GRAFTWERK:A structured approach for optimising dialysis grafts

Patients with renal failure depend on multiple dialysis sessions per week to purify the blood from waste substances. During a dialysis session, an artificial kidney is connected to the bloodstream of the patient. Because there are no blood vessels in the human body that are suitable for connecting an artificial kidney, the blood vessels required for this are surgically created. Often, a so-called graft is used for this: a plastic vessel that is connected between an artery and a vein. Unfortunately, these grafts often only function 2 years, after which a new graft has to be constructed. This is of course a major burden for these patients. This thesis investigated how, with the help of computer models, a graft can be designed that can achieve longer durability. Multiple graft adjustments are proposed that can be beneficial for the durability of a graft. Future experimental studies have to show if these graft adjustments indeed lead to better clinical performance

Simulation of Radiation-Induced Damage Distribution to evaluate Models for Higher-Order Chromosome Organisation

The structure of chromatin at the level of the 30 nm fibre has been studied in considerable detail, but little is known about how this fibre is arranged within the interphase chromosome territory. Over the years, various polymer models were developed to simulate chromosome structure, for example the random-walk/giant-loop (RWGL) model, the multi-loop subcompartment (MLS) model, and the interconnected-fibre-loop model (Friedland et al., 1999). These models differ mainly in the size and arrangement of the chromatin loops and, correspondingly, in the predicted distribution of chromatin density within the nucleus. It occurred to us that densely ionising radiation can be used to probe the actual distribution of chromatin density in human interphase cells. In contrast to sparsely ionising radiation (e.g. X-rays), which induces DNA double-strand breaks (DSB) that are distributed randomly within the nucleus, irradiation with densely ionising accelerated ions leads to spatial clustering of DSB. This inhomogeneity in DSB localisation, together with an inhomogeneity of DNA density within the nucleus, causes an over-dispersion in the resulting distribution of DNA fragment sizes that can be detected by pulsed-field gel electrophoresis. Using the above-mentioned chromosome models, we performed computer simulations to predict the DNA fragment size distributions resulting from irradiation with accelerated ions, and compared the predicted distributions with those obtained experimentally. We found that simulations based on the MLS model, in which local variations in chromatin density are higher than in the other models, resulted in the best agreement between calculation and experiment

Effects of the high-density lipoprotein mimetic agent CER-001 on coronary atherosclerosis in patients with acute coronary syndromes: A randomized trial

AIM: High-density lipoproteins (HDLs) have several potentially protective vascular effects. Most clinical studies of therapies targeting HDL have failed to show benefits vs. placebo. OBJECTIVE: To investigate the effects of an HDL-mimetic agent on atherosclerosis by intravascular ultrasonography (IVUS) and quantitative coronary angiography (QCA). DESIGN AND SETTING: A prospective, double-blinded, randomized trial was conducted at 51 centres in the USA, the Netherlands, Canada, and France. Intravascular ultrasonography and QCA were performed to assess coronary atherosclerosis at baseline and 3 (2-5) weeks after the last study infusion. PATIENTS: Five hundred and seven patients were randomized; 417 and 461 had paired IVUS and QCA measurements, respectively. INTERVENTION: Patients were randomized to receive 6 weekly infusions of placebo, 3 mg/kg, 6 mg/kg, or 12 mg/kg CER-001. MAIN OUTCOME MEASURES: The primary efficacy parameter was the nominal change in the total atheroma volume. Nominal changes in per cent atheroma volume on IVUS and coronary scores on QCA were also pre-specified endpoints. RESULTS: The nominal change in the total atheroma volume (adjusted means) was -2.71, -3.13, -1.50, and -3.05 mm(3) with placebo, CER-001 3 mg/kg, 6 mg/kg, and 12 mg/kg, respectively (primary analysis of 12 mg/kg vs. placebo: P = 0.81). There was also no difference among groups for the nominal change in per cent atheroma volume (0.02, -0.02, 0.01, and 0.19%; nominal P = 0.53 for 12 mg/kg vs. placebo). Change in the coronary artery score was -0.022, -0.036, -0.022, and -0.015 mm (nominal P = 0.25, 0.99, 0.55), and change in the cumulative coronary stenosis score was -0.51, 2.65, 0.71, and -0.77% (compared with placebo, nominal P = 0.85 for 12 mg/kg and nominal P = 0.01 for 3 mg/kg). The number of patients with major cardiovascular events was 10 (8.3%), 16 (13.3%), 17 (13.7%), and 12 (9.8%) in the four groups. CONCLUSION: CER-001 infusions did not reduce coronary atherosclerosis on IVUS and QCA when compared with placebo. Whether CER-001 administered in other regimens or to other populations could favourably affect atherosclerosis must await further study. Name of the trial registry: Clinicaltrials.gov; Registry's URL: http://clinicaltrials.gov/ct2/show/NCT01201837?term=cer-001&rank=2; TRIAL REGISTRATION NUMBER: NCT01201837

Labeling lateral prefrontal sulci using spherical data augmentation and context-aware training

The inference of cortical sulcal labels often focuses on deep (primary and secondary) sulcal regions, whereas shallow (tertiary) sulcal regions are largely overlooked in the literature due to the scarcity of manual/well-defined annotations and their large neuroanatomical variability. In this paper, we present an automated framework for regional labeling of both primary/secondary and tertiary sulci of the dorsal portion of lateral prefrontal cortex (LPFC) using spherical convolutional neural networks. We propose two core components that enhance the inference of sulcal labels to overcome such large neuroanatomical variability: (1) surface data augmentation and (2) context-aware training. (1) To take into account neuroanatomical variability, we synthesize training data from the proposed feature space that embeds intermediate deformation trajectories of spherical data in a rigid to non-rigid fashion, which bridges an augmentation gap in conventional rotation data augmentation. (2) Moreover, we design a two-stage training process to improve labeling accuracy of tertiary sulci by informing the biological associations in neuroanatomy: inference of primary/secondary sulci and then their spatial likelihood to guide the definition of tertiary sulci. In the experiments, we evaluate our method on 13 deep and shallow sulci of human LPFC in two independent data sets with different age ranges: pediatric (N=60) and adult (N=36) cohorts. We compare the proposed method with a conventional multi-atlas approach and spherical convolutional neural networks without/with rotation data augmentation. In both cohorts, the proposed data augmentation improves labeling accuracy of deep and shallow sulci over the baselines, and the proposed context-aware training offers further improvement in the labeling of shallow sulci over the proposed data augmentation. We share our tools with the field and discuss applications of our results for understanding neuroanatomical-functional organization of LPFC and the rest of cortex (https://github.com/ilwoolyu/SphericalLabeling). ?? 2021 The Author(s

A realistic arteriovenous dialysis graft model for hemodynamic simulations

OBJECTIVE: The hemodynamic benefit of novel arteriovenous graft (AVG) designs is typically assessed using computational models that assume highly idealized graft configurations and/or simplified boundary conditions representing the peripheral vasculature. The objective of this study is to evaluate whether idealized AVG models are suitable for hemodynamic evaluation of new graft designs, or whether more realistic models are required. METHODS: An idealized and a realistic, clinical imaging based, parametrized AVG geometry were created. Furthermore, two physiological boundary condition models were developed to represent the peripheral vasculature. We assessed how graft geometry (idealized or realistic) and applied boundary condition models of the peripheral vasculature (physiological or distal zero-flow) impacted hemodynamic metrics related to AVG dysfunction. RESULTS: Anastomotic regions exposed to high WSS (>7, ≤40 Pa), very high WSS (>40 Pa) and highly oscillatory WSS were larger in the simulations using the realistic AVG geometry. The magnitude of velocity perturbations in the venous segment was up to 1.7 times larger in the realistic AVG geometry compared to the idealized one. When applying a (non-physiological zero-flow) boundary condition that neglected blood flow to and from the peripheral vasculature, we observed large regions exposed to highly oscillatory WSS. These regions could not be observed when using either of the newly developed distal boundary condition models. CONCLUSION: Hemodynamic metrics related to AVG dysfunction are highly dependent on the geometry and the distal boundary condition model used. Consequently, the hemodynamic benefit of a novel graft design can be misrepresented when using idealized AVG modelling setups

Analyse raeumlich korrelierter DNA-Schaeden zur Bestimmung der relativen biologischen Wirksamkeit dicht-ionisierender Strahlung

Zur Quantifizierung von DNA-Doppelstrangbruechen (DSB) nach dicht-ionisierender Strahlung wurde, basierend auf einem gemischten Poissonprozess, ein Simulationsansatz entwickelt. Ausgehend von verschiedenen Modellen zur Chromatinanordnung im Saeuger- Zellkern und zur radialen Dosisverteilung wurde die lokale Dosis an einzelnen DNASegmenten gegebener Laenge und die daraus resultierende DSB-Verteilung simuliert. Die nach Simulation an 10000 Zellkernen resultierende DNA-Mengenverteilung wurde durch Variation der angenommenen DSB-Haeufigkeit pro DNA-Laengeneinheit an experimentell bestimmte DNA-Mengenverteilungen angeglichen, was eine Bestimmung der jeweiligen DSB-Rate (pro Gy und pro DNA-Laengeneinheit) ermoeglichte. Somit konnten RBE-Werte fuer die DSBInduktion nach Bestrahlungen mit Ionen im LET-Bereich von 2.1 - 14000 keV/#mu# bestimmt werden. (orig.)We developed a simulation method based on a mixed Poisson process to quantify DNA double-strand breaks induced by densely ionizing radiation. Assuming various models for the chromatin configuration in mammalian nuclei and for the radial distribution of dose, the local dose at given DNA-segments and the resulting distribution of DSB was simulated in each 10000 nuclei. By varying the DSB frequency (per DNA length unit) assumed in the simulations, the DNA mass distributions thus obtained were adjusted to experimentally determined distributions, thus allowing to determine DSB induction rates and RBEs for DSB induction after irradiations with ions in the LET range 2.1 - 14000 keV/#mu#. (orig.)SIGLEAvailable from TIB Hannover: RO 3190(616) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman

Haemodynamic optimisation of a dialysis graft design using a global optimisation approach

Disturbed flow and the resulting non-physiological wall shear stress (WSS) at the graft-vein anastomosis play an important role in arteriovenous graft (AVG) patency loss. Modifying graft geometry with helical features is a popular approach to minimise the occurrence of detrimental haemodynamics and to potentially increase graft longevity. Haemodynamic optimisation of AVGs typically requires many computationally expensive computational fluid dynamics (CFD) simulations to evaluate haemodynamic performance of different graft designs. In this study, we aimed to develop a haemodynamically optimised AVG by using an efficient meta-modelling approach. A training dataset containing CFD evaluations of 103 graft designs with helical features was used to develop computationally low-cost meta-models for haemodynamic metrics related to graft dysfunction. During optimisation, the meta-models replaced CFD simulations that were otherwise needed to evaluate the haemodynamic performance of possible graft designs. After optimisation, haemodynamic performance of the optimised graft design was verified using a CFD simulation. The obtained optimised graft design contained both a helical graft centreline and helical ridge. Using the optimised design, the magnitude of flow disturbances and the size of the anastomotic areas exposed to non-physiological WSS was successfully reduced compared to a regular straight graft. Our meta-modelling approach allowed to reduce the total number of CFD model evaluations required for our design optimisation by approximately a factor 2000. The applied efficient meta-modelling technique was successful in identifying an optimal, helical graft design at relatively low computational costs. Future studies should evaluate the in vivo benefits of the developed graft design