Self-Learning Longitudinal Control for On-Road Vehicles

Fahrerassistenzsysteme (Advanced Driver Assistance Systems) sind ein wichtiges Verkaufsargument für PKWs, fordern jedoch hohe Entwicklungskosten. Insbesondere die Parametrierung für Längsregelung, die einen wichtigen Baustein für Fahrerassistenzsysteme darstellt, benötigt viel Zeit und Geld, um die richtige Balance zwischen Insassenkomfort und Regelgüte zu treffen. Reinforcement Learning scheint ein vielversprechender Ansatz zu sein, um dies zu automatisieren. Diese Klasse von Algorithmen wurde bislang allerdings vorwiegend auf simulierte Aufgaben angewendet, die unter idealen Bedingungen stattfinden und nahezu unbegrenzte Trainingszeit ermöglichen. Unter den größten Herausforderungen für die Anwendung von Reinforcement Learning in einem realen Fahrzeug sind Trajektorienfolgeregelung und unvollständige Zustandsinformationen aufgrund von nur teilweise beobachteter Dynamik. Darüber hinaus muss ein Algorithmus, der in realen Systemen angewandt wird, innerhalb von Minuten zu einem Ergebnis kommen. Außerdem kann das Regelziel sich während der Laufzeit beliebig ändern, was eine zusätzliche Schwierigkeit für Reinforcement Learning Methoden darstellt. Diese Arbeit stellt zwei Algorithmen vor, die wenig Rechenleistung benötigen und diese Hürden überwinden. Einerseits wird ein modellfreier Reinforcement Learning Ansatz vorgeschlagen, der auf der Actor-Critic-Architektur basiert und eine spezielle Struktur in der Zustandsaktionswertfunktion verwendet, um mit teilweise beobachteten Systemen eingesetzt werden zu können. Um eine Vorsteuerung zu lernen, wird ein Regler vorgeschlagen, der sich auf eine Projektion und Trainingsdatenmanipulation stützt. Andererseits wird ein modellbasierter Algorithmus vorgeschlagen, der auf Policy Search basiert. Diesem wird eine automatisierte Entwurfsmethode für eine inversionsbasierte Vorsteuerung zur Seite gestellt. Die vorgeschlagenen Algorithmen werden in einer Reihe von Szenarien verglichen, in denen sie online, d.h. während der Fahrt und bei geschlossenem Regelkreis, in einem realen Fahrzeug lernen. Obwohl die Algorithmen etwas unterschiedlich auf verschiedene Randbedingungen reagieren, lernen beide robust und zügig und sind in der Lage, sich an verschiedene Betriebspunkte, wie zum Beispiel Geschwindigkeiten und Gänge, anzupassen, auch wenn Störungen während des Trainings einwirken. Nach bestem Wissen des Autors ist dies die erste erfolgreiche Anwendung eines Reinforcement Learning Algorithmus, der online in einem realen Fahrzeug lernt

Self-Learning Longitudinal Control for On-Road Vehicles

Reinforcement Learning is a promising tool to automate controller tuning. However, significant extensions are required for real-world applications to enable fast and robust learning. This work proposes several additions to the state of the art and proves their capability in a series of real world experiments

Pro/Anti-Inflammatory Cytokine Imbalance in Postischemic Left Ventricular Remodeling

Objectives. Cytokines play an important role in left ventricular remodeling consequent to myocardial ischemia. The aim of this study was to correlate cytokine production and lymphocyte apoptosis to post-ischemic left ventricular remodeling in patients affected by acute myocardial infarction (AMI) undergoing primary cutaneous angioplasty (PCI). Methods. In 40 patients, affected by AMI and undergoing PCI, we evaluated peripheral blood mononuclear cells (PBMCs), tumor necrosis factor-alpha (TNF-α) and interleukin 10 (IL10) production and apoptosis on day 1, day 3, day 7, 1 month and 6 months after PCI. Patients were divided into two subgroups of remodeling or not remodeling by echocardiographic criteria. Results. In the subgroup of remodeling patients, at each timepoint TNF-α production was increased significantly in comparison with the subgroup of not remodeling patients. IL10 production was statistically lower in remodeling subjects than in not remodeling ones 1 and 6 months after reperfusion. There were no differences between the two groups as regards lymphomonocyte apoptosis. Conclusions. We found an increased production of pro-inflammatory cytokine TNF-α and a corresponding decrease of anti-inflammatory/regulatory cytokine IL10 in remodeling patients and we concluded that this cytokine imbalance resulted in pro-inflammatory effects which might contribute to the progression of left ventricular remodeling

No evidence of NRAS mutation in squamous cell anal carcinoma (SCAC)

Epidermal growth factor receptor (EGFR) is usually expressed in squamous cell anal carcinoma (SCAC) and anti-EGFR agents could represent a valid treatment strategy, also considering that KRAS and BRAF mutations are rare events in this type of cancer. However, no data are available on NRAS status in SCAC. In this study we analyzed NRAS status (exons 2-4) by Pyrosequencing in a case series of 50 SCAC patients previously characterized in our laboratory for KRAS, BRAF, PIK3CA mutations and HPV and HIV infections. We found no mutation in NRAS gene. These results confirm that since the principal anti-EGFR resistance mechanisms are almost absent in SCAC, anti-EGFR agents should be considered for the treatment of this type of cancer

A case of acquired factor XIII deficiency secondary to plasmablastic lymphoma

Acquired factor XIII (FXIII) deficiency is an extremely rare and potentially fatal bleeding disorder. Immune-mediated FXIII deficiency is due to the development of anti-FXIII autoantibodies which may develop with concomitant conditions that cause immune dysregulation such as malignancies or autoimmune disorders. Clinical presentation includes delayed post-operative bleeding or spontaneous soft tissue hematomas and/or cerebral bleeding. Since screening coagulation laboratory tests (prothrombin time, activated partial thromboplastin time, and fibrinogen) are typically normal, acquired FXIII deficiency is likely to be overlooked and underdiagnosed. The management of immune-mediated FXIII deficiency is based on hemostatic therapy, autoantibody removal and eradication of the underlying etiology; however, no treatment guidelines are still available. Here we report a case of acquired FXIII deficiency associated with plasmablastic lymphoma, in order to raise awareness of this rare bleeding disorder and consent prompt life-saving management

High doses of CpG oligodeoxynucleotides stimulate a tolerogenic TLR9–TRIF pathway

CpG-rich oligodeoxynucleotides activate the immune system, leading to innate and acquired immune responses. The immune-stimulatory effects of CpG-rich oligodeoxynucleotides are being exploited as a therapeutic approach. Here we show that at high doses, CpG-rich oligodeoxynucleotides promote an opposite, tolerogenic response in mouse plasmacytoid dendritic cells in vivo and in a human in vitro model. Unveiling a previously undescribed role for TRIF and TRAF6 proteins in Toll-like receptor 9 (TLR9) signalling, we demonstrate that physical association of TLR9, TRIF and TRAF6 leads to activation of noncanonical NF-κB signalling and the induction of IRF3- and TGF-β-dependent immune-suppressive tryptophan catabolism. In vivo, the TLR9-TRIF circuit--but not MyD88 signalling--was required for CpG protection against allergic inflammation. Our findings may be relevant to an increased understanding of the complexity of Toll-like receptor signalling and optimal exploitation of CpG-rich oligodeoxynucleotides as immune modulators

Safety of COVID-19 mRNA vaccination in patients with history of acquired hemophilia A: a case series

Coronavirus disease 2019 (COVID-19) following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection called for a specific and massive vaccination campaign. Acquired hemophilia A (AHA) is a potential life-threatening coagulopathy. Hematological- targeted autoimmune conditions including immune thrombocytopenia, vaccine-induced thrombotic thrombocytopenia and AHA emerged during large-scale vaccination against SARS-CoV-2 and contributed to vaccination hesitation. The aim of the present study was to evaluate the putative recurrence of AHA after vaccination against SARS-CoV-2 with mRNA vaccines (BNT162b2 and mRNA- 1273) in patients with relatively recent history of AHA. Thirteen patients (8 women and 5 men, mean age = 63.1±16.6 years) with AHA in the previous two-to-five years were enrolled in the study. Platelet count, prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen and Factor VIII levels were evaluated 48 hours prior to each vaccine dose and 10 days post-vaccination. Clinical self-assessment and remote video visits were performed in the presence of even minor hemorrhagic signs. No major bleeding events were detected at any time-point, including evaluation at 30 days after the 3rd vaccine dose. No significant hemorrhagic changes were observed, in particular no thrombocytopenia and/or significant alterations in PTT and Factor VIII emerged across subjects. Patients with a previous history of AHA of various etiology do not seem to have an increased recurrence risk after a COVID-19 vaccination course of 3 doses with either mRNA vaccine. This finding supports this specific safety aspect in the face of the possible continuation of the vaccination campaign based on the trend of the COVID-19 pandemic

Promoter methylation of tumor suppressor genes in pre-neoplastic lesions; Potential marker of disease recurrence

Background: Epigenetic alterations of specific genes have been reported to be related to colorectal cancer (CRC) transformation and would also appear to be involved in the early stages of colorectal carcinogenesis. Little data are available on the role of these alterations in determining a different risk of colorectal lesion recurrence. The aim of the present study was to verify whether epigenetic alterations present in pre-neoplastic colorectal lesions detected by colonoscopy can predict disease recurrence. Methods. A retrospective series of 78 adenomas were collected and classified as low (35) or high-risk (43) for recurrence according to National Comprehensive Cancer Network guidelines. Methylation alterations were analyzed by the methylation-specific multiplex ligation probe assay (MS-MLPA) which is capable of quantifying methylation levels simultaneously in 24 different gene promoters. MS-MLPA results were confirmed by pyrosequencing and immunohistochemistry. Results: Higher levels of methylation were associated with disease recurrence. In particular, MLH1, ATM and FHIT gene promoters were found to be significantly hypermethylated in recurring adenomas. Unconditional logistic regression analysis used to evaluate the relative risk (RR) of recurrence showed that FHIT and MLH1 were independent variables with an RR of 35.30 (95% CI 4.15-300.06, P = 0.001) and 17.68 (95% CI 1.91-163.54, P = 0.011), respectively. Conclusions: Histopathological classification does not permit an accurate evaluation of the risk of recurrence of colorectal lesions. Conversely, results from our methylation analysis suggest that a classification based on molecular parameters could help to define the mechanisms involved in carcinogenesis and prove an effective method for identifying patients at high risk of recurrence

Genetic predisposition and induced pro-inflammatory/pro-oxidative status may play a role in increased atherothrombotic events in nilotinib treated chronic myeloid leukemia patients

Several reports described an increased risk of cardiovascular (CV) events, mainly atherothrombotic, in Chronic Myeloid Leukemia (CML) patients receiving nilotinib. However, the underlying mechanism remains elusive. The objective of the current cross-sectional retrospective study is to address a potential correlation between Tyrosine Kinase Inhibitors (TKIs) treatment and CV events. One hundred and 10 chronic phase CML patients in complete cytogenetic response during nilotinib or imatinib, were screened for CV events and evaluated for: traditional CV risk factors, pro/anti-inflammatory biochemical parameters and detrimental ORL1 gene polymorphisms (encoding for altered oxidized LDL receptor-1). Multivariate analysis of the whole cohort showed that the cluster of co-existing nilotinib treatment, dyslipidaemia and G allele of LOX-1 polymorphism was the only significant finding associated with CV events. Furthermore, multivariate analysis according to TKI treatment confirmed IVS4-14 G/G LOX-1 polymorphism as the strongest predictive factor for a higher incidence of CV events in nilotinib patients. Biochemical assessment showed an unbalanced pro-inflammatory cytokines network in nilotinib vs imatinib patients. Surprisingly, pre-existing traditional CV risk factors were not always predictive of CV events. We believe that in nilotinib patients an induced "inflammatory/oxidative status", together with a genetic pro-atherothrombotic predisposition, may favour the increased incidence of CV events. Prospective studies focused on this issue are ongoing