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Purpose: Listeria monocytogenes causes severe bacterial infections with the highest mortality rate among foodborne pathogens in Europe. Combination treatment with ampicillin and gentamicin is recommended for invasive manifestations. However, evidence to support this treatment approach remains limited due to a lack of randomised controlled trials. To explore this critical issue further, we conducted this retrospective, single-center study. Methods: We identified all patients hospitalized with invasive listeriosis at the University Medical Center Hamburg-Eppendorf between 2009 and 2020 and analyzed the effect of gentamicin combination treatment versus monotherapy on 90-day mortality. Results: In total, 36 patients with invasive listeriosis were included, of which 21 patients received gentamicin combination treatment and 15 received monotherapy. The mean age-adjusted Charlson Comorbidity Index (aaCCI) value was lower in the gentamicin combination treatment group (5.4 vs. 7.4). Neurolisteriosis was more common in the gentamicin group (81% vs. 20%). The 90-day mortality was with significantly lower in the gentamicin combination treatment group (10%) compared to the monotherapy group (60%). Multivariable cox regression analysis, adjusted for a propensity score computed based on neurolisteriosis, aaCCI and sex, revealed a significantly reduced hazard ratio of 0.07 (95% CI: 0.01–0.53, p = 0.01) for 90-day mortality for the gentamicin combination treatment. Conclusion: This retrospective study highlights the benefit of gentamicin combination treatment in reducing the 90-day mortality rate among patients with invasive listeriosis. The high prevalence of monotherapy in this study cohort raises concerns about the adequacy of antibiotic therapy in clinical practice. [ABSTRACT FROM AUTHOR]

Literature investigating the impact of COVID-19 on healthcare professionals barely addresses predictors of somatic symptom burden during the COVID-19 pandemic. As biopsychosocial models propose that not only the disease but also sociodemographic and psychosocial factors contribute to the development and maintenance of symptoms, this study investigates the predictive value of these factors for bothersome somatic symptoms in SARS-CoV-2 negative healthcare professionals. German healthcare professionals were assessed with self-rating questionnaires and underwent SARS-CoV-2 IgG antibody tests at baseline and 8 weeks later between April and August 2020. Differences in psychosocial variables between the time points were analyzed and regression analyses were performed to predict somatic symptoms at follow-up. 1185 seronegative healthcare professionals completed both assessments. Previous somatic symptom burden, higher levels of anxiety, being a nurse, younger age, higher psychological symptom burden, lower efficiency, and higher fatigability at baseline predicted somatic symptom burden at follow-up. Comparisons between baseline and follow-up showed a significant improvement in psychological impairment and deterioration of physical exhaustion. Our study applies a biopsychosocial perspective to bothersome somatic symptoms during the COVID-19 pandemic and contributes to the identification of potential risk factors as a starting point for future interventions that could support the handling of symptoms. [ABSTRACT FROM AUTHOR]

Introduction: Incidence of pancreatic neuroendocrine tumours (pNETs) is on the rise. The only curative treatment is surgical resection in localized or oligo-metastatic disease. However, patients may present with locally advanced or unresectable primary tumours. So far, no conversion therapy to achieve resectability has been established, which is partly due to lack of data on primary tumour response to therapies. Here, we specifically evaluate the primary tumour response to streptozocin/5-FU in a large cohort of metastatic pNET patients. Methods: Five ENETS centres in Germany contributed 84 patients to the study cohort for retrospective analysis. Results: Overall response rate (ORR) in primary tumours was 34% and disease control rate (DCR) 88%. ORR was different in metastases at 44% and DCR at 70%. Partial remission in primary tumours was more frequent among those located in pancreatic tail than that in pancreatic head (49% vs. 14%, p = 0.03). Correspondingly, metastases from tumours originating from pancreatic tail responded more frequently than metastases originating from pancreatic head (88.5% vs. 41.7%, p = 0.005). The median PFS of the primary tumours was longer than that in metastases (31 months vs. 16 months; p = 0.04). Considerable downsizing of the primary tumour was rare and occurred primarily in tumours located in the pancreatic tail. Conclusion: STZ/5-FU can achieve disease stabilization in a high proportion of metastatic pNET patients. In the majority of cases however it does not induce substantial downsizing of the primary tumour, thus possibly limiting its potential as conversion chemotherapy. Furthermore, the difference in response rate observed between different primary tumour locations warrants further exploration. [ABSTRACT FROM AUTHOR]

Background: Proton-pump inhibitors (PPI) are liberally prescribed in patients with liver cirrhosis. Observational studies link PPI therapy in cirrhotic patients with an increased risk for infectious complications, hepatic encephalopathy and an increased risk for hospitalization and mortality. However, patients with liver cirrhosis are also considered to be at risk for peptic ulcer bleeding. The STOPPIT trial evaluates if discontinuation of a pre-existing PPI treatment delays a composite endpoint of re-hospitalization and/or death in patients (recently) hospitalized with liver cirrhosis compared to patients on continued PPI medication. Methods: The STOPPIT-trial is a prospective, multicentre, randomized, double-blinded, placebo-controlled, parallelgroup trial. In total, 476 patients with complicated liver cirrhosis who already receive long-term PPI therapy without evidence-based indication are 1:1 randomized to receive either esomeprazole 20 mg (control group) or placebo (intervention group) for 360 days. Patients with an indication for PPI therapy (such as a recent diagnosis of peptic ulcers, severe reflux esophagitis, severe hemorrhagic gastritis, recent endoscopic therapy for oesophageal varices) are excluded. The primary composite endpoint is the time-to re-hospitalization and/or death. Secondary endpoints include rates of re-hospitalization, mortality, occurrence of infections, hepatic decompensation and acute-on-chronic liver failure. The safety endpoint is defined as manifestation of an evidence-based indication for PPI re-therapy. The impact of PPI continuation or discontinuation on the intestinal microbiota will be studied. The recruitment will take place at 18 study sites throughout Germany. Recruitment has started in April 2021. Discussion: The STOPPIT trial is the first clinical trial to study the effects of PPI withdrawal on relevant outcome variables in patients with complicated liver cirrhosis. If the hypothesis that PPI withdrawal improves clinical outcomes of cirrhosis patients is confirmed, this would argue for a strong restriction of the currently liberal prescription practice of PPIs in this population. If, on the other hand, the trial demonstrates an increased risk of gastrointestinal bleeding events in patients after PPI withdrawal, this could create a rationale for a more liberal, prophylactic PPI treatment in patients with liver cirrhosis. [ABSTRACT FROM AUTHOR]

Background: Transjugular intrahepatic portosystemic shunt (TIPS) and shunt surgery are established treatment options for portal hypertension, but have not been systematically evaluated in patients with portal hypertension due to hepatosplenic schistosomiasis (HSS), one of the neglected tropical diseases with major impact on morbidity and mortality in endemic areas. Methods: In this retrospective case study, patients with chronic portal hypertension due to schistosomiasis treated with those therapeutic approaches in four tertiary referral hospitals in Germany and Italy between 2012 and 2020 were included. We have summarized pre-interventional clinical data, indication, technical aspects of the interventions and clinical outcome. Findings: Overall, 13 patients with confirmed HSS were included. 11 patients received TIPS for primary or secondary prophylaxis of variceal bleeding due to advanced portal hypertension and failure of conservative management. In two patients with contraindications for TIPS or technically unsuccessful TIPS procedure, proximal splenorenal shunt surgery in combination with splenectomy was conducted. During follow-up (mean follow-up 23 months, cumulative follow-up time 31 patient years) no bleeding events were documented. In five patients, moderate and transient episodes of overt hepatic encephalopathy were observed. In one patient each, liver failure, portal vein thrombosis and catheter associated sepsis occurred after TIPS insertion. All complications were well manageable and had favorable outcomes. Conclusions: TIPS implantation and shunt surgery are safe and effective treatment options for patients with advanced HSS and sequelae of portal hypertension in experienced centers, but require careful patient selection. Author summary: Hepatosplenic schistosomiasis is a severe form of chronic infection with various trematodes of the genus Schistosoma, characterized by portal venous fibrosis, splenomegaly with hypersplenism, and portal hypertension with subsequent life-threatening bleeding events. While effective anthelminthic treatment is available, portal fibrosis is only partially reversible. Portal hypertension with subsequent bleeding events as a complication is hitherto insufficiently addressed. Surgical techniques are currently the best established treatment option for HSS, despite their inherent complication risk and irreversibility. Interventional procedures like TIPS have rarely been assessed in HSS with mixed results. In a series of 13 cases with follow-up periods up to 99 months and a cumulative follow-up of 30.9 years, we demonstrate excellent bleeding prophylaxis and a low adverse event rate of TIPS and–if TIPS proves infeasible–splenorenal shunt surgery. Main complications of TIPS comprise transient hepatic encephalopathy and increase of liver enzymes, especially in patients with hepatic comorbidities. Due to necessary infrastructure and skills, TIPS implantation is currently limited to specialized centers. However, we think that our study can support the establishment and development of new treatment options for schistosomiasis and, in the medium term, also improve the prognosis of this neglected tropical disease in endemic regions. [ABSTRACT FROM AUTHOR]

Summary: Background: Single‐centre studies reported alterations of faecal microbiota in patients with primary sclerosing cholangitis (PSC). As regional factors may affect microbial communities, it is unclear if a microbial signature of PSC exists across different geographical regions. Aim: To identify a robust microbial signature of PSC independent of geography and environmental influences. Methods: We included 388 individuals (median age, 47 years; range, 15‐78) from Germany and Norway in the study, 137 patients with PSC (n = 75 with colitis), 118 with ulcerative colitis (UC) and 133 healthy controls. Faecal microbiomes were analysed by 16S rRNA gene sequencing (V1‐V2). Differences in relative abundances of single taxa were subjected to a meta‐analysis. Results: In both cohorts, microbiota composition (beta‐diversity) differed between PSC patients and controls (P < 0.001). Random forests classification discriminated PSC patients from controls in both geographical cohorts with an average area under the curve of 0.88. Compared to healthy controls, many new cohort‐spanning alterations were identified in PSC, such as an increase of Proteobacteria and the bile‐tolerant genus Parabacteroides, which were detected independent from geographical region. Associated colitis only had minor effects on microbiota composition, suggesting that PSC itself drives the faecal microbiota changes observed. Conclusion: Compared to healthy controls, numerous microbiota alterations are reproducible in PSC patients across geographical regions, clearly pointing towards a microbiota composition that is shaped by the disease itself and not by environmental factors. These reproducibly altered microbial populations might provide future insights into the pathophysiology of PSC. [ABSTRACT FROM AUTHOR]

To determine epidemiological, clinical and laboratory characteristics of leptospirosis, 24 consecutive patients diagnosed with the infection between 2011 and 2017 at the University Medical Center Hamburg-Eppendorf were retrospectively analyzed. The majority of patients were male travelers who returned from Southeast Asia and had a history of freshwater-associated activities. Considering the lack of discriminatory clinical or clinical chemistry parameters, leptospirosis should be regarded as differential diagnosis in any patient with acute febrile illness, especially with a history of travel to tropical and subtropical regions or freshwater exposure. [ABSTRACT FROM AUTHOR]

Background: There is a paucity of data on fertility or pregnancy in patients with primary sclerosing cholangitis (PSC). Objective To assess fertility in PSC by comparing the number of children in a large cohort of PSC patients to healthy controls and to investigate the outcome of pregnancy, as well as the influence of pregnancy on the disease course. Design: Case series. Setting: Germany. Participants: 229 PSC patients and 569 healthy controls were evaluated for the number of children. 17 patients with PSC and at least one pregnancy, or who received a diagnosis of PSC within 6 months after delivery, were included in the more detailed analysis. Main outcome measures: Number of children per patient and control; disease activity during pregnancy and after delivery including maternal complications; longterm development of live births, fetal loss rate and the influence of medication on fetal and maternal outcome. Results: Fertility did not seem to be reduced in PSC since the number of children did not differ between PSC patients and healthy controls. 25 pregnancies in 17 female PSC patients (median age at conception 31 years) were investigated in detail. An increase in liver enzymes was documented during five pregnancies (20%) and eight times (32%) post-partum. There were no serious maternal complications. All 21 live births presented with a normal perinatal and postnatal development over a median observation time of 50 months. Two pregnancies were delivered pre-term and four fetal losses occurred early in pregnancy (<12 wk). Continuation of treatment with ursodeoxycholic acid (15/21) or azathioprine (2/21) had no negative effects on pregnancy outcome. Conclusions: Fertility does not seem to be reduced in patients with PSC, who are able to deliver healthy children without an apparent increase in risk for mother or child. [ABSTRACT FROM AUTHOR]

In this study, we directly compared coronavirus disease 2019 (COVID-19) patients hospitalized during the first (27 February–28 July 2020) and second (29 July–31 December 2020) wave of the pandemic at a large tertiary center in northern Germany. Patients who presented during the first (n = 174) and second (n = 331) wave did not differ in age (median [IQR], 59 years [46, 71] vs. 58 years [42, 73]; p = 0.82) or age-adjusted Charlson Comorbidity Index (median [IQR], 2 [1, 4] vs. 2 [0, 4]; p = 0.50). During the second wave, a higher proportion of patients were treated as outpatients (11% [n = 20] vs. 20% [n = 67]), fewer patients were admitted to the intensive care unit (43% [n = 75] vs. 29% [n = 96]), and duration of hospitalization was significantly shorter (median days [IQR], 14 [8, 34] vs. 11 [5, 19]; p < 0.001). However, in-hospital mortality was high throughout the pandemic and did not differ between the two periods (16% [n = 27] vs. 16% [n = 54]; p = 0.89). While novel treatment strategies and increased knowledge about the clinical management of COVID-19 may have resulted in a less severe disease course in some patients, in-hospital mortality remained unaltered at a high level. These findings highlight the unabated need for efforts to hamper severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) transmission, to increase vaccination coverage, and to develop novel treatment strategies to prevent mortality and decrease morbidity. [ABSTRACT FROM AUTHOR]

Competing Interests: Die Übersicht über die Interessenkonflikte der Autorinnen und Autoren ist im Anhang veröffentlicht.

Competing Interests: Die Übersicht über die Interessenkonflikte der Autorinnen und Autoren ist im Anhang des Leitlinienreports veröffentlicht.

Gastrointestinal infections are still responsible for around 60% of the infectious diseases that must be reported in Germany and are probably among the most common gastroenterological diseases. The main therapy for gastrointestinal infections remains oral fluid replacement. The recommendations for Clostridioides difficile infections (CDI) have been adapted according to the current data and based on international guidelines; vancomycin or, especially if there is an increased risk of recurrence, fidaxomicin should now be used primarily in CDI. In the case of febrile diarrhea and/or bloody diarrhea, malaria diagnosis should be carried out immediately., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Background: In summer 2011, Shiga toxin producing Escherichia coli (EHEC) serotype O104:H4 caused the most severe EHEC outbreak in Germany to date. The case of a previously recovered patient with symptomatic postinflammatory colonic stenosis following EHEC- infection prompted us to conduct a prospective study to assess the macro- and microscopic intestinal long-term damage in a cohort of patients who had suffered from severe EHEC colitis., Methods: Following EHEC infection in 2011, 182 patients were offered to participate in this study between January 2013 and October 2014 as part of the post-inpatient follow-up care at the University Medical Center Hamburg-Eppendorf and to undergo colonoscopy with stepwise biopsies. Prior to colonoscopy, medical history and persistent post-infectious complaints were assessed., Results: Out of 182 patients, 22 (12%) participated in the study, 18 (82%) were female. All patients had been hospitalized due severe EHEC enterocolitis: 20 patients (90%) had subsequently developed hemolytic uremic syndrome (HUS), 16 patients (72%) had additionally required dialysis. On assessment prior to colonoscopy, all patients denied any abdominal complaints before EHEC-infection but 8 (36%) patients reported persistent post-infectious symptoms. According to the ROME IV criteria, 4 (18%) patients met the definition for post-infectious irritable bowel syndrome (PI-IBS). In all patients with persistent symptoms, colonoscopies and histological examination were unremarkable. Only in one symptom-free patient, biopsy revealed a locally limited cryptitis of the caecum, while all patients without complaints had inconspicuous histological and endoscopical findings., Conclusion: Following infection colonic stenosis is a serious but rare long-term complication in patients who had suffered from severe enterocolitis. However, a significant proportion of these patients develop PI-IBS., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Introduction: Persistent somatic symptoms (PSS) are highly prevalent in all areas of medicine; they are disabling for patients and costly for society. The subjective symptom burden often correlates poorly with the underlying disease severity, and patients' needs for effective treatment are far from being met. Initial evidence indicates that, in addition to disease-specific pathophysiological processes, psychological factors such as expectations, somatosensory amplification and prior illness experiences contribute to symptom persistence in functional as well as in somatic diseases. However, prospective studies investigating the transition from acute to chronic somatic symptoms, integrating pathophysiological, psychological and social factors, are scarce. A better understanding of the multifactorial mechanisms of symptom persistence is crucial for developing targeted mechanism-based interventions for effective prevention and treatment of PSS. Thus, the overall aim of the interdisciplinary SOMACROSS research unit is to identify generic and disease-specific risk factors and aetiological mechanisms of symptom persistence across a range of diseases., Methods and Analysis: Seven projects will investigate risk factors and mechanisms of symptom persistence in a total of 3916 patients across 10 medical conditions. All study designs are prospective and share common assessment points, core instruments and outcome variables to allow comparison and validation of results across projects and conditions. Research will focus on the identification of generic and disease-specific mechanisms associated with unfavourable symptom course. The development of a multivariate prediction model will facilitate the understanding of the course of PSS across diseases., Ethics and Dissemination: All individual SOMACROSS studies were approved by the ethics committees of the Medical Chambers Hamburg and Münster, Germany. Findings will be disseminated through peer-reviewed publications, scientific conferences and the involvement of relevant stakeholders, patients and the lay public. This interdisciplinary research unit will fundamentally contribute to earlier recognition of patients at risk, and to the development of prevention and tailored treatment concepts for PSS., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction and Objectives: Since MELD implementation renal impairment in liver transplant (LT) recipients has become of increasing importance. This is the first study evaluating the course of renal function immediately prior to LT as predictor for long-term renal and overall outcome., Patients and Methods: In this retrospective study, 226 adults undergoing LT at the University Medical Center Hamburg-Eppendorf (2011-2015) were included. The impact of renal function over a period of 3 months prior to LT compared to renal function at the day of LT on long-term renal outcome and survival was assessed., Results: According to GFR at day of LT renal function improved (≥1 CKD stage) in 64 patients (28%), remained stable in 144 (64%) or deteriorated in 18 (8%). Improvement of renal function prior to LT did neither significantly affect 90-day (13% vs. 14%, p = 0.83), nor 5-year post-LT mortality (35% vs. 41%, p = 0.57). 50 patients (22%) with hepatorenal syndrome (HRS) received terlipressin prior to LT, but only 18 (37%) showed prolonged stabilization of renal function (improvement ≥1 CKD stage). Response to terlipressin did neither improve 90-day (p=1), 5-year mortality (p = 0.52) nor long-term renal function (p = 0.843). Nevertheless, need for dialysis pre-LT (59% vs. 34%, p = 0.005) and post-LT (62% vs. 17%, p<0.001) was associated with increased 5-year mortality., Conclusions: Improvement of renal function immediately prior to LT, either spontaneously or following terlipressin therapy, did neither ameliorate long-term renal outcome nor survival in LT recipients. Future studies need to clarify the impact of terlipressin in HRS on the transplant waiting time in LT candidates., Competing Interests: Conflicts of interest The authors declare that they have no conflict of interest., (Copyright © 2021 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.)

Background & Aims: Agents most frequently inducing idiosyncratic drug-induced liver injury (DILI) differ between countries worldwide. Besides, there is no consistent data on the best model predicting mortality or the need for liver transplantation in DILI. We here analysed the DILI cohort of our centre with regard to causative drugs and clinical outcome., Methods: A retrospective analysis of 157 consecutive severe DILI patients presenting to our tertiary care centre in Hamburg, Germany, from 2008 to 2018, was performed., Results: The most frequent putatively causative drugs were phenprocoumon (n = 21), metamizole (n = 17) and flupirtine (n = 6). The mean values of ALT, bilirubin and Model for End-stage Liver Disease (MELD) score at the time of hospitalisation were 1201 U/L (SD: 1169 U/L), 6.8 mg/dL (SD: 7 mg/dL) and 17 (SD: 8). About 71% of all cases were treated with steroids or steroids combined with n-acetylcysteine. About 12.1% of all DILI cases had a poor outcome (liver transplantation and/or death). At the time of admission, MELD score performed better than Hy's law, the ratio (R) or the new ratio (nR) on their own or combined with bilirubin, regarding sensitivity or specificity for poor outcome. MELD score had a c-statistic of 0.847 (95% CI: 0.731-0.964). Furthermore, the cut-off of 18 MELD points had a sensitivity of 88% and a specificity of 72% for poor outcome., Conclusion: Phenprocoumon and metamizole are frequent causative drugs for DILI in Germany. In comparison to other prognostic scores, MELD score ≥18 at the time of admission performed best in our cohort for the prediction of poor outcome in DILI., (© 2021 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background: Healthcare workers are among the most exposed and potentially most threatened populations of the ongoing COVID-19 pandemic. Despite some reports on numbers of infections with SARS-CoV‑2 in German healthcare workers, the courses of their clinical presentation when affected by COVID-19 are not well described., Objective: In this contribution, characteristics and progressions of infected cases among healthcare workers at the University Medical Center Hamburg-Eppendorf during the first wave of the COVID-19 pandemic will be presented., Methods: Between 1 July and 28 July 2020, 67 healthcare workers, who previously tested positive for SARS-CoV‑2 via PCR, were invited via E‑mail to participate in an anonymous online questionnaire; 39 persons participated., Results: Participants (58%) were mostly ≤ 39 years old (64%) and female (70%). Most healthcare workers were involved in direct patient management (85%), including contact with SARS-CoV‑2 positive patients (62%). All participants reported acute symptoms with a median duration of 19 days. The most frequent symptoms were fatigue (85%), anosmia (67%), cough (64%), headache (62%), and shortness of breath (51%). The disease course was mostly mild with low admission rates (5%). Ongoing symptoms lasting more than four weeks post-symptom-onset, particularly anosmia, fatigue, and shortness of breath, were reported by 38%. This group more frequently had pre-existing conditions (53% vs. 12%, p = 0.010), specifically hypertension (27% vs. 4%, p = 0.062)., Discussion: Healthcare workers reported mostly mild courses of COVID-19 despite increased contact with SARS-CoV-2 patients. However, some reported persistent symptoms months after infection., (© 2021. The Author(s).)

We sequentially assessed the presence of SARS-CoV-2 IgG antibodies in 1253 hospital workers including 1026 HCWs at the University Medical Center Hamburg-Eppendorf at three time points during the early phase of the epidemic. By the end of the study in July 2020, the overall seroprevalence was 1.8% (n = 22), indicating the overall effectiveness of infection control interventions in mitigating coronavirus disease 2019 (COVID-19) in hospital workers., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Background: The Middle East respiratory syndrome coronavirus (MERS-CoV) causes a respiratory disease with a case fatality rate of up to 35%. Given its potential to cause a public health emergency and the absence of efficacious drugs or vaccines, MERS is one of the WHO priority diseases warranting urgent research and development of countermeasures. We aimed to assess safety and tolerability of an anti-MERS-CoV modified vaccinia virus Ankara (MVA)-based vaccine candidate that expresses the MERS-CoV spike glycoprotein, MVA-MERS-S, in healthy adults., Methods: This open-label, phase 1 trial was done at the University Medical Center Hamburg-Eppendorf (Hamburg, Germany). Participants were healthy men and women aged 18-55 years with no clinically significant health problems as determined during medical history and physical examination, a body-mass index of 18·5-30·0 kg/m 2 and weight of more than 50 kg at screening, and a negative pregnancy test for women. A key exclusion criterion was a previous MVA vaccination. For the prime immunisation, participants received doses of 1 × 10 7 plaque-forming unit (PFU; low-dose group) or 1 × 10 8 PFU (high-dose group) MVA-MERS-S intramuscularly. A second identical dose was administered intramuscularly as a booster immunisation 28 days after first injection. As a control group for immunogenicity analyses, blood samples were drawn at identical study timepoints from six healthy adults, who did not receive any injections. The primary objectives of the study were safety and tolerability of the two dosage levels and reactogenicity after administration. Immunogenicity was assessed as a secondary endpoint by ELISA and neutralisation tests. T-cell immunity was evaluated by interferon-γ-linked enzyme-linked immune absorbent spot assay. All participants who were vaccinated at least once were included in the safety analysis. Immunogenicity was analysed in the participants who completed 6 months of follow-up. This trial is registered with ClinicalTrials.gov, NCT03615911, and EudraCT, 2014-003195-23 FINDINGS: From Dec 17, 2017, to June 5, 2018, 26 participants (14 in the low-dose group and 12 in the high-dose group) were enrolled and received the first dose of the vaccine according to their group allocation. Of these, 23 participants (12 in the low-dose group and 11 in the high-dose group) received a second dose of MVA-MERS-S according to their group allocation after a 28-day interval and completed follow-up. Homologous prime-boost immunisation with MVA-MERS-S revealed a benign safety profile with only transient mild-to-moderate reactogenicity. Participants had no severe or serious adverse events. 67 vaccine-related adverse events were reported in ten (71%) of 14 participants in the low-dose group, and 111 were reported in ten (83%) of 12 participants in the high-dose group. Solicited local reactions were the most common adverse events: pain was observed in 17 (65%; seven in the low-dose group vs ten in the high-dose group) participants, swelling in ten (38%; two vs eight) participants, and induration in ten (38%; one vs nine) participants. Headaches (observed in seven participants in the low-dose group vs nine in the high-dose group) and fatigue or malaise (ten vs seven participants) were the most common solicited systemic adverse events. All adverse events resolved swiftly (within 1-3 days) and without sequelae. Following booster immunisation, nine (75%) of 12 participants in the low-dose group and 11 (100%) participants in the high-dose group showed seroconversion using a MERS-CoV S1 ELISA at any timepoint during the study. Binding antibody titres correlated with MERS-CoV-specific neutralising antibodies (Spearman's correlation r=0·86 [95% CI 0·6960-0·9427], p=0·0001). MERS-CoV spike-specific T-cell responses were detected in ten (83%) of 12 immunised participants in the low-dose group and ten (91%) of 11 immunised participants in the high-dose group., Interpretation: Vaccination with MVA-MERS-S had a favourable safety profile without serious or severe adverse events. Homologous prime-boost immunisation induced humoral and cell-mediated responses against MERS-CoV. A dose-effect relationship was demonstrated for reactogenicity, but not for vaccine-induced immune responses. The data presented here support further clinical testing of MVA-MERS-S in larger cohorts to advance MERS vaccine development., Funding: German Center for Infection Research., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Aims: Drug-induced liver injury (DILI) is a heterogenous entity leading to liver damage. We have analysed the frequency, biochemical and histological patterns and clinical courses of DILI cases due to metamizole at our tertiary care centre in Hamburg, Germany., Methods: Consecutive patients with DILI who presented to our clinic were analysed retrospectively. Causes of acute hepatitis other than DILI were excluded., Results: In total, 154 DILI cases were admitted to our centre from 2008 to 2017. After phenprocoumon, metamizole was the second most frequent putative agent causing DILI (23 of all 154 DILI cases, 14,9%). The biochemical pattern on admission of metamizole-induced DILI cases was hepatocellular with median levels of alanine transaminase (779 U/L, 64-3532 U/L) by far exceeding median alkaline phosphatase levels (131 U/L, 42-578 U/L). In 17 of the 23 cases (74%) liver biopsy was performed. Moderate to severe inflammatory histological activity and severe centrilobular necrosis (>30%) was present in 76.5 and 35.3%, respectively. Metamizole was involved in 2 DILI cases progressing to acute liver failure, then receiving liver transplantation and still alive at time of assessment. Our data were supported by re-exposure in 4 patients. Furthermore, a database search for metamizole-induced liver injury in the European Medicines Agency's database identified about 300 reports on suspected metamizole-induced DILI in Europe., Conclusion: Elevation of liver enzymes or acute liver failure are not mentioned in the German drug label of metamizole as potential side effects. Our study reveals that in Germany and Europe, metamizole is a frequent and underrated agent causing DILI., (© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background:  Population-based data on the prevalence of and real-life treatment for the autoimmune liver diseases (AILD), primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH), are scarce, and such knowledge may help to improve patient care., Methods:  Data of 8.1 million individuals having health insurance with the "Techniker Krankenkasse," the largest German health insurer, were analyzed with regard to the prevalence of and prescribed medication for AILD in Germany from 2011 until 2014. Patients with viral hepatitis B infection (HBV) and alcoholic liver cirrhosis (ALC) served as control groups. Case definition was based on ICD codes., Results:  The prevalences of PBC and AIH were 36.9/100 000 inhabitants (95 % CI: 35.6-38.2) and 23.0/100 000 inhabitants (95 % CI: 22.0-24.0) in 2014, respectively. The prevalences of AILD increased from 2011 to 2014 (for PBC by 31 % and for AIH by 29 %), with the largest increase for male patients with PBC. In contrast, the prevalence of HBV declined while that of ALC remained stable. The analysis of prescribed real-life treatment revealed considerable deviations from standard treatment recommendations. Specifically, in older patients with PBC or AIH, undertreatment was common., Conclusion:  The prevalence of PBC and AIH based on ICD codes is increasing in Germany. The analysis of real-life treatment in this large and population-based cohort points to the unmet need to improve the implementation of treatment guidelines for autoimmune liver diseases in the broader medical community., Competing Interests: AK and RL are employees of the “Techniker Krankenkasse.” MS, AA, AWL, and CS do not have any conflicts of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background and Aims: Antibodies against soluble liver antigen/liver pancreas (anti-SLA/LP) are highly specific for autoimmune hepatitis (AIH) and have been linked with a more severe clinical course of the disease, frequent relapses after treatment withdrawal and worse outcome. To address definitely the clinical significance of anti-SLA/LP, we investigated a large number of anti-SLA/LP-positive and -negative patients followed in three referral centres., Methods: Prospectively collected data from 89 anti-SLA/LP-positive AIH patients (29 from Hamburg-Germany, 20 from Bologna-Italy and 40 from Larissa-Greece) were analysed retrospectively. Age- and sex-matched anti-SLA/LP-negative patients served as disease controls (n = 230; 1:2.5 ratio)., Results: In respect to baseline characteristics, anti-SLA/LP-positive patients were more frequently asymptomatic compared to anti-SLA/LP-negative (P < .05). However, anti-SLA/LP-positive patients did not differ from anti-SLA/LP-negative in terms of the overall response to treatment, disease progression and survival even though, they were less likely to achieve corticosteroid withdrawal (P < .05), needed longer treatment duration to achieve first complete response (P < .001) and relapsed more frequently after treatment withdrawal compared to anti-SLA/LP-negative patients (P = <.001)., Conclusions: We showed that anti-SLA/LP antibodies do not characterize a group of AIH patients with distinct features and cannot identify patients with a more severe form of the disease or worse survival. Most importantly, however, anti-SLA/LP-positive patients appear to require lifelong immunosuppression as they are less likely to achieve the cessation of corticosteroids and present higher relapse rates after treatment withdrawal. Therefore, close long-term monitoring should be advised in all anti-SLA/LP-positive patients after withdrawal of immunosuppressive treatment., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Chronic hepatitis delta virus (HDV) infection causes severe liver disease which often leads to cirrhosis and hepatocellular carcinoma (HCC). Aim of this study was to establish the disease severity and prognostic factors for disease outcome by analysing frequencies of clinical events and their correlation with baseline virological and biochemical parameters as well as interferon and nucleos(t)ide analogue treatment choice., Methods: We studied a single-centre cohort of 49 anti-HDAg-positive patients with HBsAg persistence for at least 6 months. Virological and biochemical parameters, interferon and nucleos(t)ide analogue treatment choice as well as clinical events during follow-up were analysed by retrospective chart review (mean follow-up time 3 years, range 0.25-7.67 years)., Results: Severe clinical events occurred in 11/49 hepatitis D patients, including HCC (8/49), death (8/49) or liver transplantation (2/49). HCCs only occurred secondary to liver cirrhosis and their event rates in this cohort of hepatitis D patients did not differ from a matched HBV mono-infected cohort with comparable frequency of liver cirrhosis. A stepwise multivariate logistic regression revealed low platelet count (p = 0. 0290) and older age (p = 0.0337) correlating most strongly with overall clinical events, while serum HDV RNA positivity at baseline did not correlate with any clinical outcome. Interferon-free but not nucleos(t)ide analogue-free patient care correlated with the occurrence of HCC at logistic regression, although only 3/18 interferon-treated patients demonstrated repeatedly negative HDV PCR results post therapy., Conclusions: Our data indicate that progressive liver disease at baseline plays a major role as predictive factor for overall clinical outcome of hepatitis D patients. In particular, HCC risk may not be underestimated in hepatitis D virus RNA negative hepatitis D patients with advanced liver fibrosis.

Background: Critically ill patients in the intensive care unit (ICU) are at high risk for developing Clostridioides difficile infections (CDI). Risk factors predicting their mortality or standardized treatment recommendations have not been defined for this cohort. Our goal is to determine outcome and mortality associated risk factors for patients at the ICU with CDI by evaluating clinical characteristics and therapy regimens., Methods: A retrospective single-centre cohort study. One hundred forty-four patients (0.4%) with CDI-associated diarrhoea were included (total 36.477 patients admitted to 12 ICUs from January 2010 to September 2015). Eight patients without specific antibiotic therapy were excluded, so 132 patients were analysed regarding mortality, associated risk factors and therapy regimens using univariate and multivariate regression., Results: Twenty-eight-day mortality was high in patients diagnosed with CDI (27.3%) compared to non-infected ICU patients (9%). Patients with non CDI-related sepsis (n = 40/132; 30.3%) showed further increase in 28-day mortality (45%; p = 0.003). Initially, most patients were treated with a single CDI-specific agent (n = 120/132; 90.9%), either metronidazole (orally, 35.6%; or IV, 37.1%) or vancomycin (18.2%), or with a combination of antibiotics (n = 12/132; 9.1%). Patients treated with metronidazole IV showed significantly longer duration of diarrhoea > 5 days (p = 0.006). In a multivariate regression model, metronidazole IV as initial therapy was an independent risk factor for delayed clinical cure. Immunosuppressants (p = 0.007) during ICU stay lead to increased 28-day mortality., Conclusion: Treatment of CDI with solely metronidazole IV leads to a prolonged disease course in critically ill patients.

Background: To evaluate clinical outcomes after either immediate or deferred initiation of antiretroviral therapy in HIV-1-infected patients, presenting late with pneumocystis pneumonia (PCP) or toxoplasma encephalitis (TE)., Methods: Phase IV, multicenter, prospective, randomized open-label clinical trial. Patients were randomized into an immediate therapy arm (starting antiretroviral therapy (ART) within 7 days after initiation of OI treatment) versus a deferred arm (starting ART after completing the OI-therapy). All patients were followed for 24 weeks. The rates of clinical progression (death, new or relapsing opportunistic infections (OI) and other grade 4 clinical endpoints) were compared, using a combined primary endpoint. Secondary endpoints were hospitalization rates after completion of OI treatment, incidence of immune reconstitution inflammatory syndrome (IRIS), virologic and immunological outcome, adherence to proteinase-inhibitor based antiretroviral therapy (ART) protocol and quality of life., Results: 61 patients (11 patients suffering TE, 50 with PCP) were enrolled. No differences between the two therapy groups in all examined primary and secondary endpoints could be identified: immunological and virologic outcome was similar in both groups, there was no significant difference in the incidence of IRIS (11 and 10 cases), furthermore 9 events (combined endpoint of death, new/relapsing OI and grade 4 events) occurred in each group., Conclusions: In summary, this study supports the notion that immediate initiation of ART with a ritonavir-boosted proteinase-inhibitor and two nucleoside reverse transcriptase inhibitors is safe and has no negative effects on incidence of disease progression or IRIS, nor on immunological and virologic outcomes or on quality of life.

Background: There are only few structured reports on inpatient management of a seasonal influenza epidemic., Objectives: A systematic description of a seasonal influenza patient population at a German university hospital to improve risk stratification and clinical care., Methods: In this monocentric, retrospective observational study of the 2017/2018 influenza season at the University Medical Center Hamburg-Eppendorf, patients with confirmed influenza infection were included., Results: Of all influenza swabs performed in the emergency department, 24% (n = 162/676) were positive. A total of 255 patients (median age 66 years) had an influenza infection (influenza A n = 79, influenza B n = 176); 27 (15.3%) were nosocomial infections. Of the 179 (70.2%) patients that were hospitalized, 51 (20%) received intensive medical care. Patients with subsequent need for intensive care had an elevated CRP level (69.5 mg/dl [SD 62.8] vs. 141.7 [SD 127.2] mg/dl) at the time of influenza diagnosis and more frequent infiltrates in X‑ray/CT of the thorax (n = 43 [33.6%] vs. n = 43 [84.3%]). Antiviral therapy with oseltamivir was administered for 74 (29.0%) patients and 11 (6.1%) patients were treated with extracorporeal membrane oxygenation (ECMO). Of the 23 (9.0%) patients who died, only four of them had been vaccinated (trivalent). Those four had an influenza B infection., Conclusion: The structured use of diagnostic tests (influenza PCR, X‑ray/CT chest and CRP) and antiviral therapy (oseltamivir) as well as targeted management of admission, intensive care capacities, and an increase in vaccination rates are important for improving patient care and optimizing the use of resources during seasonal influenza epidemics.

Background & Aims: Biliary strictures are common complications after orthotopic liver transplantation. Endoscopic retrograde cholangiography evolved as standard and percutaneous transhepatic cholangiodrainage as alternative therapy. This study analysed predictors of long-term success of biliary strictures after endoscopic retrograde cholangiography and/or percutaneous transhepatic cholangiodrainage and its impact on patient survival., Methods: All adult patients with biliary strictures receiving endoscopic retrograde cholangiography and/or percutaneous transhepatic cholangiodrainage between 2009 and 2015 at the University Medical Center Hamburg-Eppendorf were retrospectively analysed. Potential predictors of long-term success (≥12 months) were identified by univariate and logistic regression analyses. Patient survival was analysed by Kaplan-Meier method and log-rank test., Results: Hundred and sixteen patients were treated with endoscopic retrograde cholangiography and/or percutaneous transhepatic cholangiodrainage, including 67 patients with anastomotic strictures, 22 with nonanastomotic strictures and 27 with both stricture types. Eighty-five patients received endoscopic retrograde cholangiography, 17 percutaneous transhepatic cholangiodrainage and 14 both techniques. Long-term success was achieved in 60 patients (52%). Predictors of treatment failure were a preinterventional C-reactive protein >8 g/dL in anastomotic strictures (P = 0.039) and a body mass index ≤21 kg/m 2 in nonanastomotic strictures (P = 0.021). In patients who received endoscopic retrograde cholangiography only, balloon dilatation of anastomotic strictures with larger diameters favoured success (P = 0.015). Achievement of long-term success was associated with prolonged patient survival in anastomotic strictures (P = 0.036) and nonanastomotic strictures (P = 0.025), but not in combined strictures (P = 0.739)., Conclusion: In post-orthotopic liver transplantation biliary strictures treated by endoscopic retrograde cholangiography and/or percutaneous transhepatic cholangiodrainage, patient BMI and preinterventional C-reactive protein may influence prognosis. Endoscopic retrograde cholangiography with larger balloon diameter may favour success in anastomotic strictures. Long-term success by endoscopic retrograde cholangiography and/or percutaneous transhepatic cholangiodrainage is associated with superior survival in patients with anastomotic strictures and nonanastomotic strictures only., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction:  Proton pump inhibitors (PPI) are one of the most frequently prescribed drugs worldwide. In particular, in patients with liver cirrhosis prescription rates up to 78 % have been reported. PPI may be a risk factor for nosocomial infections, spontaneous bacterial peritonitis and onset of hepatic encephalopathy. Aim of this survey was to assess the prescription practice of PPI in patients with cirrhosis in Germany., Methods:  We performed a web-based survey among hepatologists and gastroenterologists. The invitations for the survey have been sent out via the newsletter of German gastroenterological societies (DGVS, BVGD and AUG)., Results:  61 persons have participated in the survey. Overall, high PPI prescription rates have been reported (58 % in inpatient and 44 % in outpatient setting). Almost half of the respondents reported that PPI are frequently prescribed without clear indication (such as abdominal discomfort). One third reported that the PPI therapy could be stopped after critical evaluation of the indication. 55 % of the respondents stated that according to their estimates PPI are associated with adverse reactions. Bleeding was only very rarely seen after termination of PPI treatment., Conclusion:  PPI are frequently prescribed among patients with liver cirrhosis in Germany. Prescribers are aware of an unclear risk-benefit ratio. Further prospective data are urgently needed to increase evidence regarding indication and duration of PPI therapy in patients with cirrhosis., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background & Aims: Routine HEV testing of blood products has recently been implemented in Great Britain and the Netherlands. The relevance of transfusion-transmitted HEV infections is still controversially discussed in Europe., Methods: All blood donations at the University Medical Center Hamburg-Eppendorf were prospectively tested for HEV RNA by pooled PCR from October 2016 to May 2017. Reactive samples were individually retested. Additionally, stored samples from previous donations of positive donors were tested to determine the duration of HEV viraemia. HEV RNA-positive donors and a control cohort were asked to answer a questionnaire., Results: Twenty-three out of 18,737 HEV RNA-positive donors were identified (0.12%). Only two of the positive donors (8.7%) presented with elevated aminotransferases at time of donation (alanine aminotransferase: 192 and 101 U/L). The retrospective analysis of all positive donors revealed that four asymptomatic donors had been HEV viraemic for up to three months with the longest duration of HEV viraemia exceeding four months. Despite the HEV-testing efforts, 14 HEV RNA-positive blood products were transfused into 12 immunocompromised and two immunocompetent patients. One recipient of these products developed fatal acute-on-chronic liver failure complicated by Pseudomonas septicemia. The questionnaire revealed that HEV RNA-positive donors significantly more often consumed raw pork meat (12 out of 18; 67%) than controls (89 out of 256; 35%; p = 0.01). In two donors, undercooked pork liver dishes were identified as the source of infection. HEV genotyping was possible in 7 out of 23 of HEV viraemic donors and six out of seven isolates belonged to HEV Genotype 3, Group 2., Conclusions: Prolonged HEV viraemia can be detected at a relatively high rate in Northern German blood donors, leading to transfusion-transmitted HEV infections in several patients with the risk of severe and fatal complications. Eating raw pork tartare represented a relevant risk for the acquisition of HEV infection., Lay Summary: The relevance of transfusion-transmitted hepatitis E virus infections has been discussed controversially. Herein, we present the first report on routine hepatitis E virus screening of blood donations at a tertiary care centre in Germany. Hepatitis E viraemia was found at a relatively high rate of 0.12% among blood donors, which represents a relevant transfusion-related risk for vulnerable patient populations., (Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Many patients with autoimmune hepatitis (AIH) develop steroid-specific side effects or require doses of steroids that are unacceptable for long-term treatment. We investigated the efficacy of budesonide as an alternative steroid for patients previously treated with prednisolone who developed side effects or were unable to reduce their dose of prednisolone below acceptable levels. We also report the effects of more than 12 months of budesonide treatment in a large cohort of patients with AIH., Methods: We performed a retrospective analysis of data from 60 patients (51 female) with AIH who were treated initially with prednisolone (mean time, 47 mo) but then switched to budesonide, managed at a single center in Germany from 2001 through June 2016. Patients were evaluated after 6 months, 12 months, 24 months, 36 months, and at the last follow-up evaluation; response to treatment with budesonide was assessed based on normal serum levels of aminotransferases and IgG (biochemical response)., Results: Thirty patients were switched to budesonide therapy because of prednisolone-induced side effects and 30 patients switched because of prednisolone dependency. Overall, a biochemical response was detected in 55% of patients after 6 months of budesonide treatment, in 70% after 12 months, and in 67% after 24 months. At the last follow-up evaluation (mean time, 63 mo) 23 patients (38%) still were receiving budesonide treatment. Fifteen patients (25%) had switched back to prednisolone therapy because of insufficient response to budesonide or its side effects. Fifteen patients with osteopenia at the beginning of budesonide treatment were followed up and evaluated by dual-energy X-ray absorptiometry. After a median of 24 months of budesonide treatment, bone mineral density had improved in 6 patients, remained stable in 8 patients, and worsened in 1 patient., Conclusions: We performed a retrospective analysis of patients with AIH that confirmed the therapeutic value of budesonide beyond 12 months of treatment in patients who are intolerant to or dependent on prednisolone. Although budesonide-induced side effects appear to be mild in real life, effectiveness was limited in a considerable proportion of patients; close monitoring is advised., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: The frequency of autochthonous hepatitis E virus (HEV) infections in Western countries has increased since the millennium, probably due to a higher awareness for HEV. The aim of this study was to analyze the epidemiological situation and regional distribution of HEV in comparison to hepatitis A - D in Germany., Methods: Data of the reported cases, patients' travel histories, and the regional distribution of hepatitis A - E virus infections from 2001 to 2017 were extracted from databases of the Robert Koch Institute. The number of publications per year on each hepatitis virus was used as a surrogate parameter for scientific awareness., Results: The incidence of HEV infections increased from 31 reported cases in 2001 to 1991 cases in 2016 with a rate of autochthonous HEV infections of 44.4 % in 2001 and 83.9 % in 2016. In 2016, the HEV incidence was 4.4/100 000 in Eastern Germany and 2.0/100 000 in Western Germany. From 2001 to 2016, the numbers of hepatitis A and C virus infections decreased, while the number of hepatitis B virus infections initially decreased followed by an increase since 2014. The incidence of hepatitis D virus infections remained low. The incidence rates of hepatitis A - D virus infections were comparable between Eastern and Western Germany in 2016. There was a strong correlation between publications on HEV and reported HEV cases (Pearson r = 0.9803, p < 0.01)., Conclusions: Especially in Eastern Germany, but also in Western Germany, the rate of reported HEV cases and the scientific awareness for this disease increased strongly since 2001., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background  The prevalence of chronic liver diseases is high in developed countries, and the leading causes are amenable to prevention. The German Lebertag is to increase awareness of the burden of chronic liver diseases in the general public. We performed a pilot study using transient elastography with liver stiffness measurement (LSM) and the controlled attenuation parameter (CAP) as a screening tool for previously unrecognized liver diseases. Patients and methods  LSM and CAP was performed in 60 individuals, and participants filled in a questionnaire reporting basic characteristics and past medical history. Results  Median LSM and CAP values were within the normal range. Participants with self-reported diabetes mellitus had significantly elevated LSM (p = 0.02) and CAP values (p = 0.002). Participants with a BMI > 30 kg/m 2 or dyslipidemia had significantly elevated CAP values (p = 0.007 and p = 0.01, respectively) with normal LSM values. Overall, 35 % of participants had elevated CAP values, indicating a high prevalence of hepatic steatosis. Discussion  In a German pilot study, diabetes mellitus was a key risk factor for increased LSM and CAP values. Prevalence of steatosis was high and comparable to other Western countries. Transient elastography is a valuable tool to identify patients with increased risk for metabolic liver diseases. In people without risk factors, LSM and CAP values were within the normal range, indicating that screening for chronic liver injury was not warranted., Competing Interests: Conflict of Interest: The authors declare that they have no conflict of interest. Funding This study was funded by the Deutsche Forschungsgemeinschaft (SFB 841)., (© Georg Thieme Verlag KG Stuttgart · New York.)

As the number of refugees rises, medical care for refugees, asylum seekers and people with unclear residence status becomes a priority task for our health system. While access to health care is restricted for these groups of people in many German states, Hamburg provides unrestricted access to healthcare for refugees by handing out health insurance cards on arrival. Daily practice shows, however, that adequate medical care is still not always easy to achieve. In this case series we demonstrate that barriers to health care still exist on many levels. We discuss these barriers and further propose strategies to improve and to secure access to adequate health care., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: There are only limited data on sofosbuvir-based treatment regimens in hepatitis C virus (HCV) genotype 4-infected patients., Aims: To evaluate safety and efficacy of sofosbuvir-based triple-therapy in HCV genotype 4 infection., Methods: All HCV genotype 4-infected patients who started sofosbuvir-based triple-therapy at our two centres between January and June 2014 were prospectively included (N=24) and compared to genotype 4 patients treated with peginterferon/ribavirin between January 2001 and December 2012 (N=63)., Results: The demographics in the sofosbuvir group and the controls were comparable (males 87.5% and 82.5%; mean age 46.7±9.0 years and 42.0±9.8 years, respectively). Sustained virological response was achieved in 83.3% in the sofosbuvir group and in 47.6% of controls (P=0.003). Fatigue (P=0.007), flu-like (P=0.015), gastrointestinal (P<0.001), dermatologic (P<0.001) and psychiatric symptoms (P=0.022) were more common in the control group., Conclusions: In our real-life cohort, sofosbuvir-based triple therapy confirmed its high efficacy and safety for chronic genotype 4 hepatitis C., (Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background & Aims: From May through July 2011 in northern Germany, there was a large outbreak of hemolytic uremic syndrome and bloody diarrhea, which was related to infections from Shiga toxin-producing Escherichia coli O104 (STEC). We investigated the depression, posttraumatic symptoms, fatigue, and health-related quality of life among patients within the first 6 months after STEC infection and aimed to identify factors associated with poor outcome., Methods: In a cohort study, we performed baseline assessments of 389 patients (69% female) 3 months after STEC infection (82 ± 36 days) and follow-up assessments of 308 of the patients 6 months afterward (199 ± 17 days). Data were collected at 13 hospitals in northern Germany. Patients completed validated self-report scales and a diagnostic interview., Results: At baseline, hemolytic uremic syndrome was diagnosed in 31% of the patients. Six months after the infection, mean self-reported severity of depression and posttraumatic symptoms and fatigue were significantly greater than in the general population, and the mean score from the mental component of health-related quality of life survey was significantly lower than average. Posttraumatic stress disorder had recently developed in 3% of patients (95% confidence interval, 1%-5%), and 43% of patients had clinically relevant fatigue (95% confidence interval, 41%-45%). The most important baseline factors associated with poor psychological health 6 months after STEC infection were previous traumatic events, neuroticism, and low social support (all P < .05)., Conclusions: Six months after the major outbreak of STEC infection in northern Germany, a substantial number of patients had poor psychological health, persistent fatigue, and impaired quality of life. For future outbreaks, patients' premorbid risk factors should be considered, which might minimize the long-term effects of infections on mental health., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Primary sclerosing cholangitis (PSC) is associated with an increased risk of hepatobiliary malignancies. However, little is known about the incidence of hepatocellular carcinoma (HCC) among patients with PSC; current recommendations on screening these patients for HCC are conflicting. We investigated the risk of HCC in patients with PSC with cirrhosis., Methods: We performed a retrospective study of patients with well-defined PSC from 2 large-volume tertiary care centers in Germany; data were collected from periods of up to 33 years. Liver cirrhosis was based on histology results or the presence of ascites, esophageal varices, or transient elastography values greater than 14 kPa. Statistical analysis was performed using the Kaplan-Meier method and the Cox proportional hazard model. Data from 509 patients (67% male), with a total of 4202 patients-years, were included in the final analysis., Results: We identified 119 patients with cirrhosis. During 292 patient-years, none of these patients developed HCC. Most HCCs were identified incidentally at the time of liver transplantation. We therefore reviewed data on liver explants from 140 patients who underwent transplantation; none were found to contain HCC. In contrast to the low numbers of HCCs among patients with PSC, 35 patients developed cholangiocarcinoma, 3 patients developed gallbladder cancer, and 9 patients developed colorectal cancer., Conclusions: Based on a retrospective analysis of more than 500 patients with PSC, we confirm their high risk for hepatobiliary malignancies. However, the risk of HCC, even among patients with cirrhosis, seems to be low--regular HCC surveillance may not be warranted., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Autoimmune hepatitis (AIH) is an uncommon autoimmune liver disease of unknown etiology. We used a genome-wide approach to identify genetic variants that predispose individuals to AIH., Methods: We performed a genome-wide association study of 649 adults in The Netherlands with AIH type 1 and 13,436 controls. Initial associations were further analyzed in an independent replication panel comprising 451 patients with AIH type 1 in Germany and 4103 controls. We also performed an association analysis in the discovery cohort using imputed genotypes of the major histocompatibility complex region., Results: We associated AIH with a variant in the major histocompatibility complex region at rs2187668 (P = 1.5 × 10(-78)). Analysis of this variant in the discovery cohort identified HLA-DRB1*0301 (P = 5.3 × 10(-49)) as a primary susceptibility genotype and HLA-DRB1*0401 (P = 2.8 × 10(-18)) as a secondary susceptibility genotype. We also associated AIH with variants of SH2B3 (rs3184504, 12q24; P = 7.7 × 10(-8)) and CARD10 (rs6000782, 22q13.1; P = 3.0 × 10(-6)). In addition, strong inflation of association signal was found with single-nucleotide polymorphisms associated with other immune-mediated diseases, including primary sclerosing cholangitis and primary biliary cirrhosis, but not with single-nucleotide polymorphisms associated with other genetic traits., Conclusions: In a genome-wide association study, we associated AIH type 1 with variants in the major histocompatibility complex region, and identified variants of SH2B3and CARD10 as likely risk factors. These findings support a complex genetic basis for AIH pathogenesis and indicate that part of the genetic susceptibility overlaps with that for other immune-mediated liver diseases., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background/aims: Mini-laparoscopy (ML) allows macroscopic assessment and biopsy under direct vision and therefore is a valuable technique in the diagnosis of liver disease. Herein we report procedure-related complications and risk factors., Methods: A total of 2731 consecutive patients underwent diagnostic ML at two university hospitals (June 1996-December 2007). ML was performed using standard technique with a 1.9mm optical instrument. Coagulation of the liver biopsy site was performed with APC. The following variables were analysed as risk factors for complications: platelet count (<50/nL), international normalized ratio (INR) (>1.5), Cirrhosis, signs of portal hypertension, prior abdominal surgery., Results: Major complications occurred in 1.0% (n=27) of patients and these were, delayed bleeding from the liver biopsy site or abdominal wall (in 0.7% of patients) and intestinal perforation (in 0.3% of patients). Two patients died after severe haemorrhage (mortality 0.07%); the other patients recovered without sequelae. Bleeding risk was increased in patients with low platelets (OR=6.1), increased INR (OR=8.9), cirrhosis (OR=1.9) and portal hypertension (OR=2.1). Logistic regression showed a significant correlation only for the concurrence of low platelets and increased INR (P = 0.001; OR=14.1); bootstrap analysis identified INR >1.5 as significant predictor (P = 0.0002). Prior abdominal surgery did not carry a significant risk for intestinal perforation (OR=1.1; P = 0.142), unless abdominal adhesions were present (OR=9.5; P = 0.0002). None of the patients required surgery for intestinal perforation., Conclusion: Mini-laparoscopy is a diagnostic technique with a low complication rate. However, in patients with increased INR, low platelets or after extensive abdominal surgery, complications may occur in up to 5%., (© 2012 John Wiley & Sons A/S.)

Objectives: Hepatitis A virus (HAV) or hepatitis B virus (HBV) superinfection is associated with an increased mortality in patients with chronic liver diseases (CLD). Despite official recommendations, it was reported that the vaccination rate against HAV is low in patients with chronic hepatitis C infection. To evaluate the situation in patients with autoimmune liver diseases, we conducted a retrospective cohort study., Methods: Susceptibility to HAV and HBV infections, course of HAV and HBV infections, vaccination rates against HAV and HBV, and efficacy of hepatitis A/B vaccines were evaluated by antibody testing in 225 patients with autoimmune liver diseases during 1,677 person-years., Results: Susceptibility to HAV/HBV infection was 51/86%. Incidence of HAV/HBV infection was 1.3/1.4 per 1,000 person-years. One HAV infection occurred, but the patient recovered spontaneously. Two patients were HBV-infected after receiving an anti-HBc-positive (antibody to hepatitis B core antigen) donor graft during orthotopic liver transplantation, and one of them developed chronic HBV infection. Vaccination rates were 11% (HBV) and 13% (HAV), respectively. Seventy-six percent of the vaccinated patients (HBV vaccine) developed anti-HBs (antibody to hepatitis surface antigen) >or=10 UI/L. Ten out of 13 vaccinated patients, showing a low or nonresponse to hepatitis B vaccine, had concomitant immunosuppressive therapy. Anti-HAV was detectable in all patients after administration of HAV vaccine., Conclusions: Patients with autoimmune liver diseases have a high susceptibility to HAV and HBV infections. Vaccination rates are low in this patient cohort and efficacy of hepatitis B vaccine is reduced due to immunosuppressive therapy. Improving adherence to vaccine recommendations is essential to prevent HAV and HBV infections in patients with autoimmune liver diseases.

Aim: To report on our large German collective and updated data of 142 patients with autoimmune hepatitis (AIH) type 1., Methods: Key investigations performed were liver biopsy, serum autoantibodies as well as serum markers such as IgG and elevated transaminases. Antinuclear antigen (ANA) and smooth muscle antigen (SMA) autoantibodies characterized type 1 AIH. Type 3 (AIH) was solely characterized by the occurrence of soluble liver antigen/liver-pancreas antigen (SLA/LP) autoantibodies either with or without ANA or SMA autoantibodies., Results: Most prevalent HLAs were A2 (68 patients, 48%), B8 (63 patients, 44%), C7 (90 patients, 63%), DR3 (49 patients, 38%), DR4 (49 patients, 38%) and DQ2 (42 patients, 30%). Compared to the Italian and North American patients, we found fewer patients with a DQ2 subtype. Furthermore, the B8-DR3-DQ2 human leucocyte antigen (HLA) was also less prominent compared to the North American patients. However, prevalences of B8, DR3, DR4, DR7, DR11 and DR13 were comparable to the Italian and North American patients. Furthermore, we report on an additional subgroup of patients with SLA/LP positive AIH. Generally, in this subgroup of patients the same HLA subtypes were favoured as the AIH type 1., Conclusion: Although HLA subtypes were comparable between these three collectives, the German patients were distinct from the Italian and North American patients with respect to DQ2 and from the North American patients with respect to B8-DR3-DQ2 HLA. A clinical correlation, e.g. difference in severity or treatability of AIH type 1, has yet to be determined.