Coupling biomechanics to a cellular level model: An approach to patient-specific image driven multi-scale and multi-physics tumor simulation

Modeling of tumor growth has been performed according to various approaches addressing different biocomplexity levels and spatiotemporal scales. Mathematical treatments range from partial differential equation based diffusion models to rule-based cellular level simulators, aiming at both improving our quantitative understanding of the underlying biological processes and, in the mid- and long term, constructing reliable multi-scale predictive platforms to support patient-individualized treatment planning and optimization. The aim of this paper is to establish a multi-scale and multi-physics approach to tumor modeling taking into account both the cellular and the macroscopic mechanical level. Therefore, an already developed biomodel of clinical tumor growth and response to treatment is self-consistently coupled with a biomechanical model. Results are presented for the free growth case of the imageable component of an initially point-like glioblastoma multiforme tumor. The composite model leads to significant tumor shape corrections that are achieved through the utilization of environmental pressure information and the application of biomechanical principles. Using the ratio of smallest to largest moment of inertia of the tumor material to quantify the effect of our coupled approach, we have found a tumor shape correction of 20\% by coupling biomechanics to the cellular simulator as compared to a cellular simulation without preferred growth directions. We conclude that the integration of the two models provides additional morphological insight into realistic tumor growth behavior. Therefore, it might be used for the development of an advanced oncosimulator focusing on tumor types for which morphology plays an important role in surgical and/or radio-therapeutic treatment planning.

Serum amino acid profiles and their alterations in colorectal cancer

Mass spectrometry-based serum metabolic profiling is a promising tool to analyse complex cancer associated metabolic alterations, which may broaden our pathophysiological understanding of the disease and may function as a source of new cancer-associated biomarkers. Highly standardized serum samples of patients suffering from colon cancer (n = 59) and controls (n = 58) were collected at the University Hospital Leipzig. We based our investigations on amino acid screening profiles using electrospray tandem-mass spectrometry. Metabolic profiles were evaluated using the Analyst 1.4.2 software. General, comparative and equivalence statistics were performed by R 2.12.2. 11 out of 26 serum amino acid concentrations were significantly different between colorectal cancer patients and healthy controls. We found a model including CEA, glycine, and tyrosine as best discriminating and superior to CEA alone with an AUROC of 0.878 (95% CI 0.815-0.941). Our serum metabolic profiling in colon cancer revealed multiple significant disease-associated alterations in the amino acid profile with promising diagnostic power. Further large-scale studies are necessary to elucidate the potential of our model also to discriminate between cancer and potential differential diagnoses. In conclusion, serum glycine and tyrosine in combination with CEA are superior to CEA for the discrimination between colorectal cancer patients and controls.

Climate and chemistry effects of a regional scale nuclear conflict

Previous studies have highlighted the severity of detrimental effects for life on earth after an assumed regionally limited nuclear war. These effects are caused by climatic, chemical and radiative changes persisting for up to one decade. However, so far only a very limited number of climate model simulations have been performed, giving rise to the question how realistic previous computations have been. This study uses the coupled chemistry climate model (CCM) SOCOL, which belongs to a different family of CCMs than previously used, to investigate the consequences of such a hypothetical nuclear conflict. In accordance with previous studies, the present work assumes a scenario of a nuclear conflict between India and Pakistan, each applying 50 warheads with an individual blasting power of 15 kt ("Hiroshima size") against the major population centers, resulting in the emission of tiny soot particles, which are generated in the firestorms expected in the aftermath of the detonations. Substantial uncertainties related to the calculation of likely soot emissions, particularly concerning assumptions of target fuel loading and targeting of weapons, have been addressed by simulating several scenarios, with soot emissions ranging from 1 to 12 Tg. Their high absorptivity with respect to solar radiation leads to a rapid self-lofting of the soot particles into the strato- and mesosphere within a few days after emission, where they remain for several years. Consequently, the model suggests earth's surface temperatures to drop by several degrees Celsius due to the shielding of solar irradiance by the soot, indicating a major global cooling. In addition, there is a substantial reduction of precipitation lasting 5 to 10 yr after the conflict, depending on the magnitude of the initial soot release. Extreme cold spells associated with an increase in sea ice formation are found during Northern Hemisphere winter, which expose the continental land masses of North America and Eurasia to a cooling of several degrees. In the stratosphere, the strong heating leads to an acceleration of catalytic ozone loss and, consequently, to enhancements of UV radiation at the ground. In contrast to surface temperature and precipitation changes, which show a linear dependence to the soot burden, there is a saturation effect with respect to stratospheric ozone chemistry. Soot emissions of 5 Tg lead to an ozone column reduction of almost 50% in northern high latitudes, while emitting 12 Tg only increases ozone loss by a further 10%. In summary, this study, though using a different chemistry climate model, corroborates the previous investigations with respect to the atmospheric impacts. In addition to these persistent effects, the present study draws attention to episodically cold phases, which would likely add to the severity of human harm worldwide. The best insurance against such a catastrophic development would be the delegitimization of nuclear weapons.

Multi-scale micro-structure generation strategy for up-scaling transport in clays

Clays and claystones are used as backfill and barrier materials in the design of waste repositories, because they act as hydraulic barriers and retain contaminants. Transport through such barriers occurs mainly by molecular diffusion. There is thus an interest to relate the diffusion properties of clays to their structural properties. In previous work, we have developed a concept for up-scaling pore-scale molecular diffusion coefficients using a grid-based model for the sample pore structure. Here we present an operational algorithm which can generate such model pore structures of polymineral materials. The obtained pore maps match the rock’s mineralogical components and its macroscopic properties such as porosity, grain and pore size distributions. Representative ensembles of grains in 2D or 3D are created by a lattice Monte Carlo (MC) method, which minimizes the interfacial energy of grains starting from an initial grain distribution. Pores are generated at grain boundaries and/or within grains. The method is general and allows to generate anisotropic structures with grains of approximately predetermined shapes, or with mixtures of different grain types. A specific focus of this study was on the simulation of clay-like materials. The generated clay pore maps were then used to derive upscaled effective diffusion coefficients for non-sorbing tracers using a homogenization technique. The large number of generated maps allowed to check the relations between micro-structural features of clays and their effective transport parameters, as is required to explain and extrapolate experimental diffusion results. As examples, we present a set of 2D and 3D simulations and investigated the effects of nanopores within particles (interlayer pores) and micropores between particles. Archie’s simple power law is followed in systems with only micropores. When nanopores are present, additional parameters are required; the data reveal that effective diffusion coefficients could be described by a sum of two power functions, related to the micro- and nanoporosity. We further used the model to investigate the relationships between particle orientation and effective transport properties of the sample.

Differential aspects of memory self-evaluation in old and very old people

The aim of this paper was to examine age-related changes and gender differences in memory self-evaluation in old people and to examine the predictive power of objective memory performance and of personality variables (neuroticism and extraversion) on memory self-evaluation. In a cross-sectional study, 301 not institutionalized people aged 65± 94, 207 male and 94 female, were tested on three parameters. Subjective memory evaluation was operationalized with three one-item ratings: temporal comparison, social comparison, situation-speci® c memory self-evaluation just after performing a memory test. Objective memory assessment (free recall) used a computerized test. Personality assessment included the two main sub-scales `extraversion’ and `neuroticism’ from the Freiburger PersoÈ nlichkeits-Inventar.The results shaved that persons of all age groups have a realistic appraisal of their age-related memory decline.No gender effects were found for any of the three forms of memory self-evaluation. The relationship between objective memory performance, personality variables and memory self-evaluation however depends on age and gender. Our results show that objective memory performance is predictive for memory self-evaluation in men aged >75 years, whereas in men <75 neuroticism is the only signi® cant predictor.Men of the older cohort seem to have adapted to the age-related memory decline whereas the young old are still coping with the ongoing changes. In women of both age groups the objective memory performance is the only and strong predictor of memory self-evaluation. Our results suggest that gender-speci® c educational socialization might be the reason for these differences.

The dementia cognitive fluctuation scale, a new psychometric test for clinicians to identify cognitive fluctuations in people with dementia.

OBJECTIVES Cognitive fluctuation (CF) is a common feature of dementia and a core diagnostic symptom for dementia with Lewy bodies (DLB). CF remains difficult to accurately and reliably detect clinically. This study aimed to develop a psychometric test that could be used by clinicians to facilitate the identification of CF and improve the recognition and diagnosis of DLB and Parkinson disease, and to improve differential diagnosis of other dementias. METHODS We compiled a 17-item psychometric test for identifying CF and applied this measure in a cross-sectional design. Participants were recruited from the North East of England, and assessments were made in individuals' homes. We recruited people with four subtypes of dementia and a healthy comparison group, and all subjects were administered this pilot scale together with other standard ratings. The psychometric properties of the scale were examined with exploratory factor analysis. We also examined the ability of individual items to identify CF to discriminate between dementia subtypes. The sensitivity and specificity of discriminating items were explored along with validity and reliability analyses. RESULTS Participants comprised 32 comparison subjects, 30 people with Alzheimer disease, 30 with vascular dementia, 29 with DLB, and 32 with dementia associated with Parkinson disease. Four items significantly discriminated between dementia groups and showed good levels of sensitivity (range: 78.6%-80.3%) and specificity (range: 73.9%-79.3%). The scale had very good levels of test-retest (Cronbach's alpha: 0.82) and interrater (0.81) reliabilities. The four items loaded onto three different factors. These items were: 1) marked differences in functioning during the daytime; 2) daytime somnolence; 3) daytime drowsiness; and 4) altered levels of consciousness during the day. CONCLUSIONS We identified four items that provide valid, sensitive, and specific questions for reliably identifying CF and distinguishing the Lewy body dementias from other major causes of dementia (Alzheimer disease and vascular dementia).

Compact low-power cortical recording architecture for compressive multichannel data acquisition

This paper introduces an area- and power-efficient approach for compressive recording of cortical signals used in an implantable system prior to transmission. Recent research on compressive sensing has shown promising results for sub-Nyquist sampling of sparse biological signals. Still, any large-scale implementation of this technique faces critical issues caused by the increased hardware intensity. The cost of implementing compressive sensing in a multichannel system in terms of area usage can be significantly higher than a conventional data acquisition system without compression. To tackle this issue, a new multichannel compressive sensing scheme which exploits the spatial sparsity of the signals recorded from the electrodes of the sensor array is proposed. The analysis shows that using this method, the power efficiency is preserved to a great extent while the area overhead is significantly reduced resulting in an improved power-area product. The proposed circuit architecture is implemented in a UMC 0.18 [Formula: see text]m CMOS technology. Extensive performance analysis and design optimization has been done resulting in a low-noise, compact and power-efficient implementation. The results of simulations and subsequent reconstructions show the possibility of recovering fourfold compressed intracranial EEG signals with an SNR as high as 21.8 dB, while consuming 10.5 [Formula: see text]W of power within an effective area of 250 [Formula: see text]m × 250 [Formula: see text]m per channel.

Ethnography of a Land-Deal. Local Perceptions and Vertical Perspectives of a Large Scale Land Acquisition Project in Northern Sierra Leone

Despite an increased scientific interest in the relatively new phenomenon of large-scale land acquisition (LSLA), data on processes on the local level remain sparse and superficial. However, knowledge about the concrete implementation of LSLA projects and the different impacts they have on the heterogeneous group of project affected people is indispensable for a deepened understanding of the phenomenon. In order to address this research gap, a team of two anthropologists and a human geographer conducted in-depth fieldwork on the LSLA project of Swiss based Addax Bioenergy in Sierra Leone. After the devastating civil war, the Sierra Leonean government created favourable conditions for foreign investors willing to lease large areas of land and to bring “development” to the country. Being one of the numerous investing companies, Addax Bioenergy has leased 57’000 hectares of land to develop a sugarcane plantation and an ethanol factory to produce biofuel for the export to the European market. Based on participatory observation, qualitative interview techniques and a network analysis, the research team aimed a) at identifying the different actors that were necessary for the implementation of this project on a vertical level and b) exploring various impacts of the project in the local context of two villages on a horizontal level. The network analysis reveals a complex pattern of companies, institutions, nongovernmental organisations and prominent personalities acting within a shifting technological and discursive framework linking global scales to a unique local context. Findings from the latter indicate that affected people initially welcomed the project but now remain frustrated since many promises and expectations have not been fulfilled. Although some local people are able to benefit from the project, the loss of natural resources that comes along with the land lease affects livelihoods of vulnerable groups – especially women and land users – considerably. However, this research doesn’t only disclose impacts on local people’s previous lives but also addresses strategies they adopt in the newly created situation that has opened up alternative spaces for renegotiations of power and legitimatisation. Therewith, this explorative study reveals new aspects of LSLA that have not been considered adequately by the investing company nor by the general academic discourse on LSLA.

Estimation and calibration of the water isotope differential diffusion length in ice core records

Palaeoclimatic information can be retrieved from the diffusion of the stable water isotope signal during firnification of snow. The diffusion length, a measure for the amount of diffusion a layer has experienced, depends on the firn temperature and the accumulation rate. We show that the estimation of the diffusion length using power spectral densities (PSDs) of the record of a single isotope species can be biased by uncertainties in spectral properties of the isotope signal prior to diffusion. By using a second water isotope and calculating the difference in diffusion lengths between the two isotopes, this problem is circumvented. We study the PSD method applied to two isotopes in detail and additionally present a new forward diffusion method for retrieving the differential diffusion length based on the Pearson correlation between the two isotope signals. The two methods are discussed and extensively tested on synthetic data which are generated in a Monte Carlo manner. We show that calibration of the PSD method with this synthetic data is necessary to be able to objectively determine the differential diffusion length. The correlation-based method proves to be a good alternative for the PSD method as it yields precision equal to or somewhat higher than the PSD method. The use of synthetic data also allows us to estimate the accuracy and precision of the two methods and to choose the best sampling strategy to obtain past temperatures with the required precision. In addition to application to synthetic data the two methods are tested on stable-isotope records from the EPICA (European Project for Ice Coring in Antarctica) ice core drilled in Dronning Maud Land, Antarctica, showing that reliable firn temperatures can be reconstructed with a typical uncertainty of 1.5 and 2 °C for the Holocene period and 2 and 2.5 °C for the last glacial period for the correlation and PSD method, respectively.

Continental-Scale Footprint of Balancing and Positive Selection in a Small Rodent (Microtus arvalis)

Genetic adaptation to different environmental conditions is expected to lead to large differences between populations at selected loci, thus providing a signature of positive selection. Whereas balancing selection can maintain polymorphisms over long evolutionary periods and even geographic scale, thus leads to low levels of divergence between populations at selected loci. However, little is known about the relative importance of these two selective forces in shaping genomic diversity, partly due to difficulties in recognizing balancing selection in species showing low levels of differentiation. Here we address this problem by studying genomic diversity in the European common vole (Microtus arvalis) presenting high levels of differentiation between populations (average FST = 0.31). We studied 3,839 Amplified Fragment Length Polymorphism (AFLP) markers genotyped in 444 individuals from 21 populations distributed across the European continent and hence over different environmental conditions. Our statistical approach to detect markers under selection is based on a Bayesian method specifically developed for AFLP markers, which treats AFLPs as a nearly codominant marker system, and therefore has increased power to detect selection. The high number of screened populations allowed us to detect the signature of balancing selection across a large geographic area. We detected 33 markers potentially under balancing selection, hence strong evidence of stabilizing selection in 21 populations across Europe. However, our analyses identified four-times more markers (138) being under positive selection, and geographical patterns suggest that some of these markers are probably associated with alpine regions, which seem to have environmental conditions that favour adaptation. We conclude that despite favourable conditions in this study for the detection of balancing selection, this evolutionary force seems to play a relatively minor role in shaping the genomic diversity of the common vole, which is more influenced by positive selection and neutral processes like drift and demographic history.

Cognitive-Behavioural Analysis System of Psychotherapy (CBASP), a drug, or their combination: differential therapeutics for persistent depressive disorder: a study protocol of an individual participant data network meta-analysis.

INTRODUCTION Despite important advances in psychological and pharmacological treatments of persistent depressive disorders in the past decades, their responses remain typically slow and poor, and differential responses among different modalities of treatments or their combinations are not well understood. Cognitive-Behavioural Analysis System of Psychotherapy (CBASP) is the only psychotherapy that has been specifically designed for chronic depression and has been examined in an increasing number of trials against medications, alone or in combination. When several treatment alternatives are available for a certain condition, network meta-analysis (NMA) provides a powerful tool to examine their relative efficacy by combining all direct and indirect comparisons. Individual participant data (IPD) meta-analysis enables exploration of impacts of individual characteristics that lead to a differentiated approach matching treatments to specific subgroups of patients. METHODS AND ANALYSIS We will search for all randomised controlled trials that compared CBASP, pharmacotherapy or their combination, in the treatment of patients with persistent depressive disorder, in Cochrane CENTRAL, PUBMED, SCOPUS and PsycINFO, supplemented by personal contacts. Individual participant data will be sought from the principal investigators of all the identified trials. Our primary outcomes are depression severity as measured on a continuous observer-rated scale for depression, and dropouts for any reason as a proxy measure of overall treatment acceptability. We will conduct a one-step IPD-NMA to compare CBASP, medications and their combinations, and also carry out a meta-regression to identify their prognostic factors and effect moderators. The model will be fitted in OpenBUGS, using vague priors for all location parameters. For the heterogeneity we will use a half-normal prior on the SD. ETHICS AND DISSEMINATION This study requires no ethical approval. We will publish the findings in a peer-reviewed journal. The study results will contribute to more finely differentiated therapeutics for patients suffering from this chronically disabling disorder. TRIAL REGISTRATION NUMBER CRD42016035886.

Europeanization, Institutional Changes and Differential Empowerment

The issue of European integration is of utmost importance for contemporary Swiss politics, as underscored by the presence of three decision-making processes relating to bilateral agreements with the EU, and two additional processes with a strong European dimension (the telecommunication act and the immigration law), among the 11 most important processes of the early 2000s. Previous chapters have highlighted substantial differences between domestic and Europeanized decision-making processes in terms of institutional design and decision-making structures. Chapters 2 and 3 suggest that the peculiarities of the three decision-making processes relating to bilateral agreements go along with specific power configurations among political actors. Chapter 5 draws our attention to the impact of Europeanization on the specific decision-making structure at work in a given policy process.