Background
Automated driving will be of high value in the future. While in partial-automated driving the driver must always monitor the traffic situation, a paradigm shift is taking place in the case ...of conditional automated driving (Level 3 according to SAE). From this level of automation onwards, the vehicle user is released from permanent vehicle control and environmental monitoring and is allowed to engage in Non-Driving Related Tasks (NDRT) in his or her newly gained spare time. These tasks can be performed until a take-over request informs the user to resume vehicle control. As the driver is still considered to be the fall-back level, this aspect of taking over control is considered especially critical.
Methods
While previous research projects have focused their studies on the factors influencing the take-over request, this paper focuses on the effects of NDRT on the user of the vehicle during conditional automated driving, especially on the human workload. NDRT (such as Reading, Listening, Watching a movie, Texting and Monitoring ride) were examined within a static driving simulator at the Institute of Ergonomics & Human Factors with 56 participants in an urban environment. These NDRT were tested for mental workload and the ability to take over in a critical situation. To determine the perceived workload, the subjective workload, psychophysiological activity as well as performance-based parameters of a secondary competing task performed by a were used.
Results
This study revealed that the selected NDRT vary significantly in their mental workload and that the workload correlates with the length of the time needed for take over control. NDRT which are associated with a high workload (such as Reading or Texting) also lead to longer reaction times.
Zusammenfassung
Hochautomatisierte Fahrzeuge werden in der Lage sein, die Fahrzeugführung selbständig zu übernehmen, während sich die Fahrer_innen mit fahrfremden Tätigkeiten beschäftigen können. In ...kritischen Situationen, die das Automatisierungssystem nicht allein bewältigen kann, wird es jedoch weiterhin Übernahmeaufforderungen an den Fahrer/die Fahrerin geben. In diesem Beitrag wird untersucht, welche Modalitäten für Übernahmeaufforderungen entsprechend einer Reiz-Reaktions-Kompatibilität geeignet sind. Dazu wurden drei unterschiedliche Schnittstellen-Varianten entwickelt und mit insgesamt 126 Proband_innen in zwei unabhängigen Fahrsimulator-Studien überprüft. Innerhalb der ersten Studie wurden eine visuelle, eine vibrotaktile oder eine multimodale (Kombination aus visueller, vibrotaktiler und akustischer) Übernahmeaufforderung untersucht. Die zweite Studie konzentrierte sich auf die mentale Beanspruchung und die Rückübernahmefähigkeit bei Ausführung verschiedener fahrfremder Tätigkeiten während hochautomatisierter Fahrt. Diese Studie ergab, dass die Dauer der Kontrollübernahme nach einer multimodalen Rückübernahmeaufforderung mit der mentalen Beanspruchung der fahrfremden Tätigkeiten korreliert.
Praktische Relevanz
: Die Untersuchung unterschiedlicher Modalitäten für die Informationsübermittlung bei einer Rückübernahmeaufforderung trägt dazu bei, dass in automatisierten Fahrzeugen Modalitäten gewählt werden, die zum einen eine kurze Reaktionszeit der Fahrer_innen unterstützen und zum anderen eine subjektiv positive Bewertung hervorrufen.
Dem automatisierten Fahren wird künftig eine hohe Bedeutung zukommen. Nicht nur die Sicherheit und Effizienz des Straßenverkehrs sollen erhöht, sondern auch Emissionen reduziert und die Mobilität ...verbessert werden. Während bei der teilautomatisierten Fahrt der Fahrzeugnutzende stets das Verkehrsgeschehen überwachen muss, vollzieht sich ab dem hochautomatisierten Fahren (Level 3 nach SAE (2018)) ein Paradigmenwechsel. Ab dieser Automatisierungsstufe wird der Fahrzeugnutzende von der Pflicht der dauerhaften Fahrzeugführung und Umgebungsüberwachung entbunden und kann sich in seiner neu gewonnenen Freizeit mit fahrfremden Tätigkeiten (FFT) beschäftigen. Diese Tätigkeiten dürfen so lange ausgeführt werden, bis ein Signal den Nutzer darauf hinweist die Fahrzeugkontrolle wieder aufzunehmen. Da der Fahrzeugführer dennoch als Rückfallebene gilt, wird dieser Aspekt der Kontrollübernahme als besonders kritisch angesehen. Während bisherige Forschungsvorhaben die Einflussfaktoren auf die Rückübernahmeaufforderung im Fokus ihrer Studie untersuchten, liegt das Hauptaugenmerk dieser Arbeit auf den Auswirkungen der FFT auf den Fahrzeugnutzenden während der hochautomatisierten Fahrt. Dafür wird zunächst ein Literaturüberblick über den aktuellen Stand der Forschung gegeben und darauf aufbauend Forschungslücken identifiziert. Basierend auf einer Online-Umfrage (N = 164) und einer Cover-Story-Fahrsimulatorstudie (N = 30) werden aus Nutzersicht relevante fahrfremde Tätigkeiten („Text lesen“, „Hörbuch hören“, „Video schauen“, „Texting“ und „Fahrt beobachten“) bestimmt. Mittels eines Untersuchungsmodells auf Basis des Belastungs-Beanspruchungs-Konzepts nach Luczak (1975, modifiziert von Rohmert 1984) werden die aus der systematischen Literaturrecherche geschlussfolgerten Forschungsfragen mit Hilfe von Leithypothesen visualisiert. Anhand der Hauptstudie (N = 56) werden die FFT in einem statischen Fahrsimulator des Instituts für Arbeitswissenschaft (Technische Universität Darmstadt) auf die mentale Beanspruchung, das Situationsbewusstsein und die Rückübernahmefähigkeit in einer kritischen Situation überprüft. Die vorliegende Arbeit untersucht mittels triangulärem Ansatz aus dem subjektiven Empfinden, der psychophysiologischen Aktivität sowie leistungsbasierten Kennwerten einer konkurrierenden Sekundäraufgabe in Form eines Reiz-Reaktionszeittests die Auswirkungen visueller, auditiver, taktiler und kognitiver Belastungen durch naturalistische FFT. Hierbei zeigt sich, dass sich die ausgewählten FFT in ihrer mentalen Beanspruchung signifikant unterscheiden. Das Situationsbewusstsein wird in drei zeitlichen Varianten erforscht. Neben dem vorhandenen Situationsbewusstsein bei Ausführung einer FFT wird auch der Aufbauprozess des Situationsbewusstseins im Detail analysiert. Die Ergebnisse zeigen, dass sich die zeitliche Rückübernahmefähigkeit ebenfalls signifikant in Abhängigkeit von der ausgeführten FFT unterscheidet. Folglich wirkt sich sowohl die untersuchte Variable der mentalen Beanspruchung als auch die des vorhandenen Situationsbewusstseins signifikant auf die Rückübernahmezeit aus. Schlussendlich liefert diese Arbeit neben der Beantwortung der Forschungsfragen auch Gestaltungsempfehlungen für zukünftige hochautomatisierte Fahrzeugkonzepte.
Cancer stem cells drive disease progression and relapse in many types of cancer. Despite this, a thorough characterization of these cells remains elusive and with it the ability to eradicate cancer ...at its source. In acute myeloid leukemia (AML), leukemic stem cells (LSCs) underlie mortality but are difficult to isolate due to their low abundance and high similarity to healthy hematopoietic stem cells (HSCs). Here, we demonstrate that LSCs, HSCs, and pre-leukemic stem cells can be identified and molecularly profiled by combining single-cell transcriptomics with lineage tracing using both nuclear and mitochondrial somatic variants. While mutational status discriminates between healthy and cancerous cells, gene expression distinguishes stem cells and progenitor cell populations. Our approach enables the identification of LSC-specific gene expression programs and the characterization of differentiation blocks induced by leukemic mutations. Taken together, we demonstrate the power of single-cell multi-omic approaches in characterizing cancer stem cells.
Animal models point towards a key role of brain-derived neurotrophic factor (BDNF), insulin-like growth factor-I (IGF-I) and vascular endothelial growth factor (VEGF) in mediating exercise-induced ...structural and functional changes in the hippocampus. Recently, also platelet derived growth factor-C (PDGF-C) has been shown to promote blood vessel growth and neuronal survival. Moreover, reductions of these neurotrophic and angiogenic factors in old age have been related to hippocampal atrophy, decreased vascularization and cognitive decline. In a 3-month aerobic exercise study, forty healthy older humans (60 to 77years) were pseudo-randomly assigned to either an aerobic exercise group (indoor treadmill, n=21) or to a control group (indoor progressive-muscle relaxation/stretching, n=19). As reported recently, we found evidence for fitness-related perfusion changes of the aged human hippocampus that were closely linked to changes in episodic memory function. Here, we test whether peripheral levels of BDNF, IGF-I, VEGF or PDGF-C are related to changes in hippocampal blood flow, volume and memory performance. Growth factor levels were not significantly affected by exercise, and their changes were not related to changes in fitness or perfusion. However, changes in IGF-I levels were positively correlated with hippocampal volume changes (derived by manual volumetry and voxel-based morphometry) and late verbal recall performance, a relationship that seemed to be independent of fitness, perfusion or their changes over time. These preliminary findings link IGF-I levels to hippocampal volume changes and putatively hippocampus-dependent memory changes that seem to occur over time independently of exercise. We discuss methodological shortcomings of our study and potential differences in the temporal dynamics of how IGF-1, VEGF and BDNF may be affected by exercise and to what extent these differences may have led to the negative findings reported here.
•Exercise-related changes in BDNF, IGF, VEGF and PDGF were measured in older adults•Changes in hippocampal perfusion, volume (via 7T MRI) and memory were assessed•Fitness-related vascular hippocampal plasticity was not linked to growth factors•Changes in IGF-I, hippocampal volume and memory were linked independent of exercise•Potential reasons for negative findings and methodological shortcomings are discussed
Although there is an agreement about the local structural order of semiconducting polymers such as poly(3-hexylthiophene) (P3HT), there is still a debate over the impact of molecular doping. One ...prevalent interpretation is that dopant molecules intercalate in the π–π stacking of crystallites; however, this idea has recently been challenged. We present here electron diffraction measurements of P3HT doped with the two dopants 2,3,5,6-tetrafluoro-7,7,8,8-tetracyanoquinodimethane (F4TCNQ) and molybdenum tris1-(methoxycarbonyl)-2-(trifluoromethyl)-ethane-1,2-dithiolene (Mo(tfd-CO2Me)3), which have considerably different sizes and shapes, processed by different doping techniques. We observe a reduction in the π–π spacing of P3HT upon doping with both dopant molecules and doping techniques. These data are not consistent with both of the dopants intercalating in the π–π stacks and an alternative explanation is, therefore, required to explain these results. Density functional theory calculations for P3HT model oligomers suggest that the polaron delocalizes between adjacent chains and thus leads to attractive forces that reduce the π–π spacing, without the physical presence of any dopant molecules. Our study emphasizes that not only geometric effects induced by dopant molecules lead to the observed reduction of π–π spacing, but the charging itself.
Immunotherapy can become a crucial therapeutic option to improve prognosis for lung cancer patients. First clinical trials with therapies targeting the programmed cell death receptor PD-1 and its ...ligand PD-L1 have shown promising results in several solid tumors. However, in lung cancer the diagnostic, prognostic and predictive value of these immunologic factors remains unclear.
The impact of both factors was evaluated in a study collective of 321 clinically well-annotated patients with non-small lung cancer (NSCLC) using immunohistochemistry.
PD-1 expression by tumor infiltrating lymphocytes (TILs) was found in 22%, whereas tumor cell associated PD-L1 expression was observed in 24% of the NSCLC tumors. In Fisher's exact test a positive correlation was found for PD-L1 and Bcl-xl protein expression (p = 0.013). Interestingly, PD-L1 expression on tumor cells was associated with improved overall survival in pulmonary squamous cell carcinomas (SCC, p = 0.042, log rank test), with adjuvant therapy (p = 0.017), with increased tumor size (pT2-4, p = 0.039) and with positive lymph node status (pN1-3, p = 0.010). These observations were confirmed by multivariate cox regression models.
One major finding of our study is the identification of a prognostic implication of PD-L1 in subsets of NSCLC patients with pulmonary SCC, with increased tumor size, with a positive lymph node status and NSCLC patients who received adjuvant therapies. This study provides first data for immune-context related risk stratification of NSCLC patients. Further studies are necessary both to confirm this observation and to evaluate the predictive value of PD-1 and PD-L1 in NSCLC in the context of PD-1 inhibition.
Purpose
Insufficient antimicrobial exposure is associated with worse outcomes in sepsis. We evaluated whether therapeutic drug monitoring (TDM)-guided antibiotic therapy improves outcomes.
Methods
...Randomized, multicenter, controlled trial from January 2017 to December 2019. Adult patients (
n
= 254) with sepsis or septic shock were randomly assigned 1:1 to receive continuous infusion of piperacillin/tazobactam with dosing guided by daily TDM of piperacillin or continuous infusion with a fixed dose (13.5 g/24 h if eGFR ≥ 20 mL/min). Target plasma concentration was four times the minimal inhibitory concentration (range ± 20%) of the underlying pathogen, respectively, of
Pseudomonas aeruginosa
in empiric situation. Primary outcome was the mean of daily total Sequential Organ Failure Assessment (SOFA) score up to day 10.
Results
Among 249 evaluable patients (66.3 ± 13.7 years; female, 30.9%), there was no significant difference in mean SOFA score between patients with TDM (7.9 points; 95% CI 7.1–8.7) and without TDM (8.2 points; 95% CI 7.5–9.0) (
p
= 0.39). Patients with TDM-guided therapy showed a lower 28-day mortality (21.6% vs. 25.8%, RR 0.8, 95% CI 0.5–1.3,
p
= 0.44) and a higher rate of clinical (OR 1.9; 95% CI 0.5–6.2,
p
= 0.30) and microbiological cure (OR 2.4; 95% CI 0.7–7.4,
p
= 0.12), but these differences did not reach statistical significance. Attainment of target concentration was more common in patients with TDM (37.3% vs. 14.6%, OR 4.5, CI 95%, 2.9–6.9,
p
< 0.001).
Conclusion
TDM-guided therapy showed no beneficial effect in patients with sepsis and continuous infusion of piperacillin/tazobactam with regard to the mean SOFA score. Larger studies with strategies to ensure optimization of antimicrobial exposure are needed to definitively answer the question.
Abstract
Aims
Inflammation is a key driver of atherosclerosis and myocardial infarction (MI), and beyond proteins and microRNAs (miRs), long noncoding RNAs (lncRNAs) have been implicated in ...inflammation control. To obtain further information on the possible role of lncRNAs in the context of atherosclerosis, we obtained comprehensive transcriptome maps of circulating immune cells (peripheral blood mononuclear cells, PBMCs) of early onset MI patients. One lncRNA significantly suppressed in post-MI patients was further investigated in a murine knockout model.
Methods and results
Individual RNA-sequencing (RNA-seq) was conducted on PBMCs from 28 post-MI patients with a history of MI at age ≤50 years and stable disease ≥3 months before study participation, and from 31 healthy individuals without manifest cardiovascular disease or family history of MI as controls. RNA-seq revealed deregulated protein-coding transcripts and lncRNAs in post-MI PBMCs, among which nuclear enriched abundant transcript (NEAT1) was the most highly expressed lncRNA, and the only one significantly suppressed in patients. Multivariate statistical analysis of validation cohorts of 106 post-MI patients and 85 controls indicated that the PBMC NEAT1 levels were influenced (P = 0.001) by post-MI status independent of statin intake, left ventricular ejection fraction, low-density lipoprotein or high-density lipoprotein cholesterol, or age. We investigated NEAT1−/− mice as a model of NEAT1 deficiency to evaluate if NEAT1 depletion may directly and causally alter immune regulation. RNA-seq of NEAT1−/− splenocytes identified disturbed expression and regulation of chemokines/receptors, innate immunity genes, tumour necrosis factor (TNF) and caspases, and increased production of reactive oxygen species (ROS) under baseline conditions. NEAT1−/− spleen displayed anomalous Treg and TH cell differentiation. NEAT1−/− bone marrow-derived macrophages (BMDMs) displayed altered transcriptomes with disturbed chemokine/chemokine receptor expression, increased baseline phagocytosis (P < 0.0001), and attenuated proliferation (P = 0.0013). NEAT1−/− BMDMs responded to LPS with increased (P < 0.0001) ROS production and disturbed phagocytic activity (P = 0.0318). Monocyte-macrophage differentiation was deregulated in NEAT1−/− bone marrow and blood. NEAT1−/− mice displayed aortic wall CD68+ cell infiltration, and there was evidence of myocardial inflammation which could lead to severe and potentially life-threatening structural damage in some of these animals.
Conclusion
The study indicates distinctive alterations of lncRNA expression in post-MI patient PBMCs. Regarding the monocyte-enriched NEAT1 suppressed in post-MI patients, the data from NEAT1−/− mice identify NEAT1 as a novel lncRNA-type immunoregulator affecting monocyte-macrophage functions and T cell differentiation. NEAT1 is part of a molecular circuit also involving several chemokines and interleukins persistently deregulated post-MI. Individual profiling of this circuit may contribute to identify high-risk patients likely to benefit from immunomodulatory therapies. It also appears reasonable to look for new therapeutic targets within this circuit.
The virulence of intracellular pathogens such as Leishmania major (L. major) relies largely on their ability to undergo cycles of replication within phagocytes, release, and uptake into new host ...cells. While all these steps are critical for successful establishment of infection, neither the cellular niche of efficient proliferation, nor the spread to new host cells have been characterized in vivo. Here, using a biosensor for measuring pathogen proliferation in the living tissue, we found that monocyte-derived Ly6C+CCR2+ phagocytes expressing CD11c constituted the main cell type harboring rapidly proliferating L. major in the ongoing infection. Synchronization of host cell recruitment and intravital 2-photon imaging showed that these high proliferating parasites preferentially underwent cell-to-cell spread. However, newly recruited host cells were infected irrespectively of their cell type or maturation state. We propose that among these cells, CD11c-expressing monocytes are most permissive for pathogen proliferation, and thus mainly fuel the cycle of intracellular proliferation and cell-to-cell transfer during the acute infection. Thus, besides the well-described function for priming and activating T cell effector functions against L. major, CD11c-expressing monocyte-derived cells provide a reservoir for rapidly proliferating parasites that disseminate at the site of infection.
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