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Objective: Oxygen has been used liberally in ICUs for a long time to prevent hypoxia in ICU- patients. Current evidence suggests that paO 2 >300 mmHg should be avoided, it remains uncertain whether an "optimal level" exists. We investigated how "mild" hyperoxia influences diseases and in-hospital mortality., Design: This is a retrospective study., Setting: 112 mechanically ventilated ICU-patients were enrolled., Patients or Participants: 112 ventilated patients were included and categorized into two groups based on the median paO 2 values measured in initial 24 h of mechanical ventilation: normoxia group (paO 2 ≤ 100 mmHg, n = 43) and hyperoxia group patients (paO 2 > 100 mmHg, n = 69)., Interventions: No interventions were performed., Main Variables of Interest: The primary outcome was the incidence of pulmonary events, the secondary outcomes included the incidence of other new organ dysfunctions and in-hospital mortality., Results: The baseline characteristics, such as age, body mass index, lactate levels, and severity of disease scores, were similar in both groups. There were no statistically significant differences in the incidence of pulmonary events, infections, and new organ dysfunctions between the groups. 27 out of 69 patients (39.1%) in the "mild" hyperoxia group and 12 out of 43 patients (27.9%) in the normoxia group died during their ICU or hospital stay (p = 0.54). The mean APACHE Score was 29.4 (SD 7.9) in the normoxia group and 30.0 (SD 6.7) in the hyperoxia group (p = 0.62)., Conclusions: We found no differences in pulmonary events, other coded diseases, and in-hospital mortality between both groups. It remains still unclear what the "best oxygen regime" is for intensive care patients., (Copyright © 2024 The Authors. Published by Elsevier España, S.L.U. All rights reserved.)

Purpose: Infections are common complications in patients following liver transplantation (LTX). The early diagnosis and prognosis of these infections is an unmet medical need even when using routine biomarkers such as C-reactive protein (CRP) and procalcitonin (PCT). Therefore, new approaches are necessary., Methods: In a prospective, observational pilot study, we monitored 30 consecutive patients daily between days 0 and 13 following LTX using the 29-mRNA host classifier IMX-BVN-3b that determine the likelihood of bacterial infections and viral infections. True infection status was determined using clinical adjudication. Results were compared to the accuracy of CRP and PCT for patients with and without bacterial infection due to clinical adjudication., Results: Clinical adjudication confirmed bacterial infections in 10 and fungal infections in 2 patients. 20 patients stayed non-infected until day 13 post-LTX. IMX-BVN-3b bacterial scores were increased directly following LTX and decreased until day four in all patients. Bacterial IMX-BVN-3b scores detected bacterial infections in 9 out of 10 patients. PCT concentrations did not differ between patients with or without bacterial, whereas CRP was elevated in all patients with significantly higher levels in patients with bacterial infections., Conclusion: The 29-mRNA host classifier IMX-BVN-3b identified bacterial infections in post-LTX patients and did so earlier than routine biomarkers. While our pilot study holds promise future studies will determine whether these classifiers may help to identify post-LTX infections earlier and improve patient management., Clinical Trial Notation: German Clinical Trials Register: DRKS00023236, Registered 07 October 2020, https://drks.de/search/en/trial/DRKS00023236., (© 2024. The Author(s).)

miR-Blood is a high-quality, small RNA expression atlas for the major components of human peripheral blood (plasma, erythrocytes, thrombocytes, monocytes, neutrophils, eosinophils, basophils, natural killer cells, CD4+ T cells, CD8+ T cells, and B cells). Based on the purified blood components from 52 individuals, the dataset provides a comprehensive repository for the expression of 4971 small RNAs from eight non-coding RNA classes., (© 2024. The Author(s).)

Sepsis is defined as organ failure caused by dysregulated host response to infection. While early antibiotic treatment in patients with acute infection is essential, treating non-infectious patients must be avoided. Current guidelines recommend procalcitonin (PCT) to guide discontinuation of antibiotic treatment. For initiation of therapy, there is currently no recommended biomarker. In this study, we evaluated Host-Derived Delta-like Canonical Notch Ligand 1 (DLL1), a monocyte membrane ligand that has shown promising results in differentiating infectious from non-infectious critically ill patients. Soluble DLL1 levels were measured in plasma samples of six different cohorts. The six cohorts comprise two cohorts with non-infectious inflammatory auto-immune diseases (Hidradenitis Suppurativa, Inflammatory Bowel Disease), one cohort of bacterial skin infection, and three cohorts of suspected systemic infection or sepsis. In total, soluble DLL1 plasma levels of 405 patients were analyzed. Patients were divided into three groups: inflammatory disease, infection, and sepsis (defined according to the Sepsis-3 definition), followed by the evaluation of its diagnostic performance via Area Under the Receiver Operating Characteristics (AUROC) analyses. Patients of the sepsis group showed significantly elevated plasma DLL1 levels compared to patients with uncomplicated infections and sterile inflammation. However, patients with infections had significantly higher DLL1 levels than patients with inflammatory diseases. Diagnostic performance was evaluated and showed better performance for DLL1 for the recognition of sepsis (AUC: 0.823; CI 0.731-0.914) than C-reactive protein (AUC 0.758; CI 0.658-0.857), PCT (AUC 0.593; CI 0.474-0.711) and White Blood Cell count (AUC 0.577; CI 0.46-0.694). DLL1 demonstrated promising results for diagnosing sepsis and was able to differentiate sepsis from other infectious and inflammatory diseases., Competing Interests: Markus A. Weigand holds patent EP/25.10.17/EPA17198330 Delta like ligand for diagnosing severe infections and is co-founder of the Delta Theragnostics GmbH. All other authors declare no conflict of interest.

Acute kidney injury (AKI) secondary to sepsis results in poor outcomes and conventional kidney function indicators lack diagnostic value. Soluble urokinase plasminogen activator receptor (suPAR) is an innate immune-derived molecule implicated in inflammatory organ damage. We characterized the diagnostic ability of longitudinal serum suPAR levels to discriminate severity and course of sepsis-induced AKI (SI-AKI) in 200 critically ill patients meeting Sepsis-3 criteria. The pathophysiologic relevance of varying suPAR levels in SI-AKI was explored in a polymicrobial sepsis model in WT, (s)uPAR-knockout, and transgenic suPAR-overexpressing mice. At all time points studied, suPAR provided a robust classification of SI-AKI disease severity, with improved prediction of renal replacement therapy (RRT) and mortality compared with established kidney biomarkers. Patients with suPAR levels of greater than 12.7 ng/mL were at highest risk for RRT or death, with an adjusted odds ratio of 7.48 (95% CI, 3.00-18.63). suPAR deficiency protected mice against SI-AKI. suPAR-overexpressing mice exhibited greater kidney damage and poorer survival through inflamed kidneys, accompanied by local upregulation of potent chemoattractants and pronounced kidney T cell infiltration. Hence, suPAR allows for an innate immune-derived and kidney function-independent staging of SI-AKI and offers improved longitudinal risk stratification. suPAR promotes T cell-based kidney inflammation, while suPAR deficiency improves SI-AKI.

Rationale: Sepsis, a global health burden, is often complicated by viral infections leading to increased long-term morbidity and mortality. Interleukin-3 (IL-3) has been identified as an important mediator amplifying acute inflammation in sepsis; however, its function in the host response to viral infections during sepsis remains elusive., Objectives: To investigate the role of IL-3 during viral pneumonia in sepsis., Methods: We included septic patients from two different cohorts and used in vitro and in vivo assays. The obtained data were substantiated using a second model (SARS-CoV-2 infections)., Measurements and Main Results: Low plasma IL-3 levels were associated with increased herpes simplex virus (HSV) airway infections in septic patients, resulting in reduced overall survival. Likewise, Il-3 -deficient septic mice were more susceptible to pulmonary HSV-1 infection and exhibited higher pulmonary inflammation than control mice. Mechanistically, IL-3 increases innate antiviral immunity by promoting the recruitment of circulating plasmacytoid dendritic cells (pDCs) into the airways and by enhancing pDC-mediated T cell activation upon viral stimulation. Interestingly, the ability of IL-3 to improve adaptive immunity was confirmed in patients with SARS-CoV-2 infections., Conclusion: Our study identifies IL-3 as a predictive disease marker for viral reactivation in sepsis and reveals that IL-3 improves antiviral immunity by enhancing the recruitment and the function of pDCs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bénard, Hansen, Uhle, Klösch, Czubayko, Mittelstädt, Jacobsen, David, Podolska, Anthuber, Swierzy, Schaack, Mühl-Zürbes, Steinkasserer, Weyand, Weigand, Brenner, Krautz, Grützmann and Weber.)

Introduction: The bacterial protein toxin Pasteurella multocida toxin (PMT) mediates RANKL-independent osteoclast differentiation. Although these osteoclasts are smaller, their resorptive activity is high which helps in efficient destruction of nasal turbinate bones of pigs., Methods: The proteome of bone marrow-derived macrophages differentiated into osteoclasts with either RANKL or PMT was analysed. The results were verified by characterizing the metabolic activity using Seahorse analysis, a protein translation assay, immunoblots, real-time PCR as well as flow cytometry-based monitoring of mitochondrial activity and ROS production. A Gαq overexpression system using ER-Hoxb8 cells was used to identify Gαq-mediated metabolic effects on osteoclast differentiation and function., Results: PMT induces the upregulation of metabolic pathways, which included strong glycolytic activity, increased expression of GLUT1 and upregulation of the mTOR pathway. As OxPhos components were expressed more efficiently, cells also displayed increased mitochondrial respiration. The heterotrimeric G protein Gαq plays a central role in this hypermetabolic cell activation as it triggers mitochondrial relocalisation of pSerSTAT3 and an increase in OPA1 expression. This seems to be caused by a direct interaction between STAT3 and OPA1 resulting in enhanced mitochondrial respiration. Overexpression of Gαq mimicked the hypermetabolic phenotype observed for PMT-induced osteoclasts and resulted in higher glycolytic and mitochondrial activity as well as increased bone resorptive activity. In addition, rheumatoid arthritis (RA) patients showed an increase in GNAQ expression, especially in the synovial fluid., Discussion: Our study suggests that Gαq plays a key role in PMT-induced osteoclastogenesis. Enhanced expression of GNAQ at the site of inflammation in RA patients indicates its pathophysiological relevance in the context of inflammatory bone disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chakraborty, Handrick, Yu, Bode, Hafner, Schenz, Schaack, Uhle, Tachibana, Kamitani, Vogl and Kubatzky.)

Abstract: Background: Risk stratification of emergency department patients with suspected acute infections and/or suspected sepsis remains challenging. We prospectively validated a 29-messenger RNA host response classifier for predicting severity in these patients. Methods: We enrolled adults presenting with suspected acute infections and at least one vital sign abnormality to six emergency departments in Greece. Twenty-nine target host RNAs were quantified on NanoString nCounter and analyzed with the Inflammatix Severity 2 (IMX-SEV-2) classifier to determine risk scores as low, moderate, and high severity. Performance of IMX-SEV-2 for prediction of 28-day mortality was compared with that of lactate, procalcitonin, and quick sequential organ failure assessment (qSOFA). Results: A total of 397 individuals were enrolled; 38 individuals (9.6%) died within 28 days. Inflammatix Severity 2 classifier predicted 28-day mortality with an area under the receiver operator characteristics curve of 0.82 (95% confidence interval [CI], 0.74-0.90) compared with lactate, 0.66 (95% CI, 0.54-0.77); procalcitonin, 0.67 (95% CI, 0.57-0.78); and qSOFA, 0.81 (95% CI, 0.72-0.89). Combining qSOFA with IMX-SEV-2 improved prognostic accuracy from 0.81 to 0.89 (95% CI, 0.82-0.96). The high-severity (rule-in) interpretation band of IMX-SEV-2 demonstrated 96.9% specificity for predicting 28-day mortality, whereas the low-severity (rule-out) band had a sensitivity of 78.9%. Similarly, IMX-SEV-2 alone accurately predicted the need for day-7 intensive care unit care and further boosted overall accuracy when combined with qSOFA. Conclusions: Inflammatix Severity 2 classifier predicted 28-day mortality and 7-day intensive care unit care with high accuracy and boosted the accuracy of clinical scores when used in combination., Competing Interests: James W. Wacker, Florian Uhle, Oliver Liesenfeld, and Timothy E. Sweeney are employees and stock option holders of Inflammatix Inc. Catherine A. Hogan is a consultant for Inflammatix. E.J. Giamarellos-Bourboulis has received honoraria from Abbott CH, InflaRx GmbH, MSD Greece, XBiotech Inc., and B·R·A·H·M·S GmbH (Thermo Fisher Scientific); independent educational grants from AbbVie Inc., Abbott CH, bioMérieux Inc., Novartis, InflaRx GmbH, UCB, Sobi, and XBiotech Inc; and funding from the Horizon2020 Marie-Curie Project European Sepsis Academy (granted to the National and Kapodistrian University of Athens), the Horizon 2020 European Grants ImmunoSep and RISKinCOVID (granted to the Hellenic Institute for the Study of Sepsis), and by the Horizon Europe grant EPIC-CROWN-2 (granted to the Hellenic Institute for the Study of Sepsis). The other authors do not declare any conflict of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Shock Society.)

The early identification of sepsis in surgical intensive care patients is challenging due to the physiological postoperative alterations of vital signs and inflammatory biomarkers. Soluble Delta-like protein 1 (sDLL1) may be a potential discriminatory biomarker for this purpose. For this reason, this study aimed to evaluate sDLL1 for the identification of sepsis in a cohort of surgical intensive care patients. This study comprises a secondary analysis of a prospective observational study including 80 consecutive patients. The study groups included 20 septic shock patients, 20 patients each undergoing major abdominal surgery (MAS) and cardiac artery bypass surgery (CABG), and 20 matched control subjects (CTRL). The surveillance period was 72 h. The plasma concentration of sDLL1 was measured with ELISA. The plasma levels of sDLL1 were significantly elevated in septic patients compared to both surgical cohorts (septic vs. all postoperative time points, data are shown as median and interquartile range [IQR]; septic shock: 17,363 [12,053-27,299] ng/mL, CABG 10,904 [8692-16,250] ng/mL; MAS 6485 [4615-9068] ng/mL; CTRL 5751 [3743-7109] ng/mL; septic shock vs. CABG: p < 0.001; septic shock vs. MAS: p < 0.001). ROC analysis showed a sufficient prediction of sepsis with limited specificity (AUCROC 0.82 [0.75-0.82], sensitivity 84%, specificity 68%). The plasma levels of sDLL correlated closely with renal parameters (creatinine: correlation coefficient = 0.60, r 2  = 0.37, p < 0.0001; urea: correlation coefficient = 0.52, r 2  = 0.26, p < 0.0001), resulting in a good predictive performance of sDLL1 for the identification of acute kidney injury (AKI; AUCROC 0.9 [0.82-0.9], sensitivity 83%, specificity 91%). By quantifying the plasma concentration of sDLL1, sepsis can be discriminated from the physiological postsurgical inflammatory response in abdominal and cardiac surgical patients. However, sDLL1 has only limited specificity for the detection of sepsis in cardiac surgical patients, which may be explained by impaired renal function. Based on these findings, this study identifies the predictive value of sDLL1 for the detection of AKI, making it a potential biomarker for surgical intensive care patients.Trial registration DRKS00013584, Internet Portal of the German Clinical Trials Register (DRKS), registration date 11.07.2018, https://www.drks.de/drks&#95;web/navigate.do?navigationId=trial.HTML&TRIAL&#95;ID=DRKS00013584 ., (© 2022. The Author(s).)

Background: After liver transplantation (LTX), patients are susceptible to opportunistic infections resulting in reduced outcomes within the early post-transplantation period. The postoperative monitoring of LTX patients has gained much importance in recent years. However, reliable plasmatic markers predicting 90-day outcomes are still lacking., Methods: In the post hoc analysis of a prospective, observational study, butyrylcholinesterase (BChE), mid-regional proadrenomedullin (MR-proADM), as well as conventional inflammatory markers (procalcitonin, C-reactive protein) were evaluated in 93 patients at seven consecutive timepoints within the first 28 days following LTX., Results: Persistently reduced activity of BChE and elevated MR-proADM levels indicated reduced 90-day survival following LTX. Furthermore, reduced BChE and increased MR-proADM activity could indicate early post-transplantation bacterial infections, whereas conventional inflammatory biomarkers showed no diagnostic efficacy within the observation period., Conclusion: Concurrent assessment of BChE and MR-proADM activity might serve as a bedside diagnostic tool for early bacterial infections following liver transplantation. Thus, a combined utilization of the two biomarkers may be a useful tool in the risk evaluation of patients following liver transplantation.

Objective: Cardiopulmonary bypass (CPB) can lead to systemic inflammation, which is associated with higher morbidity. Therefore, we investigated the metabolism of isolated blood monocytes before and after CPB compared to healthy controls., Methods: In this prospective, monocentric, observational study, we included 30 patients undergoing CPB and 20 controls. We isolated monocytes from heparinized blood and investigated their metabolism by using Seahorse technology before (t0), 4 h (t4), and 24 h (t24) after the start of the CPB. We also examined programmed cell death 1 ligand (PD-L1), PD-L2, V-domain Ig suppressor of T cell activation (VISTA), and human leukocyte antigen-DR isotype (HLA-DR) using fluorescence-activated cell sorting analysis. Additionally, we investigated plasma cytokine levels in patients without and after ex vivo stimulation., Results: CPB-induced inflammatory responses are shown by significantly elevated plasma interleukin-6 levels in the CPB group compared to baseline and controls [t0: 0 ng/ml (95%CI 0-0 ng/ml); t4: 0.16 ng/ml (95%CI 0.1-0.197 ng/ml), p < 0.0001; t24: 0.11 ng/ml (95% CI 0.1-0.16 ng/ml), p < 0.0001, and controls: 0 ng/ml (95% CI 0-0 ng/ml)]. The cytokine release in the ex vivo stimulation is reduced for lipopolysaccharide stimulation at t4 [t0: 35.68 ng/ml (95% CI 22.17-46.57 ng/ml) vs. t4: 15.02 (95% CI 10.25-24.78 ng/ml), p < 0.0001]. Intracellular metabolism of monocytes after CPB showed a protracted shift to aerobic glycolysis [t0: 179.2 pmol/min (95% CI 138.0-205.1 pmol/min) vs. t24: 250.1 pmol/min (95% CI 94.8-300.2 pmol/min), p < 0.0001]. Additionally, we observed an altered metabolism in monocytes in patients undergoing cardiac surgery compared to controls even before any surgical procedure [t0: 179.2 pmol/min (95% CI 138.0-205.1) vs. controls 97.4 (95% CI 59.13-144.6 pmol/min), p = 0.0031]., Conclusion: After CPB, patients' monocytes show a shift in metabolism from oxidative phosphorylation to aerobic glycolysis, which is associated with energy-demanding and proinflammatory processes. This is the first study to show changes in monocyte immunometabolism in cardiac surgery. Monocytes of patients undergoing cardiac surgery were leaning toward aerobic glycolysis even before any surgical procedure was conducted. Leaving the question of the pathophysiological mechanisms for future studies to be investigated and paving the way for potential therapy approaches preventing inflammatory effects of CPB., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mayer, Altvater, Schenz, Arif, Karck, Leuschner, Weigand, Uhle and Lichtenstern.)

Immunotherapies have recently gained traction as highly effective therapies in a subset of late-stage cancers. Unfortunately, only a minority of patients experience the remarkable benefits of immunotherapies, whilst others fail to respond or even come to harm through immune-related adverse events. For immunotherapies within the PD-1/PD-L1 inhibitor class, patient stratification is currently performed using tumor (tissue-based) PD-L1 expression. However, PD-L1 is an accurate predictor of response in only ~30% of cases. There is pressing need for more accurate biomarkers for immunotherapy response prediction. We sought to identify peripheral blood biomarkers, predictive of response to immunotherapies against lung cancer, based on whole blood microRNA profiling. Using three well-characterized cohorts consisting of a total of 334 stage IV NSCLC patients, we have defined a 5 microRNA risk score (miRisk) that is predictive of overall survival following immunotherapy in training and independent validation (HR 2.40, 95% CI 1.37-4.19; P < 0.01) cohorts. We have traced the signature to a myeloid origin and performed miRNA target prediction to make a direct mechanistic link to the PD-L1 signaling pathway and PD-L1 itself. The miRisk score offers a potential blood-based companion diagnostic for immunotherapy that outperforms tissue-based PD-L1 staining., (© 2022. The Author(s).)

Background: Vasoplegic syndrome is associated with increased morbidity and mortality in patients undergoing cardiac surgery. This retrospective, single-center study aimed to evaluate the effect of early use of methylene blue (MB) on hemodynamics after an intraoperative diagnosis of vasoplegic syndrome (VS)., Methods: Over a 10-year period, all patients diagnosed with intraoperative VS (hypotension despite treatment with norepinephrine ≥0.3 μg/kg/min and vasopressin ≥1 IE/h) while undergoing heart surgery and cardiopulmonary bypass were identified, and their data were examined. The intervention group received MB (2 mg/kg intravenous) within 15 min after the diagnosis of vasoplegia, while the control group received standard therapy. The two groups were matched using propensity scores., Results: Of the 1022 patients identified with VS, 221 received MB intraoperatively, and among them, 60 patients received MB within 15 min after the diagnosis of VS. After early MB application, mean arterial pressure was significantly higher, and vasopressor support was significantly lower within the first hour ( p = 0.015) after the diagnosis of vasoplegia, resulting in a lower cumulative amount of norepinephrine ( p = 0.018) and vasopressin ( p = 0.003). The intraoperative need of fresh frozen plasma in the intervention group was lower compared to the control group ( p = 0.015). Additionally, the intervention group had higher creatinine values in the first three postoperative days ( p = 0.036) without changes in dialysis incidence. The 90-day survival did not differ significantly ( p = 0.270)., Conclusion: Our results indicate the additive effects of MB use during VS compared to standard vasopressor therapy only. Early MB administration for VS may significantly improve the patients' hemodynamics with minor side effects.

Background: Sepsis is a challenge in emergency medicine, as this life-threatening organ dysfunction, caused by a dysregulated host response to an infection, presents manifold and therefore is often recognized too late., Objectives: Recently published surviving sepsis campaign and German S3 guidelines provide recommendations for diagnosis and therapy of sepsis in an in-hospital or intensive care setting, but do not particularly address out-of-hospital emergency medical care. We aim to work out the evidence base with regard to the out-of-hospital care of patients with suspected sepsis and to derive treatment recommendations for emergency medical services., Conclusions: Therapy of sepsis and septic shock is summarized in bundles, whereby the first bundle should ideally be completed within the first hour-in analogy to "golden hour" concepts in other emergency medical entities, such as trauma care. In the out-of-hospital setting, therapy focuses on securing vital parameters, according to the ABCDE scheme, with a particular focus on volume therapy. Further procedures within the 1 h bundle, such as lactate measurement, obtaining microbiological samples, and starting an anti-infective therapy, are broadly available in hospital only. The aim is to control the site of infection as soon as possible. Therefore, an appropriate designated hospital should be chosen carefully and informed in advance, in order to initiate and pave the way for further clinical diagnostic and treatment paths. Moreover, structured and target-oriented handovers, as well as regular training, are required., (© The Author(s) 2021.)

Background: The ultimate goal of haemodynamic therapy is to improve microcirculatory tissue and organ perfusion. Hyperspectral imaging (HSI) has the potential to enable noninvasive microcirculatory monitoring at bedside., Methods: HSI (Tivita ® Tissue System) measurements of tissue oxygenation, haemoglobin, and water content in the skin (ear) and kidney were evaluated in a double-hit porcine model of major abdominal surgery and haemorrhagic shock. Animals of the control group (n = 7) did not receive any resuscitation regime. The interventional groups were treated exclusively with either crystalloid (n = 8) or continuous norepinephrine infusion (n = 7)., Results: Haemorrhagic shock led to a drop in tissue oxygenation parameters in all groups. These correlated with established indirect markers of tissue oxygenation. Fluid therapy restored tissue oxygenation parameters. Skin and kidney measurements correlated well. High dose norepinephrine therapy deteriorated tissue oxygenation. Tissue water content increased both in the skin and the kidney in response to fluid therapy., Conclusions: HSI detected dynamic changes in tissue oxygenation and perfusion quality during shock and was able to indicate resuscitation effectivity. The observed correlation between HSI skin and kidney measurements may offer an estimation of organ oxygenation impairment from skin monitoring. HSI microcirculatory monitoring could open up new opportunities for the guidance of haemodynamic management.

Background: Hyperspectral imaging (HSI) could provide extended haemodynamic monitoring of perioperative tissue oxygenation and tissue water content to visualize effects of haemodynamic therapy and surgical trauma. The objective of this study was to assess the capacity of HSI to monitor skin microcirculation and possible relations to perioperative organ dysfunction in patients undergoing pancreatic surgery., Methods: The hyperspectral imaging TIVITA® Tissue System was used to evaluate superficial tissue oxygenation (StO2), deeper layer tissue oxygenation (near-infrared perfusion index (NPI)), haemoglobin distribution (tissue haemoglobin index (THI)) and tissue water content (tissue water index (TWI)) in 25 patients undergoing pancreatic surgery. HSI parameters were measured before induction of anaesthesia (t1), after induction of anaesthesia (t2), postoperatively before anaesthesia emergence (t3), 6 h after emergence of anaesthesia (t4) and three times daily (08:00, 14:00, 20:00 ± 1 h) at the palm and the fingertips until the second postoperative day (t5-t10). Primary outcome was the correlation of HSI with perioperative organ dysfunction assessed with the perioperative change of SOFA score., Results: Two hundred and fifty HSI measurements were performed in 25 patients. Anaesthetic induction led to a significant increase of tissue oxygenation parameters StO2 and NPI (t1-t2). StO2 and NPI decreased significantly from t2 until the end of surgery (t3). THI of the palm showed a strong correlation with haemoglobin levels preoperatively (t2: r = 0.83, p < 0.001) and 6 h postoperatively (t4: r = 0.71, p = 0.001) but not before anaesthesia emergence (t3: r = 0.35, p = 0.10). TWI of the palm and the fingertip rose significantly between pre- and postoperative measurements (t2-t3). Higher blood loss, syndecan level and duration of surgery were associated with a higher increase of TWI. The perioperative change of HSI parameters (∆t1-t3) did not correlate with the perioperative change of the SOFA score., Conclusion: This is the first study using HSI skin measurements to visualize tissue oxygenation and tissue water content in patients undergoing pancreatic surgery. HSI was able to measure short-term changes of tissue oxygenation during anaesthetic induction and pre- to postoperatively. TWI indicated a perioperative increase of tissue water content. Perioperative use of HSI could be a useful extension of haemodynamic monitoring to assess the microcirculatory response during haemodynamic therapy and major surgery., Trial Registration: German Clinical Trial Register, DRKS00017313 on 5 June 2019., (© 2021. The Author(s).)

Elevated blood lactate levels are frequently found in critically ill patients and thought to result from tissue hypoperfusion and cellular oxygen shortage. Considering the close relationship between immune cell function and intracellular metabolism, lactate is more than a glycolytic waste molecule but able to regulate the immune response. Our aim was to elucidate the temporal and mechanistic effect of extracellular lactate on monocytes. To this end, primary human monocytes and the human monocytic cell line MonoMac6 were stimulated with various toll-like-receptor agonists after priming with Na-L-lactate under constant pH conditions. As readout, cytokine production was measured, real-time assessment of intracellular energy pathways was performed, and intracellular metabolite concentrations were determined. Irrespective of the immunogenic stimulus, short-term Na-lactate-priming strongly reduced cytokine production capacity. Lactate and hexoses accumulated intracellularly and, together with a decreased glycolytic flux, indicate a lactate-triggered impairment of glycolysis. To counteract intracellular hyperglycemia, glucose is shunted into the branching polyol pathway, leading to sorbitol accumulation. In contrast, long-term priming with Na-L-lactate induced cellular adaption and abolished the suppressive effect. This lactate tolerance is characterized by a decreased cellular respiration due to a reduced complex-I activity. Our results indicate that exogenous lactate shapes monocyte function by altering the intracellular energy metabolism and acts as a metabolic checkpoint of monocyte activation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Schenz, Heilig, Lohse, Tichy, Bomans, Büttner, Weigand and Uhle.)

Glioblastoma multiforme (GBM) is the most common malignant brain tumour in adults. The poor prognosis and short median overall survival of patients with GBM is associated with resistance to therapy after surgical and adjuvant treatment. The expression of various acetylcholine receptors (AChR) in GBM has been widely reported. The present study aimed to investigate the expression of cholinergic system-related genes in primary GBM and to explore the antiproliferative effect of 3-(2,4-dimethoxybenzylidene) anabaseine (GTS-21) in GBM cell lines. Therefore, the expression of 28 genes associated with the cholinergic system was detected using a customized RT 2 Profiler PCR Array in 44 GBM and 5 healthy control brain tissue samples. In addition, the activity of GTS-21, an alpha 7 subunit nicotinic AChR (α7 nAChR) agonist, and that of α-bungarotoxin (α-BTX), an α7 nAChR antagonist, was determined in primary and established GBM cells. Therefore, the A172, U87 and G28 cell lines and primary GBM cells were treated with GTS-21, ACh or nicotine. Cell viability was evaluated using MTT assay at 24, 48 and 72 h following cell treatment with the corresponding compounds. The results revealed that the expression of cholinergic system-related components was notably downregulated, except that of cholinergic receptor nicotinic alpha 7 subunit ( CHRNA7 ), in primary GBM and U87 cells. However, the dominant-negative duplicate form of CHRNA7 was also downregulated. Furthermore, A172 and G28 cells exhibited a heterogeneous gene expression pattern. Additionally, GTS-21 inhibited the proliferation of GBM cells in a dose- and time-dependent manner. Interestingly, treatment with α-BTX restored the proliferation of U87 cells, but not that of A172 and G28 cells. Collectively, the findings of the present study suggested that GTS-21 may inhibit the proliferation of GBM cells and may therefore serve as a novel therapeutic approach to the treatment of GBM, which warrants further investigation., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2021, Spandidos Publications.)

Recent data suggest that the type of anesthesia used during the resection of solid tumors impacts the long-term survival of patients favoring total-intravenous-anesthesia (TIVA) over inhalative-anesthesia (INHA). Here we sought to query this impact on survival in patients undergoing resection of glioblastoma (GBM). All patients receiving elective resection of a newly diagnosed, isocitrate-dehydrogenase-1-(IDH1)-wildtype GBM under general anesthesia between January 2010 and June 2017 in the Department of Neurosurgery, Heidelberg University Hospital, were included. Patients were grouped according to the applied anesthetic technique. To adjust for potential prognostic confounders, patients were matched in a 1:2 ratio (TIVA vs. INHA), taking into account the known prognostic factors: age, extent of resection, O-6-methylguanine-DNA-methyltransferase-(MGMT)-promoter-methylation-status, pre-operative Karnofsky-performance-index and adjuvant radio- and chemotherapy. The primary endpoint was progression-free-survival (PFS) and the secondary endpoint was overall-survival (OS). In the study period, 576 patients underwent resection of a newly diagnosed, IDH-wildtype GBM. Patients with incomplete follow-up-data, on palliative treatment, having emergency or awake surgery; 54 patients remained in the TIVA-group and 417 in the INHA-group. After matching, 52 patients remained in the TIVA-group and 92 in the INHA-group. Median PFS was 6 months in both groups. The median OS was 13.5 months in the TIVA-group and 13.0 months in the INHA-group. No significant survival differences associated with the type of anesthesia were found either before or after adjustment for known prognostic factors. This retrospective study supports the notion that the current anesthetic approaches employed during the resection of IDH-wildtype GBM do not impact patient survival., (© 2020. The Author(s).)

Elucidating the mechanisms contributing to the dysregulated host response to infection as part of the syndrome is a current challenge in sepsis research. Peripheral blood mononuclear cells are widely used in immunological studies. Density gradient centrifugation, a common method, is of limited use for blood drawn from patients with sepsis. A significant number of low-density granulocytes co-purify contributing to low purity of isolated peripheral blood mononuclear cells. Whole blood anticoagulated with lithium heparin was drawn from patients with sepsis (n=14) and healthy volunteers (n=11). Immediately after drawing, the plasma fraction was removed and PBMC were isolated from the cellular fraction by density gradient centrifugation. Samples derived from patients with sepsis were subsequently incubated with cluster of differentiation 15 MicroBeads and granulocytes were depleted using magnetic-activated cell sorting. Core cellular functions as antigen presentation and cytokine secretion were analyzed in cells isolated from healthy volunteers (n=3) before and after depletion to confirm consistent functionality. We report here that depleting CD15 + cells after density gradient centrifugation is a feasible way to get rid of the low-density granulocyte contamination. Afterwards, the purity of isolated, functionally intact peripheral blood mononuclear cells is comparable to healthy volunteers. Information on the isolation purity and identification of the containing cell types are necessary for good comparability between different studies. Depletion of CD15 + cells after density gradient centrifugation is an easy but highly efficient way to gain a higher quality and more reliability in studies using peripheral blood mononuclear cells from septic patients without affecting the functionality of the cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Schenz, Obermaier, Uhle, Weigand and Uhle.)

In response to the unmet need for timely accurate diagnosis and prognosis of acute infections and sepsis, host-immune-response-based tests are being developed to help clinicians make more informed decisions including prescribing antimicrobials, ordering additional diagnostics, and assigning level of care. One such test (InSep™, Inflammatix, Inc.) uses a 29-mRNA panel to determine the likelihood of bacterial infection, the separate likelihood of viral infection, and the risk of physiologic decompensation (severity of illness). The test, being implemented in a rapid point-of-care platform with a turnaround time of 30 min, enables accurate and rapid diagnostic use at the point of impact. In this report, we provide details on how the 29-biomarker signature was chosen and optimized, together with its molecular, immunological, and medical significance to better understand the pathophysiological relevance of altered gene expression in disease. We synthesize key results obtained from gene-level functional annotations, geneset-level enrichment analysis, pathway-level analysis, and gene-network-level upstream regulator analysis. Emerging findings are summarized as hallmarks on immune cell interaction, inflammatory mediators, cellular metabolism and homeostasis, immune receptors, intracellular signaling and antiviral response; and converging themes on neutrophil degranulation and activation involved in immune response, interferon, and other signaling pathways.

The zoonotic SARS-CoV-2 virus that causes COVID-19 continues to spread worldwide, with devastating consequences. While the medical community has gained insight into the epidemiology of COVID-19, important questions remain about the clinical complexities and underlying mechanisms of disease phenotypes. Severe COVID-19 most commonly involves respiratory manifestations, although other systems are also affected, and acute disease is often followed by protracted complications. Such complex manifestations suggest that SARS-CoV-2 dysregulates the host response, triggering wide-ranging immuno-inflammatory, thrombotic, and parenchymal derangements. We review the intricacies of COVID-19 pathophysiology, its various phenotypes, and the anti-SARS-CoV-2 host response at the humoral and cellular levels. Some similarities exist between COVID-19 and respiratory failure of other origins, but evidence for many distinctive mechanistic features indicates that COVID-19 constitutes a new disease entity, with emerging data suggesting involvement of an endotheliopathy-centred pathophysiology. Further research, combining basic and clinical studies, is needed to advance understanding of pathophysiological mechanisms and to characterise immuno-inflammatory derangements across the range of phenotypes to enable optimum care for patients with COVID-19., Competing Interests: Declaration of interests MSW has received unrestricted funding from Sartorius. GL reports personal fees from Swedish Orphan Biovitrum. TSp and JCS disclose institutional funding (received by the University of Bern) from Orion Pharma, Abbott Nutrition International, B Braun Medical, CSEM, Edwards Lifesciences, Kenta Biotech, Maquet Critical Care, Omnicare Clinical Research, Nestlé, Pierre Fabre Pharma, Pfizer, Bard Medica, Abbott, Anandic Medical Systems, PanGas Healthcare, Bracco, Hamilton Medical, Fresenius Kabi, Getinge Group Maquet, Dräger, Teleflex Medical, GlaxoSmithKline, Merck Sharp and Dohme, Eli Lilly, Baxter, Astellas, AstraZeneca, CSL Behring, Novartis, Covidien, Nycomed, Phagenesis, and Hemotune. MGN reports grants from GlaxoSmithKline and ViiV Healthcare, and was a scientific founder of TTxD. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

We investigate the feasibility of molecular-level sample classification of sepsis using microarray gene expression data merged by in silico meta-analysis. Publicly available data series were extracted from NCBI Gene Expression Omnibus and EMBL-EBI ArrayExpress to create a comprehensive meta-analysis microarray expression set (meta-expression set). Measurements had to be obtained via microarray-technique from whole blood samples of adult or pediatric patients with sepsis diagnosed based on international consensus definition immediately after admission to the intensive care unit. We aggregate trauma patients, systemic inflammatory response syndrome (SIRS) patients, and healthy controls in a non-septic entity. Differential expression (DE) analysis is compared with machine-learning-based solutions like decision tree (DT), random forest (RF), support vector machine (SVM), and deep-learning neural networks (DNNs). We evaluated classifier training and discrimination performance in 100 independent iterations. To test diagnostic resilience, we gradually degraded expression data in multiple levels. Clustering of expression values based on DE genes results in partial identification of sepsis samples. In contrast, RF, SVM, and DNN provide excellent diagnostic performance measured in terms of accuracy and area under the curve (>0.96 and >0.99, respectively). We prove DNNs as the most resilient methodology, virtually unaffected by targeted removal of DE genes. By surpassing most other published solutions, the presented approach substantially augments current diagnostic capability in intensive care medicine., Competing Interests: The authors have declared that no competing interests exist.

Background: Modern anesthesia strives to offer personalized concepts to meet the patient's individual needs in sight of clinical outcome. Still, little is known about the impact of anesthesia on the plasma metabolome, although many metabolites have been shown to modulate the function of various immune cells, making it particularly interesting in the context of oncological surgery. In this study longitudinal dynamics in the plasma metabolome during general anesthesia in patients undergoing pancreatic surgery were analyzed., Materials and Methods: Prospective, observational study with 10 patients diagnosed with pancreatic (pre-) malignancy and subjected to elective resection surgery under general anesthesia. Plasma metabolites ( n = 630) were quantified at eight consecutive perioperative timepoints using mass spectrometry-based targeted metabolomics., Results: 39 metabolites significantly changed during the perioperative period. Tryptophan concentrations decreased by 45% with the maximum decrease after anesthesia induction ( p = 6.24E-07), while taurine synthesis increased ( p = 1.46E-04). Triacylglycerides and lysophosphatidylcholines were significantly reduced with increased liberation of free monounsaturated fatty acids ( p = 0.03). Carnitine levels decreased significantly ( p = 9.30E-04)., Conclusions: The major finding of this study was perioperative tryptophan depletion and increased taurine synthesis. Both are essential for immune cell function and are therefore of significant interest for perioperative management. Further studies are needed to identify influencing anesthetic factors., Competing Interests: CONFLICTS OF INTEREST Authors have no conflicts of interest to declare., (Copyright: © 2021 Mock-Ohnesorge et al.)

Background: Postoperative abdominal infections belong to the most common triggers of sepsis and septic shock in intensive care units worldwide. While monocytes play a central role in mediating the initial host response to infections, sepsis-induced immune dysregulation is characterized by a defective antigen presentation to T-cells via loss of Major Histocompatibility Complex Class II DR (HLA-DR) surface expression. Here, we hypothesized a sepsis-induced differential occupancy of the CCCTC-Binding Factor (CTCF), an architectural protein and superordinate regulator of transcription, inside the Major Histocompatibility Complex Class II (MHC-II) region in patients with postoperative sepsis, contributing to an altered monocytic transcriptional response during critical illness., Results: Compared to a matched surgical control cohort, postoperative sepsis was associated with selective and enduring increase in CTCF binding within the MHC-II. In detail, increased CTCF binding was detected at four sites adjacent to classical HLA class II genes coding for proteins expressed on monocyte surface. Gene expression analysis revealed a sepsis-associated decreased transcription of (i) the classical HLA genes HLA-DRA, HLA-DRB1, HLA-DPA1 and HLA-DPB1 and (ii) the gene of the MHC-II master regulator, CIITA (Class II Major Histocompatibility Complex Transactivator). Increased CTCF binding persisted in all sepsis patients, while transcriptional recovery CIITA was exclusively found in long-term survivors., Conclusion: Our experiments demonstrate differential and persisting alterations of CTCF occupancy within the MHC-II, accompanied by selective changes in the expression of spatially related HLA class II genes, indicating an important role of CTCF in modulating the transcriptional response of immunocompromised human monocytes during critical illness., Competing Interests: The authors have declared that no competing interests exist.

Many milestones in medical history rest on animal modeling of human diseases. The SARS-CoV-2 pandemic has evoked a tremendous investigative effort primarily centered on clinical studies. However, several animal SARS-CoV-2/COVID-19 models have been developed and pre-clinical findings aimed at supporting clinical evidence rapidly emerge. In this review, we characterize the existing animal models exposing their relevance and limitations as well as outline their utility in COVID-19 drug and vaccine development. Concurrently, we summarize the status of clinical trial research and discuss the novel tactics utilized in the largest multi-center trials aiming to accelerate generation of reliable results that may subsequently shape COVID-19 clinical treatment practices. We also highlight areas of improvement for animal studies in order to elevate their translational utility. In pandemics, to optimize the use of strained resources in a short time-frame, optimizing and strengthening the synergy between the preclinical and clinical domains is pivotal., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Sepsis is a severe life-threatening syndrome caused by dysregulated host responses to infection. Biomarkers that allow for monitoring the patient's immune status are needed. Recently, a flow cytometry-based detection of in vivo inflammasome activation by formation of cytoplasmic aggregates of ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) has been proposed. Here we report on the frequency of ASC-speck + leukocytes correlating with the survival of sepsis. 25 patients with sepsis were sampled consecutively for 7 days. Blood, serum samples and patient data were collected according to the guidelines of the PredARRT-Sep-Trial. Flow cytometric analysis was performed on fresh whole blood samples to investigate the formation of ASC-specks in leukocyte subsets. Serum samples were analyzed for production of IL-1ß, IL-18 and additional inflammatory markers. ASC-speck formation was found to be increased in leukocytes from sepsis patients compared to healthy donor controls. The absolute number of ASC-speck + neutrophils peaked on day 1. For monocytes, the highest percentage and maximum absolute number of ASC-speck + cells were detected on day 6 and day 7. Inflammatory cytokines were elevated on day 1 and declined thereafter, with exception of IL-18. Survival analysis showed that patients with lower absolute numbers of ASC-speck + monocytes (<1,650 cells/ml) on day 6 had a lower probability to survive, with a hazard ratio (HR) of 10.178. Thus, the frequency of ASC-speck + monocytes on day 6 after onset of sepsis may serve to identify patients at risk of death from sepsis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cui, Oehrl, Ahmad, Brenner, Uhle, Nusshag, Rupp, Funck, Meisel, Weigand, Morath and Schäkel.)

The effects of a moderately elevated intra-abdominal pressure (IAP) on lung mechanics in acute respiratory distress syndrome (ARDS) have still not been fully analyzed. Moreover, the optimal positive end-expiratory pressure (PEEP) in elevated IAP and ARDS is unclear. In this paper, 18 pigs under general anesthesia received a double hit lung injury. After saline lung lavage and 2 h of injurious mechanical ventilation to induce an acute lung injury (ALI), an intra-abdominal balloon was filled until an IAP of 10 mmHg was generated. Animals were randomly assigned to one of three groups (group A = PEEP 5, B = PEEP 10 and C = PEEP 15 cmH 2 O) and ventilated for 6 h. We measured end-expiratory lung volume (EELV) per kg bodyweight, driving pressure (ΔP), transpulmonary pressure (ΔP L ), static lung compliance (C stat ), oxygenation (P/F ratio) and cardiac index (CI). In group A, we found increases in ΔP (22 ± 1 vs. 28 ± 2 cmH 2 O; p = 0.006) and ΔP L (16 ± 1 vs. 22 ± 2 cmH 2 O; p = 0.007), with no change in EELV/kg (15 ± 1 vs. 14 ± 1 mL/kg) when comparing hours 0 and 6. In group B, there was no change in ΔP (26 ± 2 vs. 25 ± 2 cmH 2 O), ΔP L (19 ± 2 vs. 18 ± 2 cmH 2 O), C stat (21 ± 3 vs. 21 ± 2 cmH 2 O/mL) or EELV/kg (12 ± 2 vs. 13 ± 3 mL/kg). ΔP and ΔP L were significantly lower after 6 h when comparing between group C and A (21 ± 1 vs. 28 ± 2 cmH 2 O; p = 0.020) and (14 ± 1 vs. 22 ± 2 cmH 2 O; p = 0.013)). The EELV/kg increased over time in group C (13 ± 1 vs. 19 ± 2 mL/kg; p = 0.034). The P/F ratio increased in all groups over time. CI decreased in groups B and C. The global lung injury score did not significantly differ between groups (A: 0.25 ± 0.05, B: 0.21 ± 0.02, C: 0.22 ± 0.03). In this model of ALI, elevated IAP, ΔP and ΔP L increased further over time in the group with a PEEP of 5 cmH 2 O applied over 6 h. This was not the case in the groups with a PEEP of 10 and 15 cmH 2 O. Although ΔP and ΔP L were significantly lower after 6 hours in group C compared to group A, we could not show significant differences in histological lung injury score.

Purpose: Despite antifungal prophylaxis, liver transplanted patients are endangered by invasive fungal infections (IFI). Routinely used microbiological procedures are hallmarked by significant weaknesses, which may lead to a delay in antifungal treatment., Methods: Culture-based fungal findings, routinely used biomarkers of infection/inflammation (e.g., procalcitonin or C-reactive protein), as well as corresponding plasma concentrations of soluble Intercellular Adhesion Molecule (ICAM)-1 were analysed in 93 patients during a period of 28 days following liver transplantation (LTX)., Results: Plasmatic sICAM-1 was significantly elevated in patients affected by an IFI within the first 28 days in comparison to fungally colonised or unobtrusive LTX patients. sICAM-1 might therefore be helpful for the identification of IFI patients after LTX (e.g., Receiver Operating Characteristic (ROC)-Area Under the Curve (AUC): 0.714 at 14d after LTX). The diagnostic performance of sICAM-1 was further improved by its combined use with different other IFI biomarkers (e.g., midregional proadrenomedullin)., Conclusion: The diagnostic deficiencies of routinely used microbiological procedures for IFI detection in patients after LTX may be reduced by plasmatic sICAM-1 measurements. Clinical Trial Notation . German Clinical Trials Register: DRKS00005480.

Opportunistic bacterial infections are dreaded risks in patients following liver transplantation (LTX), even though patients receive an antibiotic prophylaxis. The timely recognition of such an infection may be delayed, as culture-based diagnostic methods are linked with a relevant gap in performance. We measured plasma concentrations of Delta-like canonical Notch ligand 1 (DLL1) in 93 adult patients at seven consecutive time points after liver transplantation and correlated the results to the occurrence of culture-proven bacterial infection or a complicated clinical course (composite endpoint of two or more complications: graft rejection or failure, acute kidney failure, acute lung injury, or 90-day mortality). Patients exhibited elevated plasma concentrations after liver transplantation over the whole 28 d observation time. Patients with bacterial infection showed increased DLL1 levels compared to patients without infection. Persistent elevated levels of DLL1 on day 7 and afterward following LTX were able to indicate patients at risk for a complicated course. Plasma levels of DLL1 following LTX may be useful to support an earlier detection of bacterial infections in combination with C-reactive protein (CRP) and procalcitonin (PCT), or they may lead to risk stratification of patients as a single marker for post-operative complications. (Clinical Trial Notation. German Clinical Trials Register: DRKS00005480).

Background: Accurate pre-operative evaluation of cardiovascular risk is vital to identify patients at risk for major adverse cardiovascular and cerebrovascular events (MACCE) after noncardiac surgery. Elevated presepsin (sCD14-ST) is associated with peri-operative MACCE in coronary artery disease (CAD) patients after noncardiac surgery., Objectives: Validating the prognostic utility of presepsin for MACCE after noncardiac surgery., Design: Prospective patient enrolment and blood sampling, followed by post hoc evaluation of pre-operative presepsin for prediction of MACCE., Setting: Single university centre., Patients: A total of 222 CAD patients undergoing elective, inpatient noncardiac surgery., Intervention: Pre-operative presepsin measurement., Main Outcome Measures: MACCE (cardiovascular death, myocardial infarction, myocardial ischaemia and stroke) at 30 days postsurgery., Results: MACCE was diagnosed in 23 (10%) patients. MACCE patients presented with increased pre-operative presepsin (median [IQR]; 212 [163 to 358] vs. 156 [102 to 273] pgml, P = 0.023). Presepsin exceeding the previously derived threshold of 184 pg ml was associated with increased 30-day MACCE rate. After adjustment for confounders, presepsin more than 184 pg ml [OR = 2.8 (95% confidence interval 1.1 to 7.3), P = 0.03] remained an independent predictor of peri-operative MACCE. Predictive accuracy of presepsin was moderate [area under the curve (AUC) = 0.65 (0.54 to 0.75), P = 0.023]. While the basic risk model of revised cardiac risk index, high-sensitive cardiac troponin T and N-terminal fragment of pro-brain natriuretic peptide resulted in an AUC = 0.62 (0.48 to 0.75), P = 0.072, addition of presepsin to the model led to an AUC = 0.67 (0.56 to 0.78), P = 0.009 and (ΔAUC = 0.05, P = 0.438). Additive risk predictive value of presepsin was demonstrated by integrated discrimination improvement analysis (integrated discrimination improvement = 0.023, P = 0.022). Net reclassification improvement revealed that the additional strength of presepsin was attributed to the reclassification of no-MACCE patients into a lower risk group., Conclusion: Increased pre-operative presepsin independently predicted 30-day MACCE in CAD patients undergoing major noncardiac surgery. Complementing cardiovascular risk prediction by inflammatory biomarkers, such as presepsin, offers potential to improve peri-operative care. However, as prediction accuracy of presepsin was only moderate, further validation studies are needed., Trial Registration: Clinicaltrials.gov: NCT03105427.

Introduction: Normalisation of macrocirculatory parameters during resuscitation therapy does not guarantee the restoration of microcirculatory perfusion in critical illness due to haemodynamic incoherence. Persistent microcirculatory abnormalities are associated with severity of organ dysfunction and mandate the development of bedside microcirculatory monitoring. A novel hyperspectral imaging (HSI) system can visualise changes in skin perfusion, oxygenation and water content at the bedside. We aim to evaluate the effectiveness of HSI for bedside monitoring of skin microcirculation and the association of HSI parameters with organ dysfunction in patients with sepsis and major abdominal surgery., Methods and Analysis: Three independent groups will be assessed and separately analysed within a clinical prospective observational study: (1) 25 patients with sepsis or septic shock (according to sepsis-3 criteria), (2) 25 patients undergoing pancreatic surgery and (3) 25 healthy controls. Patients with sepsis and patients undergoing pancreatic surgery will receive standard therapy according to local protocols derived from international guidelines. In addition, cardiac output of perioperative patients and patients with sepsis will be measured. Healthy controls undergo one standardised evaluation. The TIVITA Tissue System is a novel HSI system that uses the visible and near-infrared spectral light region to determine tissue microcirculatory parameters. HSI analysis (hand/knee) will be done in parallel to haemodynamic monitoring within defined intervals during a 72-hour observation period. HSI data will be correlated with the Sequential Organ Failure Assessment score, global haemodynamics, inflammation and glycocalyx markers, surgical complications and 30-day outcome., Ethics and Dissemination: The protocol has been approved by the local ethics committee of the University of Heidelberg (S-148/2019). Study results will be submitted to peer-reviewed journals and medical conferences., Trial Registration Number: DRKS00017313; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Patients undergoing esophageal cancer surgery are at high risk of developing severe pulmonary complications. Beneficial effects of minimally invasive esophagectomy had been discussed recently, but the incidence of perioperative respiratory impairment remains unclear. This is a retrospective single-center cohort study of patients, who underwent open (OE) or laparoscopically assisted, hybrid minimally invasive abdomino-thoracic esophagectomy (LAE) for cancer regarding respiratory impairment (PaO 2 /FiO 2 ratio (P/FR) < 300 mmHg) and pneumonia. No differences were observed in the cumulative incidence of reduced P/FR between OE and LAE patients. Of note, until postoperative day (POD) 2, P/FR did not differ among both groups. Thereafter, the rate of patients with respiratory impairment was higher after OE on POD 3, 5, and 10 ( p ≤ 0.05) and tended being higher on POD 7 and 9 ( p ≤ 0.1). Although the duration of LAE procedure was slightly longer (total: p = 0.07, thoracic part: p = 0.004), the duration of surgery (Spearman's rank correlation coefficient (r sp ) = -0.267, p = 0.006), especially of laparotomy (r sp = -0.242, p = 0.01) correlated inversely with respiratory impairment on POD 3 after OE. Pneumonia occurred on POD 5 (1-25) and 8.5 (3-14) after OE and LAE, respectively, with the highest incidence after OE ( p = 0.01). In conclusion, respiratory impairment and pulmonary complications occur frequently after esophagectomy. Although early respiratory impairment is independent of the surgical approach, postoperative pneumonia rate is reduced after LAE.

Background: With more than 18 million annual new cases, cancer belongs to the major challenges of modern healthcare. Surgical resection of solid tumours under general anaesthesia is the prime therapy. Different aspects of anaesthesia are under discussion to independently influence the long-term outcome of cancer patients. Most recently, the commonly used volatile anaesthetics like sevoflurane have entered the spotlight, as retrospective studies suggest a detrimental outcome in certain cancer aetiologies with sparse mechanistic understanding. Our objective was to investigate this concept in a murine melanoma model, herein comparing the consequence of inhalative and injection anesthesia on tumour composition and growth., Methods: We used a murine model of malignant melanoma in male, adult C57BL/6 mice (n = 92), induced by the subcutaneous injection of B16-F10 cells. We either exposed the melanoma cells to sevoflurane before implantation or subjected the animals to single or double anaesthesia with either volatile or injection drugs. After a maximum follow-up of 4 weeks, leucocytes within the tumour microenvironment (TME) were comprehensively analysed by flow cytometry with focus on tumor-associated macrophages (TAM)., Results: We found that exposure of melanoma cells to sevoflurane before implantation induced long-lasting transcriptome changes and aggravated tumour growth, without extensive changes of the TME. Contrastingly, both a single and double anaesthesia with sevoflurane led to a significant reduction of TAMs (injection vs. sevoflurane: 2,0 vs. 0.3% and 1.2 vs. 0.6%, respectively), whilst increasing PD-L1 expression on the remaining cells (mean fluorescent intensity injection vs. sevoflurane: 3,804 vs. 7,143 and 9,090 vs. 32,228, respectively). No changes in tumour growth were observed in these groups., Conclusion: In sharp contrast to the detrimental impact of sevoflurane on patients' outcome reported in retrospective clinical studies, we propose here that sevoflurane might actually exert a beneficial effect by decreasing TAMs within the TME, rendering the tumour again susceptible for cytotoxic T cells and immunotherapies. Further research is warranted to delineate, how these results translate into the clinic., Competing Interests: The authors have declared that no competing interests exist.

Background: Preoperative risk prediction in patients at elevated cardiovascular risk shows limited accuracy. Platelet to lymphocyte ratio (PLR) and neutrophil to lymphocyte ratio (NLR) indicate systemic inflammation. Both have been investigated for outcome prediction in the field of oncology and cardiovascular medicine, as well as risk prediction of adverse cardiovascular events in non-surgical patients at increased cardiovascular risk., Methods: For this post-hoc analysis, we included all 38 coronary heart disease patients from the Leukocytes and Cardiovascular Perioperative Events cohort-1 study scheduled for elective non-cardiac surgery. We evaluated preoperative differential blood counts for association with major adverse cardiovascular and cerebrovascular events (MACCE) defined as the composite endpoint of death, myocardial ischemia, myocardial infarction, myocardial injury after non-cardiac surgery, or embolic or thrombotic stroke within 30 days after surgery. We used Youden's index to calculate cut-off values for PLR and NLR. Additive risk-predictive values were assessed using receiver operating characteristic curve and net reclassification (NRI) improvement analyses., Results: Patients with the composite endpoint MACCE had higher PLR and NLR (309 [206; 380] vs. 160 [132; 203], p = 0.001; 4.9 [3.5; 8.1] vs. 2.6 [2.2; 3.4]), p = 0.001). Calculated cut-offs for PLR > 204.4 and NLR > 3.1 were associated with increased risk of 30-day MACCE (OR 7, 95% CI [1.2; 44.7], p = 0.034; OR 36, 95% CI [1.8; 686.6], p = 0.001). Furthermore, NLR improved risk prediction in coronary heart disease patients undergoing non-cardiac surgery when combined with hs-cTnT or NT-proBNP (NRI total  = 0.23, p = 0.008, NRI total  = 0.26, p = 0.005)., Conclusions: Both PLR and NLR were associated with perioperative cardiovascular adverse events in coronary heart disease patients. NLR proved to be of additional value for preoperative risk stratification. Both PLR and NLR could be used as inexpensive and broadly available tools for perioperative risk assessment., Trial Registration: NCT02874508, August 22, 2016.

Immune cells drive atherosclerotic lesion progression and plaque destabilization. Coronary heart disease patients undergoing noncardiac surgery are at risk for perioperative major adverse cardiac and cerebrovascular events (MACCE). It is unclear whether differential leukocyte subpopulations contribute to perioperative MACCE and thereby could aid identification of patients prone to perioperative cardiovascular events. First, we performed a hypothesis-generating post hoc analysis of the LeukoCAPE-1 study (n = 38). We analyzed preoperative counts of 6 leukocyte subpopulations in coronary heart disease patients for association with MACCE (composite of cardiac death, myocardial infarction, myocardial ischemia, myocardial injury after noncardiac surgery, thromboembolic stroke) within 30 d after surgery. Regulatory T cells (Tregs) were the only leukocyte subgroup associated with MACCE. We found reduced Tregs in patients experiencing MACCE versus no-MACCE (0.02 [0.01; 0.03] vs. 0.04 [0.03; 0.05] Tregs nl -1 , P = 0.002). Using Youden index, we derived the optimal threshold value for association with MACCE to be 0.027 Tregs nl -1 . Subsequently, we recruited 233 coronary heart disease patients for the prospective, observational LeukoCAPE-2 study and independently validated this Treg cutoff for prediction of MACCE within 30 d after noncardiac surgery. After multivariate logistic regression, Tregs < 0.027 cells nl -1 remained an independent predictor for MACCE (OR = 2.54 [1.22; 5.23], P = 0.012). Tregs improved risk discrimination of the revised cardiac risk index based on ΔAUC (area under the curve; ΔAUC = 0.09, P = 0.02), NRI (0.26), and IDI (0.06). Preoperative Treg levels below 0.027 cells nl -1 predicted perioperative MACCE and can be measured to increase accuracy of established preoperative cardiac risk stratification in coronary heart disease patients undergoing noncardiac surgery., (© 2019 The Authors. Journal of Leukocyte Biology published by Wiley Periodicals, Inc. on behalf of Society for Leukocyte Biology.)

Introduction: Intra-abdominal hypertension (IAH) is a well-known phenomenon in critically ill patients. Effects of a moderately elevated intra-abdominal pressure (IAP) on lung mechanics are still not fully analyzed. Moreover, the optimal positive end-expiratory pressure (PEEP) in elevated IAP is unclear., Methods: We investigated changes in lung mechanics and transformation in histological lung patterns using three different PEEP levels in eighteen deeply anesthetized pigs with an IAP of 10 mmHg. After establishing the intra-abdominal pressure, we randomized the animals into 3 groups. Each of n = 6 (Group A = PEEP 5, B = PEEP 10 and C = PEEP 15 cmH2O). End-expiratory lung volume (EELV/kg body weight (bw)), pulmonary compliance (Cstat), driving pressure (ΔP) and transpulmonary pressure (ΔPL) were measured for 6 hours. Additionally, the histological lung injury score was calculated., Results: Comparing hours 0 and 6 in group A, there was a decrease of EELV/kg (27±2 vs. 16±1 ml/kg; p<0.05) and of Cstat (42±2 vs. 27±1 ml/cmH2O; p<0.05) and an increase of ΔP (11±0 vs. 17±1 cmH2O; p<0.05) and ΔPL (6±0 vs. 10±1 cmH2O; p<0.05). In group B, there was no significant change in EELV/kg (27±3 vs. 24±3 ml/kg), but a decrease in Cstat (42±3 vs. 32±1 ml/cmH20; p<0.05) and an increase in ΔP (11±1 vs. 15±1 cmH2O; p<0.05) and ΔPL (5±1 vs. 7±0 cmH2O; p<0.05). In group C, there were no significant changes in EELV/kg (27±2 vs. 29±3 ml/kg), ΔP (10±1 vs. 12±1 cmH2O) and ΔPL (5±1 vs. 7±1 cmH2O), but a significant decrease of Cstat (43±1 vs. 37±1 ml/cmH2O; p<0.05). Histological lung injury score was lowest in group B., Conclusions: A moderate elevated IAP of 10 mmHg leads to relevant changes in lung mechanics during mechanical ventilation. In our study, a PEEP of 10 cmH2O was associated with a lower lung injury score and was able to overcome the IAP induced alterations of EELV., Competing Interests: The authors have declared that no competing interests exist.

Background: Major trauma leads to complex immune reactions, known to result in a transient immunodeficiency. The long-term consequences of severe trauma on immune function and regulation as well as its clinical impact remain unclear., Methods: Six months (ranging from -12 to +5 days) after a major trauma event, 12 former trauma patients (Injury Severity Score ≥ 16) and 12 healthy volunteers were enrolled. The current clinical status and infection history since discharge were assessed by a standardized questionnaire. Immune cell subsets (cluster of differentiation (CD)4, CD8, CD14), cell surface receptor expression (programmed cell death protein 1 (PD-1), B- and T-lymphocyte attenuator (BTLA), cytotoxic T-lymphocyte-associated protein 4, toll-like receptor (TLR)-2, -4, and -5, Dectin-1, programmed death ligand 1 (PD-1L)), and human leucocyte antigen D-related receptor (HLA-DR)-expression were quantified by flow cytometry. Cytokine secretion (IL-2, -4, -6, -10, and 17A, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ) was assessed after stimulation of whole blood with LPS-, α-CD3/28, or zymosan., Results: Analysis of surface receptors on T cells revealed a significant elevation of PD-1 expression on CD4 T cells, whereas BTLA expression on CD4 and CD8 T cells was significantly suppressed in the trauma cohort. Monocytes showed a significantly reduced expression of TLR-2 and -4 as well as a reduced proportion of TLR-4 monocytes. HLA-DR receptor density revealed no significant changes between both cohorts. LPS-induced IL-6 and TNF-α secretion showed non-significant trends toward reduced values. No differences regarding clinical apparent infections could be detected., Conclusions: Six months following major trauma, changes of cell surface receptors on CD4 and CD8 T cells as well as on CD14 monocytes were present, hinting toward an immunosuppressive phenotype. Following major trauma, although IL-6 and TNF-α release after stimulation were reduced, they did not reach statistical significance. Overall, further studies are necessary to evaluate the clinical implications of these findings., Trial Registration: DRKS00009876, Internet Portal of the German Clinical Trials Register (DRKS), registration date 11.08.2016, https://www.drks.de/drks&#95;web/navigate.do?navigationId=trial.HTML&TRIAL&#95;ID=DRKS00009876.

Sepsis is a complex host response triggered by an infection, with the patient's immune system between hyper- and hypo-responsiveness being the main reason for the syndromes' development and propagation. Studies conducted in peripheral blood mononuclear cells uncovered an association between an impaired immunometabolism and the severity and outcome of the disease. With this prospective observational study, we aimed to evaluate the immunometabolic phenotype of monocytes and B cells and its association with the cell function.Monocytes and B cells were isolated from patients with sepsis (n = 10; onset, days 4 and 8) and healthy volunteers (n = 10) and subsequently analyzed for metabolic changes and human leukocyte antigen-DR (HLA-DR) expression. Contemporaneously, immune checkpoints on monocytes and the ex vivo cytokine responses (interleukins 6 and 8) upon lipopolysaccharide or zymosan stimulation were analyzed. The distribution of B cell subsets was assessed, and plasma levels of immunoglobulins and tricarboxylic acid cycle intermediates were quantified.Both monocytes and B cells exhibited decreased HLA-DR expression in patients with sepsis. Monocytes displayed a stable upregulated glycolysis while B cells augmented glycolysis and respiration over time. The monocytes' ability to respond to stimulation was stimuli-dependently reduced but recovered over time. The B cell compartment shifted toward antibody-producing subsets and elevated immunoglobulins within the first days.Our results provide evidence for the induction of a state of trained immunity in monocytes and an early but transient immunosuppressive phenotype accounting for peripheral sepsis-induced vulnerability to infections. B cells exhibit an unsustainable activation contributing to adaptive immunosuppression.

Increasing evidence supports a central role of the immune system in sepsis, but the current view of how sepsis affects immunity, and vice versa, is still rudimentary. The European Group on Immunology of Sepsis has identified major gaps that should be addressed with high priority, such as understanding how immunological alterations predispose to sepsis, key aspects of the immunopathological events during sepsis, and the long-term consequences of sepsis on patient's immunity. We discuss major unmet topics in those three categories, including the role of key immune cells, the cause of lymphopenia, organ-specific immunology, the dynamics of sepsis-associated immunological alterations, the role of the microbiome, the standardisation of immunological tests, the development of better animal models, and the opportunities offered by immunotherapy. Addressing these gaps should help us to better understand sepsis physiopathology, offering translational opportunities to improve its prevention, diagnosis, and care., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction : Sepsis, defined as a life-threatening organ dysfunction resulting from dysregulated host response to infection, is still a major challenge for healthcare systems. Early diagnosis is highly needed, yet challenging, due to the non-specificity of clinical symptoms. Rapid and targeted application of therapy strategies is crucial for patient's outcome. Areas covered : Faster and better diagnostics with high accuracy is promised by novel host response biomarkers and a wide variety of direct pathogen identification technologies, which have emerged over the last years. This review will cover both - host response-guided diagnostics and methods for direct pathogen detection. Some of the markers and technologies are already market-ready, others are more likely aspirants. We will discuss them in terms of their performance and benefit for use in clinical diagnostics. Expert opinion : Latest technological advances enable the development of promising diagnostic tests, detecting the host response as well as identifying pathogens without the need of cultivation. However, the syndrome's heterogeneity makes it difficult to develop a universal test suitable for routine use. Moreover, the robustness of the biomarkers and technologies still has to be verified. Combining these technologies and clinical routine parameters with bioinformatic methods (e.g., machine-learning algorithms) may revolutionize sepsis diagnostics.

Objectives: Sepsis-induced acute kidney injury is the dominant acute kidney injury etiology in critically ill patients and is often associated with a need for renal replacement therapy. The indication and timing of renal replacement therapy are controversially discussed. We hypothesized that the product of the G1-cell cycle arrest biomarkers tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 ([TIMP-2] × [IGFBP7]), and the soluble urokinase-type plasminogen activator receptor are of diagnostic value for the prediction of septic acute kidney injury courses requiring renal replacement therapy., Design: In this prospective study, critically ill patients were enrolled immediately after the fulfillment of Sepsis-3 criteria. Urinary [TIMP-2] × [IGFBP7] levels over time and serum soluble urokinase-type plasminogen activator receptor levels once at inclusion were measured. The primary endpoint was the development of septic acute kidney injury with the need for renal replacement therapy. Area under the receiver operating characteristic curves, de Long's tests, and logistic regression models were calculated., Setting: Two ICUs at Heidelberg University Hospital between May 2017 and July 2018., Patients: One-hundred critically ill patients with positive Sepsis-3 criteria., Interventions: None., Measurement and Main Results: Nineteen patients required renal replacement therapy. Diagnostic performance of urinary [TIMP-2] × [IGFBP7] improved over time with the highest area under the receiver operating characteristic curve of 0.89 (95% CI, 0.80-0.98) 24 hours after study inclusion. Soluble urokinase-type plasminogen activator receptor levels at inclusion showed an area under the receiver operating characteristic curve of 0.83 (0.75-0.92). The best discrimination ability for the primary outcome measure was achieved for [TIMP-2] × [IGFBP7] at 24 hours after inclusion by applying a cutoff value of greater than or equal to 0.6 (ng/mL)/1,000 (sensitivity 90.9, specificity 67.1). Soluble urokinase-type plasminogen activator receptor performed best by using a cutoff value of greater than or equal to 8.53 ng/mL (sensitivity 84.2, specificity 82.7). A combination of newly tested biomarkers with cystatin C resulted in a significantly improved diagnostic accuracy. Cystatin C in combination with [TIMP-2] × [IGFBP7] 24 hours outperformed all standard renal parameters (area under the receiver operating characteristic curve 0.93 [0.86-1.00])., Conclusions: [TIMP-2] × [IGFBP7] and soluble urokinase-type plasminogen activator receptor are promising biomarker candidates for the risk stratification of septic acute kidney injury patients with the need for renal replacement therapy.

Pulmonary complications and a poor clinical outcome are common in response to transthoracic esophagectomy, but their etiology is not well understood. Clinical observation suggests that patients undergoing pulmonary resection, a surgical intervention with similarities to the thoracic part of esophagectomy, fare much better, but this has not been investigated in detail. A retrospective single-center analysis of 181 consecutive patients after right-sided thoracotomy for either Ivor Lewis esophagectomy (n = 83) or major pulmonary resection (n = 98) was performed. An oxygenation index <300 mm Hg was used to indicate respiratory impairment. When starting surgery, respiratory impairment was seen more frequently in patients undergoing major pulmonary resection compared to esophagectomy patients (p = 0.009). On postoperative days one to ten, however, esophagectomy caused higher rates of respiratory impairment (p < 0.05) resulting in a higher cumulative incidence of postoperative respiratory impairment for patients after esophagectomy (p < 0.001). Accordingly, esophagectomy patients were characterized by longer ventilation times (p < 0.0001), intensive care unit and total postoperative hospital stays (both p < 0.0001). In conclusion, the postoperative clinical course including respiratory impairment after Ivor Lewis esophagectomy is significantly worse than that after major pulmonary resection. A detailed investigation of the underlying causes is required to improve the outcome of esophagectomy.

Background: In nonneutropenic intensive care unit (ICU) patients, current risk stratification scores lack specificity to reliably predict the risk of a prospective invasive candidiasis (IC). We aimed to explore possible associations of distinct immunological markers with different degrees of Candida affection in patients with abdominal sepsis., Methods: The presented explorative, noninterventional diagnosis study recruited patients admitted to the surgical ICU at Heidelberg University Hospital with abdominal sepsis. Over 5 days, we determined white blood cell count, 1,3-β-D-glucan, and HLA-DR expression; the amount of Th1, Th17, regulatory T, T helper, and cytotoxic T cells; Dectin-1 and TLR2-expression; the amount of T, B, and NK cells; the ex vivo secretion of IL-8 upon stimulation with LPS, flagellin, and zymosan; and the distribution of distinct T-cell cytokines in a daily manner. On day 21, patients' Candida infection status was stratified in no colonization or IC, colonization or IC., Results: A total of 26 patients were included. On day 21, five patients showed no colonization or IC, in 13 patients a colonization was detected, and eight patients were diagnosed with IC. On study inclusion, the stratification groups showed comparable values in standard laboratory parameters and morbidity scores. Decreased B and NK cell counts, as well as reduced IL-8 secretion after ex vivo stimulation with LPS or flagellin seemed to be associated with a higher risk of subsequent Candida colonization. Even lower values could distinguish the therapy-relevant difference between prospective IC from colonization alone., Conclusions: We were able to show distinct immune system impairments in early abdominal sepsis by specific immune-based measurements. A possible association of these impairments with a subsequent Candida affection is shown.

Background: Sepsis is a life-threatening syndrome, resulting from a dysbalanced host response to infection. However, especially the early, pro-inflammatory immune response in sepsis is similar to other inflammatory conditions without infectious cause, e.g., trauma or surgery. This aspect challenges the value of current biomarkers for diagnosis, as these are often broadly induced. We earlier identified Delta-like Protein 1 (DLL1), a canonical Notch ligand, to be released from monocytes upon bacterial stimulation. Considering the importance of monocytes in the pathophysiology of sepsis, we hypothesized that this mechanism might occur also in the clinical setting and DLL1 might serve as a biomarker of life-threatening bacterial infection. Methods: We combined samples from three different studies, including subgroups of patients with sepsis ( n = 80), surgical patients ( n = 50), trauma patients ( n = 36), as well as healthy controls ( n = 50). We assessed plasma concentrations of DLL1 using ELISA. We performed Area-under-receiver-operator-curve (AUROC) analysis to evaluate the diagnostic performance of DLL1 compared to leucocytes, C-reactive protein (CRP), and procalcitonin (PCT). Results: Plasma concentrations of DLL1 were strongly elevated already at sepsis onset and maintained elevated until day 7. In contrast, neither surgical patients nor patients after severe trauma presented with elevated levels, while conventional biomarkers of inflammation (e.g., leucocytes and CRP), responded. AUROC analysis revealed a cut-off of 30 ng/ml associated with the best diagnostic performance, yielding a superior accuracy of 91% for DLL1, compared to 75, 79, and 81% for CRP, leucocytes, and PCT. Conclusion: DLL1 is a novel host-derived biomarker for the diagnosis of sepsis with a better performance compared to established ones, most likely due to its high robustness in non-infectious inflammatory responses. Clinical Trial Registration: POCSEP-Trial DRKS00008090; MIRSI DRKS00005463; SPRINT DRKS00010991.

Background: Perioperative major adverse cardiovascular and cerebrovascular events (MACCEs) are incompletely understood, and risk prediction is imprecise. Atherogenic leukocytes are crucial in cardiovascular events. However, it is unclear if surgical interventions affect leukocyte counts or activation status. Therefore, we investigated whether noncardiac surgery in patients with elevated cardiovascular risk is associated with changes in atherogenic leukocyte subsets and if these changes are related to perioperative MACCEs., Methods: We enrolled 40 patients in this single-center prospective observational cohort study. Total leukocytes and subpopulations, including classical, intermediate, and nonclassical monocytes and natural killer and regulatory T cells, were quantified before surgery, at 2 and 6 hours after skin incision, and at postoperative days 1 and 2 (POD1+2). The monocyte activation marker presepsin (sCD14-ST) was measured post hoc to determine differentiation of classical to nonclassical monocytes. We evaluated presepsin for prediction of the composite primary end point MACCE (cardiovascular death, myocardial infarction, myocardial ischemia, and stroke) at 30 days. Its additive value to risk assessment based on high-sensitive cardiac troponin T and N-terminal probrain natriuretic peptide (NT-proBNP) was analyzed., Results: We evaluated 38 patients, of whom 5 (13%) reached MACCE. In the entire cohort, classical monocytes continuously increased and peaked at POD1 (0.35 [0.23-0.43] cells per nanoliter blood [nL] vs 0.45 [0.31-0.66] cells·nL, preoperative [pre-OP] vs POD1, P = .002). Intermediate monocytes doubled by POD1 (0.017 [0.013-0.021] vs 0.036 [0.022-0.043] cells·nL, pre-OP versus POD1, P = .0003). Nonclassical monocytes decreased (0.022 [0.012-0.032] vs 0.012 [0.005-0.023] cells·nL, pre-OP vs 6 hours, P = .003). In our patient population, we did not detect changes in any of the other predefined leukocyte subsets investigated. In patients experiencing a MACCE, classical monocyte expansion was reduced (0.081 [-0.16 to 0.081] cells·nL vs 0.179 [0.081 to 0.292] cells·nL, MACCE versus non-MACCE, P = .016). Patients in the event group presented with elevated pre-OP presepsin (1528 [406-1897] pg·mL vs 123 [82.2-174] pg·mL, MACCE versus non-MACCE, P = .0001). Presepsin was associated with MACCE (area under the curve = 0.964, [0.846-0.998], P = .001). Presepsin above the calculated threshold >184 pg·mL was superior to high-sensitive cardiac troponin T for improvement of NT-proBNP-based risk prediction (28 [74%] vs 22 [58%] correctly classified patients, P = .014)., Conclusions: Noncardiac surgery was associated with an increase in atherogenic leukocyte subsets. In a post hoc analysis, elevated pre-OP presepsin was associated with MACCE and improved NT-proBNP-based risk assessment. After validation in an independent data set, a presepsin cutoff of 184 pg·mL might qualify to complement NT-proBNP-based risk prediction, thereby increasing the proportion of correctly identified high-risk patients.

Purpose: Despite antifungal prophylaxis following liver transplantation (LTX), patients are at risk for the development of subsequent opportunistic infections, such as an invasive fungal disease (IFD). However, culture-based diagnostic procedures are associated with relevant weaknesses., Methods: Culture and next-generation sequencing (NGS)-based fungal findings as well as corresponding plasma levels of ß-D-glucan (BDG), galactomannan (GM), interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), interleukin (IL)-2, -4, -6, -10, -17A and mid-regional proadrenomedullin (MR-proADM) were evaluated in 93 patients at 6 consecutive time points within 28 days following LTX., Results: A NGS-based diagnostic approach was shown to be suitable for the early identification of fungal pathogens in patients following LTX. Moreover, MR-proADM and IL-17A in plasma proved suitable for the identification of patients with an IFD., Conclusion: Plasma measurements of MR-proADM and IL-17A as well as a NGS-based diagnostic approach were shown to be attractive methodologies to attenuate the weaknesses of routinely used culture-based diagnostic procedures for the determination of an IFD in patients following LTX. However, an additional confirmation within a larger multicenter trial needs to be recommended., Trial Registration: German Clinical Trials Register: DRKS00005480 .

Study Design: Retrospective analysis., Objectives: Sepsis, one of the most frequent and life-threatening complications on intensive care units (ICUs), is associated with a need for mechanical ventilation (MV) as well as adverse respiratory outcomes in hospitalized individuals. However, it has poorly been investigated in patients with spinal cord injury (SCI); a population at high risk for pulmonary and infectious complications., Setting: Spinal Cord Injury Center, Heidelberg University Hospital., Methods: Over a 5-year period, 182 individuals with SCI requiring MV during their ICU stay were analyzed. Data assessment included demographics, medical characteristics, focus and causative pathogen of sepsis, length of stay, weaning outcomes, and mortality., Results: Sepsis was recorded in 28 patients (15%), containing a subgroup of individuals suffering from infectious SCI and co-occurring primary sepsis with Staphylococcus aureus as the predominant microorganism. In most individuals, sepsis was found as secondary complication, which was associated with pulmonary foci, Gram-negative bacteria, and high mortality. More than 80% of individuals with secondary sepsis required induction of MV due to respiratory failure. Furthermore, respiratory failure was found to be independent of sepsis focus, spectrum of causative pathogens, SCI etiology, or severity of injury. Subsequent weaning from the respirator was prolonged in more than 90% with a high proportion of weaning failure., Conclusions: Sepsis predominantly occurs as a secondary complication after SCI and is associated with detrimental outcomes. Although the lung is frequently affected as a failing organ, not all sepsis foci are pulmonary. Awareness of both actual sepsis focus and causative pathogen is central to initiate an adequate sepsis treatment.

Background: Critically ill patients, especially following trauma or extensive surgery, experience a systemic immune response, consisting of a pro-inflammatory as well as a counterbalancing anti-inflammatory response. Pro-inflammation is necessary for the initiation of homeostatic control and wound healing of the organism. However, when the counterbalancing mechanisms dominate, a condition of secondary immunodeficiency occurs, which renders the patient susceptible for opportunistic or secondary infections. However, the incidence of this condition is yet illusive. Methods: For a period of 3 months (May to July 2017), 110 consecutive patients admitted to the surgical ICU of the Heidelberg University Hospital, a tertiary university hospital, were enrolled in the study. Monocyte HLA-DR (mHLA-DR), a long-known surrogate of monocyte function, was assessed quantitatively once on admission utilizing a novel point-of-care flow cytometer with single-use cartridges (Accelix system). Patients were followed up for further 28 days and data on ICU stay, antibiotic therapy, microbiological findings, and mechanical ventilation were recorded. Statistical analysis was performed to evaluate the incidence of immunosuppression-defined by different thresholds-as well as its consequence in terms of outcome and clinical course. Results: Depending on the HLA-DR threshold applied for stratification (≤8,000/≤5,000/≤2,000 molecules/cell), a large group of patients (85.5/68.2/40.0%) already presented with a robust decrease of HLA-DR on admission, independent of the cause for critical illness. Analyzed for survival, neither threshold was able to stratify patients with a higher mortality. However, both thresholds of 2,000 and 5,000 were able to discriminate patients with longer ICU stay, ventilation time and duration of antibiotic therapy, as well as higher count of microbiological findings. Moreover, a mHLA-DR value ≤2,000 molecules/cell was associated with higher incidence of overall antibiotic therapy. Conclusion: Single assessment of mHLA-DR using a novel point-of-care flow cytometer is able to stratify patients according to their risk of a complicated course. Therefore, this device overcomes the technical boundaries for measuring cellular biomarkers and paves the way for future studies involving personalized immunotherapy to patients with a high immunological risk profile independent of their background. Trial Registration: German Clinical Trials Register; ID: DRKS00012348.