Als die Geschichte laufen lernte – Spielfilme als historische Quelle? Das Beispiel sowjetischer Werke der dreißiger Jahre

1. Die "wichtigste aller Künste" 2. Das Wirkliche im Fiktiven und das Fiktive im Wirklichen 3. Der totalitäre Film? 4. Filmanalyse 5. Filmfundorte 6. Bibliographi

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH,non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least oneaccompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpointsfor the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes

NASH limits anti-tumour surveillance in immunotherapy-treated HCC.

Hepatocellular carcinoma (HCC) can have viral or non-viral causes1-5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+ T cells or TNF neutralization, suggesting that CD8+ T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment

Diplomatie als interkulturelle Kommunikation

Am 12. Oktober 1960 ergriff Nikita Sergeevič Chruščev in der UNO während der Rede des philippinischen Delegierten Lorenzo Sumolong seinen Schuh, schlug damit auf seinen Tisch und ereiferte sich: „Warum darf dieser Nichtsnutz, dieser Speichellecker, dieser Fatzke, dieser Imperialistenknecht und Dummkopf – warum darf dieser Lakai der amerikanischen Imperialisten hier Fragen behandeln, die nicht zur Sache gehören?“ Chruščev war zunächst mit seinem Auftritt sehr zufrieden – er berichtete seinem Berater Oleg Trojanovskij, er habe etwas verpasst; sie hätten großen Spaß gehabt. Die sowjetische Presse verschwieg den Vorfall, während sich die westliche über die „Schusterdiplomatie“ halb ereiferte, halb amüsierte. Interessant ist, dass hier vollkommen unterschiedliche Vorstellungen von „Diplomatie“ zum Ausdruck kamen. Während der konsternierte Chruščev meinte, die UNO sei ein Parlament wie das House of Commons in London, wo es zur Kultur des Hauses gehöre, durch Raunen, Rufen und Gesten seinen Unmut kundzutun, fand die westliche diplomatische Welt ihr Urteil bestätigt, dass der sowjetische Partei- und Regierungschef im besten Fall ein Politclown, im schlechtesten einfach unzurechnungsfähig sei. Der berühmte Vorfall in der UNO macht deutlich, dass auf westlicher Seite eine klare Norm diplomatischen Verhaltens existierte, an der Chruščev gemessen wurde, während dieser experimentierte, improvisierte und etwaige Normen ignorierte

A Unifying Framework For Hybrid Planning And Scheduling

Abstract. Many real-world application domains that demand planning and scheduling support do not allow for a clear separation of these capabilities. Typically, an adequate mixture of both methodologies is required, since some aspects of the underlying planning problem imply consequences on the scheduling part and vice versa. Several integration efforts have been undertaken to couple planning and scheduling methods, most of them using separate planning and scheduling components which iteratively exchange partial solutions until both agree on a result. This paper presents a framework that provides a uniform integration of hybrid planning –the combination of operator based partial order planning and abstraction based hierarchical task network planning – and a hierarchical scheduling approach. It is based on a proper formal account of refinement planning, which allows for the formal definition of hybrid planning, scheduling, and search strategies. In a first step, the scheduling functionality is used to produce plans that comply with time restrictions and resource bounds. We show how the resulting framework is thereby able to perform novel kinds of search strategies that opportunistically interleave what used to be separate planning and scheduling processes.

Dealing with continuous resources in AI planning

Abstract. This paper presents an approach towards probabilistic planning with continuous resources. It adopts stochastic concepts for continuous probabilities and integrates them into a STRIPS-based planning framework. The approach enables the construction of plans that are guaranteed to meet certain probability thresholds w.r.t. the consumption of critical resources. Furthermore, the consumption probabilities of multiple resources can be accumulated and thus an overall probability for a successful execution of an aggregate plan can be computed. We extend our approach to HTN-based planning and show how heuristics can be derived that lead to plans with a minimized average value/variance of their overall resource consumption.

From abstract crisis to concrete relief – A preliminary report on combining state abstraction and HTN planning

Abstract. Flexible support for crisis management can definitely be improved by making use of advanced planning capabilities. However, the complexity of the underlying domain often causes intractable efforts in modeling the domain as well as a huge search space to be explored by the system. A way to overcome these problems is to impose a structure not only according to tasks but also according to relationships between and properties of the objects involved, thereby using so-called decomposition axioms. We outline the prototype of a system that is capable of tackling planning for complex application domains. It is based on a well-founded combination of action and state abstractions. The paper presents the basic techniques and provides a formal semantic foundation of the approach. It introduces the planning system and illustrates its underlying principles by examples taken from the crisis management domain used in our ongoing project.

On the Identification and Use of Hierarchical Resources in Planning and Scheduling

Many real-world planning applications have to deal with resource allocation problems, and so does planning in the domain of crisis management assistance. In order to support resource allocation in these kind of applications, we present a new approach to the integration of scheduling capabilities and planning. The proposed methodology relies on a hybrid planner, which combines action and state abstraction by integrating hierarchical task network (HTN) planning and state based partial order causal link (POCL) planning into a common framework. We extend the abstraction mechanism of the planner to different kinds of abstraction for resources, namely subsumption, approximation, qualification, and aggregation