Identification of Serum Interleukin-22 as Novel Biomarker in Pulmonary Hypertension: A Translational Study.

Growing evidence suggests the crucial involvement of inflammation in the pathogenesis of pulmonary hypertension (PH). The current study analyzed the expression of interleukin (IL)-17a and IL-22 as potential biomarkers for PH in a preclinical rat model of PH as well as the serum levels in a PH patient collective. PH was induced by monocrotalin (60 mg/kg body weight s.c.) in 10 Sprague Dawley rats (PH) and compared to 6 sham-treated controls (CON) as well as 10 monocrotalin-induced, macitentan-treated rats (PH_MAC). Lung and cardiac tissues were subjected to histological and immunohistochemical analysis for the ILs, and their serum levels were quantified using ELISA. Serum IL levels were also measured in a PH patient cohort. IL-22 expression was significantly increased in the lungs of the PH and PH_MAC groups (p = 0.002), whereas increased IL17a expression was demonstrated only in the lungs and RV of the PH (p < 0.05) but not the PH_MAC group (p = n.s.). The PH group showed elevated serum concentrations for IL-22 (p = 0.04) and IL-17a (p = 0.008). Compared to the PH group, the PH_MAC group demonstrated a decrease in IL-22 (p = 0.021) but not IL17a (p = n.s.). In the PH patient collective (n = 92), increased serum levels of IL-22 but not IL-17a could be shown (p < 0.0001). This elevation remained significant across the different etiological groups (p < 0.05). Correlation analysis revealed multiple significant relations between IL-22 and various clinical, laboratory, functional and hemodynamic parameters. IL-22 could serve as a promising inflammatory biomarker of PH with potential value for initial diagnosis, functional classification or even prognosis estimation. Its validation in larger patients' cohorts regarding outcome and survival data, as well as the probability of promising therapeutic target structures, remains the object of further studies.

Next Generation Sequencing Outperforms Cultivation-Based Methods for Detection of Bacterial Genera in Bile After Liver Transplantation.

Background and aims: Bacterial cholangitis is a common complication in patients with ischemic type biliary lesions and/or anastomotic strictures after liver transplantation (LTX). Patients frequently need antibiotics and endoscopic retrograde cholangiography (ERC) to improve the bile flow. Antibiotic treatment is based on findings in standard microbiological cultivation (SMC) of bile. However, the cultivation techniques are limited to a subset of bacteria easy-to-cultivate. Therefore, the aim of our study was to evaluate the value of next generation sequencing as an additional diagnostic tool to SMC in ischemic type biliary lesions and/or anastomotic strictures. Methods: We sequenced the V1-V2 region of the 16S rRNA gene in 242 stored bile samples in patients after LTX and compared the results with findings of SMC. SMC was performed in n = 135 (56%) fresh bile samples in addition to NGS. SMC was part of the clinical routine in these patients. Results: NGS detected bacterial genera in bile samples more often than SMC (P = 5.42 × 10-74). SMC showed insufficient discovery of bacterial genera compared to NGS with better performance in patients receiving antibiotics prior to ERC. SMC missed many bacterial genera detected by NGS. Conclusions: NGS was more sensitive in detecting bacteria in bile than SMC, no clinical parameters could be used to improve discovery rates in SMC and many genera were missed by SMC. Therefore, NGS should be used in a combined approach with SMC for improved diagnostics to achieve more specific and targeted antibiotic treatments.

Cultivation-based characterization of biliary microbiota in bile samples collected during routine endoscopic retrograde cholangiography: 10 years of experience at a tertiary center.

INTRODUCTION: Bile has long been considered sterile. Recent studies show that bacteria can frequently be detected in bile and certain bacterial species are associated with bile duct-associated liver disease. OBJECTIVES: To detect bacterial species and antibiotic resistance in bile in bile duct-associated liver disease. METHODOLOGY: To evaluate microbiological findings of bile samples obtained during ERCP at a tertiary center from 2009 to 2019. RESULTS: There were 1885 bile samples from 992 patients examined by cultural microbiological analysis. Germs were detected in 91% of the samples. Most bile samples (n) were obtained from patients who had undergone liver transplantation (LTX; n = 556), followed by patients with primary sclerosing cholangitis (PSC; n = 287). Enterococci were detected in 67% of samples, followed by E. coli (32.2%) and Klebsiella (28.2%). Of 1151 enterococci detected, 13.1% were vancomycin (VRE)s and of 216 staphylococci detected, 10% were ORSA. The proportion of VRE increased with the number of tests performed during ERCPs ( P  < 0.01; chi-square) and increased 2.5-fold over 10 years, whereas the detection of ORSA remained stable. Patients with cholecystolithiasis were significantly more likely to have evidence of VRE in bile compared to LTX and PSC patients ( P  = 0.02, P  < 0.01; chi-square). The most abundant bacterial genera showed highly statistically significant differences in their levels of liver enzymes and c-reactive protein ( P  < 0.001). CONCLUSION: Knowledge of the bacterial composition of bile in various bile duct-associated liver diseases may allow more targeted antibiotic use in the future.

The Safety and Efficacy of Ultrasound-Accelerated Catheter-Directed Thrombolysis in Patients with Intermediate-High-Risk Pulmonary Embolism: Bo-NE-Experience.

Ultrasound-accelerated thrombolysis (USAT) is an advanced interventional therapy for patients with intermediate-high-risk pulmonary embolism (PE) who deteriorated on anticoagulation or for high-risk patients for whom systemic thrombolysis is contraindicated. The aim of this study is to investigate the safety and efficacy of this therapy with a focus on the improvement of vital signs and laboratory parameters. Seventy-nine patients with intermediate-high-risk PE were treated with USAT from August 2020 to November 2022. The therapy significantly decreased the mean RV/LV ratio from 1.2 ± 0.22 to 0.9 ± 0.2 (p < 0.001) as well as the mean PAPs from 48.6 ± 11 to 30.1 ± 9.0 mmHg (p < 0.001). The respiratory and heart rate decreased significantly (p < 0.001). Serum creatinine decreased significantly from 1.0 ± 0.35 to 0.9 ± 0.3 (p < 0.001). There were 12 access-associated complications, which could be treated conservatively. One patient had haemothorax after the therapy and had to be operated on. USAT is an effective therapy for patients with intermediate-high-risk PE, with favourable hemodynamic, clinical, and laboratory outcomes.

Use of Autotransfusion following Percutaneous Thrombectomy for Cardiogenic Shock Due to Pulmonary Embolism in a Single Session-A Case Report.

A 64-year-old male patient was admitted to the catheterization laboratory with a suspected myocardial infarction and in cardiogenic shock. Upon further investigation, a massive bilateral pulmonary embolism with signs of right heart dysfunction was discovered, leading to a decision to perform a direct interventional treatment with a thrombectomy device for thrombus aspiration. The procedure was successful in removing almost the entirety of the thrombotic material from the pulmonary arteries. The patient's hemodynamics stabilized and oxygenation improved instantly. The procedure required a total of 18 aspiration cycles. Each aspiration contained approx. 60 mL blood amounting to a total of approx. 1080 mL of blood. During the procedure, a mechanical blood salvage system was used to resupply 50% of the blood via autotransfusion that would otherwise have been lost. The patient was transferred to the intensive care unit for post-interventional care and monitoring. A CT angiography of the pulmonary arteries after the procedure confirmed the presence of only minor residual thrombotic material. The patient's clinical, ECG, echocardiographic, and laboratory parameters returned to normal or near normal ranges. The patient was discharged shortly after in stable conditions on oral anticoagulation.

BISCIT: Biliary interventions in critically ill patients with secondary sclerosing cholangitis-a study protocol for a multicenter, randomized, controlled parallel group trial.

BACKGROUND: Progress of cholangitis to cholangiosepsis is a frequent observation in patients with secondary sclerosing cholangitis in critically ill patients (SSC-CIP). Adequate biliary drainage may reduce episodes of cholangiosepsis and therefore stabilize liver function and improve survival. The primary objective of the BISCIT study is to demonstrate that scheduled biliary interventions will reduce incidence of cholangiosepsis, liver transplantation, or death in patients with SSC-CIP. METHODS: A total of 104 patients will be randomized at ten study sites. Patients with SSC-CIP, confirmed by endoscopic retrograde cholangiography (ERC), will be randomized 1:1 either in the intervention group which will be treated with scheduled biliary interventions (i.e., therapeutic ERC) every 8 weeks for 6 months or in the control group which will receive standard of care. The randomization will be stratified by center. The composite primary efficacy endpoint is defined as (1) occurrence of death, (2) necessity of liver transplantation, or (3) occurrence of cholangiosepsis within 6 months following randomization. DISCUSSION: Prospective evaluation of endoscopic treatment procedures is urgently needed to establish an evidence-based therapeutic treatment algorithm in SSC-CIP. A positive trial result could change the current standard of care for patients with SSC-CIP. The results of this study will be disseminated through presentations at international congresses, workshops, and peer-reviewed publications. TRIAL REGISTRATION: The trial was registered at ClinicalTrials.gov (NCT05396755, date of registration: May 31, 2022, last update: May 31, 2022).

Intravascular Lithotripsy in Calcified Peripheral Lesions: Single-Center JEN-Experience.

Peripheral artery disease (PAD) shows increasing need for revascularization therapy. Interventional success in calcified lesions is limited. Here, intravascular lithotripsy (IVL), modifying intimal and medial calcium, is a promising treatment approach. A single-center, prospective all-comers registry for patients undergoing peripheral IVL was established to examine treatment success in PAD with severe vessel calcification. Periprocedural safety events as well as short-term and intermediate follow-up clinical data were evaluated. Between December 2018 and January 2021 all consecutive patients receiving peripheral lithotripsy at our center were analyzed. Clinical and angiographic data were evaluated. Angiographic images were analyzed using a semiautomatic software for quantitative vessel analysis. Eighty-five lesions in 61 limbs were treated with IVL in 51 patients presenting with Rutherford classes 2 to 5. Most lesions (68%) were localized in the superficial femoral artery. Mean calcified lesion length was 102.5 mm (10-390 mm), with a median peripheral arterial calcium score of 3, indicating a highly calcified status. In 58% of the patients, IVL was used as a stand-alone therapy. IVL resulted in a mean acute luminal gain of 2.6 ± 0.9 mm, resulting in stenosis reduction by 42.1 ± 15%. Mean ankle brachial index (ABI) improved significantly from 0.6 to 0.8 ( p < 0.0001) on day 1 after the intervention and remained stable at 6 months. This large real-world data of peripheral IVL reports compelling safety in a complex patient cohort. For the first time, clinical follow-up data demonstrated a sustained significant improvement in ABI after 6 months.

EKOS™ Jena Experience: Safety, Feasibility, and Midterm Outcomes of Percutaneous Ultrasound-Assisted Catheter-Directed Thrombolysis in Patients with Intermediate-High-Risk or High-Risk Pulmonary Embolism.

Background: Percutaneous catheter-based ultrasound-assisted thrombolysis (UACDT) is recommended for patients with intermediate-high-risk or high-risk pulmonary embolism (PE) in whom systemic thrombolysis has failed or is contraindicated. Aim: To evaluate the safety and efficiency of UACDT in patients with intermediate-high-risk or high-risk PE. Methods: Between October 2017 and January 2020, we performed UACDT using the EkoSonic™ Endovascular System (EKOS™) in 51 patients (21 males, age 63 ± 18 years) with a sPESI of 1.3 ± 0.7. The EKOS™-catheter was implanted within 24 h after admission. Over 15 hours, 11.5 mg of alteplase was administered per catheter. We evaluated right ventricular stress and cardiac biomarkers before and after UACDT. Results: 24 h post-UACDT, median RV/LV ratio decreased from 1.13 to 0.96 (p < 0.001) and the mean sPAP decreased from 47 ± 3 to 32 ± 2 mmHg + CVP (p < 0.0002). There were 6 major bleeding events resulting in transfusion. No stroke, myocardial infarction, right heart decompensation, or recurrent PE occurred. 31 patients (63%) were discharged without any signs of right ventricular stress. After at least 3 months, 73% of our patients did not show any signs of right ventricular dysfunction. The mean RV/LV ratio decreased to 0.75 ± 0.03 (p < 0.0001) in comparison with pre-UACDT, sPAP to 23 mmHg + CVP (p < 0.0001), and BNP to 40 pg/ml (p < 0.0001). Conclusions: The treatment with UACDT reduced right heart stress during the first 24 hours and midterm in patients with intermediate-high-risk or high-risk PE at an acceptable rate of severe complications.

The biliary microbiome in ischaemic-type biliary lesions can be shaped by stenting but is resilient to antibiotic treatment.

This study aims to characterize the biliary microbiome as neglected factor in patients with ischaemic-type biliary lesions (ITBL) after liver transplantation. Therefore, the V1-V2 region of the 16S rRNA gene was sequenced in 175 bile samples. Samples from patients with anastomotic strictures (AS) served as controls. Multivariate analysis and in silico metagenomics were applied cross-sectionally and longitudinally. The microbial community differed significantly between ITBL and AS in terms of alpha and beta diversity. Both, antibiotic treatment and stenting were associated independently with differences in the microbial community structure. In contrast to AS, in ITBL stenting was associated with pronounced differences in the biliary microbiome, whereas no differences associated with antibiotic treatment could be observed in ITBL contrasting the pronounced differences found in AS. Bacterial pathways involved in the production of antibacterial metabolites were increased in ITBL with antibiotic treatment. After liver transplantation, the biliary tract harbours a complex microbial community with significant differences between ITBL and AS. Fundamental changes in the microbial community in ITBL can be achieved with biliary stenting. However, the effect of antibiotic treatment in ITBL was minimal. Therefore, antibiotics should be administered wisely in order to reduce emerging resistance of the biliary microbiome towards external antibiotics.