Bottom up ethics - neuroenhancement in education and employment

Neuroenhancement involves the use of neurotechnologies to improve cognitive, affective or behavioural functioning, where these are not judged to be clinically impaired. Questions about enhancement have become one of the key topics of neuroethics over the past decade. The current study draws on in-depth public engagement activities in ten European countries giving a bottom-up perspective on the ethics and desirability of enhancement. This informed the design of an online contrastive vignette experiment that was administered to representative samples of 1000 respondents in the ten countries and the United States. The experiment investigated how the gender of the protagonist, his or her level of performance, the efficacy of the enhancer and the mode of enhancement affected support for neuroenhancement in both educational and employment contexts. Of these, higher efficacy and lower performance were found to increase willingness to support enhancement. A series of commonly articulated claims about the individual and societal dimensions of neuroenhancement were derived from the public engagement activities. Underlying these claims, multivariate analysis identified two social values. The Societal/Protective highlights counter normative consequences and opposes the use enhancers. The Individual/Proactionary highlights opportunities and supports use. For most respondents these values are not mutually exclusive. This suggests that for many neuroenhancement is viewed simultaneously as a source of both promise and concern

Platelet GPIIb supports initial pulmonary retention but inhibits subsequent proliferation of melanoma cells during hematogenic metastasis

Platelets modulate the process of cancer metastasis. However, current knowledge on the direct interaction of platelets and tumor cells is mostly based on findings obtained in vitro. We addressed the role of the platelet fibrinogen receptor glycoprotein IIb (integrin alpha IIb) for experimental melanoma metastasis in vivo. Highly metastatic B16-D5 melanoma cells were injected intravenously into GPIIb-deficient (GPIIb(-/-)) or wildtype (WT) mice. Acute accumulation of tumor cells in the pulmonary vasculature was assessed in real-time by confocal videofluorescence microscopy. Arrest of tumor cells was dramatically reduced in GPIIb(-/-) mice as compared to WT. Importantly, we found that mainly multicellular aggregates accumulated in the pulmonary circulation of WT, instead B16-D5 aggregates were significantly smaller in GPIIb(-/-) mice. While pulmonary arrest of melanoma was clearly dependent on GPIIb in this early phase of metastasis, we also addressed tumor progression 10 days after injection. Inversely, and unexpectedly, we found that melanoma metastasis was now increased in GPIIb(-/-) mice. In contrast, GPIIb did not regulate local melanoma proliferation in a subcutaneous tumor model. Our data suggest that the platelet fibrinogen receptor has a differential role in the modulation of hematogenic melanoma metastasis. While platelets clearly support early steps in pulmonary metastasis via GPIIb-dependent formation of platelet-tumor-aggregates, at a later stage its absence is associated with an accelerated development of melanoma metastases

Statistical breathing curve sampling to quantify interplay effects of moving lung tumors in a 4D Monte Carlo dose calculation framework

Purpose: The interplay between respiratory tumor motion and dose application by intensity modulated radio-therapy (IMRT) techniques can potentially lead to undesirable and non-intuitive deviations from the planned dose distribution. We developed a 4D Monte Carlo (MC) dose recalculation framework featuring statistical breathing curve sampling, to precisely simulate the dose distribution for moving target volumes aiming at a comprehensive assessment of interplay effects. Methods: We implemented a dose accumulation tool that enables dose recalculations of arbitrary breathing curves including the actual breathing curve of the patient. This MC dose recalculation framework is based on linac log-files, facilitating a high temporal resolution up to 0.1 s. By statistical analysis of 128 different breathing curves, interplay susceptibility of different treatment parameters was evaluated for an exemplary patient case. To facilitate prospective clinical application in the treatment planning stage, in which patient breathing curves or linac log-files are not available, we derived a log-file free version with breathing curves generated by a random walk approach. Interplay was quantified by standard deviations sigma in D-5%, D(50% )and D-95%. Results: Interplay induced dose deviations for single fractions were observed and evaluated for IMRT and volumetric arc therapy (sigma(D95%) up to 1.3 %) showing a decrease with higher fraction doses and an increase with higher MU rates. Interplay effects for conformal treatment techniques were negligible (sigma < 0.1%). The log-file free version and the random walk generated breathing curves yielded similar results (deviations in sigma < 0.1 %) and can be used as substitutes for interplay assessment. Conclusion: It is feasible to combine statistically sampled breathing curves with MC dose calculations. The universality of the presented framework allows comprehensive assessment of interplay effects in retrospective and prospective clinically relevant scenarios

Dose-guided patient positioning in proton radiotherapy using multicriteria-optimization

Proton radiotherapy (PT) requires accurate target alignment before each treatment fraction, ideally utilizing 3D in-room X-ray computed tomography (CT) imaging. Typically, the optimal patient position is determined based on anatomical landmarks or implanted markers. In the presence of non-rigid anatomical changes, however, the planning scenario cannot be exactly reproduced and positioning should rather aim at finding the optimal position in terms of the actually applied dose. In this work, dose-guided patient alignment, implemented as multicriterial optimization (MCO) problem, was investigated in the scope of intensity-modulated and double-scattered PT (IMPT and DSPT) for the first time. A method for automatically determining the optimal patient position with respect to pre-defined clinical goals was implemented. Linear dose interpolation was used to access a continuous space of potential patient shifts. Fourteen head and neck (H&N) and eight prostate cancer patients with up to five repeated CTs were included. Dose interpolation accuracy was evaluated and the potential dosimetric advantages of dose-guided over bony-anatomy-based patient alignment investigated by comparison of clinically relevant target and organ-at-risk (OAR) dose-volume histogram (DVH) parameters. Dose interpolation was found sufficiently accurate with average pass-rates of 90% and 99% for an exemplary H&N and prostate patient, respectively, using a 2% dose-difference criterion. Compared to bony-anatomy-based alignment, the main impact of automated MCO-based dose-guided positioning was a reduced dose to the serial OARs (spinal cord and brain stem) for the H&N cohort. For the prostate cohort, under-dosage of the target structures could be efficiently diminished. Limitations of dose-guided positioning were mainly found in reducing target over-dosage due to weight loss for H&N patients, which might require adaptation of the treatment plan. Since labor-intense online quality-assurance is not required for dose-guided patient positioning, it might, nevertheless, be considered an interesting alternative to full online re-planning for initially mitigating the effects of anatomical changes

The framing of innovation among European research funding actors: Assessing the potential for \u2018responsible research and innovation\u2019 in the food and health domain

Responsible Research and Innovation (RRI) has recently emerged as a new framework for science and technology governance. The concept articulates the need for mutual exchange by which societal actors become responsive to each other early on in the process of innovation, with a view to facilitate ethically acceptable and sustainable innovation. There is relatively limited evidence to explore the extent to which the process of research and innovation under the terms of RRI is realised in practice, particularly in the context of food and health research. Although research to date has been examining innovation from the point of view of inputs and outputs\u2014R&D funding and patents\u2014we propose to examine the cognitive framing of innovation that shapes decisions of those who constitute a part of the innovation chain. This paper explores how the concept of innovation is understood and used in policy implementation, with a particular focus upon \u2018food and health\u2019 science and research policy and funding. Our analysis is based on 55 interviews of various actors engaged in research funding decision-making across eight European countries. Three themes emerged from the analysis: concept of innovation; conditions for innovation; and drivers of innovation; through these themes, the cognitive framing was drawn out. The cognitive framing suggests that innovation in the food and health domain is perceived to be focused on biosciences and marketable applications to the neglect of social sciences and broader public interest; that the \u2018\u2018innovation network\u201d is primarily viewed as centred around scientific/technical and industrial actors; and that the demand-pull dynamic is relevant to innovation in the area of food and health, despite having been relegated in contemporary thinking and policies around innovation. These findings point to the inadequate consideration of the normative issues \u2014 how problems are to be defined and addressed \u2014 among national research funders in the food and health domain, and indicate a gap between the ideas of innovation under the terms of RRI and innovation as conceptualised by those involved in its governance

Investigating deformable image registration and scatter correction for CBCT-based dose calculation in adaptive IMPT

International audiencePurpose:This work aims at investigating intensity corrected cone-beam x-ray computed tomography (CBCT) images for accurate dose calculation in adaptive intensity modulated proton therapy (IMPT) for prostate and head and neck (H&N) cancer. A deformable image registration (DIR)-based method and a scatter correction approach using the image data obtained from DIR as prior are characterized and compared on the basis of the same clinical patient cohort for the first time.Methods:Planning CT (pCT) and daily CBCT data (reconstructed images and measured projections) of four H&N and four prostate cancer patients have been considered in this study. A previously validated Morphons algorithm was used for DIR of the planning CT to the current CBCT image, yielding a so-called virtual CT (vCT). For the first time, this approach was translated from H&N to prostate cancer cases in the scope of proton therapy. The warped pCT images were also used as prior for scatter correction of the CBCT projections for both tumor sites. Single field uniform dose and IMPT (only for H&N cases) treatment plans have been generated with a research version of a commercial planning system. Dose calculations on vCT and scatter corrected CBCT (CBCT cor) were compared by means of the proton range and a gamma-index analysis. For the H&N cases, an additional diagnostic replanning CT (rpCT) acquired within three days of the CBCT served as additional reference. For the prostate patients, a comprehensive contour comparison of CBCT and vCT, using a trained physician’s delineation, was performed.Results:A high agreement of vCT and CBCT cor was found in terms of the proton range and gamma-index analysis. For all patients and indications between 95% and 100% of the proton dose profiles in beam’s eye view showed a range agreement of better than 3 mm. The pass rate in a (2%,2 mm) gamma-comparison was between 96% and 100%. For H&N patients, an equivalent agreement of vCT and CBCT cor to the reference rpCT was observed. However, for the prostate cases, an insufficient accuracy of the vCT contours retrieved from DIR was found, while the CBCT cor contours showed very high agreement to the contours delineated on the raw CBCT.Conclusions:For H&N patients, no considerable differences of vCT and CBCT cor were found. For prostate cases, despite the high dosimetric agreement, the DIR yields incorrect contours, probably due to the more pronounced anatomical changes in the abdomen and the reduced soft-tissue contrast in the CBCT. Using the vCT as prior, these inaccuracies can be overcome and images suitable for accurate delineation and dose calculation in CBCT-based adaptive IMPT can be retrieved from scatter correction of the CBCT projections

Platelet-tumor-aggregate formation <i>in vivo</i>.

<p><b>a)</b> GFP-transfected B16-D5 melanoma cells were injected intravenously into wildtype mice. After 1 hour, lung tissue was obtained for immunofluorescence analysis. Photomicrographs show mouse lung tissue stained with antibodies directed against platelet GPIIb (CD41, red) and B16-D5 (GFP, green); nuclei were stained with DAPI (blue). Bars, 40μm. Images were taken using a Leica DMRB epifluoresence microscope, 20x objective. <b>b-d)</b> Arrest of DCF-tagged B16-D5 melanoma cells was visualized in the pulmonary vasculature by intravital confocal videofluorescence microscopy (IVM) in GPIIb^+/+ and GPIIb^-/- littermate mice immediately and after 1 hour. <b>b)</b> Number of metastatic events was quantified. Results are given as percentage of firmly adherent B16-D5 in GPIIb^-/- mice compared to its WT littermate (n = 5–6 experiments per group; *<i>P</i><0.01 acute; **<i>P</i><0.001 after 1 hour). <b>c)</b> Size of B16-aggregates was quantified. Results are given as percentage of B16-aggregate size in GPIIb^-/- mice compared to its WT littermate (n = 5–6; *<i>P</i><0.05 after 1 hour). <b>d)</b> Photomicrographs show representative IVM images obtained in GPIIb^+/+ and GPIIb^-/-. In GPIIb^+/+ mice, arrest of large multicellular aggregates is frequently observed (left). Arrest of DCF-tagged B16-D5 is visualized in precapillary vessels (right). Bars, 20μm. <b>d e-f)</b> GPIIb^+/+ (WT) or GPIIb^-/- platelets were injected into GPIIb^-/- mice just prior to administration of DCF-labeled B16-D5. IVM was performed immediately and after 1 hour. <b>e)</b> Number of metastatic events was quantified. Results are given as percentage of firmly adherent B16-D5 in GPIIb^-/- littermates receiving GPIIb^-/- platelets (n = 4; *<i>P</i><0.05). <b>f)</b> Size of B16-aggregates was quantified. Results are given as percentage of B16-aggregate size in GPIIb^-/- littermates receiving GPIIb^-/- platelets (n = 3; P = n.s.).</p