in vivo. We demonstrate that the ubiquitous pCAG promoter in the modRosa26 locus now offers high transgene expression. While tissue-specific promoters were all active in their cognate tissues they additionally led to rare ectopic expression. To achieve high expression levels in a tissue-specific manner, we therefore combined Flp-RMCE for rapid ES cell targeting, the pCAG promoter for high transgene levels and Cre/LoxP conditional transgene activation using well-characterized Cre lines. Using this approach we generated a Cre/LoxP-inducible reporter mouse line with high EGFP expression levels that enables cell tracing in live cells. A second reporter line expressing luciferase permits efficient monitoring of Cre activity in live animals. Thus, targeting the modRosa26 locus by RMCE minimizes the effort required to target ES cells and generates a tool for the use exogenous promoters in combination with single-copy transgenes for predictable expression in mice.

Since the advent of highly pathogenic variants of avian influenza virus (HPAIV), the main focus of avian influenza research has been the characterization and detection of HPAIV hemagglutinin (HA) from H5 and H7 subtypes. However, due to the high mutation and reassortation rate of influenza viruses, in theory any influenza strain may acquire increased pathogenicity irrespective of its subtype. A comprehensive antigenic characterization of influenza viruses encompassing all 16 HA and 9 neuraminidase subtypes will provide information useful for the design of differential diagnostic tools, and possibly, vaccines. We have expressed recombinant HA proteins from 3 different influenza virus HA subtypes in the baculovirus system. These proteins were used to generate polyclonal rabbit antisera, which were subsequently employed in epitope scanning analysis using peptide libraries spanning the entire HA. Here, we report the identification and characterization of linear, HA subtype-specific as well as inter subtype-conserved epitopes along the HA proteins. Selected subtype-specific epitopes were shown to be suitable for the differentiation of anti-HA antibodies in an ELISA.

BACKGROUND: Aggregation and misfolded alpha-synuclein is thought to be central in the pathogenesis of Parkinson's disease (PD). Heat-shock proteins (HSPs) that are involved in refolding and degradation processes could lower the aggregate load of alpha-synuclein and thus be beneficial in alpha-synucleinopathies. METHODOLOGY/PRINCIPAL FINDINGS: We co-overexpressed human A53T point-mutated alpha-synuclein and human HSP70 in mice, both under the control of Thy1 regulatory sequences. Behavior read-outs showed no beneficial effect of HSP70 expression in mice. In contrast, motor coordination, grip strength and weight were even worse in the alpha-synucleinopathy model in the presence of HSP70 overexpression. Biochemical analyses revealed no differences in alpha-synuclein oligomers/aggregates, truncations and phosphorylation levels and alpha-synuclein localization was unchanged in immunostainings. CONCLUSION/SIGNIFICANCE: Overexpressing HSP70 in a mouse model of alpha-synucleinopathy did not lower the toxic load of alpha-synuclein species and had no beneficial effect on alpha-synuclein-related motor deficits.

Myelin-associated glycoprotein (MAG) is a sialic acid binding Ig-like lectin (Siglec) which has been characterized as potent myelin-derived inhibitor of neurite outgrowth. Two members of the Nogo-receptor (NgR) family, NgR1 and NgR2, have been identified as neuronal binding proteins of MAG. In addition, gangliosides have been proposed to bind to and confer the inhibitory activity of MAG on neurons. In this study, we investigated the individual contribution of NgRs and gangliosides to MAG-mediated inhibition of sensory neurons derived from dorsal root ganglia (DRG) of ngr1, ngr2 or ngr1/ngr2 deletion mutants. We found no disinhibition of neurite growth in the absence of either NgR1 or NgR2. Sensory neurons deficient for both NgR proteins displayed only a moderate reduction of MAG-mediated inhibition of neurite growth. If treated with Vibrio cholerae neuraminidase (VCN), inhibition by MAG is further attenuated but still not annulled. Thus, disrupting all known protein and ganglioside receptors for MAG in sensory neurons does not fully abolish its inhibitory activity pointing to the existence of as yet unidentified receptors for MAG. Moreover, by employing a variety of protein mutants, we identified the Ig-like domains 4 or 5 of MAG as necessary and sufficient for growth arrest, whereas abolishing MAG's ability to bind to sialic acid did not interfere with its inhibitory activity. These findings provide new insights into the inhibitory function of MAG and suggest similarities but also major differences in MAG inhibition between sensory and central nervous system (CNS) neurons.