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BackgroundA recently developed haemostatic peptide gel for endoscopic application has been introduced to improve the management of gastrointestinal bleeding. The aim of this pilot study was to evaluate the feasibility, safety, efficacy and indication profiles of PuraStat in a clinical setting.MethodsIn this prospective observational multicentre pilot study, patients with acute non-variceal gastrointestinal bleeding (upper and lower) were included. Primary and secondary application of PuraStat was evaluated. Haemoglobin, prothrombin time, platelets and transfusion behaviour were documented before and after haemostasis. The efficacy of PuraStat was assessed during the procedure, at 3 days and 1 week after application.Results111 patients with acute gastrointestinal bleeding were recruited into the study. 70 percent (78/111) of the patients had upper gastrointestinal bleeding and 30% (33/111) had lower gastrointestinal bleeding. After primary application of PuraStat, initial haemostatic success was achieved in 94% of patients (74/79, 95% CI 88–99%), and in 75% of the patients when used as a secondary haemostatic product, following failure of established techniques (24/32, 95% CI 59–91%). The therapeutic success rates (absence of rebleeding) after 3 and 7 days were 91% and 87% after primary use, and 87% and 81% in all study patients. Overall rebleeding rate at 30 day follow-up was 16% (18/111). In the 5 patients who finally required surgery (4.5%), PuraStat allowed temporary haemostasis and stabilisation.ConclusionsPuraStat expanded the therapeutic toolbox available for an effective treatment of gastrointestinal bleeding sources. It could be safely applied and administered without complications as a primary or secondary therapy. PuraStat may additionally serve as a bridge to surgery in order to achieve temporary haemostasis in case of refractory severe bleeding, possibly playing a role in preventing immediate emergency surgery.

INTRODUCTION:Despite growing awareness of post-coronavirus disease 2019 (COVID-19) cholangiopathy as one of the most serious long-term gastrointestinal consequences of COVID-19, the endoscopic features of this disease are still poorly characterized. This study aimed to more precisely define its endoscopic features and to outline the role of endoscopic retrograde cholangiopancreatography (ERCP) in the management of this entity.METHODS:In this observational study, 46 patients with confirmed post-COVID-19 cholangiopathy were included.RESULTS:Based on the endoscopic features observed in 141 ERCP procedures, post-COVID-19 cholangiopathy can be classified as a variant of secondary sclerosing cholangitis in critically ill patients. It appeared early in the course of intensive care treatment of patients with COVID-19 (cholestasis onset 4.5 days after intubation, median). This form of cholangiopathy was more destructive than stricturing in nature and caused irreversible damage to the bile ducts. A centripetal pattern of intrahepatic bile duct destruction, the phenomenon of vanishing bile ducts, the absence of extrahepatic involvement, and the presence of intraductal biliary casts (85% of patients) were typical cholangiographic features of post-COVID-19 cholangiopathy. This cholangiopathy was often complicated by small peribiliary liver abscesses with isolation of Enterococcus faecium and Candida spp. in bile culture. The prognosis was dismal, with a 1-year liver transplantation-free survival rate of 44%. In particular, patients with peribiliary liver abscesses or destruction of the central bile ducts tended to have a poor prognosis (n.s.). As shown by multivariate analysis, bilirubin levels (on intensive care unit day 25-36) negatively correlated with liver transplantation-free survival (hazard ratio 1.08, P < 0.001). Interventional endoscopy with cast removal had a positive effect on cholestasis parameters (gamma-glutamyl transpeptidase, alkaline phosphatase, and bilirubin); approximately 60% of all individual values decreased.DISCUSSION:Gastrointestinal endoscopy makes an important contribution to the management of post-COVID-19 cholangiopathy. ERCP is not only of great diagnostic and prognostic value but also has therapeutic value and therefore remains indispensable.

Background Sepsis-induced immunosuppression is a frequent cause of opportunistic infections and death in critically ill patients. A better understanding of the underlying mechanisms is needed to develop targeted therapies. Circulating bile acids with immunosuppressive effects were recently identified in critically ill patients. These bile acids activate the monocyte G-protein coupled receptor TGR5, thereby inducing profound innate immune dysfunction. Whether these mechanisms contribute to immunosuppression and disease severity in sepsis is unknown. The aim of this study was to determine if immunosuppressive bile acids are present in endotoxemia and septic shock and, if so, which patients are particularly at risk. Methods To induce experimental endotoxemia in humans, ten healthy volunteers received 2 ng/kg E. coli lipopolysaccharide (LPS). Circulating bile acids were profiled before and after LPS administration. Furthermore, 48 patients with early (shock onset within < 24 h) and severe septic shock (norepinephrine dose > 0.4 μg/kg/min) and 48 healthy age- and sex-matched controls were analyzed for circulating bile acids. To screen for immunosuppressive effects of circulating bile acids, the capability to induce TGR5 activation was computed for each individual bile acid profile by a recently published formula. Results Although experimental endotoxemia as well as septic shock led to significant increases in total bile acids compared to controls, this increase was mild in most cases. By contrast, there was a marked and significant increase in circulating bile acids in septic shock patients with severe liver failure compared to healthy controls (61.8 µmol/L vs. 2.8 µmol/L, p  = 0.0016). Circulating bile acids in these patients were capable to induce immunosuppression, as indicated by a significant increase in TGR5 activation by circulating bile acids (20.4% in severe liver failure vs. 2.8% in healthy controls, p  = 0.0139). Conclusions Circulating bile acids capable of inducing immunosuppression are present in septic shock patients with severe liver failure. Future studies should examine whether modulation of bile acid metabolism can improve the clinical course and outcome of sepsis in these patients. Graphical abstract

Introduction In recent years the development of secondary sclerosing cholangitis in critically ill patients (SSC-CIP) has increasingly been perceived as a separate disease entity. About possible trigger mechanisms of SSC-CIP has been speculated, systematic investigations on this issue are still lacking. The purpose of this study was to evaluate the prevalence and influence of promoting factors. Methods Temporality, consistency and biological plausibility are essential prerequisites for causality. In this study, we investigated the temporality and consistency of possible triggers of SSC-CIP in a large case series. Biological plausibility of the individual triggers is discussed in a scientific context. SSC-CIP cases were recruited retrospectively from 2633 patients who underwent or were scheduled for liver transplantation at the University Hospital Charité, Berlin. All patients who developed secondary sclerosing cholangitis in association with intensive care treatment were included. Possible trigger factors during the course of the initial intensive care treatment were recorded. Results Sixteen patients (68% males, mean age 45.87 ± 14.64 years) with a confirmed diagnosis of SSC-CIP were identified. Of the 19 risk factors investigated, particularly severe hypotension with a prolonged decrease in mean arterial blood pressure (MAP) to <65 mmHg and systemic inflammatory response syndrome (SIRS) were established as possible triggers of SSC-CIP. The occurrence of severe hypotension appears to be the first and most significant step in the pathogenesis. It seems that severe hypotension has a critical effect on the blood supply of bile ducts when it occurs together with additional microcirculatory disturbances. Conclusions In critically ill patients with newly acquired cholestasis the differential diagnosis of SSC-CIP should be considered when they have had an episode of haemodynamic instability with a prolonged decrease in MAP, initial need for large amounts of blood transfusions or colloids, and early development of a SIRS.

Background Increasing evidence suggests that secondary sclerosing cholangitis (SSC), which can lead to cirrhosis or liver failure, may be a hepatobiliary long-term complication of COVID-19. The aim of this study was to estimate the frequency and outcome of this COVID-19 sequela and to identify possible risk factors. Methods This observational study, conducted at University Hospital Charité Berlin and Unfallkrankenhaus Berlin, Germany, involved hospitalized patients with COVID-19 pneumonia, including 1082 ventilated COVID-19 patients. We compared COVID-19 patients who developed SSC with a COVID-19 control group by univariate and multivariate analyses. Results SSC occurrence after COVID-19 was observed exclusively in critically ill patients with invasive ventilation, albeit with extreme clustering among them. One in every 43 invasively ventilated COVID-19 patients developed this complication. Risk factors preceding the development of secondary sclerosing cholangitis in critically ill COVID-19 patients (SSC-CIP) were signs of systemic reduced blood oxygen supply (e.g., low PaO 2 /FiO 2 , ischemic organ infarctions), multi-organ failure (high SOFA score) at admission, high fibrinogen levels and intravenous ketamine use. Multivariate analysis confirmed fibrinogen and increased plasma lactate dehydrogenase as independent risk factors associated with cholangiopathy onset. The 1-year transplant-free survival rate of COVID-19-associated SSC-CIP was 40%. Conclusions COVID-19 causes SSC-CIP in a substantial proportion of critically ill patients. SSC-CIP most likely develops due to severe tissue hypoxia and fibrinogen-associated circulatory disturbances. A significant increase of patients with SSC-CIP is to be expected in the post-COVID era.

Background Endoscopic surveillance in patients with long-standing inflammatory bowel disease (IBD) improves early detection of intraepithelial neoplasia (IEN). We aimed to compare three different endoscopic surveillance strategies in the detection of IEN. Methods One hundred fifty surveillance colonoscopies (ulcerative colitis, UC n  = 141; Crohn's disease, CD n  = 9) were carried out. Random quadrant biopsies were taken (group I, n  = 50). Chromoendoscopy with indigo carmine was performed and subsequently quadrant biopsies were collected (group II, n  = 50). Patients in group III ( n  = 50) underwent confocal endomicroscopy (CEM), and CEM-guided as well as random quadrant biopsies were taken (group III, n  = 50). The findings of CEM were correlated to conventional histology. Patients with high-grade IEN underwent surgery or strict follow-up by patients' request. Results In group I (1531 biopsies), no IEN was detected by histology. In group II (1,811 biopsies), chromoendoscopy-guided biopsies revealed high-grade IEN in two patients (4% detection rate). In four patients of group III (1477 biopsies), areas with high-grade IEN were clearly visible by CEM and confirmed by histology (8% detection rate, p  < 0.05). Of six patients with high-grade IEN, five patients underwent proctocolectomy. Colorectal cancer was detected in one out of five patients. Conclusion Targeted biopsy protocols guided by either chromoendoscopy or CEM led to higher detection rates of IEN and are thus mandatory for surveillance colonoscopies in patients with long-standing UC. Random biopsy protocols should be replaced by chromoendoscopy-guided protocols.

β-Glucan derived from cell walls of is a potent immune modulator. It has been shown to induce trained immunity in monocytes via epigenetic and metabolic reprogramming and to protect from lethal sepsis if applied prior to infection. Since β-glucan-trained monocytes have not been classified within the system of mononuclear phagocytes we analyzed these cells metabolically, phenotypically and functionally with a focus on monocyte-to-macrophage differentiation and compared them with naïve monocytes and other types of monocyte-derived cells such as classically (M1) or alternatively (M2) activated macrophages and monocyte-derived dendritic cells (moDCs). We show that β-glucan inhibits spontaneous apoptosis of monocytes independent from autocrine or paracrine M-CSF release and stimulates monocyte differentiation into macrophages. β-Glucan-differentiated macrophages exhibit increased cell size and granularity and enhanced metabolic activity when compared to naïve monocytes. Although β-glucan-primed cells expressed markers of alternative activation and secreted higher levels of IL-10 after lipopolysaccharide (LPS), their capability to release pro-inflammatory cytokines and to kill bacteria was unaffected. Our data demonstrate that β-glucan priming induces a population of immune competent long-lived monocyte-derived macrophages that may be involved in immunoregulatory processes.

Carbon nanotube yarns (CNY) are a novel carbonaceous material and have received a great deal of interest since the beginning of the 21st century. CNY are of particular interest due to their useful heat conducting, electrical conducting, and mechanical properties. The electrical conductivity of carbon nanotube yarns can also be influenced by functionalization and annealing. A systematical study of this post synthetic treatment will assist in understanding what factors influences the conductivity of these materials. In this investigation, it is shown that the electrical conductivity can be increased by a factor of 2 and 5.5 through functionalization with acids and high temperature annealing respectively. The scale of the enhancement is dependent on the reducing of intertube space in case of functionalization. For annealing, not only is the highly graphitic structure of the carbon nanotubes (CNT) important, but it is also shown to influence the residual amorphous carbon in the structure. The promising results of this study can help to utilize CNY as a replacement for common materials in the field of electrical wiring.