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Background: The aim was to investigate the noise and bias properties of quantitative 177Lu-SPECT with respect to the number of projection angles, and the number of subsets and iterations in the OS-EM reconstruction, for different total acquisition times. Methods: Experimental SPECT acquisition of six spheres in a NEMA body phantom filled with 177Lu was performed, using medium-energy collimators and 120 projections with 180 s per projection. Bootstrapping was applied to generate data sets representing acquisitions with 20 to 120 projections for 10 min, 20 min, and 40 min, with 32 noise realizations per setting. Monte Carlo simulations were performed of 177Lu-DOTA-TATE in an anthropomorphic computer phantom with three tumours (2.8 mL to 40.0 mL). Projections representing 24 h and 168 h post administration were simulated, each with 32 noise realizations. Images were reconstructed using OS-EM with compensation for attenuation, scatter, and distance-dependent resolution. The number of subsets and iterations were varied within a constrained range of the product number of iterations × number of projections ≤ 2400 . Volumes-of-interest were defined following the physical size of the spheres and tumours, the mean activity-concentrations estimated, and the absolute mean relative error and coefficient of variation (CV) over noise realizations calculated. Pareto fronts were established by analysis of CV versus mean relative error. Results: Points at the Pareto fronts with low CV and high mean error resulted from using a low number of subsets, whilst points at the Pareto fronts associated with high CV but low mean error resulted from reconstructions with a high number of subsets. The number of projection angles had limited impact. Conclusions: For accurate estimation of the 177Lu activity-concentration from SPECT images, the number of projection angles has limited importance, whilst the total acquisition time and the number of subsets and iterations are parameters of importance. [ABSTRACT FROM AUTHOR]

The energy metabolism of the brain is poorly understood partly due to the complex morphology of neurons and fluctuations in ATP demand over time. To investigate this, we used metabolic models that estimate enzyme usage per pathway, enzyme utilization over time, and enzyme transportation to evaluate how these parameters and processes affect ATP costs for enzyme synthesis and transportation. Our models show that the total enzyme maintenance energy expenditure of the human body depends on how glycolysis and mitochondrial respiration are distributed both across and within cell types in the brain. We suggest that brain metabolism is optimized to minimize the ATP maintenance cost by distributing the different ATP generation pathways in an advantageous way across cell types and potentially also across synapses within the same cell. Our models support this hypothesis by predicting export of lactate from both neurons and astrocytes during peak ATP demand, reproducing results from experimental measurements reported in the literature. Furthermore, our models provide potential explanation for parts of the astrocyte-neuron lactate shuttle theory, which is recapitulated under some conditions in the brain, while contradicting other aspects of the theory. We conclude that enzyme usage per pathway, enzyme utilization over time, and enzyme transportation are important factors for defining the optimal distribution of ATP production pathways, opening a broad avenue to explore in brain metabolism. [ABSTRACT FROM AUTHOR]

Background: A 3D printing grid-based method was developed to construct anthropomorphic phantoms with non-uniform activity distributions, to be used for evaluation of quantitative SPECT images. The aims were to characterize the grid-based method and to evaluate its capability to provide realistically shaped phantoms with non-uniform activity distributions. Methods: Characterization of the grid structures was performed by printing grid-filled spheres. Evaluation was performed by micro-CT imaging to investigate the printing accuracy and by studying the modulation contrast ( C M ) in SPECT images for 177Lu and 99mTc as a function of the grid fillable-volume fraction (FVF) determined from weighing. The grid-based technique was applied for the construction of two kidney phantoms and two thyroid phantoms, designed using templates from the XCAT digital phantoms. The kidneys were constructed with a hollow outer container shaped as cortex, an inner grid-based structure representing medulla and a solid section representing pelvis. The thyroids consisted of two lobes printed as grid-based structures, with void hot spots within the lobes. The phantoms were filled with solutions of 177Lu (kidneys) or 99mTc (thyroids) and imaged with SPECT. For verification, Monte Carlo simulations of SPECT imaging were performed for activity distributions corresponding to those of the printed phantoms. Measured and simulated SPECT images were compared qualitatively and quantitatively. Results: Micro-CT images showed that printing inaccuracies were mainly uniform across the grid. The relationships between the FVF from weighing and C M were found to be linear (r = 0.9995 and r = 0.9993 for 177Lu and 99mTc, respectively). The FVF-deviations from the design were up to 15% for thyroids and 4% for kidneys, mainly related to possibilities of cleaning after printing. Measured and simulated SPECT images of kidneys and thyroids exhibited similar activity distributions and quantitative comparisons agreed well, thus verifying the grid-based method. Conclusions: We find the grid-based technique useful for the provision of 3D printed, realistically shaped, phantoms with non-uniform activity distributions, which can be used for evaluation of different quantitative methods in SPECT imaging. [ABSTRACT FROM AUTHOR]

Background: Dosimetry in radionuclide therapy often requires the calculation of average absorbed doses within and between spatial regions, for example, for voxel‐based dosimetry methods, for paired organs, or across multiple tumors. Formation of such averages can be made in different ways, starting from different definitions. Purpose: The aim of this study is to formally specify different averaging strategies for absorbed doses, and to compare their results when applied to absorbed dose distributions that are non‐uniform within and between regions. Methods: For averaging within regions, two definitions of the average absorbed dose are considered: the simple average over the region (the region average) and the average when weighting by the mass density (density‐weighted region average). The latter is shown to follow from the definition of mean absorbed dose according to the ICRU, and to be consistent with the MIRD formalism. For averaging between different spatial regions, three definitions follow: the volume‐weighted, the mass‐weighted, and the unweighted average. With respect to characterizing non‐uniformity, the different average definitions lead to the use of dose‐volume histograms (DVHs) (region average), dose‐mass histograms (DMHs) (density‐weighted region average), and unweighted histograms (unweighted average). Average absorbed doses are calculated for three worked examples, starting from the different definitions. The first, schematic, example concerns the calculation of the average absorbed dose between two regions with different volumes or mass densities. The second, stylized, example concerns voxel‐based dosimetry, for which the average absorbed‐dose rate within a region is calculated. The geometries studied include three 177Lu‐filled voxelized spheres, where the sphere masses are held constant while the material compositions, densities, and volumes are varied. For comparison, the mean absorbed‐dose rates obtained using unit‐density sphere S‐values are also included. The third example concerns SPECT/CT‐based tumor dosimetry for five patients undergoing therapy with 177Lu‐PSMA and six patients undergoing therapy with 177Lu‐DOTA‐TATE, for which the average absorbed‐dose rates across multiple tumors are calculated. For the second and third examples, analyses also include representations by histograms. Results: Example 1 shows that the average absorbed doses, calculated using different definitions, can differ considerably if the masses and absorbed doses for two regions are markedly different. From example 2 it is seen that the density‐weighted region average is stable under different activity and density distributions and is also in line with results using S‐values. In contrast, the region average varies as function of the activity distribution. In example 3, the absorbed dose rates for individual tumors differ by (1.1 ± 4.3)% and (−0.1 ± 0.4)% with maximum deviations of +34.4% and −1.4% for 177Lu‐PSMA and 177Lu‐DOTA‐TATE, respectively, when calculated as region averages or density‐weighted region averages, with largest deviations obtained when the density is non‐uniform. The average absorbed doses calculated across all tumors are similar when comparing mass‐weighted and volume‐weighted averages but these differ substantially from unweighted averages. Conclusion: Different strategies for averaging of absorbed doses within and between regions can lead to substantially different absorbed‐dose estimates. At reporting of radionuclide therapy dosimetry, it is important to specify the averaging strategy applied. [ABSTRACT FROM AUTHOR]

Single-cell RNA sequencing combined with genome-scale metabolic models (GEMs) has the potential to unravel the differences in metabolism across both cell types and cell states but requires new computational methods. Here, we present a method for generating cell-type-specific genome-scale models from clusters of single-cell RNA-Seq profiles. Specifically, we developed a method to estimate the minimum number of cells required to pool to obtain stable models, a bootstrapping strategy for estimating statistical inference, and a faster version of the task-driven integrative network inference for tissues algorithm for generating context-specific GEMs. In addition, we evaluated the effect of different RNA-Seq normalization methods on model topology and differences in models generated from single-cell and bulk RNA-Seq data. We applied our methods on data from mouse cortex neurons and cells from the tumor microenvironment of lung cancer and in both cases found that almost every cell subtype had a unique metabolic profile. In addition, our approach was able to detect cancer-associated metabolic differences between cancer cells and healthy cells, showcasing its utility. We also contextualized models from 202 single-cell clusters across 19 human organs using data from Human Protein Atlas and made these available in the web portal Metabolic Atlas, thereby providing a valuable resource to the scientific community. With the ever-increasing availability of single-cell RNA-Seq datasets and continuously improved GEMs, their combination holds promise to become an important approach in the study of human metabolism. [ABSTRACT FROM AUTHOR]

It is natural to assume that every value bearer must be good, bad, or neutral. This paper argues that this assumption is false if value incomparability is possible. More precisely, if value incommensurability is possible, then there is a fourth category of absolute value, in addition to the good, the bad, and the neutral. [ABSTRACT FROM AUTHOR]

Background: Somatostatin receptor 68Ga PET imaging is standard for evaluation of a patient's suitability for 177Lu peptide receptor radionuclide therapy of neuroendocrine tumours (NETs). The 68Ga PET serves to ensure sufficient somatostatin receptor expression, commonly evaluated qualitatively. The aim of this study is to investigate the quantitative relationships between uptake in 68Ga PET and absorbed doses in 177Lu therapy. Method: Eighteen patients underwent [68Ga]Ga-DOTA-TATE PET imaging within 20 weeks prior to their first cycle of [177Lu]Lu-DOTA-TATE. Absorbed doses for therapy were estimated for tumours, kidney, spleen, and normal liver parenchyma using a hybrid SPECT/CT–planar method. Gallium-68 activity concentrations were retrieved from PET images and also used to calculate SUVs and normalized SUVs, using blood and tissue for normalization. The 68Ga activity concentrations per injected activity, SUVs, and normalized SUVs were compared with 177Lu activity concentrations 1 d post-injection and 177Lu absorbed doses. For tumours, for which there was a variable number per patient, both inter- and intra-patient correlations were analysed. Furthermore, the prediction of 177Lu tumour absorbed doses based on a combination of tumour-specific 68Ga activity concentrations and group-based estimates of the effective half-lives for grade 1 and 2 NETs was explored. Results: For normal organs, only spleen showed a significant correlation between the 68Ga activity concentration and 177Lu absorbed dose (r = 0.6). For tumours, significant, but moderate, correlations were obtained, with respect to both inter-patient (r = 0.7) and intra-patient (r = 0.45) analyses. The correlations to absorbed doses did not improve when using 68Ga SUVs or normalized SUVs. The relationship between activity uptakes for 68Ga PET and 177Lu SPECT was stronger, with correlation coefficients r = 0.8 for both inter- and intra-patient analyses. The 177Lu absorbed dose to tumour could be predicted from the 68Ga activity concentrations with a 95% coverage interval of − 65% to 248%. Conclusions: On a group level, a high uptake of [68Ga]Ga-DOTA-TATE is associated with high absorbed doses at 177Lu-DOTA-TATE therapy, but the relationship has a limited potential with respect to individual absorbed dose planning. Using SUV or SUV normalized to reference tissues do not improve correlations compared with using activity concentration per injected activity. [ABSTRACT FROM AUTHOR]

According to Act Consequentialism, an act is right if and only if its outcome is not worse than the outcome of any alternative to that act. This view, however, leads to deontic paradoxes if the alternatives to an act are all other acts that can be done in the situation. A typical response is to only apply this rightness criterion to maximally specific acts and to take the alternatives to a maximally specific act to be the other maximally specific acts that can be done in the situation. (This view can then be supplanted by a separate account for the rightness of acts that are not maximally specific.) This paper defends a rival view, Binary Act Consequentialism, where, for any voluntary act, that act is right if and only if its outcome is not worse than the outcome of not doing that act. Binary Act Consequentialism, which dates back to Jeremy Bentham, has few supporters. A number of seemingly powerful objections have been considered fatal. In this paper, I rebut these objections and put forward a positive argument for the view. [ABSTRACT FROM AUTHOR]

Background: In recent years, a lot of effort has been put in the enhancement of medical imaging using artificial intelligence. However, limited patient data in combination with the unavailability of a ground truth often pose a challenge to a systematic validation of such methodologies. The goal of this work was to investigate a recently proposed method for an artificial intelligence-based generation of synthetic SPECT projections, for acceleration of the image acquisition process based on a large dataset of realistic SPECT simulations. Methods: A database of 10,000 SPECT projection datasets of heterogeneous activity distributions of randomly placed random shapes was simulated for a clinical SPECT/CT system using the SIMIND Monte Carlo program. Synthetic projections at fixed angular increments from a set of input projections at evenly distributed angles were generated by different u-shaped convolutional neural networks (u-nets). These u-nets differed in noise realization used for the training data, number of input projections, projection angle increment, and number of training/validation datasets. Synthetic projections were generated for 500 test projection datasets for each u-net, and a quantitative analysis was performed using statistical hypothesis tests based on structural similarity index measure and normalized root-mean-squared error. Additional simulations with varying detector orbits were performed on a subset of the dataset to study the effect of the detector orbit on the performance of the methodology. For verification of the results, the u-nets were applied to Jaszczak and NEMA physical phantom data obtained on a clinical SPECT/CT system. Results: No statistically significant differences were observed between u-nets trained with different noise realizations. In contrast, a statistically significant deterioration was found for training with a small subset (400 datasets) of the 10,000 simulated projection datasets in comparison with using a large subset (9500 datasets) for training. A good agreement between synthetic (i.e., u-net generated) and simulated projections before adding noise demonstrates a denoising effect. Finally, the physical phantom measurements show that our findings also apply for projections measured on a clinical SPECT/CT system. Conclusion: Our study shows the large potential of u-nets for accelerating SPECT/CT imaging. In addition, our analysis numerically reveals a denoising effect when generating synthetic projections with a u-net. Clinically interesting, the methodology has proven robust against camera orbit deviations in a clinically realistic range. Lastly, we found that a small number of training samples (e.g., ~ 400 datasets) may not be sufficient for reliable generalization of the u-net. [ABSTRACT FROM AUTHOR]

Independence is the condition that, if X is preferred to Y, then a lottery between X and Z is preferred to a lottery between Y and Z given the same probability of Z. Is it rationally required that one's preferences conform to Independence? The main objection to this requirement is that it would rule out the alleged rationality of Allais and Ellsberg Preferences. In this paper, I put forward a sequential dominance argument with fairly weak assumptions for a variant of Independence (called Independence for Constant Prospects), which shows that Allais and Ellsberg Preferences are irrational. Hence this influential objection (that is, the alleged rationality of Allais and Ellsberg Preferences) can be rebutted. I also put forward a number of sequential dominance arguments that various versions of Independence are requirements of rationality. One of these arguments is based on very minimal assumptions, but the arguments for the versions of Independence which are strong enough to serve in the standard axiomatization of Expected Utility Theory need notably stronger assumptions. [ABSTRACT FROM AUTHOR]

Is an outcome where many people are saved and one person dies better than an outcome where the one is saved and the many die? According to the standard utilitarian justification, the former is better because it has a greater sum total of well-being. This justification involves a controversial form of moral aggregation, because it is based on a comparison between aggregates of different people's well-being. Still, an alternative justification—the Argument for Best Outcomes—does not involve moral aggregation. I extend the Argument for Best Outcomes to show that any utilitarian evaluation can be justified without moral aggregation. [ABSTRACT FROM AUTHOR]

Single-cell technologies have been widely used in biological studies and generated a plethora of single-cell data to be interpreted. Due to the inclusion of the priori metabolic network knowledge as well as gene–protein–reaction associations, genome-scale metabolic models (GEMs) have been a powerful tool to integrate and thereby interpret various omics data mostly from bulk samples. Here, we first review two common ways to leverage bulk omics data with GEMs and then discuss advances on integrative analysis of single-cell omics data with GEMs. We end by presenting our views on current challenges and perspectives in this field. • Methods of integration of bulk data with metabolic models. • Methods of integration of single-cell data with metabolic models. • Challenges in single-cell data analysis with metabolic models. [ABSTRACT FROM AUTHOR]

Single-cell RNA sequencing has become a valuable tool for investigating cell types in complex tissues, where clustering of cells enables the identification and comparison of cell populations. Although many studies have sought to develop and compare different clustering approaches, a deeper investigation into the properties of the resulting populations is lacking. Specifically, the presence of misclassified cells can influence downstream analyses, highlighting the need to assess subpopulation purity and to detect such cells. We developed DSAVE (Down-SAmpling based Variation Estimation), a method to evaluate the purity of single-cell transcriptome clusters and to identify misclassified cells. The method utilizes down-sampling to eliminate differences in sampling noise and uses a log-likelihood based metric to help identify misclassified cells. In addition, DSAVE estimates the number of cells needed in a population to achieve a stable average gene expression profile within a certain gene expression range. We show that DSAVE can be used to find potentially misclassified cells that are not detectable by similar tools and reveal the cause of their divergence from the other cells, such as differing cell state or cell type. With the growing use of single-cell RNA-seq, we foresee that DSAVE will be an increasingly useful tool for comparing and purifying subpopulations in single-cell RNA-Seq datasets. [ABSTRACT FROM AUTHOR]

A standard liberal claim is that freedom of choice is not only instrumentally valuable but also intrinsically valuable, that is, valuable for its own sake. I argue that each one of five conditions should hold if freedom of choice is intrinsically valuable: First, if rational people may differ as to which option is the most preferred in an option set, the offered freedom of choice has some intrinsic value. Second, if an option set is expanded with an option that must be less preferred than the already available options by any rational person, the intrinsic value of the offered freedom of choice does not increase. Third, if an option set is expanded, the intrinsic value of the offered freedom of choice does not decrease. Fourth, if an option set has only one option, it does not offer any intrinsically good freedom of choice. And, fifth, the relation 'at least as good freedom of choice as' is transitive. The trouble is that there exists a counter‐example to the conjunction of these conditions. Hence freedom of choice is not intrinsically valuable. [ABSTRACT FROM AUTHOR]

Moral obligation and permissibility are usually thought to be interdefinable. Following the pattern of the duality definitions of necessity and possibility, we have that something's being permissible could be defined as its not being obligatory to not do it. And that something's being obligatory could be defined as its not being permissible to not do it. In this paper, I argue that neither direction of this alleged interdefinability works. Roughly, the problem is that a claim that some act is obligatory or permissible entails that there is a moral law, whereas a negative claim that some act is not obligatory or not permissible does not. Nevertheless, one direction of the interdefinability can potentially be salvaged. I argue that, if we do not require the conceptual possibility of moral dilemmas, then there is a way to plausibly define obligation in terms of permissibility. I conclude that permissibility is the only feasible deontic primitive. [ABSTRACT FROM AUTHOR]

The article discusses issues associated with standard objection to backward induction. Topics discusses exploitation scheme against agents with cyclic preferences, money-pump argument based on a sequence of trade offers, backward induction in the Standard Money Pump, standard objection to backward induction and well-known exploitation scheme that works against agents with cyclic preferences who use backward induction.

Cell-type specific gene expression profiles are needed for many computational methods operating on bulk RNA-Seq samples, such as deconvolution of cell-type fractions and digital cytometry. However, the gene expression profile of a cell type can vary substantially due to both technical factors and biological differences in cell state and surroundings, reducing the efficacy of such methods. Here, we investigated which factors contribute most to this variation. We evaluated different normalization methods, quantified the variance explained by different factors, evaluated the effect on deconvolution of cell type fractions, and examined the differences between UMI-based single-cell RNA-Seq and bulk RNA-Seq. We investigated a collection of publicly available bulk and single-cell RNA-Seq datasets containing B and T cells, and found that the technical variation across laboratories is substantial, even for genes specifically selected for deconvolution, and this variation has a confounding effect on deconvolution. Tissue of origin is also a substantial factor, highlighting the challenge of using cell type profiles derived from blood with mixtures from other tissues. We also show that much of the differences between UMI-based single-cell and bulk RNA-Seq methods can be explained by the number of read duplicates per mRNA molecule in the single-cell sample. Our work shows the importance of either matching or correcting for technical factors when creating cell-type specific gene expression profiles that are to be used together with bulk samples. [ABSTRACT FROM AUTHOR]

Daniel C. Dennett has long maintained that the Consequence Argument for incompatibilism is confused. In a joint work with Christopher Taylor, he claims to have shown that the argument is based on a failure to understand Logic 101. Given a fairly plausible account of having the power to cause something, they claim that the argument relies on an invalid inference rule. In this paper, I show that Dennett and Taylor's refutation does not work against a better, more standard version of the Consequence Argument. Therefore, Dennett and Taylor's alleged refutation fails. [ABSTRACT FROM AUTHOR]

Kurt Gödel's version of the Ontological Proof derives rather than assumes the crucial (yet controversial) Possibility Claim, that is, the claim that it is possible that something God-like exists. Gödel's derivation starts off with a proof of the Possible Instantiation of the Positive, that is, the principle that, if a property is positive, it is possible that there exists something that has that property. I argue that Gödel's proof of this principle relies on some implausible axiological assumptions. Nevertheless, I present a proof of the Possible Instantiation of the Positive, which only relies on plausible axiological principles. Nonetheless, Gödel's derivation of the Possibility Claim also needs a substantial axiological assumption, which is still open to doubt. [ABSTRACT FROM AUTHOR]

Background: Although the importance of quantitative SPECT has increased tremendously due to newly developed therapeutic radiopharmaceuticals, there are still no accreditation programs to harmonize SPECT imaging. Work is currently underway to develop an accreditation for quantitative 177Lu SPECT/CT. The aim of this study is to verify whether the positioning of the spheres within the phantom has an influence on the recovery and thus needs to be considered in SPECT harmonization. In addition, the effects of these recovery coefficients on a potential partial volume correction as well as absorbed-dose estimates are investigated. Methods: Using a low-dose CT of a SPECT/CT acquisition, a computerized version of the NEMA body phantom was created using a semi-automatic threshold-based method. Based on the mass-density map, the detector orbit, and the sphere centers, realistic SPECT acquisitions of all possible 720 sphere configurations of both the PET and the SPECT versions of the NEMA Body Phantom were generated using Monte Carlo simulations. SPECT reconstructions with different numbers of updates were performed without (CASToR) and with resolution modeling (STIR). Recovery coefficients were calculated for all permutations, reconstruction methods, and phantoms, and their dependence on the sphere positioning was investigated. Finally, the simulation-based findings were validated using SPECT/CT acquisitions of six different sphere configurations. Results: Our analysis shows that sphere positioning has a significant impact on the recovery for both of the reconstruction methods and the phantom type. Although resolution modeling resulted in significantly higher recovery, the relative variation in recovery within the 720 permutations was even larger. When examining the extreme values of the recovery, reconstructions without resolution modeling were influenced primarily by the sphere position, while with resolution modeling the volume of the two adjacent spheres had a larger influence. The SPECT measurements confirmed these observations, and the recovery curves showed good overall agreement with the simulated data. Conclusion: Our study shows that sphere positioning has a significant impact on the recovery obtained in NEMA sphere phantom measurements and should therefore be considered in a future SPECT accreditation. Furthermore, the single-measurement method normally performed for PVC should be reconsidered to account for the position dependency. [ABSTRACT FROM AUTHOR]

Given reductionism about people, personal persistence must fundamentally consist in some kind of impersonal continuity relation. Typically, these continuity relations can hold from one to many. And, if they can, the analysis of personal persistence must include a non-branching clause to avoid non-transitive identities or multiple occupancy. It is far from obvious, however, what form this clause should take. This paper argues that previous accounts are inadequate and develops a new proposal. [ABSTRACT FROM AUTHOR]

A compelling requirement on normative theories is that they should be satisfiable, that is, in every possible choice situation with a finite number of alternatives, there should be at least one performable act such that, if one were to perform that act, one would comply with the theory. In this paper, I argue that, given some standard assumptions about free will and counterfactuals, Objective Act Consequentialism violates this requirement. [ABSTRACT FROM AUTHOR]

Purpose: A hybrid planar‐SPECT/CT method for tumor dosimetry in 177Lu‐DOTATATE therapy, applicable to datasets consisting of multiple conjugate‐view images and one SPECT/CT, is developed and evaluated. Methods: The imaging protocol includes conjugate‐view imaging at 1, 24, 96, and 168 h post infusion (p.i.) and a SPECT/CT acquisition 24 h p.i. The dosimetry method uses the planar images to estimate the shape of the time–activity concentration curve, which is then rescaled to absolute units using the SPECT‐derived activity concentration. The resulting time‐integrated activity concentration coefficient (TIACC) is used to calculate the tumor‐absorbed dose. Semiautomatic segmentation techniques are applied for tumor delineation in both planar and SPECT images, where the planar image segmentation is accomplished using an active‐rays‐based technique. The selection of tumors is done by visual inspection of planar and SPECT images and applying a set of criteria concerning the tumor visibility and possible interference from superimposed activity uptakes in the planar images. Five different strategies for determining values from planar regions of interest (ROIs), based on entire or partial ROIs, and with and without background correction, are evaluated. Evaluation is performed against a SPECT/CT‐based method on data from six patients where sequential conjugate‐view and SPECT/CT imaging have been performed in parallel and against ground truths in Monte Carlo simulated images. The patient data are also used to evaluate the interoperator variability and to assess the validity of the developed criteria for tumor selection. Results: For patient images, the hybrid method produces TIACCs that are on average 6% below those of the SPECT/CT only method, with standard deviations for the relative TIACC differences of 8%–11%. Simulations show that the hybrid and SPECT‐based methods estimate the TIACCs to within approximately 10% for tumors larger than around 10 ml, while for smaller tumors, all methods underestimate the TIACCs due to underestimations of the activity concentrations in the SPECT images. The planar image segmentation has a low operator dependence, with a median Dice similarity coefficient of 0.97 between operators. The adopted criteria for tumor selection manage to discriminate the tumors for which the absorbed‐dose deviations between the hybrid and SPECT methods are the highest. Conclusions: The hybrid method is found suitable for studies of tumor‐absorbed doses in radionuclide therapy, provided that selection criteria regarding the visibility and overlapping activities in the planar images are applied. [ABSTRACT FROM AUTHOR]

The article focuses on the American philosopher John Rawls's version of the Difference Principle. Topics discussed include in Rawls's theory, the Difference Principle is subordinate to the Principle of Justice; mentions the relevant comparisons for identifying the least advantaged are made in terms of primary goods; and also mentions the Difference Principle is only supposed to be applied to the choice of the basic structure of society.

Derek Parfit’s argument against the platitude that identity is what matters in survival does not work given his intended reading of the platitude, namely, that what matters in survival to some future time is being identical with someone who is alive at that time. I develop Parfit’s argument so that it works against the platitude on the intended reading. [ABSTRACT FROM AUTHOR]

Jeremy Bentham is often interpreted as defending a satisficing, rather than maximizing, version of utilitarianism, where an act is right as long as it produces more pleasure than pain. This lack of maximization is surprising given Bentham's maximizing slogan 'the greatest happiness of the greatest number'. Against the satisficing interpretation, I argue that Bentham consistently defends a maximizing version of utilitarianism, where an act's consequences are compared to those of not performing the act. I show that following this version of utilitarianism requires that one realizes the greatest happiness for all affected individuals. [ABSTRACT FROM AUTHOR]

Background: Monte Carlo simulations provide accurate models of nuclear medicine imaging systems as they can properly account for the full physics of photon transport. The accuracy of the model included in the maximum-likelihood-expectation-maximization (ML-EM) reconstruction limits the overall accuracy of the reconstruction results. In this paper, we present a Monte Carlo-based ML-EM reconstruction method for pinhole single-photon emission computed tomography (SPECT) that has been incorporated into the SIMIND Monte Carlo program. The Monte Carlo-based model, which accounts for all of the physical and geometrical characteristics of the camera system, is used in the forward-projection step of the reconstruction, while a simpler model based on ray-tracing is used for back-projection. The aim of this work was to investigate the quantitative accuracy of this combination of forward- and back-projectors in the clinical pinhole camera GE Discovery NM 530c. Results: The total activity was estimated in Tc-filled spheres with volumes between 0.5 and 16 mL. The total sphere activity was generally overestimated but remained within 10% of the reference activity defined by the phantom preparation. The recovered activity converged towards the reference activity as the number of iterations increased. Furthermore, the recovery of the activity concentrations within the physical boundaries of the spheres increased with increasing sphere volume. Additionally, the Monte Carlo-based reconstruction enabled recovery of the true activity concentration in the myocardium of a cardiac phantom mounted in a torso phantom regardless of whether the torso was empty or water-filled. A qualitative comparison to data reconstructed using the clinical reconstruction algorithm showed that the two methods performed similarly, although the images reconstructed using the clinical software were more uniform due to the incorporation of noise regularization and post-filtration in that reconstruction technique. Conclusions: We developed a Monte Carlo-based reconstruction method for pinhole SPECT and evaluated it using phantom measurements. The combination of a Monte Carlo-based forward-projector and a simplified analytical ray-tracing back-projector produced quantitative images of acceptable image quality. No explicit calibration is necessary in this method since the forward-projector model maintains a relationship between the number of counts and activity. [ABSTRACT FROM AUTHOR]

Over the last 15 years, genome‐scale metabolic models (GEMs) have been reconstructed for human and model animals, such as mouse and rat, to systematically understand metabolism, simulate multicellular or multi‐tissue interplay, understand human diseases, and guide cell factory design for biopharmaceutical protein production. Here, we describe how metabolic networks can be represented using stoichiometric matrices and well‐defined constraints for flux simulation. Then, we review the history of GEM development for quantitative understanding of Homo sapiens and other relevant animals, together with their applications. We describe how model develops from H. sapiens to other animals and from generic purpose to precise context‐specific simulation. The progress of GEMs for animals greatly expand our systematic understanding of metabolism in human and related animals. We discuss the difficulties and present perspectives on the GEM development and the quest to integrate more biological processes and omics data for future research and translation. We truly hope that this review can inspire new models developed for other mammalian organisms and generate new algorithms for integrating big data to conduct more in‐depth analysis to further make progress on human health and biopharmaceutical engineering. [ABSTRACT FROM AUTHOR]

An essay is presented on the strengthened consequence argument for incompatibilism. It aims to show the truth of determinism from the remote past and the laws of nature with argument that relies on two inference rules. It explores the relationship between unavoidability and logical necessity represented by material implication.

Background: Dosimetry in radionuclide therapy has the potential to allow for a treatment tailored to the individual patient. One therapeutic radiopharmaceutical where patient-specific dosimetry is feasible is Lu-DOTATATE, used for the treatment of neuroendocrine tumours. The emission of gamma photons by Lu allows for imaging with SPECT (single photon emission computed tomography). One important step for dosimetry using this imaging technique is the SPECT image segmentation, which needs to be robust and accurate for the estimated quantities to be reliable. This work investigates different methods for automatic tumour delineation in Lu-DOTATATE SPECT images. Three segmentation methods are considered: a fixed 42% threshold (FT), the Otsu method (OM) and a method based on Fourier surfaces (FS). Effects of including resolution compensation in the iterative SPECT image reconstruction are also studied. Evaluation is performed based on Monte Carlo-simulated SPECT images from 24 h and 336 h post injection (p.i.), for determination of the volume, activity concentration and dice similarity coefficient. In addition, patient data are used to investigate the correspondence of tumour volumes when delineated in SPECT or morphological CT or MR images. Patient data are also used to examine the sensitivity to the operator-dependent initialization. Results: For simulated images from 24 h p.i. reconstructed without resolution compensation, a volume and activity-concentration root-mean-square error below 15% is typically obtained for tumours above approximately 10 cm when using OM or FS, while FT performs considerably worse. When including resolution compensation, the tumour volume becomes underestimated and the activity concentration overestimated. The FS method appears to be robust to noise, as seen for the 336 h images. The differences between the tumour volumes estimated from the SPECT images and the volumes estimated from morphological images are generally larger than the discrepancies seen for the simulated data sets. Conclusions: Segmentation results are encouraging for future dosimetry of tumours with volumes above approximately 10 cm. Using resolution compensation in the reconstruction may have a negative effect on volume estimation. [ABSTRACT FROM AUTHOR]

Erik Carlson puts forward a new way of defining monadic value predicates, such as 'good', in terms of dyadic value relations, such as 'better'. Earlier definitions of this kind have the unwanted feature that they rule out some reasonable axiologies by conceptual fiat. Carlson claims that his definitions do not have this drawback. In this paper, I argue that they do. [ABSTRACT FROM AUTHOR]

In an alleged counter-example to the completeness of rational preferences, a career as a clarinettist is compared with a career in law. It seems reasonable to neither want to judge that the law career is at least as preferred as the clarinet career nor want to judge that the clarinet career is at least as preferred as the law career. The two standard interpretations of examples of this kind are, first, that the examples show that preferences are rationally permitted to be incomplete and, second, that the examples show that preferences are rationally permitted to be indeterminate. In this paper, I shall argue that the difference between these interpretations is crucial for the money-pump argument for transitivity, which is the standard argument that rational preferences are transitive. I shall argue that the money-pump argument for transitivity fails if preferences are rationally permitted to be incomplete but that it works if preferences are rationally permitted to be indeterminate and rationally required to be complete. [ABSTRACT FROM AUTHOR]

According to the widely held anti-aggregation principle, it is wrong to save a larger number of people from minor harms rather than a smaller number from much more serious harms. This principle is a central part of many influential and anti-utilitarian ethical theories. According to the sequential-dominance principle, one does something wrong if one knowingly performs a sequence of acts whose outcome would be worse for everyone than the outcome of an alternative sequence of acts. The intuitive appeal of the sequential-dominance principle should be obvious; everyone is knowingly made worse off if it is violated. In this paper, I present a number of cases where one is forced to violate either the anti-aggregation principle or the sequential-dominance principle. I show that these principles conflict regardless of whether one accepts a counterfactual or a temporal, worsening view of harm. Moreover, I show that this result holds regardless of how much worse a harm has to be in order to count as a much more serious harm. [ABSTRACT FROM AUTHOR]

In this paper, I argue against defining either of 'good' and 'better' in terms of the other. According to definitions of 'good' in terms of 'better', something is good if and only if it is better than some indifference point. Against this approach, I argue that the indifference point cannot be defined in terms of 'better' without ruling out some reasonable axiologies. Against defining 'better' in terms of 'good', I argue that this approach either cannot allow for the incorruptibility of intrinsic goodness or it breaks down in cases where both of the relata of 'better' are bad. [ABSTRACT FROM AUTHOR]

One of the principles on how to act under moral uncertainty, My Favourite Theory, says roughly that a morally conscientious agent chooses an option that is permitted by the most credible moral theory. In defence of this principle, we argue that it prescribes consistent choices over time, without relying on intertheoretic comparisons of value, while its main rivals are either plagued by moral analogues of money pumps or in need of a method for making non-arbitrary intertheoretic comparisons. We rebut the arguments that have been levelled against My Favourite Theory and offer some arguments against intertheoretic comparisons of value. [ABSTRACT FROM AUTHOR]

In the 1960's, Lars Bergström and Hector-Neri Castañeda noticed a problem with alternative acts and consequentialism. The source of the problem is that some performable acts are versions of other performable acts and the versions need not have the same consequences as the originals. Therefore, if all performable acts are among the agent's alternatives, act consequentialism yields deontic paradoxes. A standard response is to restrict the application of act consequentialism to certain relevant alternative sets. Many proposals are based on some variation of maximalism, that is, the view that act consequentialism should only be applied to maximally specific acts. In this paper, I argue that maximalism cannot yield the right prescriptions in some cases where one can either (i) form at once the intention to do an immediate act and form at a later time the intention to do a succeeding act or (ii) form at once the intention to do both acts and where the consequences of (i) and (ii) differ in value. Maximalism also violates normative invariance, that is, the condition that if an act is performable in a situation, then the normative status of the act does not depend on what acts are performed in the situation. Instead of maximalism, I propose that the relevant alternatives should be the exhaustive combinations of acts the agent can jointly perform without performing any other act in the situation. In this way, one avoids the problem of act versions without violating normative invariance. Another advantage is that one can adequately differentiate between possibilities like (i) and (ii). [ABSTRACT FROM AUTHOR]

Joshua Gert and Wlodek Rabinowicz have developed frameworks for value relations that are rich enough to allow for non-standard value relations such as parity. Yet their frameworks do not allow for any non-standard preference relations. In this paper, I shall defend a symmetry between values and preferences, namely, that for every value relation, there is a corresponding preference relation, and vice versa. I claim that if the arguments that there are non-standard value relations are cogent, these arguments, mutatis mutandis, also show that there are non-standard preference relations. Hence frameworks of Gert and Rabinowicz's type are either inadequate since there are cogent arguments for both non-standard value and preference relations and these frameworks deny this, or they lack support since the arguments for non-standard value relations are unconvincing. Instead, I propose a simpler framework that allows for both non-standard value and preference relations. [ABSTRACT FROM AUTHOR]

This work presents a new mathematical formulation of biologically effective dose (BED) for radiation therapy where effects of repair need to be considered. The formulation is based on the observation that the effects of repair, both during protracted irradiation and of incomplete repair between fractions, can be written using a convolution, i.e. BED(T ) = ∫ ∞ -∞ RT (t )dt + 1 /α/β ∫∞ -∞ RT (t ) [RT (t ) ⊕ I(t )] dt, where T is the total irradiation time, RT (t ) is the absorbed dose rate as a function of time t and I(t ) is the function describing repair. To validate this formulation, the previously published expressions for instant and protracted irradiation are first summarized. Then, by analytical derivation, it is shown that the new formulation gives identical results. The calculation of BED can thus be treated within one single mathematical framework, applicable in external beam therapy, brachytherapy, radionuclide therapy, or a combination of these treatment modalities. Moreover, the new formulation allows for a straightforward incorporation of different repair models and has the advantage of being numerically applicable. [ABSTRACT FROM AUTHOR]

We have previously shown analytically that the biologically effective dose (BED), including effects of repair during irradiation and of incomplete repair between fractions, can be formulated using a convolution between the absorbed dose rate function and the function describing repair. In this work, a discrete formalism is derived along with its implementation via the fast Fourier transform. The implementation takes the intrinsic periodicity of the discrete Fourier transform into consideration, as well as possible inconsistencies that may arise due to discretization and truncation of the functions describing the absorbed dose rate and repair. Numerically and analytically calculated BED values are compared for various situations in external beam radiotherapy, brachytherapy and radionuclide therapy, including the use of different repair models. The numerical method is shown to be accurate and versatile since it can be applied to any kind of absorbed dose rate function and allows for the incorporation of different repair models. Typical accuracies for clinically realistic examples are in the order of 10-3% to 10-5%. The method has thus the potential of being a useful tool for the calculation of BED, also in situations with complicated irradiation patterns or repair functions. [ABSTRACT FROM AUTHOR]

Abstract: One of the important challenges for MALDI imaging mass spectrometry (MALDI-IMS) is the unambiguous identification of measured analytes. One way to do this is to match tryptic peptide MALDI-IMS m/z values with LC-MS/MS identified m/z values. Matching using current MALDI-TOF/TOF MS instruments is difficult due to the variability of in situ time-of-flight (TOF) m/z measurements. This variability is currently addressed using external calibration, which limits achievable mass accuracy for MALDI-IMS and makes it difficult to match these data to downstream LC-MS/MS results. To overcome this challenge, the work presented here details a method for internally calibrating data sets generated from tryptic peptide MALDI-IMS on formalin-fixed paraffin-embedded sections of ovarian cancer. By calibrating all spectra to internal peak features the m/z error for matches made between MALDI-IMS m/z values and LC-MS/MS identified peptide m/z values was significantly reduced. This improvement was confirmed by follow up matching of LC-MS/MS spectra to in situ MS/MS spectra from the same m/z peak features. The sum of the data presented here indicates that internal calibrants should be a standard component of tryptic peptide MALDI-IMS experiments. This article is part of a Special Issue entitled: Imaging Mass Spectrometry: A User’s Guide to a New Technique for Biological and Biomedical Research. [Copyright &y& Elsevier]

Abstract: Deleted in liver cancer 1 (DLC1) is a tumor suppressor protein that is frequently downregulated in various tumor types. DLC1 contains a Rho GTPase activating protein (GAP) domain that appears to be required for its tumor suppressive functions. Little is known about the molecular mechanisms that regulate DLC1. By mass spectrometry we have mapped a novel phosphorylation site within the DLC1 GAP domain on serine 807. Using a phospho-S807-specific antibody, our results identify protein kinase D (PKD) to phosphorylate this site in DLC1 in intact cells. Although phosphorylation on serine 807 did not directly impact on in vitro GAP activity, a DLC1 serine-to-alanine exchange mutant inhibited colony formation more potently than the wild type protein. Our results thus show that PKD-mediated phosphorylation of DLC1 on serine 807 negatively regulates DLC1 cellular function. [ABSTRACT FROM AUTHOR]

MALDI imaging mass spectrometry (MALDI-IMS) allows acquisition of mass data for metabolites, lipids, peptides and proteins directly from tissue sections. IMS is typically performed either as a multiple spot profiling experiment to generate tissue specific mass profiles, or a high resolution imaging experiment where relative spatial abundance for potentially hundreds of analytes across virtually any tissue section can be measured. Crucially, imaging can be achieved without prior knowledge of tissue composition and without the use of antibodies. In effect MALDI-IMS allows generation of molecular data which complement and expand upon the information provided by histology including immuno-histochemistry, making its application valuable to both cancer biomarker research and diagnostics. The current state of MALDI-IMS, key biological applications to ovarian cancer research and practical considerations for analysis of peptides and proteins on ovarian tissue are presented in this review. [ABSTRACT FROM AUTHOR]

The small-improvement argument is usually considered the most powerful argument against comparability, viz the view that for any two alternatives an agent is rationally required either to prefer one of the alternatives to the other or to be indifferent between them. We argue that while there might be reasons to believe each of the premises in the small-improvement argument, there is a conflict between these reasons. As a result, the reasons do not provide support for believing the conjunction of the premises. Without support for the conjunction of the premises, the small-improvement argument for incomparability fails. [ABSTRACT FROM AUTHOR]

This article develops a new measure of freedom of choice based on the proposal that a set offers more freedom of choice than another if, and only if, the expected degree of dissimilarity between a random alternative from the set of possible alternatives and the most similar offered alternative in the set is smaller. Furthermore, a version of this measure is developed, which is able to take into account the values of the possible options. [ABSTRACT FROM AUTHOR]

• OH-PBDE concentration of 4 ng/g ww was detected in perch from the Baltic Sea. • Several biomarkers showed significant non-linear seasonal variation. • EROD activity, lactate, and glucose concentration correlated positively with OH-PBDE. • Lipid percentage and liver somatic index correlated negatively with OH-PBDE. Hydroxylated polybrominated diphenyl ethers (OH-PBDEs), naturally produced by algae and cyanobacteria in the Baltic Sea, are potent disrupters of energy metabolism as well as endocrine disruptors and neurotoxins. In this study, European perch (Perca fluviatilis) from the Baltic Sea were sampled from May until October. OH-PBDEs and ten biomarkers were measured in each individual (n = 84 over 18 sampling time points) to study potential correlations between exposure to OH-PBDEs and changes in biomarkers. Several biomarkers showed significant non-linear seasonal variation. In the perch, ethoxyresorufin-O-deethylase (EROD) activity, plasma lactate concentration, and plasma glucose concentration showed a significant positive log-linear correlation with OH-PBDEs, whereas lipid percentage and liver somatic index showed a significant negative log-linear correlation with OH-PBDEs. These results strengthen the concern that OH-PBDEs could cause negative health effects for fish in the Baltic Sea. [ABSTRACT FROM AUTHOR]

Background There is no concensus on the optimal treatment time for unstable hips in the newborn. We analyzed the efficiency of a treatment program that has been used for 10 years at our hospital, in which all unstable hips (subluxatable, Barlow-positive and Ortolani-positive) are treated with the von Rosen splint for 6 weeks. Patients and methods Between 1988 and 1997, 32,171 children were born alive at the hospital. During this period 247 children had a clinically unstable hip diagnosed. 223 of the 247 children underwent a radiographic follow-up after 5–15 years. Results 1 patient with bilateral instability and treated with a splint for 6 weeks showed a dislocated left hip at the radiographic examination at 8 months, which is part of the screening program, and needed operative treatment. 1 patient did not follow the treatment program and showed a dislocated hip at the age of 3. Another 4 patients required more treatment than the 6 weeks with the splint. We found no dysplastic hips at the radiographic follow-up. There was no late dysplasia and there were no late dislocations in children born in Lund between 1988 and 1997 who were diagnosed at other Swedish centers that treat developmental dysplasia of the hip (DDH). Interpretation We conclude that the present screening and 6-week treatment in a von Rosen splint prevent almost all cases of late dysplasia and late dislocation of the hip. [ABSTRACT FROM AUTHOR]

Deficiency of thiamine (vitamin B 1) has been demonstrated in several species in the northern hemisphere and is suggested as a cause for declining populations. European perch from the Baltic Sea show negative temporal trends for several health biomarkers and poor recruitment of unknown cause. In this study, thiamine status of perch liver from the Baltic Sea was studied with emphasis on seasonal variation. During spring the thiamine concentration increased, reached a higher level during the summer and then decreased again during autumn. Despite this variation the thiamine concentration was always sufficient in the perch liver. These results indicate that direct thiamine deficiency is an unlikely explanation for the health effects observed in adult female perch from the Baltic Sea. • No evidence of thiamine deficiency in adult perch from the Baltic Sea. • Higher thiamine concentrations during summer compared to spring and autumn. • The cause of poor health in Baltic Sea perch is not known. [ABSTRACT FROM AUTHOR]

Background: Recently, 177Lu-dotatate therapy for neuroendocrine tumours has received regulatory approval. Dosimetry can be used to optimize treatment on an individual basis, but there is no international consensus as to how it should be done.The aim of this study is to determine a feasible and accurate dosimetry method to guide individualized peptide receptor radionuclide therapy (PRRT) for patients with neuroendocrine tumours.As part of a clinical trial on 177Lu-dotatate therapy, renal dosimetry was performed for all patients in each treatment cycle, using a hybrid planar-SPECT/CT method. In the present study, we use the image data acquired from 22 patients and 119 cycles and define a set of alternative treatment planning strategies, each representing a simplification in terms of image acquisition and dosimetric calculations. The results from the simplified strategies are compared to the results from the protocol-prescribed hybrid planar-SPECT/CT-based method by analysing differences both in per-cycle and total cumulative absorbed dose (AD) analyses.Results: In general, the SPECT-based methods gave results that were largely consistent with the protocol-specified hybrid method, both in the per-cycle and cumulative AD analyses. Notably, performing one SPECT/CT per cycle at 96 h yielded ADs that were very similar to the protocol method. The methods using planar dosimetry resulted in larger variations, as expected, while giving 4 cycles to all patients resulted in the largest inter-individual differences in cumulative AD.Conclusions: Performing one SPECT/CT at 96 h in every treatment cycle gives sufficiently reliable dosimetric results to base individualized treatment planning on, with a reasonable demand on resources. [ABSTRACT FROM AUTHOR]