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Introduction: For over 30 years, ascites has been postulated to facilitate fibrinolysis in patients with liver cirrhosis. In contrast to previous research employing conventional coagulation tests, this study aimed to characterize hemostatic interactions between blood and ascites using the rotational thromboelastometry (ROTEM). Methods: Blood samples – pure or mixed with ascites in a ratio of 1:1 – from cirrhotic patients (n = 10) were subjected to ROTEM analysis. In addition, a negative control group was built with cirrhotic patients (n = 10) whose blood was mixed with physiologic sodium chloride (0.9% NaCl) solution in a ratio of 1:1. Subsequently, ROTEM measurements were subjected to statistical analysis. Results: During ascites challenge, clotting time (CT, measured in seconds) was significantly prolonged in EXTEM (blood: 70.40 ± 20.40 vs. ascites/blood: 109.8 ± 47.7) and APTEM (blood: 66.50 ± 14.55 vs. ascites/blood: 138.7 ± 105.8), likely reflecting a dilution effect. However, CT in INTEM remained unchanged, suggesting a sustained intrinsic pathway function. Maximal clot firmness (measured in millimeters) in FIBTEM decreased significantly (blood: 14.70 ± 9.55 vs. ascites/blood: 6.00 ± 5.66), thus indicating depletion of fibrinogen in ascites. Strikingly, maximum lysis (measured in %) significantly decreased in EXTEM (blood: 9.30 ± 2.79 vs. ascites/blood: 5.50 ± 2.84), APTEM (blood: 8.50 ± 3.10 vs. ascites/blood: 5.60 ± 2.88), and INTEM (blood: 7.50 ± 2.27 vs. ascites/blood: 5.10 ± 3.48). Conclusions: ROTEM provided new evidence that ascites may not primarily induce fibrinolysis in cirrhotic patients. This finding seems to be of significant importance for the clinical management of cirrhotic patients experiencing complications, for example, abdominal hemorrhage after liver biopsy or paracentesis; here, replacement of prothrombin complex concentrates and/or fibrinogen concentrates may prove more beneficial than the use of fresh frozen plasma or antifibrinolytic drugs.

Background. Previous research reported adverse clinical outcomes in association with systemic inflammation (SI) after transcatheter aortic valve replacement (TAVR). However, data characterizing the impact of SI, as reflected by postprocedural routine inflammatory parameters (pRIP), on clinical outcome of patients undergoing TAVR are sparse. Objectives. In light of this, the present work aimed to analyze incidence and clinical significance of pRIP after transapical (TA) and transfemoral (TF)-TAVR. Methods and Results. Data of 81 high-risk consecutive patients undergoing TAVR in our center from 2017 to 2018 were analyzed in a retrospective manner. 40 out of 81 patients (49, 4%) were treated via TF access (group A) and 41 patients via TA access (group B). Incidence, cause, and amplitude of pRIP were analyzed in relation to pre- and peri-interventional data. Assessment of outcomes was conducted according to the valve academic research consortium (VARC-2). Postprocedural C-reactive protein (pCRP) and leucocytes (pL) were significantly increased in patients undergoing TA-TAVR (group B) vs. TF-TAVR (group A; 12.1 ± 9.7 vs. 22.1 ± 7.9 mg/dl, p p = 0.002); however, there was no significant difference regarding incidence of postprocedural fever (pF) ≥38.0°C (12.5% vs. 22%, p = 0.37). Furthermore, we observed a vast (though insignificant) trend towards a longer fever duration in group B vs. group A (9.9 ± 14.9 vs. 3.2 ± 5.9 hours, p = 0.06). Further analysis identified pCRP >30 mg/dl (hazard ratio (HR) 3.15, confidence interval (CI) 1.22–8.14, p = 0.018) and European System for Cardiac Operative Risk Evaluation (logistic EuroSCORE I (ES)) >20% (HR 2.95, CI 1.17–7.47, p = 0.02) as predictors of mortality; in this context, we also discovered a marginally significant trend for pL > 14/nl (HR 2.44, CI 0.97–6.14, p = 0.05). Multivariate analysis by use of the fisher`s exact test revealed a significant association between pCRP >30 mg/dl and ES >20% ( p 30 mg/dl, ES>20%, and pL > 14/nl are hallmark of adverse prognosis and require further investigation.

ObjectiveWe aimed to evaluate the effects of combining the Simplified-Acute-Physiology-Score (SAPS) 2 or the SAPS 3 with Interleukin-6 (IL-6) or Procalcitonin (PCT) or C-Reactive Protein (CRP) concentrations for predicting in-hospital mortality.Material and methodsThis retrospective study was conducted in an interdisciplinary 22-bed intensive care unit (ICU) at a German university hospital. Within an 18-month period, SAPS 2 and SAPS 3 were calculated for 514 critically ill patients that were admitted to the internal medicine department. To evaluate discrimination performance, the area under the receiver operating characteristic curves (AUROCs) and the 95% confidence intervals (95% CIs) were calculated for each score, exclusively or in combination with IL-6 or PCT or CRP. DeLong test was used to compare different AUROCs.ResultsThe SAPS 2 exhibited a better discrimination performance than SAPS 3 with AUROCs of 0.81 (95% CI, 0.76-0.86) and 0.72 (95% CI, 0.66-0.78), respectively. Overall, combination of the SAPS 2 with IL-6 showed the best discrimination performance (AUROC 0.82; 95% CI, 0.77-0.87), albeit not significantly different from SAPS2. IL-6 performed better than PCT and CRP with AUROCs of 0.75 (95% CI, 0.69-0.81), 0.72 (95% CI, 0.66-0.77) and 0.65 (95% CI, 0.59-0.72), respectively. Performance of the SAPS 3 improved significantly when combined with IL-6 (AUROC 0.76; 95% CI, 0.69-0.81) or PCT (AUROC 0.73; 95% CI, 0.67-0.78).ConclusionsOur analysis provided evidence that the risk stratification performance of the SAPS 3 and, to a lesser degree, also of the SAPS 2 can increase when combined with IL-6. A more accurate detection of aberrant or dysregulated systemic immunological responses (by IL-6) may explain the higher performance achieved by SAPS 3 + IL-6 vs. SAPS 3. Thus, implementation of IL-6 in critical care scores can improve prediction outcomes, especially in patients experiencing acute inflammatory conditions; however, statistical results may vary across hospital types and/or patient populations with different case mix.

Purpose The purpose was to analyze and compare the performance of Simplified Acute Physiology Score (SAPS) II and SAPS 3 (North Europe Logit) in an intensive care unit (ICU) for internal disorders at a German university hospital. Materials and methods This retrospective study was conducted at a single-center 12-bed ICU sector for Internal Medicine in Essen, Germany, within an 18-month period. Data for adult ICU patients (N = 548) were evaluated. SAPS II and SAPS 3 scores were assessed along with the predicted mortality rates. Discrimination was evaluated by calculating the area under the receiver operating characteristic curve, and calibration was evaluated using the Hosmer-Lemeshow goodness-of-fit C-test. The ratios of observed-to-expected deaths (standardized mortality ratio, SMR) were calculated along with the 95% confidence intervals (95% CIs). Results The in-hospital mortality rate was 22.6%, which provided an SMR of 0.91 (95% CI, 0.77-0.99) for SAPS II and 0.62 (95% CI, 0.52-0.71) for SAPS 3. Both SAPS II and SAPS 3 exhibited acceptable discrimination, with an area under the receiver operating characteristic curve of 0.84 (95% CI, 0.79-0.89) and 0.73 (95% CI, 0.67-0.79), respectively. However, SAPS II demonstrated superior SMR-based discrimination, which was closer to the observed mortality rate, compared with SAPS 3. Calibration curves exhibited similar performance based on the Hosmer-Lemeshow goodness-of-fit C-test results: χ 2 = 7.10 with P = .525 for SAPS II and χ 2 = 3.10 with P = .876 for SAPS 3. Interestingly, both scores overpredicted mortality. Conclusions In this study, SAPS 3 overestimated mortality and therefore appears less suitable for risk evaluation in comparison to SAPS II.

Liver cirrhosis yearly causes 1.2 million deaths worldwide, ranking as the 10th leading cause of death in the most developed countries. High susceptibility to infections along with a significant risk for infection-related mortality justifies the description of liver cirrhosis as the world’s most common immunodeficiency syndrome. Liver cirrhosis is an end-stage organic disease hallmarked by a multifaceted immune dysfunction due to deterioration of antimicrobial recognition and elimination mechanisms in macrophages along with an impaired antigen presentation ability in circulating monocytes. Bacterial translocation supports—and is supported by—uncontrolled activation of immune cell responses and/or loss of toll-like receptor (TLR) tolerance, which can turn exaggerated inflammatory responses to systemic inflammation. Lipopolysaccharide (LPS) or endotoxin boosts systemic inflammatory activity through activation of TLR-2- and TLR-4-dependent pathways and facilitate a massive production of cytokines. This, in turn, results into elevated secretion of reactive oxygen species (ROS), which further enhances intestinal hyperpermeability and thus sustains a vicious circle of events widely known as “leaky gut.” Albumin can be of particular benefit in cirrhotic patients with spontaneous bacterial peritonitis and/or hepatorenal syndrome type of acute kidney injury (HRS-AKI) due to anti-inflammatory and antioxidative stress as well as volume-expanding properties and endothelial-stabilizing attributes. However, presence of autoantibodies against albumin in patients with liver cirrhosis has been described. Although previous research suggested that these antibodies should be regarded as naturally occurring antibodies (NOA), the origin of the antialbumin immune response is obscure. High occurrence of NAO/albumin complexes in patients with liver disease might reflect a limited clearance capacity due to bypassing portal circulation. Moreover, high burden of oxidized albumin is associated with less favorable outcome in patients with liver cirrhosis. To date, there is no data available as to whether oxidized forms of albumin result in neoepitopes recognized by the immune system. Nevertheless, it is reasonable to hypothesize that these alterations may have the potential to induce antialbumin immune responses and thus favor systemic inflammation.

Critically ill patients with liver cirrhosis are at risk of developing severe infections and specifically sepsis and/or septic shock. The subjects of this chapter are the epidemiology of and prognosis and critical care therapy for septic patients with liver failure. Severe hepatic dysfunction in association with sepsis and/or septic shock can result in a high mortality rate and requires intensive care management with specific expertise.

Decompensated cirrhosis is characterized by high hospitalization rates and costs, frequent readmissions, and poor short-term survival. Patients admitted to the hospital with acute variceal bleeding and/or hepatic encephalopathy and/or renal dysfunction are at serious risk for developing infection and/or sepsis; in turn, this renders them highly susceptible to the development of multi-system organ failure. The lack of standardized intensive care unit management protocols in patients with cirrhosis along with only few data reports from longitudinal clinical trials makes it difficult for hepatologists and critical care specialists to provide uniform evidence for clinical practice that could safely consolidate favorable outcomes such as lower hospitalization rates and/or mortality. Based on a rigorous online search of the scientific literature as well as a longtime clinical experience of the authors in the field of hepatology and critical care medicine, this work represents a focused effort to elucidate the specific bio-morbidity of advanced liver diseases in relation to the aforementioned challenges in clinical management. Further meta-analyses and/or systematic reviews are needed to enable clinicians to develop more effective strategies to bridge patients with decompensated liver disease to recompensation or liver transplantation.

Everolimus (EVR) is a mammalian target of rapamycin (mTOR) inhibitor commonly used for immunosuppression (IS) after liver transplantation (LT). However, there are concerns about whether mTOR inhibitors may move the hemostatic balance toward a higher likelihood of thrombosis. The present study aimed to investigate potential coagulation disorders after the administration of EVR. We evaluated 54 patients after conversion to an EVR-based IS regimen (n = 26) and compared those patients with patients who were switched to extended-release tacrolimus (TAC) but had never received EVR (n = 28). At baseline and again at 1 month and 6 months after conversion, we measured international normalized ratio, activated partial thromboplastin time, and anticoagulation and fibrinolysis factors, and we performed rotational thromboelastometry (ROTEM). Data were analyzed with a Mann-Whitney U test, a repeated-measure analysis of variance, and a Fisher's exact test. Statistical significance was set at the level of P ≤ 0.05. Plasma levels of von Willebrand factor, fibrinogen, and factor VIII were significantly higher than baseline levels at 1 month and 6 months after conversion of IS to EVR (P < 0.001); plasma levels of protein C, protein S, and plasminogen also increased significantly (P < 0.001). ROTEM confirmed a significant increase in maximum clot firmness in EXTEM, INTEM, and FIBTEM assays (P < 0.001). In all assays, maximum lysis was significantly lower than baseline levels at 1 month and 6 months after conversion to EVR. Patients converted to IS with extended-release TAC exhibited no significant changes in coagulation variables. Retrospective analysis showed a significantly higher incidence of thromboembolic complications among patients treated with EVR-based IS than among those treated with extended-release TAC (P < 0.01). In conclusion, the administration of EVR after LT seems to modify hemostasis to a procoagulant state. Thrombophilia screening before conversion may determine which patients will benefit from conversion to EVR-based IS.

Simultaneous detection of anti-HBs and HBV DNA is a rare serological combination and has been described in acute and chronic HBV infection. To scrutinize viral and clinical patterns associated with concurrent detection of anti-HBs and HBV DNA. Simultaneous detection of anti-HBs and HBV DNA was observed in 64/1444 (4.4%) patients treated for HBV infection at the University Hospital of Essen from 2006 to 2016 (8 with acute, 20 with reactivated, and 36 chronic HBV infection). Clinical data and laboratory parameters were analyzed. Regions of the small hepatitis B surface antigen (SHB) and the reverse transcriptase (RT) were sequenced using next generation sequencing (NGS). Among the 64 patients with detectable HBV DNA and anti-HBs, 17 were HBsAg negative (HBsAg[-]), and two had acute liver failure. Patients with acute HBV infection had fewer genotype specific amino acid substitutions in the SHB region than patients with reactivated HBV infection (4 [4.5] vs 9 [16.25], P = 0.043). However, we could observe a significantly higher number of mutations in the a-determinant region when comparing chronically infected patients to patients with acute infection (0 [1] vs 1 [1], P = 0.044). The ratio of nonsynonymous to synonymous mutations (Ka/Ks) was on average1 for the SHB region and1 for the RT region. The Ka/Ks ratio (1) in the SHB region indicates that anti-HBs might have exerted selection pressure on the HBsAg. In three cases the diagnosis of acute HBV infection would have been at least delayed by only focusing on HBsAg testing.

Objective To analyze and compare the performance of the Simplified-Acute-Physiology-Score (SAPS) 2 and SAPS 3 among intermediate care patients with internal disorders. Materials and methods We conducted a retrospective single-center analysis in patients (n = 305) admitted to an intermediate-care-unit (ImCU) for internal medicine at the University Hospital Essen, Germany. We employed and compared the SAPS 2 vs. the SAPS 3 scoring system for the assessment of disease severity and prediction of mortality rates among patients admitted to the ImCU within an 18-month period. Both scores, which utilize parameters recorded at admission to the intensive-care-unit (ICU), represent the most widely applied scoring systems in European intensive care medicine. The area-under-the-receiver-operating-characteristic-curve (AUROC) was used to evaluate the SAPS 2 and SAPS 3 discrimination performance. Ultimately, standardized-mortality-ratios (SMRs) were calculated alongside their respective 95%-confidence-intervals (95% CI) in order to determine the observed-to-expected death ratio and calibration belt plots were generated to evaluate the SAPS 2 and SAPS 3 calibration performance. Results Both scores provided acceptable discrimination performance, i.e., the AUROC was 0.71 (95% CI, 0.65–0.77) for SAPS 2 and 0.77 (95% CI, 0.72–0.82) for SAPS 3. Against the observed in-hospital mortality of 30.2%, SAPS 2 showed a weak performance with a predicted mortality of 17.4% and a SMR of 1.74 (95% CI, 1.38–2.09), especially in association with liver diseases and/or sepsis. SAPS 3 performed accurately, resulting in a predicted mortality of 29.9% and a SMR of 1.01 (95% CI, 0.8–1.21). Based on Calibration belt plots, SAPS 2 showed a poor calibration-performance especially in patients with low mortality risk (P

Background & Aims Patients with progressive liver disease exhibit complex coagulation disorders. Factor XIII plays a crucial role in the last steps of haemostasis, and its deficiency is associated with an increased incidence of bleeding diathesis. However, current conventional coagulation tests cannot detect factor XIII deficiency. In this study, we examined factor XIII activity and the ability of rotational thromboelastometry to detect factor XIII deficiency and bleeding diathesis in patients with cirrhosis. Methods We retrospectively studied 74 patients with cirrhosis, comparing the results of conventional coagulation tests (international normalized ratio, activated partial thromboplastin time, platelet count, fibrinogen level), rotational thromboelastometry, factor XIII activity and clinical scores. Results Patients with cirrhosis exhibited reduced factor XIII activity. Factor XIII activity was positively correlated with conventional coagulation parameters and rotational thromboelastometry values, such as maximum clot formation (MCF)extem (r=.48, P

Objective: The spectrum of neuropsychiatric illness (NI) associated with the Human Immunodeficiency Virus (HIV) and/or the Hepatitis C Virus (HCV) is far reaching and significantly impacts the clinical presentation and outcome of infected persons; however, the etiological and pathophysiological background remains partially understood. The present work was aimed to investigate the potential significance of formin binding protein 1 (FNBP-1)-dependent pathways in NI-pathogenesis by elaborating on previous microarray-based research in HIV and/or HCV-infected patients receiving interferon-? (IFN-?) immunotherapy via a rigorous data mining procedure. Methods: Using microarray data of peripheral whole blood (PB) samples obtained from HCV mono-infected persons (n=25, Affymetrix? HG-U133A_2) 12 h before and after the 1st dose of pegylated IFN-? (PegIFN-?), we reapplied the same analytical algorithm that we had developed and published in an earlier study with HIV/HCV coinfected subjects (N=28, Affymetrix? HG-U133A), in order to evaluate reproducibility of potential NI-related molecular findings in an independent cohort. Results: Among 28 gene expression profiles (HIV/HCV: N=9 vs. HCV: N=19) selected by applying different thresholds (a Mean Fold Difference value (MFD) in gene expression of ? 0.38 (log2) and/or P value from

Im Feld der chronischen Hepatitis B und C wurden wahrend der letzten Jahren Indikationskriterien sowie Behandlungsziele mit zunehmender Reliabilitat definiert und Therapiekonzepte durch klinische Studien etabliert. Daruber hinaus wurden intensiviert alternative Therapien erforscht, um einem grosen Problemkollektiv, dem der Nonresponder, eine therapeutische Option zu gewahrleisten. Dennoch bleibt die Indikationsstellung zur Therapie in den meisten Problemfallen noch eine Frage der Abwagung zwischen dringendem Handlungsbedarf und realistischer Erfolgsaussicht. Patienten mit einer Koinzidenz [Koinfektion, Immunsuppression, Infektion durch Mutanten (HBV) oder ungunstigen Genotyp (HCV) bei bestehender Leberzirrhose etc.] stellen weitere Sondergruppen dar, fur die die Therapieindikation in Abhangigkeit vom Risiko fur eine Progredienz bzw. Dekompensation der zugrundeliegenden Lebererkrankung individuell gestellt werden soll.

Introduction Changes in thyroid hormone levels, mostly as non-thyroidal illness syndrome (NTIS), have been described in many diseases. However, the relationship between acute liver failure (ALF) and thyroid hormone levels has not yet been clarified. The present study evaluates potential correlations of select thyroid functional parameters with ALF. Methods 84 consecutively recruited ALF patients were grouped according to the outcome of ALF (spontaneous recovery: SR; transplantation or death: NSR). TSH, free thyroxine (fT4), free triiodothyronine (fT3), T4, and T3 were determined. Results More than 50% of patients with ALF presented with abnormal thyroid parameters. These patients had greater risk for an adverse outcome than euthyroid patients. SR patients had significantly higher TSH, T4, and T3 concentrations than NSR patients. Albumin concentrations were significantly higher in SR than in NSR. In vitro T3 treatment was not able to rescue primary human hepatocytes from acetaminophen induced changes in mRNA expression. Conclusions In patients with ALF, TSH and total thyroid hormone levels differed significantly between SR patients and NSR patients. This might be related to diminished liver-derived transport proteins, such as albumin, in more severe forms of ALF. Thyroid parameters may serve as additional indicators of ALF severity.

Objective: This study was aimed to correlate in vivo interferon (IFN) inducible gene (IFIG) expression and IFIG induction with viral-load (VL) and VL-kinetics of Human-Immunodeficiency-Virus (HIV) or Hepatitis-C-Virus (HCV) in HIV-positive patients treated with pegylated IFN-alpha-2a (PegIFNα). Methods: HIV mono-infected patients (N=8) and HIV/HCV co-infected patients (N=23, without HIV-viremia) were treated with PegIFNα (180 μg/week) for 12 and 48 weeks, respectively. Blood sampling for monitoring IFIG expression occurred at day_0 and week_3, _6 and _12 for HIV mono-infected patients vs. only at day_0 and week_48 for HIV/ HCV co-infected subjects. IFIG expression (N=20) was measured in peripheral blood mononuclear cells by bDNAassay. VL levels/changes in plasma were analyzed for correlation with IFIG expression/induction at/between selected time points. Overall, P+0.42/P

Increased baseline expression and lack of induction of interferon-stimulated genes (ISG) are strong negative predictors of therapeutic response to PegIFN/RBV in patients co-infected with HIV and hepatitis C virus (HCV). This study specifically addressed whether ISG-15 expression influences therapeutic responses in 20 HIV/HCV genotype-1 subjects undergoing HCV treatment. Non-responders had significantly higher baseline expression and selective induction of ISG-15 after IFN-α treatment relative to participants with sustained virological response. High baseline levels of ISG-15 were also associated with less induction of ISG with treatment. These results support a role for ISG-15 as a prognostic indicator and resistance factor to IFN-α.