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Zusammenfassung Hintergrund Die Mortalität bei Sepsis bleibt hoch. Verschiedene Techniken zur extrakorporalen Zytokinelimination wurden als zusätzliche therapeutische Maßnahmen bei Sepsis und septischem Schock untersucht. Ziele Zusammenfassung einer Auswahl extrakorporaler Blutreinigungstechniken und der aktuellen Erkenntnisse in der klinischen Anwendung mit besonderem Schwerpunkt auf dem therapeutischen Plasmaaustausch. Methoden Nicht systematische Literaturrecherche. Ergebnisse Verschiedene extrakorporale Blutreinigungstechniken mit unterschiedlichen Evidenzniveaus hinsichtlich Zytokinelimination, Verbesserung der Hämodynamik und Verringerung der Mortalität werden derzeit klinisch eingesetzt. Die am ausführlichsten untersuchten Modalitäten umfassen die hochvolumige Hämofiltration/Dialyse mit und ohne High-Cut-off-Filter sowie Hämoadsorptionstechniken (einschließlich CytoSorb- und Polymyxin-B-Filter). Trotz teilweise ermutigender Beobachtungen bezüglich der Entfernung proinflammatorischer Zytokine und verbesserten Hämodynamik zeigten randomisierte Studien bislang keinen positiven Einfluss auf das Überleben. Aufgrund der Verwendung von Spenderplasma als Substitutionsflüssigkeit stellt der therapeutische Plasmaaustausch das einzige Verfahren dar, das zusätzlich verbrauchte protektive Faktoren ersetzen kann. Schlussfolgerungen Die Anwendung extrakorporaler Blutreinigungsmethoden kann für Sepsispatienten außerhalb klinischer Studien bisher nicht empfohlen werden, da derzeit keine Beweise für ihre Wirksamkeit vorliegen. Zukünftige Untersuchungen sollten darauf abzielen, das untersuchte Patientenkollektiv hinsichtlich des klinischen Schweregrads, des Zeitpunkts der Intervention und verschiedener inflammatorischer (Sub-)Phänotypen zu homogenisieren.

Sepsis, a life-threatening organ dysfunction, continues to cause considerable morbidity. Reliable animal models to evaluate therapeutic options are urgently required, however, some of the most esta...

Purpose This paper aims to better understand a firm’s market research function’s (MRF) roles and influences on the different uses of market research information (MRI) (instrumental, conceptual and symbolic) in the firm. Design/methodology/approach This study uses a mixed-methods design: In a qualitative study among marketing managers (n = 9) and market researchers (n = 10); different roles of a firm’s MRF are scrutinized. The quantitative study among corporate users of MRI (n = 235) tests a conceptual model on the MRF-related determinants of MRI uses, using structural equation modeling. Findings When the MRF exhibits methodological, market and business expertise and interacts with market research users, these features indirectly influence instrumental, conceptual, and symbolic uses, through MRI quality perceived by the users. The users’ knowledge of market research methods, the function’s integrity, top management support, and decentralized decision-making have various beneficial influences on the three uses of MRI. Research limitations/implications Broadly speaking, this research expands the theoretical understanding of marketing-related organizational learning processes. It considers message, source, recipient, and context variables to explain changes in attitude and behavior, related to MRI uses. Practical implications Overall, corporations should use MRI more thoroughly. Treating the MRF as a strategic asset rather than just another internal service provider increases its value to the firm. Firms should thus bolster the MRF’s different roles, namely, internal colleague, service provider, customer representative, quality assurance, and knowledge broker. Originality/value This paper is the first to comprehensively analyze the MRF’s role in MRI generation and various uses. It identifies three expertise dimensions of the MRF to fully leverage the MRF’s value to the organization and empirically underscores theoretical writings on the MRF’s roles in the firm.

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2022. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2022 . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from https://link.springer.com/bookseries/8901 .

Background: Veno-venous (VV) extracorporeal membrane oxygenation (ECMO) is increasingly used to support patients with severe acute respiratory distress syndrome (ARDS). In case of additional cardio-circulatory failure, some experienced centers upgrade the VV-ECMO with an additional arterial backflow cannula (termed VVA-ECMO). Here we analyzed short- and long-term outcome together with potential predictors of mortality. Methods: Retrospective analysis of outcome in VV ECMO patients with ARDS that received VVA upgrade due to acute cardio-circulatory deterioration from 2008-2021 at three ECMO referral centers.Results: We identified 73 VVA ECMO patients that either required an upgrade from VV to VVA (n=53) or were directly triple cannulated (n=20), most commonly for concomitant right-sided heart failure. Median (Interquartile Range) age was 49 (28-57) years and SOFA score was 14 (12-17) at VVA ECMO upgrade. ECMO support was required over 12 (6-22) days and ICU length of stay was 32 (16-46) days. Overall ICU mortality was 48% and hospital mortality 51%. Two additional patients died after hospital discharge while the remaining patients survived up to two years (with six patients being lost to follow-up). A SOFA score > 14 at the day of VVA upgrade and higher lactate level were independent predictors of mortality in the multivariate regression analysis.Conclusions: In this analysis, the use of VVA ECMO in patients with initial ARDS and concomitant cardiocirculatory failure was associated with a hospital survival of about 50%, and most of these patients survived up to 2 years. A SOFA score >14 and elevated lactate levels at the day of VVA upgrade predict unfavorable outcome.

The factors that influence survival during severe infection are unclear. Extracellular chromatin drives pathology, but the mechanisms enabling its accumulation remain elusive. Here, we show that in murine sepsis models, splenocyte death interferes with chromatin clearance through the release of the DNase I inhibitor actin. Actin-mediated inhibition was compensated by upregulation of DNase I or the actin scavenger gelsolin. Splenocyte death and neutrophil extracellular trap (NET) clearance deficiencies were prevalent in individuals with severe COVID-19 pneumonia or microbial sepsis. Activity tracing by plasma proteomic profiling uncovered an association between low NET clearance and increased COVID-19 pathology and mortality. Low NET clearance activity with comparable proteome associations was prevalent in healthy donors with low-grade inflammation, implicating defective chromatin clearance in the development of cardiovascular disease and linking COVID-19 susceptibility to pre-existing conditions. Hence, the combination of aberrant chromatin release with defects in protective clearance mechanisms lead to poor survival outcomes.

SummaryHyperinflammation, coagulopathy and immune dysfunction are prominent in patients with severe infections. Extracellular chromatin clearance by plasma DNases suppresses such pathologies in mice but whether severe infection interferes with these pathways is unclear. Here, we show that patients with severe SARS-CoV-2 infection or microbial sepsis exhibit low extracellular DNA clearance capacity associated with the release of the DNase inhibitor actin. Unlike naked DNA degradation (DNase), neutrophil extracellular trap degradation (NETase) was insensitive to G-actin, indicating distinct underlying mechanisms. Activity-based proteomic profiling of severely ill SARS-CoV-2 patient plasma revealed that patients with high NETase and DNase activities exhibited 18-fold higher survival compared to patients with low activity proteomic profiles. Remarkably, low DNA clearance capacity was also prominent in healthy individuals with chronic inflammation, suggesting that pre-existing inflammatory conditions may increase the risk for mortality upon infection. Hence, functional proteomic profiling illustrates that non-redundant DNA clearance activities protect critically ill patients from mortality, uncovering protein combinations that can accurately predict mortality in critically ill patients.

Background Disruption of the endothelial glycocalyx (eGC) is observed in septic patients and its injury is associated with multiple-organ failure and inferior outcomes. Besides this biomarker function, increased blood concentrations of shedded eGC constituents might play a mechanistic role in septic organ failure. We hypothesized that therapeutic plasma exchange (TPE) using fresh frozen plasma might influence eGC-related pathology by removing injurious mediators of eGC breakdown while at the time replacing eGC protective factors. Methods We enrolled 20 norepinephrine-dependent (NE > 0.4 μg/kg/min) patients with early septic shock (onset Results SDF demonstrated a decrease in eGC thickness in septic patients compared to healthy individuals (p = 0.001). Circulating HS levels were increased more than sixfold compared to controls and decreased significantly following TPE [controls: 16.9 (8–18.6) vs. septic patients before TPE: 105.8 (30.8–143.4) μg/ml, p p p = 0.001; vs. septic patients after TPE: 13.2 (11.2–31.8), p Conclusions Septic shock results in profound degradation of the eGC and an acquired deficiency of the protective regulator Hpa-2. TPE removed potentially injurious eGC degradation products and partially attenuated Hpa-2 deficiency. Trial registration clinicaltrials.gov NCT04231994, retrospectively registered 18 January 2020

Background: Recently, a randomized controlled trial (RCT) demonstrated rapid but individually variable hemodynamic improvement with therapeutic plasma exchange (TPE) in patients with septic shock. Prediction of clinical efficacy in specific sepsis treatments is fundamental for individualized sepsis therapy.Methods: In the original RCT patients with septic shock of < 24 h duration and norepinephrine (NE) requirement ≥ 0.4 μg/kg/min received standard of care (SOC) or SOC + one single TPE. Here we report all clinical and biological endpoints of this study. Subgroup analysis of NE reduction and 28-day mortality was performed to investigate characteristics that could be associated with clinical response.Results: Early hemodynamic stabilization was preserved in the TPE group for 24 hours and was accompanied by a reduction of lactate suggestive for shock reversal. A reduction of injurious mediators (such as PCT, vWF:Ag, Angpt-2, sTie-2) and a repletion of exhausted protective factors (such as AT-III, Protein C, ADAMTS-13) could be observed in the TPE but not in the SOC group. Significant NE reduction (> 50% from baseline) upon TPE occurred more often in patients with 1) a pulmonary focus of infection, 2) profound respiratory failure (pO2/FiO2 0.6 μg/kg/min and lactate >0.4 mmol/l) as well as 4) substantial degree of organ failure (SOFA Score > 16) at randomization. Patients with a pulmonary focus of infection had a 28-day mortality of 15% in the TPE group while it was 42% in the SOC group. Conclusions: Adjunctive TPE is associated with the removal of injurious mediators and repletion of consumed protective factors altogether leading to preserved hemodynamic stabilization in refractory septic shock. It is We identified potential response predictors (lung focus, PF ratio < 150, higher SOFA score etc.) that might guide future designing of large RCTs that will further evaluate TPE with regard to hard endpoints. Trial registration: Retrospectively registered 18th January 2020 at clinicaltrials.gov (Identifier: NCT04231994), https://clinicaltrials.gov/ct2/show/NCT04231994?term=NCT04231994&draw=2&rank=1

ObjectIntra-tumoral hemorrhage is considered an imaging characteristic of advanced cancer disease. However, data on the influence of intra-tumoral hemorrhage in patients with brain metastases (BM) remains scarce. We aimed at investigating patients with BM who underwent neurosurgical resection of the metastatic lesion for a potential impact of preoperative hemorrhagic transformation on overall survival (OS).MethodsBetween 2013 and 2018, 357 patients with BM were surgically treated at the authors’ neuro-oncological center. Preoperative magnetic resonance imaging (MRI) examinations were assessed for the occurrence of malignant hemorrhagic transformation.Results122 of 375 patients (34%) with BM revealed preoperative intra-tumoral hemorrhage. Patients with hemorrhagic transformed BM exhibited a median OS of 5 months compared to 12 months for patients without intra-tumoral hemorrhage. Multivariate analysis revealed preoperative hemorrhagic transformation as an independent and significant predictor for worsened OS.ConclusionsThe present study identifies preoperative intra-tumoral hemorrhage as an indicator variable for poor prognosis in patients with BM undergoing neurosurgical treatment.

Background: Brain metastases (BM) indicate advanced states of cancer disease and cranial surgery represents a common treatment modality. In the present study, we aimed to identify the risk factors for a reduced survival in patients receiving a surgical treatment of BM derived from non-small cell lung cancer (NSCLC). Methods: A total of 154 patients with NSCLC that had been surgically treated for BM at the authors’ institution between 2013 and 2018 were included for a further analysis. A multivariate analysis was performed to identify the predictors of a poor overall survival (OS). Results: The median overall survival (mOS) was 11 months (95% CI 8.2–13.8). An age &gt, 65 years, the infratentorial location of BM, elevated preoperative C-reactive protein levels, a perioperative red blood cell transfusion, postoperative prolonged mechanical ventilation (&gt, 48 h) and the occurrence of postoperative adverse events were identified as independent factors of a poor OS. Conclusions: The present study identified several predictors for a worsened OS in patients that underwent surgery for BM of NSCLC. These findings might guide a better risk/benefit assessment in the course of metastatic NSCLC therapy and might help to more sufficiently cope with the challenges of cancer therapy in these advanced stages of disease.

SummaryThe mechanisms regulating immune dysfunction during sepsis are poorly understood. Here, we show that neutrophil-derived myeloperoxidase delays the onset of immune dysfunction during systemic candidiasis by controlling microbes captured by splenic marginal zone (MZ) macrophages. In contrast, SIGNR1-mediated microbe capture accelerates MZ colonization and immune dysfunction by triggering T cell death, T cell-dependent chromatin release and the synergistic induction of G-CSF by histones and fungi. Histones and G-CSF promote the prevalence of immature Ly6Glow neutrophils with defective oxidative burst, by selectively shortening the lifespan of mature Ly6Ghigh neutrophils. Consistently, T cell deficiency, or blocking SIGNR1, G-CSF or histones delayed neutrophil dysfunction. Furthermore, histones and G-CSF in the plasma of sepsis patients, shortened neutrophil lifespan and correlated with neutrophil mortality markers associated with a poor prognosis. Hence, the compromise of internal antimicrobial barrier sites drives neutrophil dysfunction by selectively modulating neutrophil lifespan via pathogenic T cell death, extracellular histones, and G-CSF.

Simple Summary Patients with brain metastasis are at a severe stage of cancer, and brain surgery can prevent neurological morbidity. However, the success of brain surgery might require a patient’s physical integrity prior to the operation. In the present study, we asked whether a preoperative physical decline affects survival in patients with brain metastasis from lung cancer. In order to measure the physical condition, we used a commonly-known index—the so-called frailty index—and additionally measured the thickness of a particular masticatory muscle as muscle loss correlates to physical decline. We found that a decreased muscle thickness was accompanied by worsened survival for patients < 65 years and an increased frailty index correlated to worsened survival for patients ≥ 65 years. These results encourage to use of the frailty index and muscle thickness as easily available parameters in order to more sufficiently estimate individual treatment success in patients with metastatic lung cancer. Abstract Neurosurgical resection represents an important therapeutic pillar in patients with brain metastasis (BM). Such extended treatment modalities require preoperative assessment of patients’ physical status to estimate individual treatment success. The aim of the present study was to analyze the predictive value of frailty and sarcopenia as assessment tools for physiological integrity in patients with non-small cell lung cancer (NSCLC) who had undergone surgery for BM. Between 2013 and 2018, 141 patients were surgically treated for BM from NSCLC at the authors’ institution. The preoperative physical condition was assessed by the temporal muscle thickness (TMT) as a surrogate parameter for sarcopenia and the modified frailty index (mFI). For the ≥65 aged group, median overall survival (mOS) significantly differed between patients classified as ‘frail’ (mFI ≥ 0.27) and ‘least and moderately frail’ (mFI < 0.27) (15 months versus 11 months (p = 0.02)). Sarcopenia revealed significant differences in mOS for the

Background Extra Corporeal Membrane Oxygenation (ECMO) has become an accepted treatment option for severely ill patients. Due to a limited availability of ECMO support therapy, patients must often be transported to a specialised centre before or after cannulation. According to the ELSO guidelines, an ECMO specialist should be present for such interventions. Here we describe the safety and efficacy of a reduced team approach involving one anaesthesiologist, experienced in specialised intensive care medicine, and a specialised critical care nurse. Methods This study is a 10 years retrospective, single institution analysis of all data collected between January 2007 and December 2016 from the medical records at the University Hospital Bonn, Germany. Results The Bonner mobile ECMO team was deployed in 170 cases for on-site evaluation for ECMO support therapy. 4 (2.4%) patients died prior to arrival or during the implementation of ECMO support. Of the remaining 166 patients, 126 were cannulated at the referring site, 40 were transported without ECMO. Of those, 21 were subsequently cannulated out our centre. 19 patients never received ECMO treatment. The primary indication for ECMO treatment was ARDS (159/166 patients). Veno-venous ECMO was initiated in 137, whilst 10 patients received veno-arterial ECMO treatment. Mean transportation time was 75 ± 36 min, and mean transport distance was 56 ± 57 km. In total, 26 complications were observed, three being directly transport-related. The overall survival was 55%. Conclusions Initiation of extracorporeal membrane oxygenation and subsequent transport can be safely and efficiently performed by a two-man team with good outcome. Electronic supplementary material The online version of this article (10.1186/s12871-019-0687-9) contains supplementary material, which is available to authorized users.

Memory B cells seem to be more durable than antibodies and thus crucial for the long-term immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here we investigate SARS-CoV-2 spike-specific memory B cells and their dependence on CD4+ T cell help in different settings of coronavirus disease 2019 (COVID-19). Compared with severely ill individuals, those who recovered from mild COVID-19 develop fewer but functionally superior spike-specific memory B cells. Generation and affinity maturation of these cells is best associated with IL-21+CD4+ T cells in recovered individuals and CD40L+CD4+ T cells in severely ill individuals. The increased activation and exhaustion of memory B cells observed during COVID-19 correlates with CD4+ T cell functions. Intriguingly, CD4+ T cells recognizing membrane protein show a stronger association with spike-specific memory B cells than those recognizing spike or nucleocapsid proteins. Overall, we identify CD4+ T cell subsets associated with the generation of B cell memory during SARS-CoV-2 infection., Graphical abstract, Pušnik et al. report that individuals who recovered from mild COVID-19 develop fewer but functionally superior SARS-CoV-2 spike-specific memory B cells than individuals with severe disease. The development and activation of those cells are associated with distinct CD4+ T cell functions in both clinical outcomes of COVID-19.

Background: The SARS-CoV-2 pandemic has challenged many of our current routine practices in the treatment and care of patients. Given the critical importance of blood donation and transfusion we analyzed 92 blood samples of individuals infected with SARS-CoV-2 stratified by symptoms. Study Design and Methods: We therefore tested blood samples for SARS-CoV-2 via RT-PCR targeting the E gene. In addition, we tested each blood sample for anti-SARS-CoV-2 IgG antibodies via ELISA and performed plaque reduction neutralization tests. Results: SARS-CoV-2 RNA was absent in the blood of mild to asymptomatic patients (57 individuals) and only detectable in individuals with severe COVID-19 who were admitted to the intensive care unit (35 individuals) (n = 6/92 [6.5%]; p = 0.023 Fisher’s exact test). Interestingly, anti-spike IgG antibodies were not significantly higher in intensive care unit patients compared to mild patients, but we found that their neutralizing capacity was disproportionately increased (p < 0.001). Conclusion: Our observations support the hypothesis that there are no potential hazards from blood or plasma transfusion of SARS-CoV-2-positive individuals with mild flu-like symptoms and more importantly of asymptomatic individuals.

Surgical resection is highly effective in the treatment of tumor-related epilepsy (TRE) in patients with brain metastases (BM). Nevertheless, some patients suffer from postoperative persistent epilepsy which negatively impacts health-related quality of life. Therefore, early identification of patients with potentially unfavorable seizure outcome after BM resection is important. Patients with TRE that had undergone surgery for BM at the authors’ institution between 2013 and 2018 were analyzed with regard to preoperatively identifiable risk factors for unfavorable seizure outcome. Tumor tissue and tumor necrosis ratios were assessed volumetrically. According to the classification of the International League Against Epilepsy (ILAE), seizure outcome was categorized as favorable (ILAE 1) and unfavorable (ILAE 2–6) after 3 months in order to avoid potential interference with adjuvant cancer treatment. Among all 38 patients undergoing neurosurgical treatment for BM with concomitant TRE, 34 patients achieved a favorable seizure outcome (90%). Unfavorable seizure outcome was significantly associated with larger tumor volumes (p = 0.012), a midline shift > 7 mm (p = 0.025), and a necrosis/tumor volume ratio > 0.2 (p = 0.047). The present study identifies preoperatively collectable risk factors for unfavorable seizure outcome in patients with BM and TRE. This might enable to preselect for highly vulnerable patients with postoperative persistent epilepsy who might benefit from accompanying neuro-oncological expertise during further systemical treatment regimes.

Mortality in sepsis remains high. Various techniques for extracorporeal cytokine removal have been investigated as additional therapeutic measures in sepsis and septic shock. To summarize a selection of extracorporeal blood purification techniques, with a special focus on therapeutic plasma exchange, and their current evidence in clinical use. Non-systematic literature review. Various extracorporeal blood purification techniques with different levels of evidence regarding cytokine removal, vasopressor sparing effects and reduction of mortality are currently in clinical use. Most extensively studied modalities include high-volume hemofiltration/dialysis with and without high cut-off filters a well as hemoadsorption techniques (including CytoSorb, and polymyxin-B filters). Despite partly encouraging observations regarding removal of inflammatory cytokines and hemodynamic stabilization, results from randomized studies did not show an effect on survival. Due to use of donor plasma as substitution fluid, therapeutic plasma exchange represents the only modality able to additionally replace protective and consumed factors. The use of extracorporeal blood purification methods cannot be recommended for sepsis patients outside of clinical trials given the current lack of evidence of their efficacy. Future investigations should aim to homogenize the studied patient collective in respect to clinical sepsis severity, time point of intervention and different inflammatory (sub-)phenotypes.

Background: Metastatic melanoma disease is accompanied by highly systemic inflammatory responses. The prognostic value of preoperative laboratory inflammation markers in brain metastatic melanoma patients has not been adequately investigated so far. Methods: Preoperative inflammatory blood parameters were correlated to overall survival (OS) rates in melanoma patients that underwent surgery for brain metastasis (BM) between 2013 and 2019 at the authors’ institution. Receiver operating characteristic (ROC) analyses were used for cutoff determination of routine laboratory parameters. Results: Median OS in the present cohort of 30 melanoma patients with surgically treated BM was 7 months (95% confidence interval (CI) 5.7–8.3). Initial elevated C-reactive protein (CRP) levels (&gt, 10 mg/L), neutrophil-to-lymphocyte ratio (NLR) ≥ 4, platelet-to-lymphocyte ratio (PLR) ≥ 145, and lymphocyte-to-monocyte ratio (LMR) &lt, 2 were associated with significantly reduced OS rates. Conclusions: The present study identifies several preoperative peripheral inflammatory markers as indicators for poor prognosis in melanoma patients with BM undergoing neurosurgical treatment. Elevated initial CRP values, higher NLR and PLR, and lower LMR were associated with reduced OS and, thus, might be incorporated into preoperative interdisciplinary treatment planning and counseling for affected patients.

Intracerebral hemorrhage (ICH) is a frequently disabling or fatal disease. The localizationof ICH often allows an etiological association. However, in atypical/lobar ICH, the cause of bleedingis less obvious. Therefore, we present prospective histopathological and radiological studies whichwere conducted within the diagnostic workup to identify causes for lobar ICH other than hypertension.From 2016 to 2018, 198 patients with spontaneous, non-traumatic ICH requiring neurosurgicalmonitoring were enrolled in an institutional prospective patient registry. Patients with deep-seatedICH and/or hemorrhagically transformed cerebral infarcts were excluded from further analysis.Data to evaluate the source of bleeding based on histopathological and/or radiological workup wereprospectively evaluated and analyzed. After applying the inclusion criteria and excluding patientswith incomplete diagnostic workup, a total of 52 consecutive patients with lobar ICH were furtheranalyzed. Macrovascular disease was detected in 14 patients with lobar ICH (27%). In 11 patients,diagnostic workup identified cerebral amyloid angiopathy-related ICH (21%). In addition, five patientswith tumor-related ICH (10%) and six patients with ICH based on infectious pathologies(11%) were identified. In four patients, the cause of bleeding remained unknown despite extensivediagnostic workup (8%). The present prospective registry study demonstrates a higher probabilityto identify a cause of bleeding other than hypertension in patients with lobar ICH. Therefore, athorough diagnostic work-up in patients with ICH is essential to accelerate treatment and furtherimprove outcome or prevent rebleeding

While management of patients with deep-seated intracerebral hemorrhage (ICH) is well established, there are scarce data on patients with ICH who require prolonged mechanical ventilation (PMV) during the course of their acute disease. Therefore, we aimed to determine the influence of PMV on mortality in patients with ICH and to identify associated risk factors. From 2014 to May 2020, all patients with deep-seated ICH who were admitted to intensive care for &gt, 3 days were included in further analyses. PMV is defined as receiving mechanical ventilation for more than 7 days. A total of 42 out of 94 patients (45%) with deep-seated ICH suffered from PMV during the course of treatment. The mortality rate after 90 days was significantly higher in patients with PMV than in those without (64% versus 22%, p &lt, 0.0001). Multivariate analysis identified “ICH volume &gt, 30 mL” (p = 0.001, OR 5.3) and “admission SOFA score &gt, 5” (p = 0.007, OR 4.2) as significant and independent predictors for PMV over the course of treatment in deep-seated ICH. With regard to the identified risk factors for PMV occurrence, these findings might enable improved guidance of adequate treatment at the earliest possible stage and lead to a better estimation of prognosis in the course of ICH treatment.

Inhibitory control may be vital in elite sport. The authors examined the link between athletic expertise, inhibitory control, and sport performance in a two-part quasi experiment. Inhibitory control was indexed using the Stop-Signal Task, athlete expertise was categorized on literary recommendations, and sport performance was assessed using athlete and coach ratings. Study 1 examined cross-sectional and longitudinal patterns of inhibitory control across athletic expertise. Study 2 investigated whether the inhibitory control–sport performance relationship was moderated by expertise. Study 1 showed that expertise was linked to greater inhibitory control cross-sectionally and longitudinally. Study 2 revealed that expertise was related to superior performance on the Stop-Signal Task and athlete and coach performance ratings, and this relationship was moderated by athletic expertise. Inhibitory control relates to sport performance, increases with greater athlete expertise, and develops longitudinally. Long-term participation in sport may bring about changes in inhibitory control, which may lead to improved sport performance.

Background Extracorporeal membrane oxygenation (ECMO) support in acute respiratory failure may be lifesaving, but bleeding and thromboembolic complications are common. The optimal anticoagulation strategy balancing these factors remains to be determined. This retrospective study compared two institutional anticoagulation management strategies focussing on oxygenator changes and both bleeding and thromboembolic events. Methods We conducted a retrospective observational cohort study between 04/2015 and 02/2020 in two ECMO referral centres in Germany in patients receiving veno-venous (VV)-ECMO support for acute respiratory failure for > 24 h. One centre routinely applied low-dose heparinization aiming for a partial thromboplastin time (PTT) of 35–40 s and the other routinely used a high-dose therapeutic heparinization strategy aiming for an activated clotting time (ACT) of 140–180 s. We assessed number of and time to ECMO oxygenator changes, 15-day freedom from oxygenator change, major bleeding events, thromboembolic events, 30-day ICU mortality, activated clotting time and partial thromboplastin time and administration of blood products. Primary outcome was the occurrence of oxygenator changes depending on heparinization strategy; main secondary outcomes were the occurrence of severe bleeding events and occurrence of thromboembolic events. The transfusion strategy was more liberal in the low-dose centre. Results Of 375 screened patients receiving VV-ECMO support, 218 were included in the analysis (117 high-dose group; 101 low-dose group). Disease severity measured by SAPS II score was 46 (IQR 36–57) versus 47 (IQR 37–55) and ECMO runtime was 8 (IQR 5–12) versus 11 (IQR 7–17) days (P = 0.003). There were 14 oxygenator changes in the high-dose group versus 48 in the low-dose group. Freedom from oxygenator change at 15 days was 73% versus 55% (adjusted HR 3.34 [95% confidence interval 1.2–9.4]; P = 0.023). Severe bleeding events occurred in 23 (19.7%) versus 14 (13.9%) patients (P = 0.256) and thromboembolic events occurred in 8 (6.8%) versus 19 (19%) patients (P = 0.007). Mortality at 30 days was 33.3% versus 30.7% (P = 0.11). Conclusions In this retrospective study, ECMO management with high-dose heparinization was associated with lower rates of oxygenator changes and thromboembolic events when compared to a low-dose heparinization strategy. Prospective, randomized trials are needed to determine the optimal anticoagulation strategy in patients receiving ECMO support.

Simple Summary Meningiomas are most commonly benign intracranial tumors, and surgical resection represents the treatment modality of choice. However, especially for patients of higher age and with increasing comorbidities, brain surgery might be accompanied by the need for postoperative prolonged intensive care, which might impair intended operative benefit. In the present study, we therefore analyzed prolonged mechanical ventilation (PMV) as an indicator variable for such intensive care treatment with regard to potential effects on mortality after meningioma resection in patients aged 70 years and older. We found that patients with postoperative PMV exhibited a profoundly increased probability to die within 1 year after surgery. Based on these findings, we identified risk factors for postoperative PMV occurrence and developed an easy-to-use score which allows us to estimate the risk of PMV occurrence preliminary to the surgical resection. We believe that this score might help to more sufficiently guide patients in the course of risk–benefit assessment and preoperative counseling. Abstract Indication for surgical treatment in patients with intracranial meningioma must include both clinical aspects and an individual risk–benefit stratification, especially in geriatric patients. Prolonged mechanical ventilation (PMV) has not been investigated for its potential effects in patients with meningioma. We therefore analyzed the impact of PMV on mortality in geriatric patients who had undergone meningioma resection. Between 2009 and 2019, 261 patients aged ≥ 70 years were surgically treated for intracranial meningioma at our institution. PMV was defined as postoperative invasive ventilation of >7 days. Postoperative PMV was present in 17 of 261 geriatric meningioma patients (7%). Twenty-five geriatric patients (10%) died within 1 year after surgery. A scoring system (“ACKT”) based on the variables of age, preoperative C-reactive protein (CRP) value, Karnofsky performance scale and tumor size supports prediction of postoperative PMV (sensitivity 73%, specificity 84%). PMV is significantly associated with increased mortality after surgical treatment of meningiomas in geriatric patients. Furthermore, we suggest a novel score (“ACKT”) to preoperatively estimate the risk of PMV occurrence, which might help to guide future risk–benefit assessment and patient counseling in the geriatric meningioma population.

Objective: The need for continuous renal replacement therapy (CRRT) in patients with deep-seated intracerebral hemorrhage (ICH) requires sustained intensive care and often postpones further rehabilitation therapy. Therefore, an early identification of patients at risk is essential.Methods: From 2014 to 2019, all patients with deep-seated ICH who were admitted to intensive care for >3 days were included in the further analysis and retrospectively reviewed for the need for CRRT. All patients underwent CRRT with regional citrate anticoagulation for continuous veno-venous hemodialysis (CVVHD). Outcome was evaluated after 3 months using the modified Rankin scale. A multivariate analysis was performed to identify potential predictors for CRRT in patients with deep-seated ICH.Results: After applying the inclusion criteria, a total of 87 patients with deep-seated spontaneous ICH were identified and further analyzed. During the first 48 h after admission, 21 of these patients developed early acute kidney injury (AKI; 24%). During treatment course, CRRT became necessary in nine patients suffering from deep-seated ICH (10%). The multivariate analysis revealed “development of AKI during the first 48 h” [p = 0.025, odds ratio (OR) 6.1, 95% confidence interval (CI) 1.3–29.8] and “admission procalcitonin (PCT) value >0.5 μg/l” (p = 0.02, OR 7.7, 95% CI 1.4–43.3) as independent and significant predictors for CRRT in patients with deep-seated ICH.Conclusions: Elevated serum levels of procalcitonin on admission as well as early development of acute renal injury are independent predictors of the need for renal replacement therapy in patients with deep-seated intracerebral bleeding. Therefore, further research is warranted to identify these vulnerable patients as early as possible to enable adequate treatment.

ObjectiveAlthough the treatment of glioblastoma patients is well established in neuro-oncological surgery, precious scarce data is available on patients with glioblastoma requiring postoperative prolonged mechanical ventilation (PMV). Therefore, the aim of the present study was to determine the influence of PMV on overall survival (OS) in patients with glioblastoma.MethodsPatients with newly diagnosed glioblastoma who had undergone surgical therapy and complete subsequent neuro-oncological treatment at the authors’ neuro-oncological center from January 2013 to December 2018 were selected and included in the further analysis. PMV was defined as mechanical ventilation for more than 24 h after surgery. Survival analyses were performed, including established prognostic factors such as age, Karnofsky performance score, MGMT-promoter methylation status and extent of resection.ResultsA total of 240 patients with newly diagnosed glioblastoma and subsequent surgical treatment were identified. 13 patients (5%) suffered from PMV during the treatment course of glioblastoma. All but one patient were successfully weaned from mechanical ventilation. Patients suffering from PMV achieved significantly less often favorable functional outcome after 3, 6, 9, and 12 months compared to patients without PMV. Multivariate analysis revealed PMV to constitute a significant prognostic factor for OS, independent of other prognostic factors (pConclusionsThe present study identifies PMV as significantly associated with impaired functional outcome and poor OS in patients suffering from newly diagnosed glioblastoma. These findings encourage further efforts to investigate/assess this prognostic factor in future studies.

Background: There is wide variability in anticoagulation strategies for veno-venous (VV-) extracorporeal membrane oxygenation (ECMO) for acute respiratory failure. Methods: We conducted a retrospective comparison of unfractionated heparin (UFH)-based anticoagulation strategies between two ECMO centers: 1 - high dose (HD) group: Two hourly ACT-based therapeutic anticoagulation with a target of 140-180s. 2 - low dose (LD) group: Thrice daily PTT-based prophylactic anticoagulation with UFH with a pro-thrombin time (PTT) target of 35-40s. The primary outcome was number of oxygenator changes per patient. Secondary outcomes were coagulation studies, and severe bleeding and thromboembolic events. Results: 215 patients were included (HD group 116, LD group 99). Disease severity in both groups was comparable (SAPS score 47.4±13.7 vs 48.0±12.9, p=0.710). Consistent with the chosen strategy, the mean PTT was longer in the HD group (51±17s vs 39±8s, p Conclusion: A LD heparinization strategy in VV-ECMO was associated with more oxygenator changes and more thromboembolic events compared to HD heparinization. No differences were seen regarding severe bleeding events and in-hospital mortality. Overall, the data favor the HD strategy, at least in patients not at high risk of bleeding.

The impact of dehydration at admission of patients with spontaneous intracerebral hemorrhage (ICH) on short-term mortality remains ambiguous due to scarce data. All of the consecutive patients with spontaneous ICH, who were referred to our neurovascular center in 2018/19, were assessed for hydration status on admission. Dehydration was defined by a blood urea-to-creatinine ratio > 80. In a cohort of 249 patients, 76 patients (31%) were dehydrated at the time of admission. The following factors were significantly and independently associated with increased 30-day mortality in multivariate analysis: “signs of cerebral herniation” (p = 0.008), “initial midline shift > 5 mm” (p < 0.001), “ICH score > 3” (p = 0.007), and “admission dehydration status” (p = 0.007). The results of the present study suggest that an admission dehydration status might constitute a significant and independent predictor of short-term mortality in patients with spontaneous ICH.

First described in the mid-1960s, acute respiratory distress syndrome (ARDS) is a life-threatening form of respiratory failure with an overall mortality rate of approximately 40%. Despite significant advances in the understanding and treatment of ARDS, no substantive pharmacologic therapy has proven to be beneficial, and current management continues to be primarily supportive. Beyond their antibacterial activity, several antibiotics such as macrolides and tetracyclines exert pleiotropic immunomodulatory effects that might be able to rectify the dysregulated inflammatory response present in patients with ARDS. This review aims to provide an overview of preclinical and clinical studies that describe the immunomodulatory effects of antibiotics in ARDS. Moreover, the underlying mechanisms of their immunomodulatory properties will be discussed. Further studies are necessary to investigate their full therapeutic potential and to identify ARDS phenotypes which are most likely to benefit from their immunomodulatory effects.

Introduction: The NLRP3 inflammasome is a key factor in innate immunity and plays a pivotal role in driving acute lung injury via IL-1β and IL-18. Recent studies highlighted the immunomodulatory effects of tetracyclines (TET) in the treatment of inflammatory diseases and identified inhibition of NLRP3 inflammsome as a potential mechanism. Aim: We investigated in a murine model whether TET reduces NLRP3 inflammasome-mediated lung inflammation and improves outcome. Methods: Mice were challenged with LPS i.t. and treated by i.p. injection of TET from d 0 for 10 d. Lung injury was determined by measurement of i) albumin concentration by ELISA, ii) neutrophil population by flow cytometry (both in BALF) and iii) histopathology. Concentration of IL-1β, IL-6, IL-18 and TNFα was measured by multiplex assay in BALF. The effect of TET on NLRP3 inflammasome was tested in BMDMs after stimulation with LPS plus nigericin. Concentration of IL-1β and TNFα was determined by ELISA and cleavage of caspase-1 via western blot. Results: TET treated mice showed significantly reduced weight loss and mortality (43% vs. 7%) compared to PBS treated animals. TET treatment diminished lung injury in terms of lower albumin (325±35 vs 144±16µg/ml) concentration and number of neutrophils. Histopathology showed reduced lung injury in TET-treated animals. TET decreased exclusively the concentration of IL-1β (152±16 vs 86±8 pg/ml) and IL-18 in BALF. TET selectively inhibited IL-1β secretion and caspase-1 activation after NLRP3 stimulation. Conclusions: Current study demonstrates that TET reduces acute lung injury in mice via inhibiting NLRP3 inflammasome activation, thereby reducing morbidity and mortality.

(1) Background: As elements of the standard admission blood panel, lactate and glucose represent potential biomarkers for outcome prediction. In patients with intracranial hemorrhage (ICH), data on the predictive value of these blood values is exceedingly sparse. (2) Methods: Between 2014 and August 2020, all patients with deep-seated ICH referred to the neurovascular center at the authors’ institution were included in the subsequent study. Serum levels of lactate and glucose at the time of admission were compared with mortality at 90 days. In addition, a multivariate analysis was performed in order to identify independent admission predictors for 90-day mortality. (3) Results: Among the 102 patients with deep-seated ICH, elevated lactate and glucose levels on admission were significantly associated with increased mortality at 90 days. Multivariate logistic regression analysis identified “ICH score ≥3” (p = 0.004) along with “admission hyperlactatemia” (p = 0.025) and “admission hyperglycemia” (p = 0.029) as independent and significant predictors of 90-day mortality in patients with deep-seated ICH. (4) Conclusions: Initially elevated lactate and glucose levels after spontaneous intracerebral hemorrhage are associated with poor outcome, suggesting a potential application for future prognostic models when considered in conjunction with other parameters.

Acute respiratory distress syndrome (ARDS) is a heterogeneous syndrome with multiple underlying diseases. Particularly epithelial damage results from direct (e.g., pneumonia) rather than indirect lung injury (e.g., nonpulmonary sepsis), which is more likely associated with endothelial damage. Hence, targeting ARDS patients based on their molecular phenotypes is a promising approach to improve outcome. With regard to distinct inflammatory responses and subsequent lung damage in direct ARDS due to the causing pathogen, we quantified markers of epithelial and endothelial damage and pro-inflammatory cytokines in patients with ARDS triggered by bacterial, viral, and atypical pathogen pneumonia or indirect ARDS. The serum levels of interleukin-6 (IL-6) and interleukin-8 (IL-8), lung epithelial injury markers surfactant protein D (SP-D), and soluble receptor for advanced glycation end-products (sRAGE) as well as endothelial injury marker angiopoietin-2 (Ang-2) from 49 patients with distinct types of ARDS were analyzed by multiplex immunoassay. Epithelial damage marker SP-D was significantly higher in direct ARDS caused by viral and atypical pathogens in contrast to ARDS caused by typical bacterial pneumonia and nonpulmonary sepsis. In contrast, sRAGE levels did not differ due to the causing pathogen. Patients with atypical pathogen pneumonia related ARDS showed significantly lower Ang-2 levels compared to patients with viral and indirect ARDS. Patients with viral and atypical pneumonia related ARDS possessed significantly lower serum IL-6 levels compared to bacterial pneumonia related ARDS and IL-6 levels in atypical pneumonia related ARDS were significantly lower than in indirect ARDS. Current findings report a potential difference in ARDS biomarkers due to the underlying disease and pathogen.

Sepsis, a life threating syndrome characterized by organ failure after infection, is the most common cause of death in hospitalized patients. The treatment of sepsis is generally supportive in nature, involving the administration of intravenous fluids, vasoactive substances and oxygen plus antibiotics to eliminate the pathogen. No drugs have been approved specifically for the treatment of sepsis, and clinical trials of potential therapies have failed to reduce mortality - suggesting that new approaches are needed. Abnormalities in the immune response elicited by the pathogen, ranging from excessive inflammation to immunosuppression, contribute to disease pathogenesis. Although hundreds of immunomodulatory agents are potentially available, it remains unclear which patient benefits from which immune therapy at a given time point. Results indicate the importance of personalized therapy, specifically the need to identify the type of intervention required by each individual patient at a given point in the disease process. To address this issue will require using biomarkers to stratify patients based on their individual immune status. This article reviews recent and ongoing clinical investigations using immunostimulatory or immunosuppressive therapies against sepsis including non-pharmacological and novel preclinical approaches.

(1) Background: With the rise of multi-/pan-drug resistant (MDR/PDR) pathogens, the less utilized antibiotic Colistin has made a comeback. Colistin fell out of favor due to its small therapeutic range and high potential for toxicity. Today, it is used again as a last resort substance in treating MDR/PDR pathogens. Although new guidelines with detailed recommendations for Colistin dosing are available, finding the right dose in critically ill patients with renal failure remains difficult. Here, we evaluate the efficiency of the current guidelines&rsquo, recommendations by using high resolution therapeutic drug monitoring of Colistin. (2) Methods: We analyzed plasma levels of Colistin and its prodrug colisthimethate sodium (CMS) in 779 samples, drawn from eight PDR-infected ICU patients, using a HPLC-MS/MS approach. The impact of renal function on proper Colistin target levels was assessed. (3) Results: CMS levels did not correlate with Colistin levels. Over-/Underdosing occurred regardless of renal function and mode of renal replacement therapy. Colistin elimination half-time appeared to be longer than previously reported. (4) Conclusion: Following dose recommendations from the most current guidelines does not necessarily lead to adequate Colistin plasma levels. Use of Colistin without therapeutic drug monitoring might be unsafe and guideline adherence does not warrant efficient target levels in critically ill patients.

Introduction: A significant increase of the p-wave of a real-time intracavitary electrocardiography is a reliable and safe method to confirm the central venous catheter tip position close to the atrium. However, conflicting data about the feasibility of electrocardiography exist in patients with atrial fibrillation. Methods: An observational prospective case–control cohort study was set up to study the feasibility and accuracy of the electrocardiography-controlled central venous catheter tip placement in 13 patients with atrial fibrillation versus 10 patients with sinus rhythm scheduled for elective surgery. Each intervention was crosschecked with ultrasound-guided positioning via right supraclavicular fossa view and chest radiography. Ultrasound-guided supraclavicular venipuncture of the right subclavian vein and guidewire advancement were performed. A B-mode view of the superior vena cava and the right pulmonary artery was obtained to visualize the J-tip of the guidewire. The central venous catheter was advanced over the guidewire and the electrocardiography was derived from the J-tip of the guidewire protruding from the central venous catheter tip. Electrocardiography was read for increased p- and atrial fibrillation waves, respectively, and insertion depth was compared with the ultrasound method. Results: Electrocardiography indicated significantly increasing fibrillation and p-waves, respectively, in all patients and ultrasound-guided central venous catheter positioning confirmed a tip position within the lower third of the superior vena cava. Conclusion: Electrocardiography-guided central venous catheter tip positioning is a feasible real-time method for patients with atrial fibrillation. Combined with ultrasound, the electrocardiography-controlled central venous catheter placement may eliminate the need for postinterventional radiation exposure.

Synthetic oligonucleotides (ODNs) containing CpG motifs stimulate human plasmacytoid dendritic cells (pDCs) to produce type-1 interferons (IFNs) and proinflammatory cytokines. Previous studies demonstrated that interferon regulatory factors (IRFs) play a central role in mediating CpG-induced pDC activation. This work explores the inverse effects of IRF5 and IRF8 (also known as IFN consensus sequence-binding protein) on CpG-dependent gene expression in the human CAL-1 pDC cell line. This cell line shares many of the phenotypic and functional properties of freshly isolated human pDCs. Results from RNA interference and microarray studies indicate that IRF5 upregulates TLR9-driven gene expression whereas IRF8 downregulates the same genes. Several findings support the conclusion that IRF8 inhibits TLR9-dependent gene expression by directly blocking the activity of IRF5. First, the inhibitory activity of IRF8 is only observed when IRF5 is present. Second, proximity ligation analysis shows that IRF8 and IRF5 colocalize within the cytoplasm of resting human pDCs and cotranslocate to the nucleus after CpG stimulation. Taken together, these findings suggest that IRF5 and IRF8, two transcription factors with opposing functions, control TLR9 signaling in human pDCs.

Aims The incidence of secondary systemic fungal infections has sharply increased in bacterial septic patients. Antimycotics exhibit immunomodulatory properties, yet these effects are incompletely understood in secondary systemic fungal infections following bacterial sepsis. We investigated a model of systemic inflammation to determine whether antimycotics (liposomal amphotericin B (L-AMB), itraconazol (ITC), and anidulafungin (ANI)) modulate the gene and protein expression as well as the phagocytic activity of lipopolysaccharide (LPS)-stimulated human monocytes. Main methods THP-1 monocytes were incubated with L-AMB, ITC or ANI and LPS. Gene expression levels of cytokines (TNF- , IL-1 , IL-6, and IL-10) were measured after 2 h, 6 h, and 24 h. Cytokine protein levels were evaluated after 24 h and phagocytic activity was determined following co-incubation with Escherichia coli. Key findings All antimycotics differentially modulated the gene and protein expression of cytokines in sepsis-like conditions. In the presence of LPS, we identified L-AMB as immunosuppressive, whereas ITC demonstrated pro-inflammatory properties. Both compounds induced remarkably less phagocytosis. Significance Our study suggests that antimycotics routinely used in septic patients alter the immune response in sepsis-like conditions by modulating cytokine gene and protein expression levels and phagocytic activity. Future treatment strategies should consider the immune status of the host and apply antimycotics accordingly in bacterial septic patients with secondary fungal infections.

Conventional antibiotics exhibit immunomodulatory properties beneficial in the treatment of sepsis. Antibiotic-resistant Gram-positive bacteria have become a problem in sepsis therapy, giving rise to increased use of last-resort antibiotics; for example, linezolid (LIN), vancomycin (VAN) and daptomycin (DAP). As the immunomodulatory properties of these antibiotics in treating sepsis are unknown, this study examined the effect of VAN, LIN and DAP on the immune response under sepsis-like conditions in vitro. Lipopolysaccharide (LPS)-activated THP-1 monocytes were incubated with LIN, VAN or DAP. Gene expression of cytokines (TNFα, IL-1β, IL-6, IL-10) and Toll-like receptors (TLR1, 2, 4, 6, 7 and 9) was monitored and phagocytosis was determined following coincubation with E. coli. The antibiotics differentially modulated the gene expression of the investigated cytokines. While LIN and VAN upregulated the expression of all TLRs, DAP downregulated mRNA levels of TLR1, TLR2 and TLR6, which recognize pathogen-associated molecular patterns from Gram-positive bacteria. In addition, LIN inhibited, whereas VAN promoted the phagocytic activity of monocytes. Our results suggest that LIN and VAN possess pro-inflammatory properties, whereas DAP might reduce the immune response to Gram-positive bacteria in sepsis. Furthermore, VAN might be beneficial in the prevention of Gram-negative infections by increasing the phagocytosis of E. coli.

Type I interferon (IFN) is a critical mediator of autoimmune diseases such as systemic lupus erythematosus (SLE) and Aicardi-Goutieres Syndrome (AGS). The recently discovered cyclic-GMP-AMP (cGAMP) synthase (cGAS) induces the production of type I IFN in response to cytosolic DNA and is potentially linked to SLE and AGS. Suppressive oligodeoxynucleotides (ODN) containing repetitive TTAGGG motifs present in mammalian telomeres have proven useful in the treatment of autoimmune diseases including SLE. In this study, we demonstrate that the suppressive ODN A151 effectively inhibits activation of cGAS in response to cytosolic DNA, thereby inhibiting type I IFN production by human monocytes. In addition, A151 abrogated cGAS activation in response to endogenous accumulation of DNA using TREX1-deficient monocytes. We demonstrate that A151 prevents cGAS activation in a manner that is competitive with DNA. This suppressive activity of A151 was dependent on both telomeric sequence and phosphorothioate backbone. To our knowledge this report presents the first cGAS inhibitor capable of blocking self-DNA. Collectively, these findings might lead to the development of new therapeutics against IFN-driven pathologies due to cGAS activation.

Although pediatric emergence delirium (ED) is common, preventive and therapeutic pharmacological treatment is the matter of an international controversial discussion and evidence on different options is partially vague. We therefore examined clinical routine in prevention strategies and postoperative therapy of ED with respect to clinical experience in pediatric anesthesia. A web-based survey was developed investigating routine management (prevention and treatment) of ED, facility structure, and patient population. The link was sent to all enlisted members of the German Society of Anesthesiology. We analyzed 1229 questionnaires. Overall, 88% reported ED as a relevant clinical problem; however, only 5% applied assessment scores to define ED. Oral midazolam was reported as standard premedication by 84% of respondents, the second largest group was ‘no premedication’ (5%). The first choice prevention strategy was to perform total intravenous (propofol) anesthesia (63%). The first choice therapeutic pharmacological treatment depended on clinical experience. Therapeutic propofol was preferentially chosen by more experienced anesthesiologists (5 to >20 patients per week, n = 538), while lesser experienced colleagues (

Suppressive oligodeoxynucleotides (Sup ODN) express repetitive TTAGGG motifs that have proven useful in the treatment/prevention of numerous inflammatory and autoimmune diseases. The mechanism underlying the immunosuppressive activity of Sup ODN is incompletely understood. Regulatory T cells (T reg ) play a key role in controlling a variety of pathologic autoimmune responses. T reg are generated from activated CD4 + T cells in a process that involves the phosphorylation of STAT family members. Current studies demonstrate that Sup ODN promote the differentiation of CD4 + CD25 − T cells into functionally active iT reg in vitro. When administered in vivo, Sup ODN promote the generation of iT reg in response to peptide challenge. Central to this effect is the ability of Sup ODN to block the phosphorylation of STAT1. These findings clarify the mechanism underlying the therapeutic activity of Sup ODN and support their use in T reg -based immunotherapy.

Consumers increasingly demand an improvement of animal welfare, in particular a refrainment from surgical interventions such as tail docking and castration. The aim of the study was to investigate effects of simultaneous implementation of elevated welfare standards under field conditions on valid indicators at the abattoir and product quality. Six different pig farms from birth to fattening were reimbursed for implementing elevated welfare standards (no tail docking in all and no castration of male piglets). Farmers were free to try Improvac® treatments and boar fattening. At the abattoir, welfare indicators like swellings and conditions of ears, claws, skin and tails were inspected on carcasses (pigs: n >1866). Meat quality was evaluated (n >185). Fixed effects of sex (females and barrows, Improvac® treated boars, boars) and farm were included in mixed models and Pearson correlations were calculated (SAS 9.4). Results were condensed with a Failure Mode and Effects Analysis (FMEA). Two farms managed to deliver around 90% of pigs with intact tails, whereas one completely failed (80% tails shorter than 1/3 of original length). Sex affected almost all welfare indicators, with least impairments in the females and barrows group and most in boars (P < 0.01). FMEA revealed concerns regarding animal welfare and meat quality in boars and immense variation between farms. For example, drip losses showed an interaction between sex and farm, suggesting that some farms provide better conditions for Improvac® treated pigs and boars than others. Besides that, transport duration from fattening location to abattoir correlated with swelling on fore and hind legs (0.15< r< 0.17; P < 0.001), but did not affect tail classification. In conclusion, the implementation of elevated animal welfare standards was highly dependent on the farm-specific management. Because used indicators were successfully assessed on the carcasses, they seem to be valid for future reward systems.