EValueAction: a proposal for policy evaluation in simulation to support interactive imitation learning

The up-and-coming concept of Industry 5.0 foresees human-centric flexible production lines, where collaborative robots support human workforce. In order to allow a seamless collaboration between intelligent robots and human workers, designing solutions for non-expert users is crucial. Learning from demonstration emerged as the enabling approach to address such a problem. However, more focus should be put on finding safe solutions which optimize the cost associated with the demonstrations collection process. This paper introduces a preliminary outline of a system, namely EValueAction (EVA), designed to assist the human in the process of collecting interactive demonstrations taking advantage of simulation to safely avoid failures. A policy is pre-trained with human-demonstrations and, where needed, new informative data are interactively gathered and aggregated to iteratively improve the initial policy. A trial case study further reinforces the relevance of the work by demonstrating the crucial role of informative demonstrations for generalization

Arbitrage pricing theory for idiosyncratic variance factors

We develop an Arbitrage Pricing Theory framework extension to study the pricing of squared returns/volatilities. We analyze the interplay between factors at the return level and those in idiosyncratic variances. We confirm the presence of a common idiosyncratic variance fac- tor, but do not find evidence that this represents a missing risk factor at the (linear) return level. Thereby, we consistently identify idiosyncratic returns. The price of the idiosyncratic variance factor identified by squared returns is small relative to the price of market variance risk. The quadratic pricing kernels induced by our model are in line with standard economic intuition

Quantitative DCE-MRI demonstrates increased blood perfusion in Hoffa’s fat pad signal abnormalities in knee osteoarthritis, but not in patellofemoral pain

Objective: Infrapatellar fat pad (IPFP) fat-suppressed T2 (T2FS) hyperintense regions on MRI are an important imaging feature of knee osteoarthritis (OA) and are thought to represent inflammation. These regions are also common in non-OA subjects, and may not always be linked to inflammation. Our aim was to evaluate quantitative blood perfusion parameters, as surrogate measure of inflammation, within T2FS-hyperintense regions in patients with OA, with patellofemoral pain (PFP) (supposed OA precursor), and control subjects. Methods: Twenty-two knee OA patients, 35 PFP patients and 43 healthy controls were included and underwent MRI, comprising T2 and DCE-MRI sequences. T2FS-hyperintense IPFP regions were delineated and a reference region was drawn in adjacent IPFP tissue with normal signal intensity. After fitting the extended Tofts pharmacokinetic model, quantitative DCE-MRI perfusion parameters were compared between the two regions within subjects in each subgroup, using a paired Wilcoxon signed-rank test. Results: T2FS-hyperintense IPFP regions were present in 16 of 22 (73%) OA patients, 13 of 35 (37%) PFP patients, and 14 of 43 (33%) controls. DCE-MRI perfusion parameters were significantly different between regions with and without a T2FS-hyperintense signal in OA patients, demonstrating higher Ktrans compared to normal IFPF tissue (0.039 min−1 versus 0.025 min−1, p = 0.017) and higher Ve (0.157 versus 0.119, p = 0.010). For PFP patients and controls no significant differences were found. Conclusions: IPFP T2FS-hyperintense regions are associated with higher perfusion in knee OA patients in contrast to identically appearing regions in PFP patients and controls, pointing towards an inflammatory pathogenesis in OA only. Key Points: • Morphologically identical appearing T2FS-hyperintense infrapatellar fat pad regions show different perfusion in healthy subjects, subjects with patellofemoral pain, and subjects with knee osteoarthritis. • Elevated DCE-MRI perfusion parameters within T2FS-hyperintense infrapatellar fat pad regions in patients with osteoarthritis suggest an inflammatory pathogenesis in osteoarthritis, but not in patellofemoral pain and healthy subjects

Potential of Donation After Unexpected Circulatory Death Programs Defined by Their Demographic Characteristics

BACKGROUND. Donation after unexpected circulatory death (uDCD) donors are often suggested to increase the number of donor organs. In 2014, a uDCD protocol was implemented in three transplant centers in the Netherlands which unfortunately did not result in additional transplantations. This study was initiated to identify demographic factors influencing the potential success of uDCD programs. METHODS. Dutch resuscitation databases covering various demographic regions were analyzed for potential donors. The databases were compared with the uDCD implementation project and successful uDCD programs in Spain, France, and Russia. RESULTS. The resuscitation databases showed that 61% of all resuscitated patients were transferred to an emergency department. Age selection reduced this uDCD potential to 46% with only patients aged 18–65 years deemed eligible. Of these patients, 27% died in the emergency department. The urban region of Amsterdam showed the largest potential in absolute numbers (52 patients/y). Comparison with the uDCD implementation project showed large similarities in the percentage of potential donors; however, in absolute numbers, it showed a much smaller potential. Calculation of the potential per million persons and the extrapolation of the potential based on the international experience revealed the largest potential in urban regions. CONCLUSIONS. Implementation of a uDCD program should not only be based on the number of potential donors calculated from resuscitation databases. They show promising potential uDCD percentages for large rural regions and small urban regions; however, actual numbers per hospital are low, leading to insufficient exposure rates. It is, therefore, recommendable to limit uDCD programs to large urban regions

Quantitative volume and dynamic contrast-enhanced MRI derived perfusion of the infrapatellar fat pad in patellofemoral pain

Background: Patellofemoral pain (PFP) is a common knee condition and possible precursor of knee osteoarthritis (OA). Inflammation, leading to an increased perfusion, or increased volume of the infrapatellar fat pad (IPFP) may induce knee pain. The aim of the study was to compare quantitative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters, as imaging biomarkers of inflammation, and volume of the IPFP between patients with PFP and controls and between patients with and without IPFP edema or joint effusion. Methods: Patients with PFP and healthy controls were included and underwent non-fat suppressed 3D fast-spoiled gradient-echo (FSPGR) and DCE-MRI. Image registration was applied to correct for motion. The IPFP was delineated on FSPGR using Horos software. Volume was calculated and quantitative perfusion parameters were extracted by fitting extended Tofts' pharmacokinetic model. Differences in volume and DCE-MRI parameters between patients and controls were tested by linear regression analyses. IPFP edema and effusion were analyzed identically. Results: Forty-three controls and 35 PFP patients were included. Mean IPFP volume was 26.04 (4.18) mL in control subjects and 27.52 (5.37) mL in patients. Median Ktrans was 0.017 (0.016) min-1 in control subjects and 0.016 (0.020) min-1 in patients. None of the differences in volume and perfusion parameters were statistically significant. Knees with effusion showed a higher perfusion of the IPFP compared to knees without effusion in patients only. Conclusions: The IPFP has been implicated as source of knee pain, but higher DCE-MR blood perfusion, an imaging biomarker of inflammation, and larger volume are not associated with PFP. Patient's knees with effusion showed a higher perfusion, pointing towards inflammation

The Tumor Immune Landscape and Architecture of Tertiary Lymphoid Structures in Urothelial Cancer

Candidate immune biomarkers have been proposed for predicting response to immunotherapy in urothelial cancer (UC). Yet, these biomarkers are imperfect and lack predictive power. A comprehensive overview of the tumor immune contexture, including Tertiary Lymphoid structures (TLS), is needed to better understand the immunotherapy response in UC. We analyzed tumor sections by quantitative multiplex immunofluorescence to characterize immune cell subsets in various tumor compartments in tumors without pretreatment and tumors exposed to preoperative anti-PD1/CTLA-4 checkpoint inhibitors (NABUCCO trial). Pronounced immune cell presence was found in UC invasive margins compared to tumor and stroma regions. CD8+PD1+ T-cells were present in UC, particularly following immunotherapy. The cellular composition of TLS was assessed by multiplex immunofluorescence (CD3, CD8, FoxP3, CD68, CD20, PanCK, DAPI) to explore specific TLS clusters based on varying immune subset densities. Using a k-means clustering algorithm, we found five distinct cellular composition clusters. Tumors unresponsive to anti-PD-1/CTLA-4 immunotherapy showed enrichment of a FoxP3+ T-cell-low TLS cluster after treatment. Additionally, cluster 5 (macrophage low) TLS were significantly higher after pre-operative immunotherapy, compared to untreated tumors. We also compared the immune cell composition and maturation stages between superficial (submucosal) and deeper TLS, revealing that superficial TLS had more pronounced T-helper cells and enrichment of early TLS than TLS located in deeper tissue. Furthermore, superficial TLS displayed a lower fraction of secondary follicle like TLS than deeper TLS. Taken together, our results provide a detailed quantitative overview of the tumor immune landscape in UC, which can provide a basis for further studies

The clonal relation of primary upper urinary tract urothelial carcinoma and paired urothelial carcinoma of the bladder

The risk of developing urothelial carcinoma of the bladder (UCB) in patients treated by radical nephroureterectomy (RNU) for an upper urinary tract urothelial carcinoma (UTUC) is 22% to 47% in the 2 years after surgery. Subject of debate remains whether UTUC and the subsequent UCB are clonally related or represent separate origins. To investigate the clonal relationship between both entities, we performed targeted DNA sequencing of a panel of 41 genes on matched normal and tumor tissue of 15 primary UTUC patients treated by RNU who later developed 19 UCBs. Based on the detected tumor-specific DNA aberrations, the paired UTUC and UCB(s) of 11 patients (73.3%) showed a clonal relation, whereas in four patients the molecular results did not indicate a clear clonal relationship. Our results support the hypothesis that UCBs following a primary surgically resected UTUC are predominantly clonally derived recurrences and not separate entities

Decomposition of Juncus seeds in a valley mire (Faroe Islands) over a 900 year period.

The influence of past depositional environments on the chemistry of sub-fossil Juncus seed coats (testa) from the top 1 m (corresponding to ca. 900 years of peat accumulation) of a peat bog in the Faroe Islands was examined. The chemistry of the testa of fresh Juncus seeds were characterised using thermally assisted pyrolysis and methylation (THM) in the presence of tetramethyl ammonium hydroxide (TMAH) and ‘type’ compounds were identified, representative of the major chemical groups in the testa (cellulose-related sugars, lignin-related phenolics, fatty acids). The abundance of the ‘type’ compounds in the products from sub-fossil testae (the internal tissues of the seeds do not survive beyond the very early stages of decomposition) was then quantified at contiguous 1 cm depth intervals. Major losses of C18 unsaturated fatty acid methyl esters and sugars were associated with the fresh to sub-fossil transition at ca. 7 cm depth. The preservation of the phenolic ferulic acid in the seed testa appears to be favoured by the input of small basaltic particles from the nearby stream channel. The mechanism by which inwash of inorganic material may be responsible for the improved chemical preservation of the Juncus seed testa is, however, unclear. The sugars were easily metabolised by microorganisms under aerobic conditions of low water table and preserved under anoxic conditions with high water table, suggesting that a drier mire surface may result in the more efficient depletion of polysaccharides and cellulose during the initial stage of decomposition in the acrotelm

Quantitative subchondral bone perfusion imaging in knee osteoarthritis using dynamic contrast enhanced MRI

Objective: Subchondral bone changes, characterized by increased bone turnover and vascularity, are believed to stimulate progression and pain in knee osteoarthritis (OA). The objective of this study was to evaluate the bone perfusion in knee OA using quantitative dynamic contrast enhanced MRI (DCE-MRI). Design: Unicompartmental knee OA patients were included and underwent 3 Tesla DCE-MRI and T2-weighted MRI. Quantitative DCE-MRI analysis of Ktrans and Kep, representing perfusion parameters, was performed to evaluate differences between the most and least affected knee compartment. First, DCE-MRI parameter differences between epimetaphyseal and subchondral bone in both femur and tibia were assessed. Second, DCE-MRI parameters in subchondral bone marrow lesions (BMLs) were compared to surrounding subchondral bone without BMLs. Results: Twenty-three patients were analyzed. Median Ktrans and Kep in epimetaphyseal bone were significantly higher (p < 0.05) in the most affected (Ktrans: 0.014; Kep: 0.054 min−1) compared to least affected (Ktrans: 0.010; Kep: 0.016 min−1) compartment. For subchondral bone, DCE-MRI parameters were significantly higher (p < 0.05) in the most affected (Ktrans: 0.019; Kep: 0.091 min−1) compared to least affected (Ktrans: 0.014; Kep: 0.058 min−1) compartment as well. Subchondral BMLs detected on fat-saturated T2-weighted images were present in all patients. Median Ktrans (0.091 vs 0.000 min−1) and Kep (0.258 vs 0.000 min−1) were significantly higher within subchondral BMLs compared to surrounding subchondral bone without BMLs (p < 0.001). Conclusions: Increased perfusion parameters in epimetaphyseal bone, subchondral bone and BMLs are observed in unicompartmental knee OA. BMLs likely account for most of the effect of the higher bone perfusion in knee OA