Sub-Riemannian Fast Marching in SE(2)

We propose a Fast Marching based implementation for computing sub-Riemanninan (SR) geodesics in the roto-translation group SE(2), with a metric depending on a cost induced by the image data. The key ingredient is a Riemannian approximation of the SR-metric. Then, a state of the art Fast Marching solver that is able to deal with extreme anisotropies is used to compute a SR-distance map as the solution of a corresponding eikonal equation. Subsequent backtracking on the distance map gives the geodesics. To validate the method, we consider the uniform cost case in which exact formulas for SR-geodesics are known and we show remarkable accuracy of the numerically computed SR-spheres. We also show a dramatic decrease in computational time with respect to a previous PDE-based iterative approach. Regarding image analysis applications, we show the potential of considering these data adaptive geodesics for a fully automated retinal vessel tree segmentation.Comment: CIARP 201

Comparison of RBE values of high- LET α-particles for the induction of DNA-DSBs, chromosome aberrations and cell reproductive death

<p>Abstract</p> <p>Background</p> <p>Various types of radiation effects in mammalian cells have been studied with the aim to predict the radiosensitivity of tumours and normal tissues, e.g. DNA double strand breaks (DSB), chromosome aberrations and cell reproductive inactivation. However, variation in correlations with clinical results has reduced general application. An additional type of information is required for the increasing application of high-LET radiation in cancer therapy: the Relative Biological Effectiveness (RBE) for effects in tumours and normal tissues. Relevant information on RBE values might be derived from studies on cells in culture.</p> <p>Methods</p> <p>To evaluate relationships between DNA-DSB, chromosome aberrations and the clinically most relevant effect of cell reproductive death, for ionizing radiations of different LET, dose-effect relationships were determined for the induction of these effects in cultured SW-1573 cells irradiated with gamma-rays from a Cs-137 source or with α-particles from an Am-241 source. RBE values were derived for these effects. Ionizing radiation induced foci (IRIF) of DNA repair related proteins, indicative of DSB, were assessed by counting gamma-H2AX foci. Chromosome aberration frequencies were determined by scoring fragments and translocations using premature chromosome condensation. Cell survival was measured by colony formation assay. Analysis of dose-effect relations was based on the linear-quadratic model.</p> <p>Results</p> <p>Our results show that, although both investigated radiation types induce similar numbers of IRIF per absorbed dose, only a small fraction of the DSB induced by the low-LET gamma-rays result in chromosome rearrangements and cell reproductive death, while this fraction is considerably enhanced for the high-LET alpha-radiation. Calculated RBE values derived for the linear components of dose-effect relations for gamma-H2AX foci, cell reproductive death, chromosome fragments and colour junctions are 1.0 ± 0.3, 14.7 ± 5.1, 15.3 ± 5.9 and 13.3 ± 6.0 respectively.</p> <p>Conclusions</p> <p>These results indicate that RBE values for IRIF (DNA-DSB) induction provide little valid information on other biologically-relevant end points in cells exposed to high-LET radiations. Furthermore, the RBE values for the induction of the two types of chromosome aberrations are similar to those established for cell reproductive death. This suggests that assays of these aberrations might yield relevant information on the biological effectiveness in high-LET radiotherapy.</p

Early Adolescent Friendship Selection Based on Externalizing Behavior: the Moderating Role of Pubertal Development. The SNARE Study

Abstract This study examined friendship (de-)selection processes in early adolescence. Pubertal development was examined as a potential moderator. It was expected that pubertal development would be associated with an increased tendency for adolescents to select their friends based on their similarities in externalizing behavior engagement (i.e., delinquency, alcohol use, and tobacco use). Data were used from the first three waves of the SNARE (Social Network Analysis of Risk behavior in Early adolescence) study (N = 1144; 50 % boys; M age = 12.7; SD = 0.47), including students who entered the first year of secondary school. The hypothesis was tested using Stochastic Actor-Based Modeling in SIENA. While taking the network structure into account, and controlling for peer influence effects, the results supported this hypothesis. Early adolescents with higher pubertal development were as likely as their peers to select friends based on similarity in externalizing behavior and especially likely to remain friends with peers who had a similar level of externalizing behavior, and thus break friendship ties with dissimilar friends in this respect. As early adolescents are actively engaged in reorganizing their social context, adolescents with a higher pubertal development are especially likely to lose friendships with peers who do not engage in externalizing behavior, thus losing an important source of adaptive social control (i.e., friends who do not engage in externalizing behavior)

Wideband THz time domain spectroscopy based on optical rectification and electro-optic sampling

We present an analytical model describing the full electromagnetic propagation in a THz time-domain spectroscopy (THz-TDS) system, from the THz pulses via Optical Rectification to the detection via Electro Optic-Sampling. While several investigations deal singularly with the many elements that constitute a THz-TDS, in our work we pay particular attention to the modelling of the time-frequency behaviour of all the stages which compose the experimental set-up. Therefore, our model considers the following main aspects: (i) pump beam focusing into the generation crystal; (ii) phase-matching inside both the generation and detection crystals; (iii) chromatic dispersion and absorption inside the crystals; (iv) Fabry-Perot effect; (v) diffraction outside, i.e. along the propagation, (vi) focalization and overlapping between THz and probe beams, (vii) electro-optic sampling. In order to validate our model, we report on the comparison between the simulations and the experimental data obtained from the same set-up, showing their good agreement

Applying a cost-based pricing model for innovative cancer treatments subject to indication expansion:A case study for pembrolizumab and daratumumab

BACKGROUND: Expanding the indication of already approved immuno-oncology drugs presents treatment opportunities for patients but also strains healthcare systems. Cost-based pricing models are discussed as a possibility for cost containment. This study focuses on two drugs, pembrolizumab (Keytruda) and daratumumab (Darzalex), to explore the potential effect of indication broadening on the estimated price when using the cost-based pricing (CBP) model proposed by Uyl-de Groot and Löwenberg (2018). METHODS: The model was used to calculate cumulative yearly prices, cumulative prices per indication, and non-cumulative indication-based prices using inputs such as research and development (R&amp;D) costs, manufacturing costs, eligible patient population, and a profit margin. A deterministic stepwise analysis and scenario analysis were conducted to examine how sensitive the estimated price is to the different input assumptions. RESULTS: The yearly cumulative cost-based prices (CBPs) ranged from €52 to €885 for pembrolizumab per vial and €823 to €31,941 for daratumumab per vial. Prices were higher in initial years or indications due to smaller patient populations, decreased over time or after additional indications. Sensitivity analysis showed that the number of eligible patients had the most significant impact on the estimated price. In the scenario analysis the profit margin contributed most to a higher CBPs for both drugs. Lower estimates resulted from assumed lower R&amp;D costs. DISCUSSION: The estimated CBPs are consistently lower than Dutch list prices for pembrolizumab (€2,861), mainly resulting from larger patient populations in registered indications. However, daratumumab's list prices fall within the range of modeled CBPs depending on the year or indication (€4,766). Both CBPs decrease over time or with additional indications. The number of eligible patients and initial R&amp;D costs have the most significant influence on the CBPs. These findings contribute to the ongoing discussions on pharmaceutical pricing, especially concerning cancer drugs with expanding indications.</p

Dialysis delivery of an adenosine A 2A agonist into the pontine reticular formation of C57BL/6J mouse increases pontine acetylcholine release and sleep

In vivo microdialysis in C57BL/6J (B6) mouse was used to test the hypothesis that activating adenosine A 2A receptors in the pontine reticular formation (PRF) increases acetylcholine (ACh) release and rapid eye movement (REM) sleep. Eight concentrations of the adenosine A 2A receptor agonist 2- p- (2-carboxyethyl)phenethylamino-5′-N-ethylcarboxamidoadenosine hydrochloride (CGS 21680; CGS) were delivered to the PRF and ACh in the PRF was quantified. ACh release was significantly increased by dialysis with 3 μm CGS and significantly decreased by dialysis with 10 and 100 μm CGS. Co-administration of the adenosine A 2A receptor antagonist 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385; 30 nm) blocked the CGS-induced increase in ACh release. In a second series of experiments, CGS (3 μm) was delivered by dialysis to the PRF for 2 h while recording sleep and wakefulness. CGS significantly decreased time in wakefulness (−51% in h 1; −54% in h 2), increased time in non-rapid eye movement (NREM) sleep (90% in h 1; 151% in h 2), and increased both time in REM sleep (331% in h 2) and the number of REM sleep episodes (488% in h 2). The enhancement of REM sleep is consistent with the interpretation that adenosine A 2A receptors in the PRF of the B6 mouse contribute to REM sleep regulation, in part, by increasing ACh release in the PRF. A 2A receptor activation may promote NREM sleep via GABAergic inhibition of arousal promoting neurons in the PRF.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66018/1/j.1471-4159.2006.03700.x.pd

Prevalence of scoliosis and impaired pulmonary function in patients with type III osteogenesis imperfecta

Purpose: Osteogenesis Imperfecta (OI) is a rare group of congenital genetic disorders that consists of a collagen synthesis defect. The most severe phenotype is type III OI. Characterized by progressive bone deformity, fragility and pulmonary impairment, causing significant morbidity and mortality. Also, multilevel spine deformities are observed, such as scoliosis. The literature on the pathophysiology of pulmonary impairment in relation to scoliosis in these patients is scarce and conflicting. This study aims to determine the prevalence of scoliosis and its relation to pulmonary function in type III OI patients. Methods: This retrospective cohort study took place between April 2020 and November 2021. Forty-two patients with type III OI were included. Anterior–posterior spine radiographs were evaluated for scoliosis. Pulmonary function was assessed using spirometry and partial pressure of carbon dioxide. Results: All 42 patients had scoliosis, with a mean curve of 66° (95% CI of range). Vital lung capacity was decreased, compared to a non-OI population (mean 1.57 L). This was correlated to the degree of scoliosis (st. β − 0.40, P = 0.03), especially in increasing thoracic curves. Restrictive lung pathophysiology was shown in our study population with a mean FEV1/FVC ratio of 0.85. Conclusions: Increasing thoracic scoliosis was correlated with decreased vital lung capacity in our study population of type III OI patients. High FEV1/FVC ratios found in this study population show restrictive lung pathophysiology. Therefore, it is plausible that the pulmonary impairment found in type III OI patients is a combined issue, partly associated to scoliosis and partly intrinsic to OI

Not Just Efficiency: Insolvency Law in the EU and Its Political Dimension

Certain insolvency law rules, like creditors’ priorities and set-off rights, have a distributive impact on creditors. Distributional rules reflect the hierarchies of values and interests in each jurisdiction and, as a result, have high political relevance and pose an obstacle to reforming the EU Insolvency Regulation. This paper will show the difficulty of reform by addressing two alternative options to regulate cross-border insolvencies in the European Union. The first one is the ‘choice model’, under which companies can select the insolvency law they prefer. Although such a model would allow distressed firms to select the most efficient insolvency law, it would also displace Member States’ power to protect local constituencies. The choice model therefore produces negative externalities and raises legitimacy concerns. The opposite solution is full harmonisation of insolvency law at EU level, including distributional rules. Full harmonisation would have the advantage of internalising all externalities produced by cross-border insolvencies. However, the EU legislative process, which is still based on negotiations between states, is not apt to decide on distributive insolvency rules; additionally, if harmonisation includes such rules, it will indirectly modify national social security strategies and equilibria. This debate shows that the choice regarding power allocation over bankruptcies in the EU depends on the progress of European integration and is mainly a matter of political legitimacy, not only of efficiency

Cross-polarized photon-pair generation and bi-chromatically pumped optical parametric oscillation on a chip

Nonlinear optical processes are one of the most important tools in modern optics with a broad spectrum of applications in, for example, frequency conversion, spectroscopy, signal processing and quantum optics. For practical and ultimately widespread implementation, on-chip devices compatible with electronic integrated circuit technology offer great advantages in terms of low cost, small footprint, high performance and low energy consumption. While many on-chip key components have been realized, to date polarization has not been fully exploited as a degree of freedom for integrated nonlinear devices. In particular, frequency conversion based on orthogonally polarized beams has not yet been demonstrated on chip. Here we show frequency mixing between orthogonal polarization modes in a compact integrated microring resonator and demonstrate a bi-chromatically pumped optical parametric oscillator. Operating the device above and below threshold, we directly generate orthogonally polarized beams, as well as photon pairs, respectively, that can find applications, for example, in optical communication and quantum optics

Melanopsin as a Sleep Modulator: Circadian Gating of the Direct Effects of Light on Sleep and Altered Sleep Homeostasis in Opn4−/− Mice

Analyses in mice deficient for the blue-light-sensitive photopigment melanopsin show that direct effects of light on behavior and EEG depend on the time of day. The data further suggest an unexpected role for melanopsin in sleep homeostasis