Weight-loss Endoscopy Trial (WET): a multi-center, randomized, controlled trial comparing weight loss in endoscopically implanted duodenal-jejunal bypass liners vs. intragastric balloons vs. a sham procedure.

INTRODUCTION: Obesity is associated with reduced life expectancy and various comorbidities. Surgical interventions are effective but accompanied by risk of serious complications. Less invasive endoscopic procedures mainly comprise the intragastric balloon (IB) and the duodenal-jejunal bypass liner (DJBL). A randomized, sham-controlled study comparing both procedures has not been undertaken so far. METHODS: We performed a randomized, patient- and assessor-blinded, controlled trial comparing weight loss in IB vs. DJBL vs. a sham procedure (2:2:1 ratio). Patients with a BMI > 35 kg/m2 or > 30 with obesity-related comorbidities were included. The IB was removed after 6 months and the DJBL after 12 months. Main objective was successful weight loss (>10% from baseline) 12 months after explantation of the devices. Secondary outcomes were changes in comorbidities, quality of life and complications. RESULTS: 33 patients were randomized. Recruitment has to be stopped suddenly in after the DJBL device lost its CE mark in Europe. 11 patients received DJBL, 15 IB and 7 were allocated to sham group. Blinding was feasible in all patients. Weight decreased from baseline until explantation (DJBL: 129.4±28.3kg to 107.4±16.7kg; IB: 118.3±22.8kg to 107.4±25.7kg; sham: 134.6±18.0kg to 131.2±14.3kg) but patients regained weight almost to baseline level 12 months after explantation. Only one patient in IB group reached the primary endpoint. Severe device-related complications were very rare. CONCLUSION: Endoscopic bariatric procedures failed to achieve effective weight loss 12 months after explantation of the devices. The results of this trial need to be interpreted with caution due to its early termination.

Clinical management, pathogen spectrum and outcomes in patients with pyogenic liver abscess in a German tertiary-care hospital.

Pyogenic liver abscesses (PLA) are life-threatening disorders and require immediate treatment, but structured evidence is sparse and treatment guidelines are not established. In a retrospective observational study of 221 adult PLA patients (mean age 63 years, 63% men) treated between 2013 and 2019 at the Leipzig University Medical Center, we characterized pathogen spectrum, clinical management and outcomes. Biliary malignancies (33%), cholelithiasis (23%) and ischemic biliary tract disease (16%) were most common causes of PLA. Comorbidities included malignancies (40%) and diabetes mellitus (35%). Abdominal ultrasound was the preferred initial imaging modality (58%). Enterobacterales (58%), enterococci (42%) and streptococci (18%) were identified as most frequent pathogens. 97% of patients were treated with antibiotics and 75% of patients underwent an invasive treatment procedure. The 30-day mortality was almost identical in patients with and without underlying malignancy (14.6% vs. 14.4%, p = 0.96), while the one-year outcome differed significantly (58.4% vs. 29.6%, p < 0.001). Positive blood cultures (OR 4.78, 95% CI 1.39 to 22.5, p = 0.023) and detection of Enterobacterales (OR 3.55, 95% CI 1.40 to 9.97, p = 0.010) were associated with increased 30-day-mortality. We conclude that ultrasound, extensive microbiologic diagnosis, adequate anti-infective therapy and early intervention are crucial for the management of PLA.

Near-infrared spectroscopy and electroencephalography neurofeedback for binge-eating disorder: an exploratory randomized trial.

BACKGROUND: Binge-eating disorder (BED) co-occurs with neurobehavioral alterations in the processing of disorder-relevant content such as visual food stimuli. Whether neurofeedback (NF) directly targeting them is suited for treatment remains unclear. This study sought to determine feasibility and estimate effects of individualized, functional near-infrared spectroscopy-based real-time NF (rtfNIRS-NF) and high-beta electroencephalography-based NF (EEG-NF), assuming superiority over waitlist (WL). METHODS: Single-center, assessor-blinded feasibility study with randomization to rtfNIRS-NF, EEG-NF, or WL and assessments at baseline (t0), postassessment (t1), and 6-month follow-up (t2). NF comprised 12 60-min food-specific rtfNIRS-NF or EEG-NF sessions over 8 weeks. Primary outcome was the binge-eating frequency at t1 assessed interview-based. Secondary outcomes included feasibility, eating disorder symptoms, mental and physical health, weight management-related behavior, executive functions, and brain activity at t1 and t2. RESULTS: In 72 patients (intent-to-treat), the results showed feasibility of NF regarding recruitment, attrition, adherence, compliance, acceptance, and assessment completion. Binge eating improved at t1 by -8.0 episodes, without superiority of NF v. WL (-0.8 episodes, 95% CI -2.4 to 4.0), but with improved estimates in NF at t2 relative to t1. NF was better than WL for food craving, anxiety symptoms, and body mass index, but overall effects were mostly small. Brain activity changes were near zero. CONCLUSIONS: The results show feasibility of food-specific rtfNIRS-NF and EEG-NF in BED, and no posttreatment differences v. WL, but possible continued improvement of binge eating. Confirmatory and mechanistic evidence is warranted in a double-blind randomized design with long-term follow-up, considering dose-response relationships and modes of delivery.

Relevance of GLP-1 receptor agonists or SGLT-2 inhibitors on the recruitment for clinical studies in patients with NAFLD.

INTRODUCTION: Guidelines increasingly recommend the use of glucagon-like peptide-1 receptor agonists (GLP-1 RA) or sodium-glucose co-transporter-2 inhibitors (SGLT2i) to prevent cardiovascular and cardiorenal endpoints. Both drugs also show beneficial effects in nonalcoholic fatty liver disease (NAFLD). Preexisting GLP-1 RA and SGLT2i therapies are frequently defined as exclusion criterion in clinical studies to avoid confounding effects. We therefore investigated how this might limit recruitment and design of NAFLD studies. METHODS: GLP-1 RA and SGLT2i prescriptions were analyzed in NAFLD patients with diabetes mellitus recruited at a tertiary referral center and from the population-based LIFE-Adult-Study. Individuals were stratified according to noninvasive parameters of liver fibrosis based on vibration-controlled transient elastography (VCTE). RESULTS: 97 individuals were recruited at tertiary care and 473 from the LIFE-Adult-Study. VCTE was available in 97/97 and 147/473 cases.GLP-1 RA or SGLT2i were used in 11.9% of the population-based cohort (LSM < 8 kPa), but in 32.0% with LSM ≥ 8 kPa. In the tertiary clinic, it was 30.9% overall, independent of LSM, and 36.8% in patients with medium and high risk for fibrotic NASH (FAST score > 0.35). At baseline, 3.1% of the patients in tertiary care were taking GLP-1 RA and 4.1% SGLT2i. Four years later, the numbers had increased to 15.5% and 21.6%. CONCLUSION: GLP-1 RA and SGLT2i are frequently and increasingly prescribed. In candidates for liver biopsy for NASH studies (VCTE ≥ 8 kPa) the use of them exceeds 30%, which needs careful consideration when designing NASH trials.

Rationale of the PAPAartis trial.

Surgical and interventional repair of thoracoabdominal aortic aneurysms improve survival significantly compared to the natural history of the disease. However, both strategies are associated with a substantial risk of spinal cord ischemia, which has been reported to occur-even in contemporary series by expert centers-in up to 12% of patients, depending on the extent of the disease. Following improved neurological outcomes after staged approaches in extensive clinical and long-term large animal studies, and the description of the "collateral network", the concept of "Minimally Invasive Staged Segmental Artery Coil Embolization" (MIS2ACE) was introduced by Etz et al. This concept of priming the collateral network in order to improve spinal cord blood supply showed promising experimental and early clinical outcomes, and consequently led to the initiation of the randomized controlled multicenter PAPAartis trial (Paraplegia Prevention in Aortic Aneurysm Repair by Thoracoabdominal Staging). This Keynote Lecture describes the background and rationale for this trial and gives an update on the current status.

Intensive heart rhythm monitoring to decrease ischemic stroke and systemic embolism-the Find-AF 2 study-rationale and design.

BACKGROUND: Atrial fibrillation (AF) is one of the most frequent causes of stroke. Several randomized trials have shown that prolonged monitoring increases the detection of AF, but the effect on reducing recurrent cardioembolism, ie, ischemic stroke and systemic embolism, remains unknown. We aim to evaluate whether a risk-adapted, intensified heart rhythm monitoring with consequent guideline conform treatment, which implies initiation of oral anticoagulation (OAC), leads to a reduction of recurrent cardioembolism. METHODS: Find-AF 2 is a randomized, controlled, open-label parallel multicenter trial with blinded endpoint assessment. 5,200 patients ≥ 60 years of age with symptomatic ischemic stroke within the last 30 days and without known AF will be included at 52 study centers with a specialized stroke unit in Germany. Patients without AF in an additional 24-hour Holter ECG after the qualifying event will be randomized in a 1:1 fashion to either enhanced, prolonged and intensified ECG-monitoring (intervention arm) or standard of care monitoring (control arm). In the intervention arm, patients with a high risk of underlying AF will receive continuous rhythm monitoring using an implantable cardiac monitor (ICM) whereas those without high risk of underlying AF will receive repeated 7-day Holter ECGs. The duration of rhythm monitoring within the control arm is up to the discretion of the participating centers and is allowed for up to 7 days. Patients will be followed for at least 24 months. The primary efficacy endpoint is the time until recurrent ischemic stroke or systemic embolism occur. CONCLUSIONS: The Find-AF 2 trial aims to demonstrate that enhanced, prolonged and intensified rhythm monitoring results in a more effective prevention of recurrent ischemic stroke and systemic embolism compared to usual care.

Smartphone-supported behavioural weight loss treatment in adults with severe obesity: study protocol for an exploratory randomised controlled trial (SmartBWL).

INTRODUCTION: Behavioural weight loss (BWL) treatment is the standard evidence-based treatment for severe obesity (SO; body mass index ≥40.0 kg/m2 or ≥35.0 kg/m2 with obesity-related comorbidity), leading to moderate weight loss which often cannot be maintained in the long term. Because weight loss depends on patients' use of weight management skills, it is important to support them in daily life. In an ecological momentary intervention design, this clinical trial aims to adapt, refine and evaluate a personalised cognitive-behavioural smartphone application (app) in BWL treatment to foster patients' weight management skills use in everyday life. It is hypothesised that using the app is feasible and acceptable, improves weight loss and increases skills use and well-being. METHODS AND ANALYSIS: In the pilot phase, the app will be adapted, piloted and optimised for BWL treatment following a participatory patient-oriented approach. In the subsequent single-centre, assessor-blind, exploratory randomised controlled trial, 90 adults with SO will be randomised to BWL treatment over 6 months with versus without adjunctive app. Primary outcome is the amount of weight loss (kg) at post-treatment (6 months), compared with pretreatment, derived from measured body weight. Secondary outcomes encompass feasibility, acceptance, weight management skills use, well-being and anthropometrics assessed at pretreatment, midtreatment (3 months), post-treatment (6 months) and 6-month follow-up (12 months). An intent-to-treat linear model with randomisation arm, pretreatment weight and stratification variables as covariates will serve to compare arms regarding weight at post-treatment. Secondary analyses will include linear mixed models, generalised linear models and regression and mediation analyses. For safety analysis (serious) adverse events will be analysed descriptively. ETHICS AND DISSEMINATION: The study was approved by the Ethics Committee of the University of Leipzig (DE-21-00013674) and notified to the Federal Institute for Drugs and Medical Devices. Study results will be disseminated through peer-reviewed publications. REGISTRATION: This study was registered at the German Clinical Trials Register (DRKS00026018), www.drks.de. TRIAL REGISTRATION NUMBER: DRKS00026018.

Confirmation of guideline-defined hepatitis C screening strategies within the 'Check-Up35+' examination in the primary care setting.

BACKGROUND AND AIMS: Screening strategies for undiagnosed infections are fundamental for hepatitis C virus (HCV) elimination. We previously investigated HCV prevalence and screening strategies in an urban primary care setting. IV drug abuse, blood transfusion before 1992, immigration, or elevated ALT were identified as risk factors in a post hoc analysis and diagnosed 83% of unknown HCV-RNA-positive cases by screening only 26% of the population. We aimed to validate prospectively the proposed screening algorithm in two independent urban and rural cohorts and to analyse for potential differences. METHODS: Anti-HCV and ALT were included in a routine check-up together with a questionnaire covering risk factors. HCV-RNA was analysed in anti-HCV-positive individuals. RESULTS: In urban and rural areas, 4323 and 9321 individuals were recruited. The anti-HCV prevalence was 0.56% and 0.49%, and 0.1% of patients were HCV-RNA-positive in both regions. Fifty-two anti-HCV positive patients including eight HCV-RNA-positive cases were unaware of the infection (number needed to screen to detect one unknown anti-HCV-positive individual: 262). At least one of the three aforementioned risk factors or elevated serum ALT was present in 3000 patients (22%). Restricting HCV screening to only those with risk factors, 52% and 75% of all anti-HCV and HCV-RNA-positive undiagnosed patients were identified (number needed to screen: 111). CONCLUSIONS: We confirm prospectively the efficiency of a risk-based HCV screening. The risk-based algorithm should be evaluated in other countries with similarly low HCV prevalence as in Germany to achieve WHO HCV elimination goals.

"There is nothing better than participating in this study": Living the PAPAartis cardiovascular randomised controlled trial.

Qualitative research can bring new dimensions of understanding decision-making process in clinical trials. Participating in a randomized clinical trial requires patients to accept complex information and make decisions in a context of uncertainty. It becomes especially complicated in the case of serious diseases in which the treatment itself implies unknown risks. This study examines these issues in the context of the PAPAartis randomized clinical trial, which aims to prevent spinal cord injuries that can occur as an adverse event following complex surgical repair of thoracoabdominal aneurysm. In this study, we accessed a group of 16 patients participating in the trial and, through in-depth interviews, sought to understand the decision-making process when taking part in the trial and their experience of it. Our results showed that patients participated for different reasons: due to trust in doctors, the hope of having a better treatment or for altruistic and collaborative reasons with science. Many patients felt they did not fully understand the extraneous information provided about the study and the complex nature of the procedure. Avoidance of paraplegia played a fundamental role in the decision to participate in this trial. Family support and the socioeconomic conditions of the patients influenced the recovery process after surgery.

Tigecycline Soft Tissue Penetration in Obese and Non-obese Surgical Patients Determined by Using In Vivo Microdialysis.

BACKGROUND AND OBJECTIVE: Tigecycline, a broad-spectrum glycylcycline antibiotic, is approved for use at a fixed dose irrespective of body weight. However, its pharmacokinetics may be altered in obesity, which would impact on the antibiotic's effectiveness. The objective of this study was to investigate the plasma and subcutaneous tissue concentrations of tigecycline in obese patients compared with those in a non-obese control group. METHODS: Fifteen obese patients (one class II and 14 class III) undergoing bariatric surgery and 15 non-obese patients undergoing intra-abdominal surgery (mainly tumour resection) received a single dose of 50 or 100 mg tigecycline as an intravenous short infusion. Tigecycline concentrations were measured up to 8 h after dosing in plasma (total concentration), in ultrafiltrate of plasma (free concentration), and in microdialysate from subcutaneous tissue, respectively. RESULTS: In obese patients, total peak plasma concentration (1.31 ± 0.50 vs 2.27 ± 1.40 mg/L) and the area under the concentration-time curve from 0 to 8 h (AUC8h,plasma: 2.15 ± 0.42 vs 2.74 ± 0.73 h⋅mg/L), as normalized to a 100 mg dose, were significantly lower compared with those of non-obese patients. No significant differences were observed regarding the free plasma concentration, as determined by ultrafiltration, or the corresponding AUC8h (fAUC8h,plasma). Concentrations in interstitial fluid (ISF) of subcutaneous tissue were lower than the free plasma concentrations in both groups, and they were lower in obese compared to non-obese patients: the AUC8h in ISF (AUC8h,ISF) was 0.51 ± 0.22 h⋅mg/L in obese and 0.79 ± 0.23 h⋅mg/L in non-obese patients, resulting in a relative tissue drug exposure (AUC8h,ISF/fAUC8h,plasma) of 0.38 ± 0.19 and 0.63 ± 0.24, respectively. CONCLUSION: Following a single dose of tigecycline, concentrations in the ISF of subcutaneous adipose tissue are decreased in heavily obese subjects, calling for an increased loading dose. EU CLINICAL TRIALS REGISTRATION NUMBER: EudraCT No. 2012-004383-22.

Endoscopic Bariatric Treatment with Duodenal-Jejunal Bypass Liner Improves Non-invasive Markers of Non-alcoholic Steatohepatitis.

PURPOSE: People with obesity often develop non-alcoholic fatty liver disease (NAFLD) and are at high risk of progression to non-alcoholic steatohepatitis (NASH). Few therapies are effective other than bariatric surgery. We therefore analyzed data from duodenal-jejunal bypass liner (DJBL) patients regarding steatosis, fibrosis, and NASH. METHODS: Consecutive DJBL patients with type 2 diabetes underwent standardized assessments up to device removal at 48 weeks. These included aspartate and alanine transaminase (AST, ALT), controlled attenuation parameter (CAP, for steatosis), and liver stiffness measurement (LSM, for fibrosis). The NAFLD fibrosis score (NFS), fibrosis-4 score (FIB4), and enhanced liver fibrosis (ELF) test were also used to assess fibrosis and the Fibroscan-AST (FAST) score to assess NASH. Mixed models were used and missing data were accounted for with multiple imputation. RESULTS: Thirty-two patients (18 female, mean age 55.1, mean BMI 40.2 kg/m2) were included. After 48 weeks, the change compared to baseline with 95% CI was a factor 0.74 (0.65 to 0.84) for AST, 0.63 (0.53 to 0.75) for ALT, and a difference of - 0.21 (- 0.28 to - 0.13) for FAST, all with p < 0.001. Fibrosis based on LSM, NFS, and ELF did not change whereas FIB4 exhibited slight improvement. Eight DJBL were explanted early due to device-related complications and eight complications led to hospitalization. CONCLUSIONS: One year of DJBL therapy is associated with relevant improvements in non-invasive markers of steatosis and NASH, but not fibrosis, and is accompanied by a substantial number of complications. Given the lack of alternatives, DJBL deserves further attention.

Prevalence of Pruritus and Association with Anxiety and Depression in Patients with Nonalcoholic Fatty Liver Disease.

Patient-reported outcomes are important in nonalcoholic fatty liver disease (NAFLD). Pruritus is of special interest for evolving therapies with farnesoid X receptor (FXR) agonists. The aim of this study was to investigate the prevalence of pruritus in a real-life NAFLD cohort and analyze associations with anxiety and depression. Pruritus was assessed using a visual analogue- (VAS) and 5-D itch-scale (5-D). Anxiety and depression were evaluated by Beck's-Depression-Inventory (BDI) and the Hospital Anxiety and Depression Scale (HADS-A, HADS-D). An optimal logistic regression model was found with a stepwise procedure to investigate variables associated with pruritus. In total, 123 NAFLD patients were recruited. VAS and 5-D were highly correlated (Spearman's correlation coefficient 0.89). Moderate/severe pruritus was reported in 19% (VAS) and 21% (5-D) of patients. Anxiety and depression were present in 12% and 4% (HADS-A and HADS-D, respectively) and 12% (BDI) of cases. There was a significant association between VAS and BDI (p = 0.019). The final multivariate model for 5-D included diabetes mellitus (OR 4.51; p = 0.01), BDI (OR 5.98; p = 0.024), and HADS-A (OR 7.75; p = 0.011). One-fifth of NAFLD patients reported moderate or severe pruritus. 5-D was significantly associated with diabetes mellitus, depression, and anxiety. These findings should be tested in larger populations and considered in candidates for treatment with FXR agonists.

Clinical implications of hepatic structure and function evaluation based on vibration-controlled transient elastography and liver maximum function capacity test in patients with nonalcoholic fatty liver disease.

BACKGROUND AND AIMS: Transient elastography [vibration-controlled transient elastography (VCTE)] noninvasively guides risk stratification in patients with nonalcoholic fatty liver disease (NAFLD). Patients with nonalcoholic steatohepatitis (NASH) and fibrosis can be identified using the FAST-score. The liver maximum function test (LiMAx) could be helpful in more precise risk stratification. This pilot study evaluated VCTE, FAST-score, and LiMAx in NAFLD patients. METHODS: NAFLD patients prospectively underwent VCTE and LiMAx. The cutoffs for high fibrosis risk were 9.3/9.6 kPa (M/XL-probe) and 331 dB/m for steatosis. A FAST-score greater than 0.67 was used to identify patients with NASH and LiMAx values below 315 µg/kg/h for impaired liver function. RESULTS: In total, 57 NAFLD patients (BMI 32 ± 6 kg/m2; 60% diabetes) were included. High risk for fibrosis and steatosis was observed in 26/57 and 28/57 cases, respectively. Overall, 19/57 patients presented impaired liver function. However, 14/26 of patients with a high risk for fibrosis had impaired liver function compared to 5/31 of those without (P = 0.0026). Similarly, 12/18 patients at high risk for NASH had impaired liver function compared to 7/39 without (P < 0.001). The subgroup with diabetes had a liver stiffness a factor of 1.8 higher, FAST-score was 0.13 higher and LiMAx values were 66 µg/kg/h lower compared to nondiabetics. CONCLUSION: There is a significant correlation between the functional liver capacity (LiMAx) and the structural liver assessment by VCTE. In cases with high liver stiffness or FAST-score, low LiMAx results may identify NAFLD patients at risk for disease progression and reduce the risk of false-positive categorization.